Journal of Clinical Neuroscience 22 (2015) 854–858
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Induction of burst suppression or coma using intravenous anesthetics in refractory status epilepticus Bong Su Kang a,1, Keun-Hwa Jung b,1, Jeong-Won Shin c, Jang Sup Moon b, Jung-Ick Byun b, Jung-Ah Lim b, Hye Jin Moon d, Young-Soo Kim e, Soon-Tae Lee b, Kon Chu b, Sang Kun Lee b,⇑ a
Department of Neurology, Korea University Anam Hospital, Seoul, South Korea Department of Neurology, Laboratory for Neurotherapeutics, Comprehensive Epilepsy Center, Biomedical Research Institute, Seoul National University Hospital, College of Medicine, Seoul National University, 101, Daehangno, Chongro-Gu, Seoul 110-744, South Korea c Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam, South Korea d Department of Neurology, Dongsan Medical Center, Keimyung University, Daegu, South Korea e Department of Neurology, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, South Korea b
a r t i c l e
i n f o
Article history: Received 3 April 2014 Accepted 5 November 2014
Keywords: Burst suppression Coma Intravenous anesthetics Outcome Refractory status epilepticus
a b s t r a c t General anesthetic-induced coma therapy has been recommended for the treatment of refractory status epilepticus (RSE). However, the influence of electroencephalographic (EEG) burst suppression (BS) on outcomes still remains unclear. This study investigated the impact of intravenous anesthetic-induced BS on the prognosis of RSE using a retrospective analysis of all consecutive adult patients who received intravenous anesthetic treatment for RSE at the Seoul National University Hospital between January 2006 and June 2011. Twenty-two of the 111 episodes of RSE were enrolled in this study. Of the 22 RSE patients, 12 (54.5%) were women and 18 (81.4%) exhibited generalized convulsive status epilepticus. Sixteen patients (72.7%) were classified as having acute symptomatic etiology, including three patients with anoxic encephalopathy, and others with remote symptomatic etiology. Only two patients (9.1%) had a favorable Status Epilepticus Severity Score (0–2) at admission. All patients received midazolam (MDZ) as a primary intravenous anesthetic drug for RSE treatment; three (13.6%) received MDZ and propofol, and one (4.5%) received MDZ and pentobarbital. The rates of mortality and poor outcome at discharge were 13.6% (n = 3) and 54.5% (n = 12), respectively. While BS was achieved in six (27.5%) patients, it was not associated with mortality or poor outcome. Induced BS was associated with prolonged hospital stay in subgroup analysis when excluding anoxic encephalopathy. Our results suggest that induction of BS for treating RSE did not affect mortality or outcome at discharge and may lead to an increased length of hospital stay. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction Refractory status epilepticus (RSE) is recognized as one of the most critical neurologic emergencies with high mortality and morbidity. RSE develops in approximately 30–40% of patients with status epilepticus (SE) and the reported mortality ranges between 19– 67% depending on the type of SE [1,2]. However, there is no universally accepted definition of RSE. Most studies have defined RSE as SE which is resistant to treatment with two or more intravenous anti-epileptic drugs (AED) [3–5], whereas others have defined it as a duration of seizure activity over 60 minutes [6,7].
⇑ Corresponding author. Tel.: +82 2 2072 2923; fax: +82 2 2072 7553. 1
E-mail address: [email protected] (S.K. Lee). These authors have contributed equally to the manuscript.
http://dx.doi.org/10.1016/j.jocn.2014.11.007 0967-5868/Ó 2014 Elsevier Ltd. All rights reserved.
Despite its clinical and socioeconomic impacts, to our knowledge the management of RSE has only been studied in small retrospective reviews [4,8] and a prospective study without controls [9]. These reports suggest that early pharmacologic coma induction using a general anesthetic, such as MDZ, propofol, or pentobarbital, can treat RSE [3,10,11]. Although recent guidelines have recommended that the general goal of anesthetic treatment is not only to suppress seizure activity but also to achieve burst suppression (BS) on electroencephalography (EEG), typically for 12–24 hours [10,11], the evidence of any correlation between BS on EEG and clinical outcomes is limited. Only limited clinical data have been reported indicating that more intensive suppression on EEG may result in fewer seizure relapses and better outcomes [12]. In contrast, a recent retrospective study suggested that seizure control without BS or isoelectric EEG may be associated with better
B.S. Kang et al. / Journal of Clinical Neuroscience 22 (2015) 854–858
functional outcome [4]. Thus, our study was designed to investigate the impact of intravenous anesthetic-induced BS on the prognosis of RSE in a tertiary referral, national epilepsy center. 2. Materials and methods We analyzed all consecutive patients who received intravenous anesthetic treatment for RSE at the Seoul National University Hospital from January 2006 to June 2011. The inclusion criteria were the following: (1) patients aged 18 years or older; (2) RSE defined as convulsive status epilepticus or non-convulsive status epilepticus (NCSE) unresponsiveness to treatment with at least two or more AED; (3) patients received intravenous anesthetic treatment for seizure control; and (4) patients received continuous EEG monitoring. Exclusion criteria were: (1) epilepsia partialis continua; (2) psychogenic SE; and (3) absence SE. We screened our computerized database to identify patients and reviewed the electronic medical record and the computerized EEG report system for variables including age, sex, history of epilepsy, history of SE, type of SE, etiology of SE, severity of SE, seizure duration (minutes) before initial treatment, AED regimen before anesthetic treatment, type of anesthetic, anesthetic treatment duration (days), results of continuous EEG monitoring during anesthetic treatment, use of additional AED for seizure control, complications, and functional status before onset and at discharge. The type of SE was classified according to the initial manifestation as generalized convulsive status epilepticus (GCSE) or NCSE. If SE began with a generalized tonic–clonic seizure with continuous convulsion or evolution to non-convulsive status, it was defined as GCSE. NSCE was defined as prolonged electrographic seizure activity resulting from non-convulsive behavioral and/or cognitive changes from the baseline [4]. The etiology of SE was classified into: (1) acute symptomatic, defined as seizures occurring concurrently with an acute neurologic insult or systemic disturbance; (2) remote symptomatic (RS) with acute precipitant; and (3) RS without acute precipitant. RS was defined as seizures occurring with a time gap following a neurologic insult associated with an increased
855
risk of seizure [13]. The severity of SE was graded using the Status Epilepticus Severity Score (STESS) according to previous guidelines, and 0–2 was regarded as a favorable score [14]. The results of continuous EEG monitoring were interpreted using the maximum level of suppression during intravenous anesthetic treatment and categorized into those that achieved BS or were isoelectric. Systemic complications were categorized into: (1) respiratory distress, defined as presence of hypoxia which required intubation and mechanical ventilation or the development of pulmonary edema; (2) cardiac distress, including hypotension, cardiac arrhythmia, hypotension (systolic blood pressure 3 Treatment Treatment delay (>60 minutes) Duration of anesthetics (days), median (IQR) Use of additional AED Outcomes In-hospital mortality Poor outcome Prolonged hospital stay (>30 days)
Yes (n = 6)
No (n = 16)
p value
57.5 (28.5–73.5) 2 (33.3%) 4 (66.7%) 0 0
61.0 (31.3–67.0) 9 (56.3%) 8 (50%) 6 (37.5%) 2 (12.5%)
0.858a 0.635 0.646 0.133 >0.999
5 (83.3%) 5 (83.3%) 6 (100%)
13 (81.3%) 11 (68.8%) 14 (87.5%)
>0.999 0.634 >0.616
2/4 (50%) 10.0 (7.8-14.0) 5 (83.3%)
5/7 (71.4%) 5 (3.0-9.8) 10 (66.7%)
0.576 0.070a 0.616
0 2 (33.3%) 5 (83.3%)
3 (18.7%) 10 (62.5%) 6 (42.9%)
0.532 0.348 0.157
a Fisher’s exact test and a Mann-Whitney U-test were used for statistical analysis. AED = anti-epileptic drugs, AS = acute symptomatic, GCSE = generalized convulsive status epilepticus, IQR = interquartile range, SE = status epilepticus, STESS = Status Epilepticus Severity Score. Data are presented as number (%) unless otherwise specified.
Table 3 Subgroup analyses according to patient outcome STESS >3 Induced BS
Clinical characteristics Type of SE = GCSE Etiology of SE = AS STESS >3 Treatment Duration of anesthetics (days), median (IQR) Additional AED
Induced BS (excluding patients with anoxia)
Yes (n = 6)
No (n = 14)
p value
Yes (n = 6)
No (n = 13)
p value
4 (83.3%) 5 (83.3%)
11 (78.6%) 10 (71.4%)
>0.999 >0.999
5 (83.3%)
10 (76.9%)
>0.999
6 (100%)
11 (84.6%)
>0.999
10.0 (7.8–14.0) 5 (83.3%)
5.0 (2.8–9.3) 7 (50%)
0.051a 0.325
10.0 (7.8–14.0) 5 (83.3%)
7.0 (3.0–14.5) 7 (53.8%)
0.179 a 0.333
Outcomes Mortality Poor outcome Prolonged hospital stay (>30 days)
0 2 (33.3%) 5 (83.3%)
3 (21.4%) 10 (71.4%) 5(41.7%)
0.521 0.161 0.152
0 2 (33.3%) 5 (83.3%)
2 (15.4%) 7 (53.8%) 3 (17.3%)
>0.999 0.628 0.05
Complications Respiratory Cardiac Infection
5 (83.3%) 2 (33.3%) 4 (66.7%)
14 (100%) 5 (35.7%) 7 (50%)
0.300 >0.999 0.642
5 (83.3%) 2 (33.3%) 4 (66.7%)
13 (100%) 4 (30.8%) 6 (46.2%)
0.316 >0.999 0.628
a Fisher’s exact test and a Mann-Whitney U-test were used for statistical analysis. AED = anti-epileptic drugs, AS = acute symptomatic, BS = burst-suppression, GCSE = generalized convulsive status epilepticus, IQR = interquartile range, SE = status epilepticus, STESS = Status Epilepticus Severity Score. Data are presented as number (%) unless otherwise specified.
(95.5%). Cardiac complication, including hypotension and arrhythmia occurred in eight patients (36.4%) and systemic infection including pneumonia occurred in 12 patients (54.5%). There was no association between achievement of BS and the development of any type of complication. No complication was associated with mortality or poor outcome in the overall sample, or in the sample with unfavorable STESS and with exclusion of anoxic etiology. 5. Discussion This is a retrospective observational study which explored the usefulness of achieving intravenous anesthetic-induced BS or isoelectric suppression when intravenous anesthetics were given to RSE patients. We found that there was no correlation between
the achievement of induced BS and outcome, including mortality and poor functional outcome at discharge. Induced BS was only associated with prolonged hospital stay in the subgroup analysis when excluding anoxic etiologies. All patients in our study received intravenous MDZ for initial RSE treatment. At our center, MDZ was initiated with a bolus of 0.2 mg/kg followed by continuous infusion at a starting rate of 1 mcg/kg/minute. The infusion rate was titrated every 30–60 minutes by an epileptologist and was increased to a maximum dose of 0.4 mg/kg/hour until BS was seen on EEG if hemodynamically tolerable. Other anesthetic agents, propofol and pentobarbital, were used according to current guidelines [10,11]. Some experts believe that rapid loading of the anesthetics until BS is achieved is associated with better outcome compared to slow up-titration. However,
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B.S. Kang et al. / Journal of Clinical Neuroscience 22 (2015) 854–858
these data were not available at the time our study was carried out and there might be individual variation in anesthetic administration due to the retrospective design of our study. There are few clinical reports regarding the optimal level of EEG suppression for RSE. A retrospective study with 35 pentobarbital-treated episodes suggested that complete suppression or a ‘‘flat record’’ led to better seizure control, with fewer relapses and a trend for better outcome compared to BS [12]. However, a review of 28 articles with 169 RSE cases (43 cases treated with MDZ, 21 propofol and 81 pentobarbital) reported that achievement of EEG background suppression was not associated with outcome, but there was a lower frequency of breakthrough seizures compared to seizure suppression (4% versus 53%, p < 0.001) [8]. None of the patients who received MDZ achieved EEG background suppression in this review. A retrospective study with 49 episodes of RSE in 47 patients reported that outcome was independent of the specific anesthetic agent used and the achievement of induced BS (six of the 20 patients who attained BS died versus two of 11 patients who did not attain BS died, p = 0.43), but use of barbiturates might be associated with achieving BS or isoelectric EEG suppression compared to the use of other anesthetic agents including MDZ [15]. Moreover, a recent retrospective study with 63 episodes of non-anoxic RSE, where MDZ was the most frequently used agent (n = 38), suggests that seizure control without BS or isoelectric EEG (n = 16) was correlated with a good functional outcome at hospital discharge compared to BS [4]. Our results are in accordance with these previous reports. Despite the lower prevalence of induced BS (28.5%) and higher proportion of unfavorable STESS (90.9%) in our study, the mortality (13.6%) seems to be lower than that reported in previous series (MDZ 17–61%; propofol 57–88%; and barbiturates 20–50%) [8,16–19]. All deaths in our series had numerous poor outcome predictors at admission. Older age, first episode of seizure and acute central nervous system disease are known predictors of mortality or poor outcome in patients with SE [20,21] and the STESS has also been verified as a prognostic factor [14]. Otherwise, the fact that more than half of patients (64.6%) received additional high-dose oral AED may also explain the low mortality. The efficacy and safety of various additional AED in RSE have been reported in recent studies [22,23]. The main limitation of this study is its retrospective design and small sample size. The small study size may be the reason that no statistically significant results were seen in our study. Also, only 9% of subjects had favorable STESS at the time of enrollment which may have contributed to the poor response of the study. However, to our knowledge, only a few studies have reported the effectiveness of intravenous anesthetic-induced BS or coma in treating RSE and these included fewer than 70 RSE patients [4,15]. Our results suggest that BS for treating RSE, especially when using MDZ, does not affect the mortality rate or rate of poor outcome at discharge, but it may lead to increased hospital stay. If BS is not beneficial compared to the suppression of epileptiform discharges when treating RSE, the patients may require dose-adjustment to reduce the intravenous anesthetic-related risks such as respiratory distress, hemodynamic instability and longer hospital stay.
Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Acknowledgements This study was supported by a grant from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI13C1558). References [1] Towne AR, Pellock JM, Ko D, et al. Determinants of mortality in status epilepticus. Epilepsia 1994;35:27–34. [2] 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;339:792–8. [3] Chen JW, Wasterlain CG. Status epilepticus: pathophysiology and management in adults. Lancet Neurol 2006;5:246–56. [4] Hocker SE, Britton JW, Mandrekar JN, et al. Predictors of outcome in refractory status epilepticus. JAMA Neurol 2013;70:72–7. [5] Jagoda A, Riggio S. Refractory status epilepticus in adults. Ann Emerg Med 1993;22:1337–48. [6] Mayer SA, Claassen J, Lokin J, et al. Refractory status epilepticus: frequency, risk factors, and impact on outcome. Arch Neurol 2002;59:205–10. [7] Hanley DF, Kross JF. Use of midazolam in the treatment of refractory status epilepticus. Clin Ther 1998;20:1093–105. [8] Claassen J, Hirsch LJ, Emerson RG, et al. Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: a systematic review. Epilepsia 2002;43:146–53. [9] Rossetti AO, Milligan TA, Vulliemoz S, et al. A randomized trial for the treatment of refractory status epilepticus. Neurocrit Care 2011;14:4–10. [10] Brophy GM, Bell R, Claassen J, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012;17:3–23. [11] Meierkord H, Boon P, Engelsen B, et al. EFNS guideline on the management of status epilepticus in adults. Eur J Neurol 2010;17:348–55. [12] Krishnamurthy KB, Drislane FW. Depth of EEG suppression and outcome in barbiturate anesthetic treatment for refractory status epilepticus. Epilepsia 1999;40:759–62. [13] Takeoka M, Holmes GL, Thiele E, et al. Topiramate and metabolic acidosis in pediatric epilepsy. Epilepsia 2001;42:387–92. [14] Rossetti AO, Logroscino G, Bromfield EB. A clinical score for prognosis of status epilepticus in adults. Neurology 2006;66:1736–8. [15] Rossetti AO, Logroscino G, Bromfield EB. Refractory status epilepticus: effect of treatment aggressiveness on prognosis. Arch Neurol 2005;62:1698–702. [16] Claassen J, Hirsch LJ, Emerson RG, et al. Continuous EEG monitoring and midazolam infusion for refractory nonconvulsive status epilepticus. Neurology 2001;57:1036–42. [17] Stecker MM, Kramer TH, Raps EC, et al. Treatment of refractory status epilepticus with propofol: clinical and pharmacokinetic findings. Epilepsia 1998;39:18–26. [18] Prasad A, Worrall BB, Bertram EH, et al. Propofol and midazolam in the treatment of refractory status epilepticus. Epilepsia 2001;42:380–6. [19] Parviainen I, Uusaro A, Kalviainen R, et al. High-dose thiopental in the treatment of refractory status epilepticus in intensive care unit. Neurology 2002;59:1249–51. [20] DeLorenzo RJ, Hauser WA, Towne AR, et al. A prospective, population-based epidemiologic study of status epilepticus in Richmond, Virginia. Neurology 1996;46:1029–35. [21] Kowalski RG, Ziai WC, Rees RN, et al. Third-line antiepileptic therapy and outcome in status epilepticus: the impact of vasopressor use and prolonged mechanical ventilation. Crit Care Med 2012;40:2677–84. [22] Hottinger A, Sutter R, Marsch S, et al. Topiramate as an adjunctive treatment in patients with refractory status epilepticus: an observational cohort study. CNS Drugs 2012;26:761–72. [23] Swisher CB, Doreswamy M, Gingrich KJ, et al. Phenytoin, levetiracetam, and pregabalin in the acute management of refractory status epilepticus in patients with brain tumors. Neurocrit Care 2012;16:109–13.
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Induction of burst suppression or coma using intravenous anesthetics in refractory status epilepticus Bong Su Kang a,1, Keun-Hwa Jung b,1, Jeong-Won Shin c, Jang Sup Moon b, Jung-Ick Byun b, Jung-Ah Lim b, Hye Jin Moon d, Young-Soo Kim e, Soon-Tae Lee b, Kon Chu b, Sang Kun Lee b,⇑ a
Department of Neurology, Korea University Anam Hospital, Seoul, South Korea Department of Neurology, Laboratory for Neurotherapeutics, Comprehensive Epilepsy Center, Biomedical Research Institute, Seoul National University Hospital, College of Medicine, Seoul National University, 101, Daehangno, Chongro-Gu, Seoul 110-744, South Korea c Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam, South Korea d Department of Neurology, Dongsan Medical Center, Keimyung University, Daegu, South Korea e Department of Neurology, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, South Korea b
a r t i c l e
i n f o
Article history: Received 3 April 2014 Accepted 5 November 2014
Keywords: Burst suppression Coma Intravenous anesthetics Outcome Refractory status epilepticus
a b s t r a c t General anesthetic-induced coma therapy has been recommended for the treatment of refractory status epilepticus (RSE). However, the influence of electroencephalographic (EEG) burst suppression (BS) on outcomes still remains unclear. This study investigated the impact of intravenous anesthetic-induced BS on the prognosis of RSE using a retrospective analysis of all consecutive adult patients who received intravenous anesthetic treatment for RSE at the Seoul National University Hospital between January 2006 and June 2011. Twenty-two of the 111 episodes of RSE were enrolled in this study. Of the 22 RSE patients, 12 (54.5%) were women and 18 (81.4%) exhibited generalized convulsive status epilepticus. Sixteen patients (72.7%) were classified as having acute symptomatic etiology, including three patients with anoxic encephalopathy, and others with remote symptomatic etiology. Only two patients (9.1%) had a favorable Status Epilepticus Severity Score (0–2) at admission. All patients received midazolam (MDZ) as a primary intravenous anesthetic drug for RSE treatment; three (13.6%) received MDZ and propofol, and one (4.5%) received MDZ and pentobarbital. The rates of mortality and poor outcome at discharge were 13.6% (n = 3) and 54.5% (n = 12), respectively. While BS was achieved in six (27.5%) patients, it was not associated with mortality or poor outcome. Induced BS was associated with prolonged hospital stay in subgroup analysis when excluding anoxic encephalopathy. Our results suggest that induction of BS for treating RSE did not affect mortality or outcome at discharge and may lead to an increased length of hospital stay. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction Refractory status epilepticus (RSE) is recognized as one of the most critical neurologic emergencies with high mortality and morbidity. RSE develops in approximately 30–40% of patients with status epilepticus (SE) and the reported mortality ranges between 19– 67% depending on the type of SE [1,2]. However, there is no universally accepted definition of RSE. Most studies have defined RSE as SE which is resistant to treatment with two or more intravenous anti-epileptic drugs (AED) [3–5], whereas others have defined it as a duration of seizure activity over 60 minutes [6,7].
⇑ Corresponding author. Tel.: +82 2 2072 2923; fax: +82 2 2072 7553. 1
E-mail address: [email protected] (S.K. Lee). These authors have contributed equally to the manuscript.
http://dx.doi.org/10.1016/j.jocn.2014.11.007 0967-5868/Ó 2014 Elsevier Ltd. All rights reserved.
Despite its clinical and socioeconomic impacts, to our knowledge the management of RSE has only been studied in small retrospective reviews [4,8] and a prospective study without controls [9]. These reports suggest that early pharmacologic coma induction using a general anesthetic, such as MDZ, propofol, or pentobarbital, can treat RSE [3,10,11]. Although recent guidelines have recommended that the general goal of anesthetic treatment is not only to suppress seizure activity but also to achieve burst suppression (BS) on electroencephalography (EEG), typically for 12–24 hours [10,11], the evidence of any correlation between BS on EEG and clinical outcomes is limited. Only limited clinical data have been reported indicating that more intensive suppression on EEG may result in fewer seizure relapses and better outcomes [12]. In contrast, a recent retrospective study suggested that seizure control without BS or isoelectric EEG may be associated with better
B.S. Kang et al. / Journal of Clinical Neuroscience 22 (2015) 854–858
functional outcome [4]. Thus, our study was designed to investigate the impact of intravenous anesthetic-induced BS on the prognosis of RSE in a tertiary referral, national epilepsy center. 2. Materials and methods We analyzed all consecutive patients who received intravenous anesthetic treatment for RSE at the Seoul National University Hospital from January 2006 to June 2011. The inclusion criteria were the following: (1) patients aged 18 years or older; (2) RSE defined as convulsive status epilepticus or non-convulsive status epilepticus (NCSE) unresponsiveness to treatment with at least two or more AED; (3) patients received intravenous anesthetic treatment for seizure control; and (4) patients received continuous EEG monitoring. Exclusion criteria were: (1) epilepsia partialis continua; (2) psychogenic SE; and (3) absence SE. We screened our computerized database to identify patients and reviewed the electronic medical record and the computerized EEG report system for variables including age, sex, history of epilepsy, history of SE, type of SE, etiology of SE, severity of SE, seizure duration (minutes) before initial treatment, AED regimen before anesthetic treatment, type of anesthetic, anesthetic treatment duration (days), results of continuous EEG monitoring during anesthetic treatment, use of additional AED for seizure control, complications, and functional status before onset and at discharge. The type of SE was classified according to the initial manifestation as generalized convulsive status epilepticus (GCSE) or NCSE. If SE began with a generalized tonic–clonic seizure with continuous convulsion or evolution to non-convulsive status, it was defined as GCSE. NSCE was defined as prolonged electrographic seizure activity resulting from non-convulsive behavioral and/or cognitive changes from the baseline [4]. The etiology of SE was classified into: (1) acute symptomatic, defined as seizures occurring concurrently with an acute neurologic insult or systemic disturbance; (2) remote symptomatic (RS) with acute precipitant; and (3) RS without acute precipitant. RS was defined as seizures occurring with a time gap following a neurologic insult associated with an increased
855
risk of seizure [13]. The severity of SE was graded using the Status Epilepticus Severity Score (STESS) according to previous guidelines, and 0–2 was regarded as a favorable score [14]. The results of continuous EEG monitoring were interpreted using the maximum level of suppression during intravenous anesthetic treatment and categorized into those that achieved BS or were isoelectric. Systemic complications were categorized into: (1) respiratory distress, defined as presence of hypoxia which required intubation and mechanical ventilation or the development of pulmonary edema; (2) cardiac distress, including hypotension, cardiac arrhythmia, hypotension (systolic blood pressure 3 Treatment Treatment delay (>60 minutes) Duration of anesthetics (days), median (IQR) Use of additional AED Outcomes In-hospital mortality Poor outcome Prolonged hospital stay (>30 days)
Yes (n = 6)
No (n = 16)
p value
57.5 (28.5–73.5) 2 (33.3%) 4 (66.7%) 0 0
61.0 (31.3–67.0) 9 (56.3%) 8 (50%) 6 (37.5%) 2 (12.5%)
0.858a 0.635 0.646 0.133 >0.999
5 (83.3%) 5 (83.3%) 6 (100%)
13 (81.3%) 11 (68.8%) 14 (87.5%)
>0.999 0.634 >0.616
2/4 (50%) 10.0 (7.8-14.0) 5 (83.3%)
5/7 (71.4%) 5 (3.0-9.8) 10 (66.7%)
0.576 0.070a 0.616
0 2 (33.3%) 5 (83.3%)
3 (18.7%) 10 (62.5%) 6 (42.9%)
0.532 0.348 0.157
a Fisher’s exact test and a Mann-Whitney U-test were used for statistical analysis. AED = anti-epileptic drugs, AS = acute symptomatic, GCSE = generalized convulsive status epilepticus, IQR = interquartile range, SE = status epilepticus, STESS = Status Epilepticus Severity Score. Data are presented as number (%) unless otherwise specified.
Table 3 Subgroup analyses according to patient outcome STESS >3 Induced BS
Clinical characteristics Type of SE = GCSE Etiology of SE = AS STESS >3 Treatment Duration of anesthetics (days), median (IQR) Additional AED
Induced BS (excluding patients with anoxia)
Yes (n = 6)
No (n = 14)
p value
Yes (n = 6)
No (n = 13)
p value
4 (83.3%) 5 (83.3%)
11 (78.6%) 10 (71.4%)
>0.999 >0.999
5 (83.3%)
10 (76.9%)
>0.999
6 (100%)
11 (84.6%)
>0.999
10.0 (7.8–14.0) 5 (83.3%)
5.0 (2.8–9.3) 7 (50%)
0.051a 0.325
10.0 (7.8–14.0) 5 (83.3%)
7.0 (3.0–14.5) 7 (53.8%)
0.179 a 0.333
Outcomes Mortality Poor outcome Prolonged hospital stay (>30 days)
0 2 (33.3%) 5 (83.3%)
3 (21.4%) 10 (71.4%) 5(41.7%)
0.521 0.161 0.152
0 2 (33.3%) 5 (83.3%)
2 (15.4%) 7 (53.8%) 3 (17.3%)
>0.999 0.628 0.05
Complications Respiratory Cardiac Infection
5 (83.3%) 2 (33.3%) 4 (66.7%)
14 (100%) 5 (35.7%) 7 (50%)
0.300 >0.999 0.642
5 (83.3%) 2 (33.3%) 4 (66.7%)
13 (100%) 4 (30.8%) 6 (46.2%)
0.316 >0.999 0.628
a Fisher’s exact test and a Mann-Whitney U-test were used for statistical analysis. AED = anti-epileptic drugs, AS = acute symptomatic, BS = burst-suppression, GCSE = generalized convulsive status epilepticus, IQR = interquartile range, SE = status epilepticus, STESS = Status Epilepticus Severity Score. Data are presented as number (%) unless otherwise specified.
(95.5%). Cardiac complication, including hypotension and arrhythmia occurred in eight patients (36.4%) and systemic infection including pneumonia occurred in 12 patients (54.5%). There was no association between achievement of BS and the development of any type of complication. No complication was associated with mortality or poor outcome in the overall sample, or in the sample with unfavorable STESS and with exclusion of anoxic etiology. 5. Discussion This is a retrospective observational study which explored the usefulness of achieving intravenous anesthetic-induced BS or isoelectric suppression when intravenous anesthetics were given to RSE patients. We found that there was no correlation between
the achievement of induced BS and outcome, including mortality and poor functional outcome at discharge. Induced BS was only associated with prolonged hospital stay in the subgroup analysis when excluding anoxic etiologies. All patients in our study received intravenous MDZ for initial RSE treatment. At our center, MDZ was initiated with a bolus of 0.2 mg/kg followed by continuous infusion at a starting rate of 1 mcg/kg/minute. The infusion rate was titrated every 30–60 minutes by an epileptologist and was increased to a maximum dose of 0.4 mg/kg/hour until BS was seen on EEG if hemodynamically tolerable. Other anesthetic agents, propofol and pentobarbital, were used according to current guidelines [10,11]. Some experts believe that rapid loading of the anesthetics until BS is achieved is associated with better outcome compared to slow up-titration. However,
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these data were not available at the time our study was carried out and there might be individual variation in anesthetic administration due to the retrospective design of our study. There are few clinical reports regarding the optimal level of EEG suppression for RSE. A retrospective study with 35 pentobarbital-treated episodes suggested that complete suppression or a ‘‘flat record’’ led to better seizure control, with fewer relapses and a trend for better outcome compared to BS [12]. However, a review of 28 articles with 169 RSE cases (43 cases treated with MDZ, 21 propofol and 81 pentobarbital) reported that achievement of EEG background suppression was not associated with outcome, but there was a lower frequency of breakthrough seizures compared to seizure suppression (4% versus 53%, p < 0.001) [8]. None of the patients who received MDZ achieved EEG background suppression in this review. A retrospective study with 49 episodes of RSE in 47 patients reported that outcome was independent of the specific anesthetic agent used and the achievement of induced BS (six of the 20 patients who attained BS died versus two of 11 patients who did not attain BS died, p = 0.43), but use of barbiturates might be associated with achieving BS or isoelectric EEG suppression compared to the use of other anesthetic agents including MDZ [15]. Moreover, a recent retrospective study with 63 episodes of non-anoxic RSE, where MDZ was the most frequently used agent (n = 38), suggests that seizure control without BS or isoelectric EEG (n = 16) was correlated with a good functional outcome at hospital discharge compared to BS [4]. Our results are in accordance with these previous reports. Despite the lower prevalence of induced BS (28.5%) and higher proportion of unfavorable STESS (90.9%) in our study, the mortality (13.6%) seems to be lower than that reported in previous series (MDZ 17–61%; propofol 57–88%; and barbiturates 20–50%) [8,16–19]. All deaths in our series had numerous poor outcome predictors at admission. Older age, first episode of seizure and acute central nervous system disease are known predictors of mortality or poor outcome in patients with SE [20,21] and the STESS has also been verified as a prognostic factor [14]. Otherwise, the fact that more than half of patients (64.6%) received additional high-dose oral AED may also explain the low mortality. The efficacy and safety of various additional AED in RSE have been reported in recent studies [22,23]. The main limitation of this study is its retrospective design and small sample size. The small study size may be the reason that no statistically significant results were seen in our study. Also, only 9% of subjects had favorable STESS at the time of enrollment which may have contributed to the poor response of the study. However, to our knowledge, only a few studies have reported the effectiveness of intravenous anesthetic-induced BS or coma in treating RSE and these included fewer than 70 RSE patients [4,15]. Our results suggest that BS for treating RSE, especially when using MDZ, does not affect the mortality rate or rate of poor outcome at discharge, but it may lead to increased hospital stay. If BS is not beneficial compared to the suppression of epileptiform discharges when treating RSE, the patients may require dose-adjustment to reduce the intravenous anesthetic-related risks such as respiratory distress, hemodynamic instability and longer hospital stay.
Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Acknowledgements This study was supported by a grant from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI13C1558). References [1] Towne AR, Pellock JM, Ko D, et al. Determinants of mortality in status epilepticus. Epilepsia 1994;35:27–34. [2] 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;339:792–8. [3] Chen JW, Wasterlain CG. Status epilepticus: pathophysiology and management in adults. Lancet Neurol 2006;5:246–56. [4] Hocker SE, Britton JW, Mandrekar JN, et al. Predictors of outcome in refractory status epilepticus. JAMA Neurol 2013;70:72–7. [5] Jagoda A, Riggio S. Refractory status epilepticus in adults. Ann Emerg Med 1993;22:1337–48. [6] Mayer SA, Claassen J, Lokin J, et al. Refractory status epilepticus: frequency, risk factors, and impact on outcome. Arch Neurol 2002;59:205–10. [7] Hanley DF, Kross JF. Use of midazolam in the treatment of refractory status epilepticus. Clin Ther 1998;20:1093–105. [8] Claassen J, Hirsch LJ, Emerson RG, et al. Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: a systematic review. Epilepsia 2002;43:146–53. [9] Rossetti AO, Milligan TA, Vulliemoz S, et al. A randomized trial for the treatment of refractory status epilepticus. Neurocrit Care 2011;14:4–10. [10] Brophy GM, Bell R, Claassen J, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012;17:3–23. [11] Meierkord H, Boon P, Engelsen B, et al. EFNS guideline on the management of status epilepticus in adults. Eur J Neurol 2010;17:348–55. [12] Krishnamurthy KB, Drislane FW. Depth of EEG suppression and outcome in barbiturate anesthetic treatment for refractory status epilepticus. Epilepsia 1999;40:759–62. [13] Takeoka M, Holmes GL, Thiele E, et al. Topiramate and metabolic acidosis in pediatric epilepsy. Epilepsia 2001;42:387–92. [14] Rossetti AO, Logroscino G, Bromfield EB. A clinical score for prognosis of status epilepticus in adults. Neurology 2006;66:1736–8. [15] Rossetti AO, Logroscino G, Bromfield EB. Refractory status epilepticus: effect of treatment aggressiveness on prognosis. Arch Neurol 2005;62:1698–702. [16] Claassen J, Hirsch LJ, Emerson RG, et al. Continuous EEG monitoring and midazolam infusion for refractory nonconvulsive status epilepticus. Neurology 2001;57:1036–42. [17] Stecker MM, Kramer TH, Raps EC, et al. Treatment of refractory status epilepticus with propofol: clinical and pharmacokinetic findings. Epilepsia 1998;39:18–26. [18] Prasad A, Worrall BB, Bertram EH, et al. Propofol and midazolam in the treatment of refractory status epilepticus. Epilepsia 2001;42:380–6. [19] Parviainen I, Uusaro A, Kalviainen R, et al. High-dose thiopental in the treatment of refractory status epilepticus in intensive care unit. Neurology 2002;59:1249–51. [20] DeLorenzo RJ, Hauser WA, Towne AR, et al. A prospective, population-based epidemiologic study of status epilepticus in Richmond, Virginia. Neurology 1996;46:1029–35. [21] Kowalski RG, Ziai WC, Rees RN, et al. Third-line antiepileptic therapy and outcome in status epilepticus: the impact of vasopressor use and prolonged mechanical ventilation. Crit Care Med 2012;40:2677–84. [22] Hottinger A, Sutter R, Marsch S, et al. Topiramate as an adjunctive treatment in patients with refractory status epilepticus: an observational cohort study. CNS Drugs 2012;26:761–72. [23] Swisher CB, Doreswamy M, Gingrich KJ, et al. Phenytoin, levetiracetam, and pregabalin in the acute management of refractory status epilepticus in patients with brain tumors. Neurocrit Care 2012;16:109–13.
