Clinical Research

Propofol and Midazolam in the Treatment of RefractoryStatus Epilepticus

*,†Avinash Prasad, †,‡Bradford B. Worrall, *,†Edward H. Bertram, and *,†,§,\,¶Thomas P. Bleck

*F.E. Dreifuss Comprehensive Epilepsy Program, †Department of Neurology, ‡Department of Health Evaluation Sciences,§Nerancy Neuroscience Intensive Care Unit,\Department of Neurological Surgery, and ¶Department of Internal Medicine,

University of Virginia, Charlottesville, Virginia, U.S.A.

Summary: Purpose:To explore outcome differences betweenpropofol and midazolam (MDL) therapy for refractory statusepilepticus (RSE).

Methods:Retrospective chart review of consecutive patientstreated for RSE between 1995 and 1999.

Results:We found 14 patients treated primarily with propo-fol and six with MDL. Propofol and MDL therapy achieved 64and 67% complete clinical seizure suppression, and 78 and67% electrographic seizure suppression, respectively. Overallmortality, although not statistically significant, was higher withpropofol (57%) than with MDL (17%) (p4 0.16). Subgroupmortality data in propofol and MDL patients based onAPACHE II (Acute Physiology and Chronic Health Evalua-tion) score did not show statistically significant differencesexcept for propofol-treated patients with APACHE II score$20, who had a higher mortality (p4 0.05). Reclassifying the

one patient treated with both agents to the MDL group elimi-nated this statistically significant difference (p4 0.22).

Conclusions:In our small sample of RSE patients, propofoland MDL did not differ in clinical and electrographic seizurecontrol. Seizure control and overall survival rates, with the goalof electrographic seizure elimination or burst suppressionrather than latter alone, were similar to previous reports. InRSE patients with APACHE II score$20, survival with MDLmay be better than with propofol. A large multicenter, prospec-tive, randomized comparison is needed to clarify these data. Ifcomparable efficacy of these agents in seizure control is borneout, tolerance with regard to hemodynamic compromise,complications, and mortality may dictate the choice ofRSE agents.Key Words: Status epilepticus—Propofol—Midazolam—Seizures—Treatment.

The mortality rate associated with status epilepticus(SE) varies between 3 and 35% depending on the age ofthe patient, the etiology of seizures, and the duration ofSE (1). Available reports of treated refractory SE (RSE)patients consist of small series (2–6). Depending on thedefinition of RSE used in these studies, mortality ratesvary between 32 and 77%. An incidence of 6,000–20,000RSE cases/year in the United States indicates the mag-nitude of the problem (7). The high prevalence of con-current systemic illnesses adds to its burden (2).

Significant advances in the management of RSE haveoccurred during the last two decades. Three agents [bar-biturates, propofol, and midazolam (MDL)] haveemerged as treatment for RSE, but success rates vary

(2–5,8–12). The total number of patients treated withthese agents remains low, and therefore a consensusabout RSE management has yet to emerge. The use ofhigh-dose barbiturates to treat RSE is associated with ahigh morbidity and mortality (13). Among the neweragents to treat RSE, propofol is efficacious and has fa-vorable pharmacokinetics (2,13). Several case reportshave described the efficacy of propofol therapy in con-trolling SE (8–10,14–25). One small, open-labeled, non-randomized study with a prospective component com-pared the outcome of RSE patients treated with propofolto 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). Theaim of this study was to examine our experience withpropofol and MDL therapy in adult patients with RSEand to explore possible differences in efficacy and com-plications.

Accepted November 11, 2000.Address correspondence and reprint requests to Dr. T. P. Bleck at

Department of Neurology, Box 394, University of Virginia, Char-lottesville, VA 22908, U.S.A. E-mail: tpb9k@virginia.edu

Epilepsia,42(3):380–386, 2001Blackwell Science, Inc.© International League Against Epilepsy

380

METHODS

Patient identificationThe medical records of consecutive RSE patients (age

17 or older) admitted and treated at University of Vir-ginia Medical Center between 1995 through 1999 werereviewed retrospectively; before this time, propofol wasnot used to treat RSE patients at our institution. Patientswere identified from the SE cases in neuroscience inten-sive care unit (ICU) admission logbook and from EEGreports that described the use of propofol or MDL. Pa-tients were categorized based on which of the two agentsthey received. If patients received both agents, the agentused for the greater time was designated.

We followed the RSE clinical criteria defined byStecker et al. (2) for inclusion. These included acuteseizures persisting >2 h, or seizures recurring at a rate ofat least two per hour without recovery to baseline be-tween seizures, despite treatment with conventional an-ticonvulsants (AEDs) including phenytoin (PHT) andlorazepam (LZP) or phenobarbital (PB). The presence ofaltered mental status was necessary, thus excludingsimple partial SE. Patients satisfying these criteria wereincluded in the study only if EEG before or during RSEtherapy showed electrographic seizures. EEGs from re-ferring hospitals were acceptable if available for reviewand met the criteria.

Pediatric patients (age 17 years or younger) were ex-cluded because their prognosis is much better than that ofadult patients, and a propofol treatment group was notavailable for comparison. Patients with a history of wit-nessed motor manifestations in the absence of electro-graphic seizures were also excluded. EEG findings ofburst suppression, suppression, or diffuse slowing alonedid not constitute criteria for inclusion.

Clinical assessmentTo assess clinical characteristics, we reviewed the in-

patient and outpatient charts and EEG of study patients.The suspected etiology of SE was determined from allavailable clinical, radiologic, or laboratory data. How-ever, contributions from other medical illnesses couldnot be entirely excluded in some patients. The durationof SE before treatment was determined from the time thefirst motor manifestation occurred. If the duration ofRSE after seizure onset was not well defined, it wasrounded off to the nearest 12 h. An APACHE II scorewas calculated for each patient at the time of RSE diag-nosis to serve as a severity-of-illness index (30). A cut-off score of $20 was chosen to indicate moderate tosevere illness, based on the observation that all patientswith scores#20 survived.

We noted the occurrences of hemodynamic compro-mise, infectious complications, number of days on a ven-tilator, and mortality. Hemodynamic compromise wasdefined as persistent or recurrent hypotension despite

pressor support, necessitating change or withdrawal ofthe RSE agent. Infectious complications included sepsis,chest radiographs showing pneumonia, and pyuria. Mor-tality included death during or within 2 weeks after thediscontinuation of RSE therapy.

Outcome assessmentClinical seizure outcome was studied independently

from electrographic seizure outcome. Data on clinicalseizures, both overt and subtle, were entirely dependenton the records. A seizure was considered subtle if itconsisted of subtle twitches of the extremities, face, ornystagmoid eye movements in an unconscious patient(31). Cessation of seizures was defined as completesuppression of motor manifestations. Clinical–electro-graphic correlation was not available for some presumedabnormal motor activities that fitted in the description ofsubtle seizures either because the EEG was not archived,or because the subtle movements occurred when inter-mittent EEG was performed. These documented abnor-mal movements, therefore, were considered seizures.Clinical seizures during planned tapering were not in-cluded in the outcome. However, clinical seizures duringmaintenance phase, when drug dosage could not be in-creased further due to complications, and after 24 h afterwithdrawal of the RSE agent, were included as treatmentfailure.

Electrographic seizure outcome was based on EEGreports and review of available archived EEG. EEG re-ports were available in the charts on a daily basis for theduration of monitoring. Board-certified electroencepha-lographers read all studies. Important segments of ar-chived EEGs on microfilm or CD-ROM were availableon all patients. These were reviewed to corroborate theEEG reports. Electrographic seizure suppression was de-fined as complete elimination of electrographic seizureregardless of burst suppression or complete suppressionof EEG activity. Periodic complexes associated with ictalmotor manifestations were considered clinical seizures.Periodic complexes without ictal motor manifestationswere also considered seizures except in a terminal pa-tient, when they were considered to represent brain dam-age, rather than ongoing SE (32). Periodic complexesseen briefly after ictal motor manifestations were con-sidered to be due to the postictal state.

Statistical analysisAll statistical tests were performed with SigmaStat 2.0

software (SPSS Corporation, Chicago, IL, U.S.A.). Stu-dent’st test was used to analyze age and duration of SEbefore treatment. The APACHE II score was analyzed bythe rank-sum test. Fisher’s exact two-tailed test was usedto analyze dichotomized variables. Duration of RSEagent infusion and days on ventilator were analyzed bythe Mann–Whitney rank sum test. Alpha was set at#0.05. Primary analyses were performed, including the

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one patient who received both agents in the propofolgroup. A sensitivity analysis was undertaken to deter-mine if reclassification of this patient to the MDL groupchanged the results.

RESULTS

DemographicsThe clinical characteristics of the patients treated with

propofol and MDL are given in Tables 1 and 2, and acomparison of their demographic data is given in Table3. Fourteen patients (eight women, six men) receivedprimarily propofol, and six patients (five women, oneman) received MDL. There was no clinically significantdemographic difference between propofol and MDL pa-tients.

Initial treatmentAll patients were admitted to the neuroscience ICU

and managed by neurointensivists. Three patients wereintubated before admission to the ICU. All except one ofthe remaining patients were intubated before initiation ofpropofol or MDL. Central venous or pulmonary arterialcatheters and arterial lines were placed in all patients.

Treatment of patients naı¨ve to conventional AEDs

consisted of standard loading doses of PHT, 20 mg/kg,and LZP, 0.05–0.1 mg/kg, i.v. Patients treated with PHTand PB before the episode of RSE received additionalloading doses if these levels were subtherapeutic. Pa-tients receiving other maintenance AEDs such as valpro-ic acid (VPA) and carbamazepine (CBZ) continued toreceive these agents. Every attempt was made to keepAED levels above therapeutic levels throughout the epi-sode of SE. No differences were observed in the serumPHT and PB levels between the two groups before ini-tiation of RSE agents (p4 0.78 and 0.28, respectively)(Tables 1 and 2).

Propofol/midazolam treatmentPropofol and MDL dose (Tables 4 and 5) depended on

individual treating physician preference and hemody-namic status. A propofol bolus dose of 1–3 mg/kg wasadministered in only five patients. Maintenance infusiondose varied typically between 1 and 10 mg/kg/h (range,0.1–24 mg/kg/h). All MDL-treated patients except onereceived an MDL bolus (dose, 2–12 mg). Maintenanceinfusion dose varied between 0.05 and 0.8 mg/kg/h. Theend point of titration of the RSE agent was elimination ofelectrographic seizure or achievement of electrographicburst suppression/suppression. After∼12 or 24 h of at-

TABLE 1. Clinical profile of refractory status epilepticus patients treated with propofol

Patient/age(yr)/sex

Cause ofrefractory status

epilepticus

Other knownmedicalillnesses

InitialEEG

Durationof SE before

therapy

APACHEII score at

RSE diagnosis

Otherdruglevels

1/17/M Encephalitis None Discrete L/R temporal ictalactivity

24 h 20 PHT 23,VPA 75

2/18/M ? Encephalitis None Generalized periodiccomplexes L > R

48 h 18 PHT 18,PB 24

3/21/M Encephalitis None Continuous ictal activity L > R 12 h 20 PHT 22,PB 34,VPA 40

4/28/M Remote symptomaticepilepsy

Static encephalopathy L hemisphere continuous ictalactivity

12 h 17 PHT 19,PB 24

5/28/F Cerebral edema Multiorgan failure, S/P livertransplant rejection

L temporal PLEDs 6 h 24 PHT 11

6/47/F Hyponatremia Malabsorption syndrome,head trauma

R frontal PLEDs 2 h 10 PHT 18

7/52/F Metastases brain Ca breast, DM, HTN Periodic complexes R > Lfrontal

24 h 26 PHT 22

8/58/F Cryptococcal meningitis Hepatic encephalopathyARF, HTN

Independent L/R continuousictal activity

12 h 29 PHT 17,PB 24

9/60/F Hypoglycemia DM Bifrontal periodic complexes 24 h 21 PHT 2610/62/F Remote symptomatic

epilepsyDM, HTN, old CVA L

MCAL/R hemisphere continuous

ictal activity24 h 28 PHT 20

11/66/Ma ? Encephalitis R ICA complete occlusion Discrete L/R temporal ictalactivity

48 h 20 PB 46,CBZ 5

12/66/M S/P Basilar art. aneurysmsurgery/brain edema

None R frontal ictal activity withgeneralization

24 h 15 PHT 20

13/76/F Intracranial hemorrhage S/P meningioma resection,CRF HTN

Discrete L/R frontal ictalactivity

16 h 20 PHT 25,PB 15

14/81/F Remote symptomaticepilepsy

DM, HTN, old CVA L PCA Discrete L occipital ictalactivity

24 h 19 PHT 14,VPA 25

ARF, acute renal failure; CBZ, carbamazepine; CRF, chronic renal failure; CVA, cerebrovascular accident; DM, diabetes mellitus, HTN, hyper-tension; ICA, internal carotid artery; L, left; MCA, middle cerebral artery; PCA, posterior cerebral artery; PB, phenobarbital; PHT, phenytoin; PLEDs,periodic lateralized epileptiform discharges; R, right; RSE, refractory status epilepticus; S/P, status post; VPA, valproic acid.

a 12-h midazolam infusion preceded propofol therapy.

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taining the goal, an attempt was made to reduce the RSEagent by approximately half.

Management while receiving RSE therapyVolume expansion with saline, and pressure support

with phenylephrine, dopamine, and norepinephrine wereused to maintain the patient’s blood pressure (BP) withinan acceptable range, as necessary. If pressure-supportmeasures did not rapidly control BP, infusion of propofolor MDL was withheld until the patient’s BP reached anacceptable value.

EEG was performed before initiating/continuing RSEagent or as soon as possible thereafter. Digital EEGmonitoring continued throughout the period of RSEtreatment. Once overt and initial subtle seizure controlwas achieved, intermittent EEG monitoring was contin-

ued for a variable period depending on patient’s clinicalcondition.

OutcomesThe outcomes of patients treated with propofol and

MDL are given in Tables 4 and 5, and they are comparedin Table 3. The propofol group had more patients (64%)with acute central nervous system (CNS) injury com-pared with the MDL group (33%) (Tables 1 and 2); andalso had a greater median duration of SE before therapy(24 vs. 17 h; Table 3). However, median duration oftherapy was greater with MDL (43 h) compared withpropofol (31 h; Table 3).

Burst suppression or complete suppression was notattempted or achieved in eight of 20 patients (three in thepropofol group and five in the MDL group). Neverthe-less, propofol and MDL therapy achieved 64 and 67%complete clinical seizure suppression, 78 and 67% elec-trographic seizure suppression, and 29 and 17% elimi-nation of all epileptiform discharges, respectively, anddid not show any difference (all p values$0.61; Table3). Subtle motor manifestations noted in seven patientswere evaluated as subtle seizures due to lack of clinical–electrographic correlation.

Table 3 presents the rates of infectious complications,hemodynamic compromise, and number of days on ven-tilator. Hemodynamic compromise was seen in two of 14patients treated with propofol but in none of six in theMDL group.

In addition to the overall mortality rates, subgroupmortality rates for moderate to severe disease (APACHEII score) were assessed. A comparison of overall mor-tality data did not show statistically significant difference(all p values$0.16). Patients with APACHE II score$20 treated with propofol had a higher mortality thandid those treated with MDL (p4 0.05). Sensitivityanalysis with reclassification of the patient treated with

TABLE 3. Summary of demographics and outcomes ofrefractory status epilepticus patients treated with propofol

and midazolam

Demographics and outcomesPropofol(n 4 14)

Midazolam(n 4 6)

Median age in yr (range) 48.6 (17–81) 48.3 (19–79)Median APACHE II score (range) 20 (10–29) 20 (7–26)Median duration of SE before

therapy in h (range) 24 (2–48) 17 (2–24)Median duration of therapy in h

(range) 31 (7–408) 43 (40–118)Clinical seizure suppression (%) (n) 64 (n4 9) 67 (n4 4)Electrographic seizure suppression

(%) (n) 78 (n4 11) 67 (n4 4)Elimination of all epileptiform

discharges (%) (n) 29 (n4 4) 17 (n4 1)Infectious complications (%) (n) 29 (n4 4) 50 (n4 3)Hemodynamic compromise (%) (n) 14 (n4 2) 0 (n4 0)Median number of days on ventilator

(range) 4 (1–32) 4 (0–11)Overall mortality (%) (n)a 57 (n4 8) 17 (n4 1)

a p value of 0.16 is a comparison of overall mortality between pro-pofol and midazolam therapies.

TABLE 2. Clinical profile of refractory status epilepticus patients treated with midazolam

Patient/age(yr)/sex

Cause ofrefractory status

epilepticus

Other knownmedicalillnesses

InitialEEG before

therapyDuration

of SE

APACHEII score at

RSE diagnosisOther

drug levels

1/19/F Remote symptomaticepilepsy

Static encephalopathy,cardiomyopathy

Discrete R > L temporalictal activity

24 h 7 PHT 22, PB 23

2/33/F Uremia DM, HTN, CVA R MCA,ESRD

L hemisphere continuousictal activity

24 h 26 PHT 18, CBZ 8

3/38/F Remote symptomaticepilepsy

Static encephalopathy R ICAcomplete occlusion

Discrete R frontal ictalactivity

8 h 11 PHT 26

4/47/M Intracerebral hemorrhage Cirrhosis liver L temporal ictal activitywith generalization

18 h 20 PHT 20, PB 9

5/74/F Ischemia–hypoxia Multiple trauma Discrete L/R temporalictal activity

2 h 25 PHT 22, PB 26

6/79/F L acute on chronic SDH ESRD, HTN Discrete L/R temporalictal activity

16 h 20 PHT 16, VPA 75

CBZ, carbamazepine; CVA, cerebrovascular accident; DM, diabetes mellitus; ESRD, end-stage renal disease; HTN, hypertension; ICA, internalcarotid artery; L, left; MCA, middle cerebral artery; PB, phenobarbital; PHT, phenytoin; R, right; RSE, refractory status epilepticus; SDH, subduralhematoma; VPA, valproic acid.

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both agents to the MDL group resulted in loss of signifi-cance (p4 0.22).

DISCUSSION

Our small series of adult RSE patients treated primar-ily with propofol (n 4 14) and MDL (n4 6) demon-strated no significant difference in the clinical or elec-trographic seizure control, infectious complications, he-modynamic compromise, and number of days onventilator. These findings do not suggest differences inefficacy between the two RSE agents for seizure controland reduction in number of days on ventilator. A largerstudy is needed, particularly to compare the infectiouscomplications and hemodynamic compromise. If compa-rable efficacy in seizure control were borne out in a largeprospective randomized control study, tolerability withregard to hemodynamic compromise, complications, andmortality with these therapies might dictate the choice ofRSE agents.

A higher percentage of patients treated with propofolshowed electrographic seizure suppression than com-plete clinical seizure suppression. This could be due tolack of continuous EEG data available for review, in-

cluding those of some motor manifestations that we in-cluded as clinical seizures. The majority of motor mani-festations resembled those described by Treiman (31);nonetheless, they could also represent side effects orwithdrawals from AEDs.

Our end point of RSE agent titration differed some-what from other studies in that either elimination of elec-trographic/clinical seizure or achievement of electro-graphic burst suppression/complete EEG suppressionwas acceptable. Complete clinical seizure suppressionseen in 65% of patients was comparable to seizure out-come (74%) achieved by Stecker et al. (2) using burstsuppression/suppression as the end point of RSE titra-tion. It is possible that lower doses of an RSE agent caneliminate the electrographic/clinical seizure without nec-essarily producing persistent burst suppression/suppres-sion. Lower doses of RSE agents may decrease thefrequency of complications including hemodynamiccompromise and will still protect the brain from seizure-induced injury (4). Experimental work supports thistheory, showing that high-frequency spike activity on theEEG is associated with neuronal injury, whereas occa-sional spikes or intermittent bursts of ictal activity do notcause apparent injury (33,34).

TABLE 4. Complications, therapy, and outcome of refractory status epilepticus patients treated with propofol

Patient Complications

Propofolbolus (mg/kg)/

infusion (mg/kg/h)

Duration ofinfusion

(h/d)

Clinicalseizure

suppression

Electrographicseizure

suppressionDays of

ventilatorClinicaloutcome

1 — 2/2.0–12.0 46 h Yes Yes 5 Alive/mild deficit2 Pneumonia 2/5.0–9.0 17 d Noa Yes 32 Alive/mild deficit3 Hemodynamic compromise 1/5.0–10.5 48 h Noa No 2 Died4 Pneumonia 2/1.0–3.0 96 h Yes Yes 4 Alive/pre-SE5 — 0/2.0–24.0 82 h Noa No 4 Died6 — 0/2.5–10.0 14 h Yes Yes 2 Alive/normal7 Pneumonia 3/2.5–5.0 18 h Noa Yes 4 Died8 Sepsis 0/2.0–5.0 22 h Noa No 12 Died9 Hemodynamic compromise 0/5.0–9.0 40 h Yes Yes 9 Died

10 — 0/3.0–5.0 7 h Yes Yes 1 Died11 — 0/2.0–3.0 48 h Yes Yes 15 Died12 — 0/1.0–4.0 72 h Yes Yes 4 Alive/mild deficit13 — 0/2.0–20.0 14 h Yes Yes 4 Died14 — 0/0.1–0.3 9 h Yes Yes 5 Alive pre-SE

Pre-SE, prestatus epilepticus.a Subtle seizures.

TABLE 5. Complications, therapy, and outcome of refractory status epilepticus patients treated with midazolam

Patients Complications

Midazolambolus/infusion

(mg/kg/h)

Durationof infusion

(h)

Clinicalseizure

suppression

Electrographicseizure

suppression

Dayson

ventilatorClinicaloutcome

1 Sepis 2/0.2–0.4 41 Noa No None Alive/pre-SE2 Pneumonia 12/0.1–0.5 45 Yes Yes 3 Alive, pre-SE3 Pneumonia 5/0.1–0.8 82 Yes Yes 8 Alive pre-SE4 None 16/0.05–0.1 118 Noa Yes 11 Alive pre-SE5 None 2/0.05–0.1 40 Yes No 3 Died6 None 0/0.5–0.1 40 Yes Yes 7 Alive/moderate deficit

Pre-Se, pre–status epilepticus.a Subtle seizures.

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Overall mortality and subgroup mortality findings inpatients with APACHE II score$20 were interesting. Ahigher mortality rate was found in the propofol-treatedpatients with APACHE II score$20 than in MDL-treated, but this finding was found after multiple com-parisons and was lost in sensitivity analysis. The overallmortality rate was nonsignificantly higher with propofol(57%) than with MDL (17%) therapy, perhaps owing tothe small sample size. Interestingly, a higher proportionof the propofol group had acute CNS injury and also hadlonger median duration of SE before therapy comparedwith the MDL group. Stecker et al. (2) also reported anonsignificantly higher mortality rate with propofol(88%) compared with high-dose barbiturate therapy(50%). In both studies, small sample size limited thestatistical power to detect a difference in overall mortal-ity, although in both cases, it was close to 40%. A largeprospective randomized series of RSE patients treated bythese agents is needed to answer whether this finding isreal.

In a small study of 16 RSE patients treated with high-dose barbiturates and propofol, overall mortality was69% compared with 45% in our series (2). The patientpopulations may be different in these studies; therefore,a direct comparison is not possible. The lower mortalityin our series may be partly attributed to lower medianAPACHE II score of 20 (range, 7–29) compared with27.5 (range, 19–38) in the previous study. This findingsuggests that the APACHE II score may be a potentpredictor of outcome in RSE therapy.

Our study has several limitations. Nonrandom assign-ment to treatment groups may have resulted in imbal-ances in the groups. Specific patient characteristics, suchas hemodynamic status at presentation, may have influ-enced treatment selection. The retrospective data collec-tion 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 ex-ploratory nature of this study, we considered many po-tentially important predictors of outcomes. Because ofthe number of comparisons, the difference between thegroups found may be due to chance.

A multiinstitutional prospective randomized study ofRSE patients could examine efficacy, complication rates,and mortality. Design questions to be addressed include(a) which RSE agents should be compared; (b) whatshould be the titration goal, electrographic seizure elimi-nation or burst suppression/suppression; and (c) whichprespecified subgroup analyses must be considered whencalculating the sample size. Because patient age, under-lying etiology (acute CNS, acute non-CNS, and remotesymptomatic), and disease severity all affect survival,any planned study would need to consider if one agent issuperior in any particular subgroup. In considering a pro-spective trial with alpha set at 0.05 and beta at 0.2 (80%

power) to detect a clinically meaningful difference inmortality rate of∼40%, 56 patients, 28 in each group,would be needed for the primary outcome, and additionalpatients would be needed for planned subgroup analyses.Although both propofol and midazolam cost∼$500 aday, other costs such as number of ICU days and numberof days on ventilator may be important to consider inassessing the cost–benefit analysis of RSE therapy.

REFERENCES

1. Working Group on Status Epilepticus. Treatment of convulsivestatus epilepticus: recommendations of the Epilepsy Foundation ofAmerica’s Working Group on Status Epilepticus. JAMA1993;270:854–9.

2. Stecker MM, Kramer TH, Raps EC, et al. Treatment of refractorystatus epilepticus with propofol: clinical and pharmacokinetic find-ings.Epilepsia1998;39:18–26.

3. Lowenstein DH, Aminoff MJ, Simon RP. Barbiturate anesthesia inthe treatment of status epilepticus: clinical experience with 14patients.Neurology1988;38:395–400.

4. Yaffe K, Lowenstein DH. Prognostic factors of pentobarbitaltherapy for refractory generalized status epilepticus.Neurology1993;43:895–900.

5. Rashkin MC, Youngs C, Penovich P. Pentobarbital treatment ofrefractory status epilepticus.Neurology1987;37:500–3.

6. Towne AR, Pellock JM, Ko D, et al. Determinants of mortality instatus epilepticus.Epilepsia1994;35:27–34.

7. Jagoda A, Riggio S. Refractory status epilepticus in adults. AnnEmerg Med1993;22:1337–48.

8. Campostrini R, Bati MB, Giorgi C, et al. Propofol in the treatmentof convulsive status epilepticus: a report of four cases. Nuova RivNeurol 1991;1:176–9.

9. Natale E, Mattaliano A, Alia G, et al. Propofol treatment of statusepilepticus: report of four cases successfully treated.Epilepsia1993;34(suppl 2):124–5.

10. Exil G, Clancy RR, Hyder DJ. Propofol treatment of refractorystatus epilepticus: a report of five pediatric cases.Epilepsia1995;36(suppl 4):124.

11. Cortina J, Ancillo P, Duarte J, et al. Intravenous midazolam sup-pression of complex partial status refractory to intravenous phe-nytoin and diazepam.Clin Neuropharmacol1993;16:468–70.

12. Kumar A, Bleck TP. Intravenous midazolam for the treatment ofrefractory status epilepticus. Crit Care Med1992;20:483–8.

13. Bleck TP. Advances in the management of refractory status epi-lepticus.Crit Care Med1993;21:955–7.

14. Shorvon S. Status epilepticus: its clinical features and treatment inchildren and adults. In: Shorvon S, ed.Emergency treatment ofstatus epilepticus. Cambridge, MA: Cambridge University Press,1994;175–292.

15. Yanny HF, Christmas D. Propofol infusions for status epilepticus[Letter]. Anesthesia1988;43:514.

16. Wood PR, Browne GPR, Pugh S. Propofol infusion for the treat-ment of status epilepticus. Lancet1988;1:480–1.

17. Chilvers CR, Laurie PS. Successful use of propofol in status epi-lepticus.Anesthesia1990;45:995–6.

18. Mackenzie SJ, Kapadia F, Grant IS. Propofol infusion for controlof status epilepticus.Anesthesia1990;45:1043–5.

19. Alia G, Natale E, Mattaliano A, et al. On two cases of statusepilepticus treated with propofol [Abstract].Epilepsia 1991;32(suppl 1):77.

20. Borgeat A, Wilder-Smith OH, et al. Propofol in the management ofstatus epilepticus: a case report.Intens Care Med1994;20:148–9.

21. Pitt-Miller PL, Elcock BJ, Maharaj M. The management of statusepilepticus with a continuous propofol infusion.Anesth Analg1994;78:1193–4.

22. Hantson P, VanBrandt N, Verbeeck R, et al. Propofol for refractorystatus epilepticus.Intens Care Med1994;20:611–2.

23. Merigan KS, Browning RG, Leeper KV. Successful treatment of

PROPOFOL AND MIDAZOLAM IN STATUS EPILEPTICUS 385

Epilepsia, Vol. 42, No. 3, 2001

amoxapine-induced refractory status epilepticus with propofol (Di-privan).Acad Emerg Med1995;2:128–33.

24. DeKrom MC, Verduin N, Visser E, et al. Status epilepticus duringvigabatrin treatment: a report of three cases. Seizure1995;4:159–62.

25. Harrison AM, Lugo RA, Schunk JE. Treatment of convulsive sta-tus epilepticus with propofol: case report.Pediatr Emerg Care1997;13:420–2.

26. Galdames PD, Silva-Rosas C, Aguilera L. Treatment of statusepilepticus with midazolam: report of four cases.Neurologia1994;9:109–11.

27. Crisp CB, Gannon R, Knauft F. Continuous infusion of midazolamhydrochloride to control status epilepticus.Clin Pharm 1988;7:322–4.

28. Parent JM, Lowenstein DH. Treatment of refractory generalizedstatus epilepticus with continuous infusion of midazolam.Neurol-ogy 1994;44:1837–40.

29. Fountain NB, Adams RE. Midazolam treatment of acute and re-fractory status epilepticus.Clin Neuropharmacol1999;22:261–7.

30. Knaus WA, Draper EA, Wagner DP, et al. APACHE II: a severityof disease classification system.Crit Care Med1985;13:818–28.

31. Treiman DM. Generalized convulsive status epilepticus in adults.Epilepsia1993;34(suppl):S2–11.

32. Lothman EW, Bertram EH, Bekenstein JW, et al. Self-sustaininglimbic status epilepticus induced by “continuous hippocampalstimulation”: electrographic and behavioral characteristics.Epi-lepsy Res1989;3:107–19.

33. Lowenstein DH, Simon R, Sharp F. The induction of 72-kDa heatshock protein-like immunoreactivity in the rat brain followingflurothyl-induced status epilepticus.Brain Res1990;531:173–82.

34. Shimosaka S, So Y, Simon R. Distribution of HSP72 induction andneuronal death following limbic seizures.Neurosci Lett1992;138:202–6.

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