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Summary: Purpose: To explore outcome differences between propofol and midazolam (MDL) therapy for refractory status epilepticus (RSE).
Methods: Retrospective chart review of consecutive patients treated for RSE between 1995 and 1999.
Results: We found 14 patients treated primarily with propofol and six with MDL. Propofol and MDL therapy achieved 64 and 67% complete clinical seizure suppression, and 78 and 67% electrographic seizure suppression, respectively. Overall mortality, although not statistically significant, was higher with propofol (57%) than with MDL (17%) (p = 0.16). Subgroup mortality data in propofol and MDL patients based on APACHE II (Acute Physiology and Chronic Health Evaluation) score did not show statistically significant differences except for propofol-treated patients with APACHE II score ≥20, who had a higher mortality (p = 0.05). Reclassifying the one patient treated with both agents to the MDL group eliminated this statistically significant difference (p = 0.22).
Conclusions: In our small sample of RSE patients, propofol and MDL did not differ in clinical and electrographic seizure control. Seizure control and overall survival rates, with the goal of electrographic seizure elimination or burst suppression rather than latter alone, were similar to previous reports. In RSE patients with APACHE II score ≥20, survival with MDL may be better than with propofol. A large multicenter, prospective, randomized comparison is needed to clarify these data. If comparable efficacy of these agents in seizure control is borne out, tolerance with regard to hemodynamic compromise, complications, and mortality may dictate the choice of RSE agents.
The mortality rate associated with status epilepticus (SE) varies between 3 and 35% depending on the age of the patient, the etiology of seizures, and the duration of SE (1). Available reports of treated refractory SE (RSE) patients consist of small series (2–6). Depending on the definition of RSE used in these studies, mortality rates vary between 32 and 77%. An incidence of 6,000–20,000 RSE cases/year in the United States indicates the magnitude of the problem (7). The high prevalence of concurrent systemic illnesses adds to its burden (2).
Significant advances in the management of RSE have occurred during the last two decades. Three agents [barbiturates, propofol, and midazolam (MDL)] have emerged as treatment for RSE, but success rates vary (2–5,8–12). The total number of patients treated with these agents remains low, and therefore a consensus about RSE management has yet to emerge. The use of high-dose barbiturates to treat RSE is associated with a high morbidity and mortality (13). Among the newer agents to treat RSE, propofol is efficacious and has favorable pharmacokinetics (2,13). Several case reports have described the efficacy of propofol therapy in controlling SE (8–10,14–25). One small, open-labeled, nonrandomized study with a prospective component compared the outcome of RSE patients treated with propofol to those treated with high-dose barbiturates (2). Open-labeled, uncontrolled studies of continuous intravenous (i.v.) MDL use in RSE demonstrated moderate efficacy (11,12,26–28) and favorable pharmacokinetics (29). The aim of this study was to examine our experience with propofol and MDL therapy in adult patients with RSE and to explore possible differences in efficacy and complications.
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Our small series of adult RSE patients treated primarily with propofol (n = 14) and MDL (n = 6) demonstrated no significant difference in the clinical or electrographic seizure control, infectious complications, hemodynamic compromise, and number of days on ventilator. These findings do not suggest differences in efficacy between the two RSE agents for seizure control and reduction in number of days on ventilator. A larger study is needed, particularly to compare the infectious complications and hemodynamic compromise. If comparable efficacy in seizure control were borne out in a large prospective randomized control study, tolerability with regard to hemodynamic compromise, complications, and mortality with these therapies might dictate the choice of RSE agents.
A higher percentage of patients treated with propofol showed electrographic seizure suppression than complete clinical seizure suppression. This could be due to lack of continuous EEG data available for review, including those of some motor manifestations that we included as clinical seizures. The majority of motor manifestations resembled those described by Treiman (31); nonetheless, they could also represent side effects or withdrawals from AEDs.
Our end point of RSE agent titration differed somewhat from other studies in that either elimination of electrographic/clinical seizure or achievement of electrographic burst suppression/complete EEG suppression was acceptable. Complete clinical seizure suppression seen in 65% of patients was comparable to seizure outcome (74%) achieved by Stecker et al. (2) using burst suppression/suppression as the end point of RSE titration. It is possible that lower doses of an RSE agent can eliminate the electrographic/clinical seizure without necessarily producing persistent burst suppression/suppression. Lower doses of RSE agents may decrease the frequency of complications including hemodynamic compromise and will still protect the brain from seizure-induced injury (4). Experimental work supports this theory, showing that high-frequency spike activity on the EEG is associated with neuronal injury, whereas occasional spikes or intermittent bursts of ictal activity do not cause apparent injury (33,34).
Overall mortality and subgroup mortality findings in patients with APACHE II score ≥20 were interesting. A higher mortality rate was found in the propofol-treated patients with APACHE II score ≥20 than in MDL-treated, but this finding was found after multiple comparisons and was lost in sensitivity analysis. The overall mortality rate was nonsignificantly higher with propofol (57%) than with MDL (17%) therapy, perhaps owing to the small sample size. Interestingly, a higher proportion of the propofol group had acute CNS injury and also had longer median duration of SE before therapy compared with the MDL group. Stecker et al. (2) also reported a nonsignificantly higher mortality rate with propofol (88%) compared with high-dose barbiturate therapy (50%). In both studies, small sample size limited the statistical power to detect a difference in overall mortality, although in both cases, it was close to 40%. A large prospective randomized series of RSE patients treated by these agents is needed to answer whether this finding is real.
In a small study of 16 RSE patients treated with high-dose barbiturates and propofol, overall mortality was 69% compared with 45% in our series (2). The patient populations may be different in these studies; therefore, a direct comparison is not possible. The lower mortality in our series may be partly attributed to lower median APACHE II score of 20 (range, 7–29) compared with 27.5 (range, 19–38) in the previous study. This finding suggests that the APACHE II score may be a potent predictor of outcome in RSE therapy.
Our study has several limitations. Nonrandom assignment to treatment groups may have resulted in imbalances in the groups. Specific patient characteristics, such as hemodynamic status at presentation, may have influenced treatment selection. The retrospective data collection limited the ability to characterize the patients fully. The small sample size renders the study underpowered, perhaps resulting in type II errors. Because of the exploratory nature of this study, we considered many potentially important predictors of outcomes. Because of the number of comparisons, the difference between the groups found may be due to chance.
A multiinstitutional prospective randomized study of RSE patients could examine efficacy, complication rates, and mortality. Design questions to be addressed include (a) which RSE agents should be compared; (b) what should be the titration goal, electrographic seizure elimination or burst suppression/suppression; and (c) which prespecified subgroup analyses must be considered when calculating the sample size. Because patient age, underlying etiology (acute CNS, acute non-CNS, and remote symptomatic), and disease severity all affect survival, any planned study would need to consider if one agent is superior in any particular subgroup. In considering a prospective trial with alpha set at 0.05 and beta at 0.2 (80% power) to detect a clinically meaningful difference in mortality rate of ∼40%, 56 patients, 28 in each group, would be needed for the primary outcome, and additional patients would be needed for planned subgroup analyses. Although both propofol and midazolam cost ∼$500 a day, other costs such as number of ICU days and number of days on ventilator may be important to consider in assessing the cost–benefit analysis of RSE therapy.