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Keywords:

  • Epilepsy;
  • Refractory status epilepticus;
  • Pentobarbital;
  • Propofol;
  • Midazolam

Abstract

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Summary:  Background: New continuous infusion antiepileptic drugs (cIV-AEDs) offer alternatives to pentobarbital for the treatment of refractory status epilepticus (RSE). However, no prospective randomized studies have evaluated the treatment of RSE. This systematic review compares the efficacy of midazolam (MDL), propofol (PRO), and pentobarbital (PTB) for terminating seizures and improving outcome in RSE patients.

Methods: We performed a literature search of studies describing the use of MDL, PRO, or PTB for the treatment of RSE published between January 1970 and September 2001, by using MEDLINE, OVID, and manually searched bibliographies. We included peer-reviewed studies of adult patients with SE refractory to at least two standard AEDs. Main outcome measures were the frequency of immediate treatment failure (clinical or electrographic seizures occurring 1 to 6 h after starting cIV-AED therapy) and mortality according to choice of agent and titration goal (cIV-AED titration to “seizure suppression” versus “EEG background suppression”).

Results: Twenty-eight studies describing a total of 193 patients fulfilled our selection criteria: MDL (n = 54), PRO (n = 33), and PTB (n = 106). Forty-eight percent of patients died, and mortality was not significantly associated with the choice of agent or titration goal. PTB was usually titrated to EEG background suppression by using intermittent EEG monitoring, whereas MDL and PRO were more often titrated to seizure suppression with continuous EEG monitoring. Compared with treatment with MDL or PRO, PTB treatment was associated with a lower frequency of short-term treatment failure (8 vs. 23%; p < 0.01), breakthrough seizures (12 vs. 42%; p < 0.001), and changes to a different cIV-AED (3 vs. 21%; p < 0.001), and a higher frequency of hypotension (systolic blood pressure <100 mm Hg; 77 vs. 34%; p < 0.001). Compared with seizure suppression (n = 59), titration of treatment to EEG background suppression (n = 87) was associated with a lower frequency of breakthrough seizures (4 vs. 53%; p < 0.001) and a higher frequency of hypotension (76 vs. 29%; p < 0.001).

Conclusions: Despite the inherent limitations of a systematic review, our results suggest that treatment with PTB, or any cIV-AED infusion to attain EEG background suppression, may be more effective than other strategies for treating RSE. However, these interventions also were associated with an increased frequency of hypotension, and no effect on mortality was seen. A prospective randomized trial comparing different agents and titration goals for RSE with obligatory continuous EEG monitoring is needed.

Refractory status epilepticus (RSE), defined as SE that fails to respond to first- and second-line therapy, occurs in 9–31% of patients with SE (1–3) and is associated with high morbidity and high mortality (4–7). Treatment of RSE has not been studied in a prospective trial, and guidelines give a spectrum of options. Although recent reviews have recommended continuous intravenous (i.v.) midazolam (MDL) (1,8,9) or continuous i.v. propofol (PRO) (10,11) as alternatives to phenobarbital (PB) or continuous i.v. pentobarbital (PTB), evidence for this treatment practice is largely anecdotal.

In accordance with evidence from prospective, double-blind, multicenter studies (2,12), most physicians agree on the use of lorazepam (LZP), with a success rate of 65%, as the initial treatment for SE, followed by phenytoin (PHT) or fosphenytoin as second-line therapy. However, in a recent survey of American neurologists, there was little agreement on third- and fourth-line therapy for RSE (authors' unpublished data). This uncertainty may reflect the fact that no large prospective trial has compared different treatment options for RSE.

In this systematic review, we compared the efficacy and outcome of all published adult RSE patients treated with one of three continuous infusions: PTB, MDL, or PRO. MDL (13,14), PRO (15,16), and PTB (17) all bind to the γ-aminobutyric acid type A receptors (GABAA), augmenting GABAergic transmission, thereby imparting anticonvulsant and sedative–hypnotic properties. All three medications can be given as i.v. infusions. However, their pharmacokinetic properties differ substantially. MDL (a 1,4-benzodiazepine belonging to the 1,2-anelated subgroup) is a fast-acting water-soluble benzodiazepine (BZD) with a half-life of 1.2 to 12.3 h (18,19). PRO (2,6-diisopropylphenol) is a very fast acting agent with a second exponential phase half-life of 34 to 56 min, reflecting its high rate of metabolic clearance, and a third-phase half-life of 184 to 480 min (20). PTB (sodium-5-ethyl-5,1-methylbutyl barbiturate) is a barbiturate with onset of action after 15–20 min and a half-life of 15–60 h (21).

We compared treatment response, complications, and mortality in RSE patients treated with PRO, MDL, or PTB. We also evaluated the efficacy of different treatment intensities as reflected in the EEG titration goal for continuous-infusion antiepileptic drug (cIV-AED) therapy, by comparing EEG background suppression (isoelectric or burst-suppression pattern) (22–24) with that of seizure suppression only (25).

METHODS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Identification of studies

We performed a literature search of studies published between January 1970 and September 2001, by using MEDLINE, OVID, and manually searched bibliographies of the identified articles. Electronic search terms included “status epilepticus,”“refractory status epilepticus,”“refractory seizures,”“pentobarbital,”“propofol,” and “midazolam.” Two investigators (J.C., S.A.M.) independently extracted details of cases from the published data.

Inclusion and exclusion criteria

All articles identified were screened for the following inclusion criteria: peer-reviewed publication of data; adult patients (older than 17 years); diagnosis of SE (>30 min of continuous seizure activity or at least two sequential seizures without full recovery of consciousness between seizures) (26); and treatment with MDL, PRO, or PTB. Patients were included in only one of the three treatment groups; when multiple cIV-AEDs were used, the patient was analyzed according to the first cIV-AED administered. In articles reporting results on both adults and children, only data on adults were included. After the initial screen, articles were selected for inclusion in the analysis only if all the patients clearly met criteria for RSE (SE that fails to respond to at least two standard AEDs, usually a BZD, and PHT or PB), and if the immediate response to cIV-AED treatment within the first 6 h was described. Exclusion criteria included simple partial or absence SE; intermittent i.v. doses of MDL, PRO, or PTB instead of cIV administration; duplicate subject reporting; and treatment with another cIV-AED (i.e., cIV-thiopental) before treatment with MDL, PRO, or PTB.

Data collection

When available, we recorded demographics (age, gender); history of epilepsy; Acute Physiology and Chronic Health Evaluation [APACHE]-2 score [an instrument used to estimate disease severity and predict mortality in intensive care unit (ICU) patients](27); total SE duration; AEDs given before cIV-AEDs; cIV-AED treatment characteristics [titration goal (seizure suppression vs. EEG background suppression to burst suppression or an isoelectric pattern), loading dose, minimal and maximal infusion rates, duration of treatment]; the type of SE [generalized convulsive SE (GCSE) vs. nonconvulsive SE (NCSE) at onset and the time of cIV-AED treatment]; breakthrough or withdrawal seizures on cIV-AED therapy; presence and type of EEG monitoring (none, intermittent, or continuous) and EEG findings; and discharge outcome assessment (change to a different cIV-AED, length of hospital stay, functional outcome defined as return to baseline, mortality). Data were not sufficient to compare the time between start of cIV-AED and first seizure control, primarily because definitions of first seizure control differed between studies, and most studies did not provide these data.

SE classification

SE was classified as GCSE if any of the following was described: “generalized tonic–clonic seizures,”“grand mal seizures,”“convulsions,”“rhythmic jerking,” or similar descriptions; if none of these was reported and EEG confirmed SE, seizures were considered NCSE, whether or not subtle movements were described. Because NCSE tends to be more refractory and the proportion of patients with NCSE was different in the three treatment groups, we analyzed outcome and treatment responses for all patients, and in patients with NCSE only.

Outcome measures

We defined immediate treatment failure as clinical or electrographic seizures occurring between 60 min and 6 h after receiving the initial loading dose of the cIV-AED; breakthrough seizures, as any clinical or EEG seizures occurring with cIV-AED therapy after the first 6 h; withdrawal seizures as any seizures occurring within 48 h after initially discontinuing or tapering the cIV-AED; and cIV-AED changed when the patient was switched from the initial to a second cIV-AED because of poor seizure control. Hypotension was coded as a side effect when vasopressors were required to stabilize blood pressure, or systolic blood pressure decreased to <100 mm Hg, and refractory hypotension as hypotension persisting despite pressors, volume substitution, and temporary reduction of the cIV-AED infusion rate.

Statistical analysis

Data analysis was performed by using commercially available statistical software (SPSS version 9.0, Chicago, IL, U.S.A.). In a univariate analysis, we used the χ2 test or Fisher's Exact test to analyze the association between outcome variables and (a) each cIV-AED against the other two combined, and (b) between two titration goals, seizure suppression versus EEG background suppression. Continuous variables were tested by using independent samples two-tailed t tests. For nonnormally distributed continuous variables, the Mann–Whitney U test was performed. Because of the large number of comparisons, significance was judged at p < 0.01.

RESULTS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The initial literature search identified 223 studies published between January 1970 and September 2001. We screened 79 articles in detail, after eliminating animal studies and review articles. Of these studies, we excluded 19 articles reporting on the treatment of children only; 12 describing RSE therapy without MDL, PRO, or PTB; six abstracts; four in which patients were initially treated with a cIV-AED not investigated in this study; three that did not meet our criteria for RSE; three in which only single i.v. doses of the investigated AEDs were used; two that did not report immediate treatment response; one study of simple partial SE; and one because of duplicate subject reporting.

One hundred ninety-three RSE patients were identified for further analysis among the 28 studies that met our inclusion criteria (Table 1). Patients were treated with MDL (n = 54) (7,28–36), PRO (n = 33) (5,15,36–44), or PTB (n = 106) (4–6,23–25,45–47)(Table 1). A prespecified treatment protocol was used in 167 cases (43 MDL, 21 PRO, 103 PTB), and in 26 (11 MDL, 12 PRO, three PTB), no protocol was described. Demographic and clinical information is summarized in Table 2.

Table 1.  Studies included in the systemic review
First authorJournalYearRSE patients treated with continuous infusion of
MidazolamPropofolPentobarbital
  • a

     These studies reported additional patients that were excluded because they did not meet the inclusion criteria. Numbers reflect all patients that were included in the systemic review.

Young GBaCan J Neurol Sci1980002
Rashkin MCNeurology1987009
Lowenstein DHaNeurology1988008
Yanny HFAnesthesia1988010
Wood PRLancet1988100
Crisp CBClin Pharm1988100
Osario IEpilepsia19890012
Mackkenzie SJAnesthesia1990020
Chilvers CRAnesthesia1990010
VanNess PCEpilepsia1990007
Campostrini RaNuova Riv Neurol1991030
Kumar AaCrit Care Med1992400
Yaffee KNeurology19930017
Cortina JClin Neuropharmacol1993100
McBurney JWJ Epilepsy1994001
Borgeat AIntens Care Med1994010
GaldamesNeurologia1994100
Hantson PIntens Care Med1994010
Parent JMaNeurology1994300
DeKrom MCTFMaSeizure1995010
Merigan KSAcad Emerg Med1995010
Mirski MACrit Care Med1995100
Krishnamurthy KBEpilepsia19960044
Stecker MMaEpilepsia1998086
Begemann MEpilepsia2000010
Naritoku DKNeurology2000200
Prasasad AaEpilepsia20017130
Claassen JaNeurology20013300
Total  5433106
Table 2.  Patient characteristics
 Continuous i.v. AEDTotal (n = 193)
Midazolam (n = 54)Propofol (n = 33)Pentobarbital (n = 106)
  • Data are presented as % (N with available data), mean ± standard deviation (N with available data), or median (N with available data) if not normally distributed.

  • AEDs, antiepileptic drugs; APACHE, Acute Physiology and Chronic Health Evaluation; GCSE, generalized convulsive status epilepticus; NCSE, nonconvulsive status epilepticus; SE, status epilepticus; CNS, central nervous system; ci.v., continuous i.v.

  • a

     unknown (n = 9) and postsurgical cases (n = 2).

  • b

     Topiramate, gabapentin, lamotrigine, paraldehyde, thiopental, clonazepam, oxazepam, vigabatrin, lidocaine, primidone, oxcarbazepine.

Demographics    
 Age (yr)51 ± 21 (54)47 ± 20 (33)46 ± 20 (62)48 ± 20 (149)
 Female gender67 (36/54)64 (21/33)53 (33/62)60 (90/149)
History of epilepsy33 (17/52)28 (8/29)38 (23/61)34 (48/142)
Primary cause of SE    
 Stroke or CNS tumor28 (15/54)21 (7/33)16 (16/102)20 (38/189)
 Epilepsy related19 (10/54)18 (6/33)21 (21/102)20 (37/189)
 Toxic–metabolic encephalopathy20 (11/54)18 (6/33)19 (19/102)19 (36/189)
 CNS infection17 (9/54)18 (6/33)20 (20/102)19 (35/189)
 Hypoxia–ischemia6 (3/54)12 (4/33)15 (15/102)12 (22/189)
 Traumatic brain injury6 (3/54)6 (2/33)5 (5/102)5 (10/189)
 Othera6 (3/54)6 (2/33)6 (6/102)6 (11/189)
Initial seizure type    
 GCSE68 (36/53)88 (22/25)89 (70/79)82 (128/157)
 NCSE32 (17/53)12 (3/25)11 (9/79)18 (29/157)
Seizure type at the time of cIV-AED    
 GCSE11 (6/53)24 (8/33)78 (73/93)49 (87/179)
 NCSE89 (47/53)76 (25/33)22 (20/93)51 (92/179)
Total duration of status epilepticus (h)30.0 (48)21.5 (28)13.0 (50)22.0 (126)
APACHE-2 score20.0 (40)24.0 (21)24.0 (6)20.0 (67)
Treatment before ci.v.-AED    
 Number of AEDs3.0 (54)2.0 (33)3.0 (62)3.0 (149)
 Phenytoin93 (50/54)91 (30/33)95 (59/62)94 (140/149)
 Benzodiazepine76 (41/54)85 (28/33)87 (54/62)83 (123/149)
 Phenobarbital57 (31/54)36 (12/33)86 (53/62)64 (96/149)
 Valproic acid43 (23/54)12 (4/33)5 (3/62)20 (30/149)
 Carbamazepine20 (11/54)12 (4/33)8 (5/62)13 (20/149)
 Any other AEDb13 (7/54)12 (4/33)15 (9/62)13 (20/149)

Patient characteristics

The majority (82%) of patients had GCSE as the initial seizure type, but 51% had NCSE at some point before starting cIV-AED therapy (Table 2). NCSE was most often treated with MDL, and GCSE, most often with PTB (Table 2). The median duration of SE was longest in MDL-treated (30 h) and shortest in PTB-treated cases (13 h). Primary causes of SE were similar in the three treatment groups.

Treatment characteristics and responses

Most patients were treated with PHT, BZDs, and PB before cIV-AED therapy (Table 2). The mean PHT level before initiation of cIV-AED treatment was 19 ± 9 μg/ml (n = 97); levels did not significantly differ among the three treatment groups. Table 3 summarizes the mean loading doses, minimal and maximal infusion rates, and the duration of cIV-AED therapy. The duration of infusion was longest with MDL (96 h) and shortest with PTB (30 h). In the entire cohort, 15% experienced short-term treatment failure (28 of 193); 25%, breakthrough seizures (37 of 150); 49%, withdrawal seizures (65 of 132); and 10% were changed to a different cIV-AED (17 of 173). Continuous EEG monitoring was performed significantly less frequently in PTB-treated patients (27%) than in patients treated with MDL or PRO (78%) (p < 0.0001; Table 3).

Table 3.  Treatment characteristics
 Continuous i.v. medication
MidazolamPropofolPentobarbital
  1. Data are presented as % (N with available data), mean ± standard deviation (N with available data), or median (N with available data) if not normally distributed. If doses were reported only as mg or mg/h, mg/kg and mg/kg/h were calculated with given or estimated body weights: for male subjects divided by 80 kg; for women, divided by 60 kg.

Doses reported533262
 Loading dose (mg/kg)0.21.013.0
 Minimal infusion rate (mg/kg/h)0.08 ± 0.042.94 ± 2.001.84 ± 1.59
 Maximal infusion rate (mg/kg/h)0.23 ± 0.176.98 ± 5.343.17 ± 2.11
Duration of continuous infusion (h)96.0 (53)36.0 (31)30.0 (61)
EEG monitoring   
 Continuous EEG monitoring80 (43/54)76 (25/33)27 (29/106)
 Intermittent EEG monitoring11 (6/54)15 (5/33)71 (75/106)
 None or unknown9 (5/54)9 (3/33)2 (2/106)
Titration goal   
 Seizure control only100 (43/43)62 (13/21)4 (3/82)
 EEG background suppression0 (0/43)38 (8/21)96 (79/82)

Effect of cIV agent on treatment response

Among patients treated with MDL, breakthrough seizures (p < 0.001) and change to a different cIV-AED (p < 0.01) were more frequent, and hypotension less frequent (p < 0.001), when compared with the other two medications combined (Fig. 1 and Table 4). PTB treatment was associated with the lowest frequency of short-term treatment failure (p < 0.01), breakthrough seizures (p < 0.001), and change to a different cIV-AED (p < 0.001), whereas hypotension (p < 0.001) was more frequent in these patients (Fig. 1 and Table 4).

image

Figure 1. Treatment response and outcome in patients with refractory status epilepticus treated with midazolam, propofol, or pentobarbital. Significance was tested with the χ2 or Fisher's exact test of each treatment against the other two. *p < 0.01; **p < 0.001.

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Table 4.  Treatment responses and outcome
 All RSE patientsNonconvulsive RSE patients
Midazolam (n = 54)Propofol (n = 33)Pentobarbital (n = 106)Midazolam (n = 47)Propofol (n = 25)Pentobarbital (n = 20)
  • Significance tested with the χ2 or Fisher's exact test for dichotomized variables and the Mann–Whitney U test for continuous variables of each treatment against the other two combined.

  • a

     p < 0.01.

  • b

     p < 0.001.

  • RSE, refractory status epilepticus; AED, antiepileptic drug.

  • c

     Hypotension not manageable with a decrease in cIV-AED infusion rate, volume adjustments, or administration of pressors, and necessitating a discontinuation or change of cIV-AEDs.

Acute failure20 (11/54)27 (9/33)8 (8/106)a23 (11/47)32 (8/25)20 (4/20)
Breakthrough seizures51 (23/45)b15 (2/13)12 (11/92)b56 (22/39)b0 (0/6)0 (0/11)a
Withdrawal seizures63 (25/40)46 (6/13)43 (34/79)66 (23/35)50 (3/6)33 (2/6)
Hypotension      
 Requiring pressors30 (14/47)b42 (10/24)77 (79/103)b30 (13/43)39 (9/23)45 (9/20)
 Refractory hypotensionc2 (1/47)8 (2/24)3 (3/103)2 (1/43)9 (2/23)0 (0/20)
ci.v.-AED changed21 (10/47)a20 (4/20)3 (3/106)b20 (8/41)25 (3/12)10 (2/20)
Mortality46 (25/54)52 (16/31)48 (49/102)47 (22/47)56 (14/25)30 (6/20)

In a subgroup analysis of patients with NCSE before cIV-AED administration (Table 4), breakthrough seizures were more frequent with MDL (p < 0.001) and less frequent with PTB treatment (p < 0.01). The number of patients with pure GCSE treated with PRO or MDL was too small to allow meaningful statistical comparisons.

Effect of titration aim on treatment response

Among 167 patients treated with a treatment protocol, 146 specified a titration aim. These were stratified into two groups: (a) “seizure suppression” (43 MDL, 13 PRO, three PTB), and (b) “EEG background suppression” (eight PRO, 79 PTB). Included in this analysis was one study that did not specify a titration goal in the protocol but specifically analyzed the effect of EEG suppression on outcome (48). Patients treated with EEG background suppression were less likely to have breakthrough seizures (4 vs. 53%; p < 0.001), and more likely to have hypotension (76 vs. 29%; p < 0.001; Fig. 2). There was no significant effect of the titration goal on short-term treatment failure, withdrawal seizures, or cIV-AED change.

image

Figure 2. Treatment response and outcome in patients with refractory status epilepticus stratified according to the titration goal into seizure control only versus EEG background suppression. Significance was tested with the χ2 or Fisher's exact test. *p < 0.05; **p < 0.01; ***p < 0.001.

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Mortality and functional outcome

Of the patients who died, 90 (48%) of 187 and only 48 (29%) of 164 returned to their premorbid functional baseline. Patients that died were older (54 ± 20 vs. 42 ± 19 years; p < 0.001), had higher APACHE-2 scores (23 ± 5 vs. 18 ± 6; p < 0.001), had longer median seizure duration (24.0 vs. 12.0 h; p = 0.01), and more often had acute symptomatic SE not related to epilepsy (79 vs. 55%; p = 0.004). Seizure type (GCSE vs. NCSE), gender, hypotension (any, and refractory), and delayed seizure control were not associated with outcome.

DISCUSSION

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Discrepancies between prospective, randomized trails and meta-analyses are well described (49–51), and this problem is particularly common when the data consist of pooled data from case series. However, in the absence of data from a prospective trial for a rare condition, carefully performed systematic reviews do often point in the correct direction (52) and provide concise summaries of the best available evidence (53). The findings of our systematic review cannot substitute for a prospective, randomized clinical trial, but may provide valuable information in the planning phase of such a study. These data are intended not to provide a firm treatment recommendation for RSE patients, but to give a concise summary of experience with these patients.

Outcome was poor overall and was not associated with the choice of cIV-AED (MDL, PRO, or PTB) or the titration goal (titration to seizure suppression or EEG-background suppression). Confirming prior studies of SE, we found mortality to be associated with older age (54,55), etiology (54–59), seizure duration (55,57), and APACHE-2 scores (7).

Because the diseases that cause SE are the most important determinants of mortality and functional outcome, treatment responses may be a more useful end point for comparing AEDs. In this review, treatment responses were most favorable with the use of PTB and when cIV-AED therapy was titrated to EEG background suppression. Specifically, PTB was associated with reduced frequency of short-term treatment failure, breakthrough seizures, and the need to switch to another agent, and titration to EEG background suppression was associated with reduced frequency of breakthrough seizures. NCSE, which is more refractory to therapy than GCSE (3), was substantially more common in MDL- and PRO- than in PTB-treated patients when cIV-AED therapy was started (Table 2), which might explain the superior treatment response seen with PTB. However, we found that PTB was associated with less frequent breakthrough seizures than were the other two agents, even when the analysis was limited to NCSE patients.

Because the vast majority of patients treated with a goal of EEG background suppression were given PTB (79 of 87), it is difficult to determine whether PTB or the titration goal per se might be responsible for the improved treatment response we observed. Another major limitation of the available data is the fact that compared with those treated with MDL or PRO, significantly fewer PTB-treated patients underwent cEEG monitoring. This discrepancy may very likely explain the lower frequency short-term treatment failure and breakthrough seizures found in PTB-treated patients. Without cEEG monitoring, the response of cIV-AED treatment can be difficult to interpret, because subclinical electrographic seizure activity can be detected in 48% of patients after control of convulsive SE (60).

Significantly fewer patients were changed from PTB to another cIV-AED when compared with MDL or PRO. This might reflect the fact that many physicians believe that PTB infusions are the ultimate escalation of RSE therapy, and the fact that at the time many of the PTB cases were treated, MDL and PRO were not yet available as treatment alternatives. Retrospectively, these questions are difficult to address and will have to be answered by a prospective trial.

The significantly higher frequency of hypotension in PTB cases probably reflects the strong cardiovascular depressant effects of this agent. Negative effects of barbiturates on cardiac tone and contractility have been reported as the main disadvantage of barbiturates (4), frequently resulting in cardiac instability (30). Confirming others, we found hypotension to be significantly less frequent with the use of MDL (1) or PRO (61,62). However, PTB was frequently titrated to EEG background suppression, which also was associated with hypotension. Hypotension was usually easily manageable with fluids, pressors, or a temporary decrease in the infusion rates of cIV-AEDs. Refractory hypotension, not easily treatable, was not associated with any one of the cIV-AEDs or titration goals.

Delayed seizure control affects treatment efficacy and mortality (55,57). The pharmacokinetic properties of MDL and PRO (18–21) suggest that these agents may be advantageous for terminating seizures more quickly than PTB. Data in our systematic review were not sufficient to compare this important outcome variable.

In addition to the generally limited conclusions that a systematic review allows, this study is limited by the small numbers of reported cases, the possibility of publication bias, the retrospective nature of its design, the lack of cEEG monitoring in many cases, and differences in ICU management between centers and between reports from the 1980s and 1990s. To minimize these limitations, we rigorously applied stringent inclusion and exclusion criteria.

A prospective, multicenter study should randomize patients to different medications (including PTB in one arm) and treatment protocols (seizure suppression alone vs. more aggressive EEG background suppression). In this trial, patients with NCSE and convulsive SE should be analyzed separately, continuous EEG monitoring must be obtained in all patients, and results should control for patient age, etiology, seizure duration before treatment, and APACHE-2 scores. In combination with neuroprotective strategies, we hope that the results of such a trial will help to improve outcome in this high-risk, critically ill patient population.

Acknowledgment: We thank Dr. Martha J. Morrell, Director of the Comprehensive Epilepsy Center at Columbia University, who provided helpful comments and suggestions in the preparation of this manuscript.

REFERENCES

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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