ORLANDO—Paramedics in the field can treat status epilepticus in adult patients safely and effectively with intravenous benzodiazepines, a recent study has concluded. However, little may be gained in the hospital by giving standard antiepileptic drugs as subsequent therapy if benzodiazepines have failed, according to another prospective, randomized study presented at the 53rd Annual Meeting of the American Epilepsy Society.

Although intravenous benzodiazepines are widely used for status epilepticus, their efficacy and safety when administered by paramedics had not been previously evaluated in a controlled study in the prehospital setting, pointed out Daniel H. Lowenstein, MD, from the Department of Neurology, University of California, San Francisco. "We hope one of the main messages of this study is that aggressive treatment of status epilepticus in the field by paramedics is something that can be advanced."

Once in the hospital, "it becomes clear that if a patient in overt status epilepticus did not respond to the first treatment, then the second and third did not help very much, and it was not until we added four or more drugs that we got a substantial improvement in the number of patients who had then responded to treatment," added David M. Treiman, MD, Chairman of the Department of Neurology at the University of Medicine and Dentistry of New Jersey, New Brunswick. He suggested that protocols for generalized convulsive status epilepticus might be revised to introduce rapid addition of intravenous general anesthesia earlier, if patients fail initial drug treatment.

A CLEAR MANDATE FOR PREHOSPITAL TREATMENT

In the first study, researchers evaluated outcomes among patients treated by paramedics for status epilepticus. A total of 205 adults with prolonged (more than or equal to 5 minutes) or repetitive generalized convulsive seizures were randomly assigned to initially receive 5 mg of diazepam, 2 mg of lorazepam, or placebo. "The rationale for the doses of the diazepam and lorazepam was based both on paramedic practices around the country as well as the published literature," Dr. Lowenstein said. If seizures continued, an identical second injection was given. All patients subsequently received standard treatment in the emergency department. Demographics were similar in all three groups, including age (averaging 50 years in the diazepam and lorazepam groups, 52 years in the placebo group), sex, baseline neurologic assessment, and etiology of status epilepticus. The study was conducted within the boundaries of San Francisco.

The primary outcome measure was the incidence of ongoing status epilepticus at the time of hospital arrival. "We had a number of secondary outcomes, the most important of which was prehospital complications—hypotension, cardiac disturbances, or respiratory interventions," Dr. Lowenstein said. Other measures included additional complications at the time of transfer to the emergency department, posttreatment duration of status epilepticus, and neurologic outcome.

"There was a much higher likelihood of patients being in status epilepticus at the time of emergency department arrival if they received placebo compared to the two active treatments," Dr. Lowenstein said. "However, there was also significant difference between the diazepam and lorazepam group, with lorazepam favoring the cessation of status epilepticus by the time the patients arrived in the emergency department." Status epilepticus was terminated in a greater proportion of patients treated with lorazepam (59%) and diazepam (43%) when compared with placebo (21%). The odds of termination were 2.7 times higher in the lorazepam group than in the diazepam group.

Although there was an increased likelihood of prehospital complications in the placebo group (23%), compared with patients treated with lorazepam (11%) or diazepam (10%), "this did not achieve statistical significance at any time during the study," Dr. Lowenstein noted. "There was also a higher intubation rate among the placebo-treated group compared to the other two, and this was significant." A higher incidence of transfer complications was not seen in any of the groups.

Most patients in status epilepticus on arrival at the hospital (73%) were admitted to the intensive care unit. Neurologic outcomes at discharge were similar among the three groups. Although there was a higher proportion of deaths in the placebo group, this was not found to be statistically significant.

The paramedics themselves were asked for subjective assessments of the complexity of patient care, Dr. Lowenstein mentioned. "They felt that the complexity of airway management was significantly higher in the placebo and the lorazepam groups compared to the patients who had received diazepam."

Is intravenous administration of benzodiazepines an effective and safe means of treating status epilepticus in the prehospital setting? The answer, said Dr. Lowenstein in conclusion, is "unambiguously yes."

IS MORE BETTER?

Protocols for treatment of status epilepticus usually recommend starting with an intravenous benzodiazepine, then trying phenytoin and phenobarbital before intravenous anesthesia is considered. However, "most protocols have evolved empirically, and they've been largely based on pharmacokinetic considerations in terms of the order with which drugs have been given," Dr. Treiman said.

To evaluate the efficacy of sequential treatments in status epilepticus protocols, Dr. Treiman and his colleagues conducted a subset analysis of a five-year VA Cooperative Study. Adults with overt or subtle generalized convulsive status epilepticus were randomly assigned to initial treatment with one of four intravenous regimens: diazepam 0.15 mg/kg followed by phenytoin 18 mg/kg; lorazepam 0.1 mg/kg; phenobarbital 15 mg/kg; or phenytoin 18 mg/kg.

"We packaged these four [regimens] in treatment kits to allow the administration of the initial drug at the appropriate dose and rate and to allow administration of a second and third drug, again in blinded fashion, if a second and third drug was necessary," Dr. Treiman said. "The order of administration for each treatment kit was determined arbitrarily."

The patients were then stratified into those who presented with overt generalized convulsive status epilepticus (384 patients) or subtle status epilepticus (134 patients). The mean age was 58.6 years in the overt group and 62.0 years in the subtle group. Both groups were predominately male (over 80%). About half of the overt status epilepticus patients were African-American (53.3%), followed by white (35.1%) and other (11.6%). In comparison, over half of the subtle status epilepticus patients were white (58.2%), followed by African-American (36.6%) and other (5.2%). About 30% of the patients in the overt status epilepticus group and 20% of the subtle group were not veterans but were cared for in university hospitals.

Success was defined as cessation of all behavioral and electrical seizure activity within 20 minutes of the start of drug infusion with no further seizure activity during the next 40 minutes. "If necessary, specified second and third drugs were given; fourth and subsequent treatments were at the discretion of the investigator," Dr. Treiman said. Overall success rates for the subsequent drugs were determined for overt and subtle groups. In addition, success rates were determined for each of the four treatments.

Among the patients with overt status epilepticus, overall success rates were highest for the initial drug (55.5%). The success rate was 7.0% for the second drug and 2.3% for the third drug. Four or more drugs were associated with a 23.2% success rate, and no drug was successful within the 12-hour protocol in 11.7%, reported Dr. Treiman.

Among the patients with subtle status epilepticus, success rates were 14.9% for the initial drug, 3.0% for the second drug, 4.5% for the third drug, and 27.6% for four or more drugs. In the remaining half of this group, no drug met the criteria for a successful result within the 12-hour protocol.

Analyses of individual drug treatment groups found similar success rates for four or more drugs among the patients with overt (17.5% to 26.7%) and subtle (23.1% to 36.1%) status epilepticus.

"The conclusion that we reached from this subset analysis of the VA Cooperative Study is that little is gained by using standard antiepileptic drugs as subsequent therapy when the first treatment fails," Dr. Treiman said. "Substantially more patients responded to four or more drugs than to the second or third drug."

"It may be that treatment protocols for generalized convulsive status epilepticus should be revised to incorporate rapid addition of intravenous general anesthesia if the initial treatment fails," Dr. Treiman proposed. Since this particular study did not assess how well general anesthesia would have worked as the second-line option, further research is needed, he concluded.

—Debra Hughes
Contributing Writer

Suggested Reading

Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J Med. 1998;338:970-976.

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.

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