TREATMENT STRATEGIES FOR STATUS EPILEPTICUS

ORLANDO--Status epilepticus is common, costly--and all too frequently deadly. Despite its seriousness, data on which to base drug treatment have been limited until relatively recently. However, the results of a five-year, randomized, double-blind, multicenter study of initial drug therapies for status epilepticus offer some guidelines for appropriate therapy for this condition.[1] The study findings were presented at the recent 29th Annual Educational and Scientific Symposium of the Society of Critical Care Medicine (SCCM). New approaches to the management of refractory status epilepticus were also discussed.

"Many people think status epilepticus is a relatively rare, somewhat esoteric neurologic condition," said Elizabeth J. Waterhouse, MD, at the SCCM meeting. "But that couldn't be further from the truth. Based on our data, we've estimated that there are 152,000 cases of status [epilepticus] in the United States every year; about 42,000 of these patients die.[2] The annual cost of inpatient care for status epilepticus may reach into the billions," added Dr. Waterhouse, an assistant professor of neurology at the Medical College of Virginia in Richmond.

A LOOK AT FOUR IV THERAPIES

The multicenter study, led by David Treiman, MD, compared four standard drug regimens for the initial treatment of status epilepticus: phenytoin (18 mg/kg), diazepam (0.15 mg/kg followed by phenytoin, 18 mg/kg), lorazepam (0.1 mg/kg), and phenobarbital (15 mg/kg). Each regimen was administered intravenously.

The study included 518 subjects; 384 of them had a confirmed diagnosis of overt generalized status epilepticus--defined as easily visible generalized convulsions. The remaining 134 patients had subtle status epilepticus, as indicated by coma and ictal discharges on an electroencephalogram (EEG); subtle convulsive movements, such as rhythmic muscle twitches or tonic eye deviation, may or may not have been present. The researchers used a precise definition of treatment success: the "absence of all clinical and electrical seizure activity during a time window from 20 to 60 minutes after the start of infusion," said Dr. Treiman, chairman of neurology at the UMDNJ--Robert Wood Johnson Medical School in New Brunswick, New Jersey.

Recurrence rates during infusion, incidence of adverse reactions, and outcome at 30 days were similar with all four drugs. In the patients with overt symptoms, the success rate was 65% for lorazepam, 58% for phenobarbital, 56% for diazepam followed by phenytoin, and 44% for phenytoin alone. Only the difference between lorazepam and phenytoin was statistically significant, Dr. Treiman noted.

"In the patients with subtle symptoms, the overall outcome was much worse," he reported. In this group, the success rate was 24% for phenobarbital, 18% for lorazepam, and about 8% for phenytoin (with or without diazepam). However, this finding was not surprising considering that patients with subtle status epilepticus are extraordinarily sick and often unresponsive to treatment.

Surprisingly, the success rate of lorazepam in patients with overt symptoms was about 20% lower in this study than in previous studies, according to Dr. Treiman. The discrepancy, he suggested, was probably due to the use of a more stringent definition for treatment success in this study. Had the researchers only required cessation of clinical seizure activity, the success rate for lorazepam in these patients would have matched that of earlier studies.

On the basis of these and other recent findings, Dr. Treiman recommends lorazepam (0.1 mg/kg) by slow intravenous push as initial therapy in patients with status epilepticus. If clinical or electrical evidence of seizure activity persists, he suggests that physicians switch to phenytoin (20 mg/kg, or the equivalent of phosphenytoin); the dose should be increased by increments of 5 mg/kg up to a total of 30 mg/kg, if necessary. An alternative approach, when the initial lorazepam infusion fails, is to go directly to intubation and general anesthesia. The rationale for this, Dr. Treiman said, is that a patient who fails to respond to lorazepam is unlikely to respond to other conventional medications.

REFRACTORY STATUS EPILEPTICUS

Status epilepticus has traditionally been considered refractory when initial therapy with lorazepam and phenytoin fails, said Thomas P. Bleck, MD, the Louise Nerancy Professor of Neurology at the University of Virginia School of Medicine in Charlottesville. However, he concurs with Dr. Treiman's statement that a second conventional drug is unlikely to be helpful when a patient with status epilepticus does not respond to the first conventional drug. Thus, Dr. Bleck also advocates that physicians move more rapidly to anesthesia when a patient has refractory status epilepticus.

He offers two key pieces of advice for physicians who may be confronted by a patient with refractory status epilepticus:

• Have a plan and be prepared to follow it. As Dr. Bleck noted, there is no time to go to the library when a patient has seizures unresponsive to standard medications.
• Use continuous EEG monitoring to gauge the treatment outcome. He used this analogy: Would you try to treat ventricular tachyarrhythmias using only the patient's pulse?

Propofol has the advantage of having a rapid onset of action. For refractory status epilepticus, it is given in relatively low doses, starting with a 3 mg/kg loading dose. The recommended maintenance dosage is 50 µg/kg/min, but this varies from patient to patient. "Although research suggests it is possible to use a very high maintenance dose (15 mg/kg/h or about 250 µg/kg/min), some patients are unable to tolerate that dose," said Dr. Bleck. "In other patients, the seizures are still not controlled at that dose. But, if the blood pressure is all right, you can keep increasing the dose--just recognize how much lipid you are giving."

Early reports linked propofol with convulsions. "But that probably was myoclonus," Dr. Bleck speculated. Nevertheless, prolonged use of propofol frequently leads to withdrawal convulsions if the treatment is abruptly discontinued, he noted.

If midazolam is used as initial therapy, treatment should begin with a "generous" loading dose, followed by a relatively low maintenance dosage (2 µg/kg/min), he said. The dosage should be titrated upward with each subsequent seizure; if necessary, it can be raised as high as 40 µg/kg/min over 24 to 36 hours. Unfortunately, tachyphylaxis often occurs in patients with refractory status epilepticus who are treated with midazolam, Dr. Bleck pointed out.

Because of its sympathomimetic effect, ketamine is an excellent alternative for refractory status epilepticus when tachyphylaxis and hypotension preclude use of benzodiazepines or barbiturates. No studies have been done to determine the optimal dose, however. "We tend to give a pretty standard anesthetic dose and then adjust it until we get control of seizures," Dr. Bleck said. Unfortunately, some patients develop dependency to ketamine and thus may become hypotensive again when weaned from the drug.

When midazolam and propofol fail to control refractory status epilepticus, Dr. Bleck suggests high-dose pentobarbital. In studies of this therapy, the average loading dose was about 8 mg/kg and the maintenance dose, about half of that. Treatment duration may be quite prolonged, he warned.

Unfortunately, prolonged treatment with pentobarbital has multiple adverse effects, which may develop within several days or weeks of initiating therapy. Among the side effects are myocardial depression, altered thermoregulation, and immune suppression, which often leads to pneumonia.

Intravenous valproate can also be used to treat refractory status epilepticus, particularly for patients you do not want to intubate. This drug has the advantage of possibly controlling seizures without producing respiratory depression.

Other medications for refractory status epilepticus include lidocaine, phenobarbital, and paraldehyde. Phenobarbital may be less likely than pentobarbital to produce hemodynamic instability. However, "If you can get paraldehyde, it's still a great drug," said Dr. Bleck. It should be given orally or rectally--not intravenously--because of the risk of inducing pulmonary embolism. Magnesium has also been studied for use in refractory status epilepticus; although it does produce neuromuscular junction blockade, it does not eliminate the underlying electrical seizure activity.

--Timothy Begany

References
1. Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med. 1998;339:792-798.
2. Waterhouse EJ, Garnett LK, Towne AR, et al. Prospective population-based study of intermittent and continuous convulsive status epilepticus in Richmond, Virginia. Epilepsia. 1999;40:752-758.

Suggested Readings
Waterhouse EJ, Vaughan JK, Barnes TY, et al. Synergistic effect of status epilepticus and ischemic brain injury on mortality. Epilepsy Res. 1998;29:175-183.
Towne AR, Waterhouse EJ, Boggs JG, et al. Prevalence of nonconvulsive status epilepticus in comatose patients. Neurology. 2000;54:340-345.
DeLorenzo RJ, Pellock JM, Towne AR, et al. Epidemiology of status epilepticus. J Clin Neurophysiol. 1995;12:316-325.
Towne AR, Pellock JM, Ko D, et al. Determinants of mortality in status epilepticus. Epilepsia. 1994;35:27-34.

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