YEBEH-04362; No of Pages 4 Epilepsy & Behavior xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Incidence and mortality of super-refractory status epilepticus in adults Anne-Mari Kantanen a,⁎, Matti Reinikainen b, Ilkka Parviainen c, Esko Ruokonen d, Marika Ala-Peijari e, Tom Bäcklund f, Juha Koskenkari g, Ruut Laitio h, Reetta Kälviäinen i a
Neurocenter, Kuopio University Hospital, University of Eastern Finland, Kuopio, Finland Intensive Care Unit, North Karelia Central Hospital, Joensuu, Finland Intensive Care Unit, Kuopio University Hospital, Kuopio, Finland d Intensive Care Unit, Kuopio University Hospital, University of Eastern Finland, Kuopio, Finland e Division of Intensive Care, Tampere University Hospital, Tampere, Finland f Department of Internal Medicine, Helsinki University Hospital, Helsinki, Finland g Department of Anesthesiology, Division of Intensive Care, Oulu University Hospital, Oulu, Finland h Department of Perioperative Services, Intensive Care and Pain Medicine, Turku University Hospital, Turku, Finland i Epilepsy Center/Neurocenter, Kuopio University Hospital, University of Eastern Finland, Kuopio, Finland b c
a r t i c l e
i n f o
Article history: Revised 26 April 2015 Accepted 28 April 2015 Available online xxxx Keywords: Mortality Status epilepticus Superrefractory ICU Incidence
a b s t r a c t Objectives: Super-refractory status epilepticus (SRSE) is defined as status epilepticus (SE) that continues or recurs 24 h or more after the onset of anesthetic therapy. We defined the incidence and outcome of SRSE in adults in Finland. Methods: We analyzed retrospectively the Finnish Intensive Care Consortium database in order to identify adult patients with SRSE treated in ICUs in Finland during a three-year period (2010–2012). The database consists of admissions to all 20 Finnish hospitals treating refractory SE (RSE) with general anesthesia in the intensive care unit (ICU). We included consecutive adult (16 years or older) patients with RSE and identified those who had SRSE. Patients with postanoxic etiologies were excluded. Results: All five university hospitals and 10/15 of the central hospitals participated. The adult referral population of the study hospitals is 3.9 million, representing 91% of the total adult population of Finland. We identified 395 patients with ICU-treated RSE, 87 (22%) of whom were classified as having SRSE. This corresponds to an annual incidence of SRSE of 0.7/100,000 (95% confidence interval [CI]: 0.6–0.9). The one-year mortality rates were 36% (95% CI: 26–46%) for patients with SRSE and 22% (95% CI: 17–27%) for patients with RSE. Mortality was highest (63%) in patients with SRSE aged over 75 years. Conclusions: Approximately 20% of patients with RSE treated in Finnish ICUs progressed to having SRSE. The incidence of SRSE, 0.7/100,000, is about 5–10% of the incidence of SE. The mortality of patients with SRSE, 36%, was comparable to earlier studies and twofold higher than the mortality of patients with RSE. This article is part of a Special Issue entitled “Status Epilepticus”. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Status epilepticus (SE) is an important neurological emergency associated with significant mortality and morbidity. Status epilepticus is considered refractory (RSE) if the first- and second-line treatments with antiepileptic drugs fail and the patient is treated with general anesthesia in the intensive care unit (ICU). Status epilepticus is defined as super-refractory (SRSE) if it continues 24 h or more after the onset of anesthesia, including those cases in which the SE recurs on the reduction or withdrawal of anesthesia [1]. Approximately 12–43% of all those ⁎ Corresponding author at: Acute Neurology, Kuopio University Hospital, Neurocenter, P.O. Box 100, 70029 Kuopio, Finland. Tel.: +358 447174860. E-mail address: anne-mari.kantanen@kuh.fi (A.-M. Kantanen).
presenting to the hospital with SE progress to having RSE and 10–15% to SRSE [1,2]. In most studies assessing SE, persistence or recurrence of seizures beyond 24 h of anesthetic treatment is not documented. The incidence of SRSE is not known [3]. The prognosis of SRSE is rather poor, and long-term mortality rates between 30 and 50% have been reported [4]. A recent hospital-based series of SRSE reported a one-year mortality of 58% [5]. Most previous SRSE studies are hospital-based case series. There are no population-based studies of SRSE [4]. Based on previous data, the three main prognostic factors of SE are the duration of SE, the patient's age, and the underlying cause [1,6]. According to a review about the outcome of patients with RSE, including those with SRSE, roughly one-third of patients die, one-third survive with mild or severe neurological deficits, and one-third recover to their baseline health [4]. Elderly patients
http://dx.doi.org/10.1016/j.yebeh.2015.04.065 1525-5050/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Kantanen A-M, et al, Incidence and mortality of super-refractory status epilepticus in adults, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.04.065
2
A.-M. Kantanen et al. / Epilepsy & Behavior xxx (2015) xxx–xxx
seem to have a worse prognosis. In addition, elderly patients are more sensitive to the harmful side effects of antiepileptic drugs (AEDs) and anesthetics used [7]. The etiology spectrum of SRSE differs from the etiologies of SE. Refractory seizures are more likely to develop as a result of severe brain injury due to trauma, infection, immunological disease, or stroke or as new-onset refractory epilepsy. The seizure types vary from convulsive to nonconvulsive [3]. The aim of the treatment is to prevent damage to the cerebral cortex by controlling the epileptic activity while treating the cause of SRSE at the same time [1,3]. This study was conducted to assess the incidence and mortality of SRSE in the adult population in Finland. We wanted also to determine how well the Finnish current care guidelines [8], recommendations on diagnostic EEG, and continuous EEG monitoring in RSE are being followed.
whereas in 28% of the patients, the diagnosis was based on clinical judgment alone. Seventy-four (85%) patients had continuous EEG monitoring during the treatment. Eighty-four (96%) patients had EEG and clinical evaluation combined when weaning from the anesthesia. Results for treatment characteristics are shown in Table 1. 3.3. Mortality and long-term outcome In the group with SRSE, the one-year mortality was 36% (95% CI: 26– 46%). When discharged from the hospital, 55% of the patients with SRSE went to primary care, 17% to specialist level care, and 17% home. Detailed outcome data are shown in Table 2. 4. Discussion
2. Material and methods We analyzed retrospectively the Finnish Intensive Care Consortium database in order to identify patients with RSE and SRSE treated in ICUs in Finland during a three-year period (2010–2012). Finland is divided into 20 hospital districts that have 15 central hospitals and 5 university hospitals that provide all the secondary and tertiary care, ICUs, and neurological services for their referral population. The Finnish Intensive Care Consortium is a body coordinating a national benchmarking program in intensive care. The Consortium database collects data from every ICU admission from all general adult ICUs in Finnish hospitals. The information on clinical characteristics, severity of illness, and outcome is validated in each ICU by local physicians [9]. We searched the database by using the ICD-10 codes for epilepsy, SE, and convulsions (G40.X, G41.X, R56.8) as well as the Acute Physiology and Chronic Health Evaluation (APACHE) II [10] diagnostic group “seizure” to identify all patients treated in an ICU for seizure disorders and included the patients that had been treated in the ICU for at least 48 h (minimum duration of treatment for patients treated with general anesthesia in ICUs). Intensive care unit physicians in each participating hospital reevaluated the patient charts to identify patients with RSE and SRSE according to the criteria. We included consecutive adult (16 years or older) patients with RSE that had seizures that failed to improve with the first- and second-line treatments with AEDs and were treated with general anesthesia in the ICU, and among this population with RSE, we identified the patients meeting the criteria for SRSE (SE continuing or recurring 24 h after the onset of the first general anesthesia). Patients with postanoxic etiologies were excluded. The statistical analyses were made with SPSS 21.0. We conducted a retrospective observational study based on a national ICU registry. The Finnish Intensive Care Consortium board granted us access to its database. These registry data are anonymous. Local hospital registry permissions were obtained.
This study reveals the relatively low incidence and high mortality of SRSE in a population-based setting. Diagnostic EEG and continuous EEG monitoring were widely used in this group of patients. 4.1. Incidence and mortality
3. Results
To our knowledge, this is the first population-based study describing the incidence and long-term mortality of SRSE. The incidence of SRSE was 0.7/100,000. The annual incidence of SE was estimated earlier at about 10–20/100,000 [11]. A rough approximation has shown that 10–15% of all SE becomes super-refractory [1–3]. In a recent hospitalbased study from Switzerland by Marchi et al., 50/467 (11%) of patients with SE needed general anesthesia, but the duration of the therapy was not indicated [12]. We may estimate that 1–3 patients per 100,000 annually need ICU treatment and anesthesia because of their RSE, but not all of them have seizures that progress into SRSE. Approximately one in every five of our patients with RSE had seizures that became super-refractory. We do not have the exact incidence of SE from our area from the same time point, but we can estimate that 5–10% of all SE becomes SRSE. The hospital mortality (10%) of patients with SRSE in our study is low compared to other studies that have reported hospital mortalities of up to 42% [4,5,13,14]. However, the hospital mortality of patients with SRSE was markedly higher than that of patients with RSE. Likewise, mortality at one year was much higher in the patients with SRSE than in the patients with RSE (36% vs. 22%). Compared to earlier studies, the long-term mortality of SRSE in our study was comparable or lower [4, 5,13,14]. The exact definitions of RSE and SRSE seem to vary between different studies, making the comparisons difficult. Also in some of the older studies, cases of postanoxic etiologies were included, resulting in higher RSE mortality. In our study, after being treated in the hospital, over 50% of the patients with SRSE were discharged to primary care and only 17% to home. This implies that the short-term neurological outcome was poor.
3.1. Study population and incidence
4.2. Diagnostics and treatment
All five university hospitals and 10 out of the 15 central hospitals participated in this study (Fig. 1). The total adult referral population of these hospitals is 3.9 million inhabitants, representing 91% of the total adult population of Finland. During the study period, altogether 56,427 patients were treated in the study ICUs. We identified 395 patients with RSE, and 87 (22%) of them were classified as having SRSE. This corresponds to an annual incidence of SRSE of 0.7/100,000 (95% CI: 0.6–0.9). The median age of patients with SRSE was 57 years (range: 17–84 years). There were 44 males (51%) and 43 females (49%).
In Finland, the national current care guidelines for SE were updated in 2009 [8]. According to the protocol, patients receive prehospital treatment with buccal midazolam or rectal diazepam; first-line benzodiazepines such as intravenous diazepam or lorazepam; and second-line medications with chosen AEDs such as fosphenytoin, valproic acid, or levetiracetam. The recommended third-line treatment is suppressive general anesthesia, monitored by continuous EEG. Neurologists and ICU physicians collaborate in the treatment of RSE. In this study, eighty-five percent of the patients had continuous EEG monitoring for evaluation of the depth of coma and burst suppression during anesthesia. Compared to a recent article on this subject in the UK, where only 33% of the trusts had continuous EEG monitoring available [15], patients with SRSE in Finland had greater access to EEG. Ninety-six percent of the patients with SRSE received two or more intravenous anesthetics
3.2. Diagnosis and treatment Sixty-three (72%) patients had a diagnostic EEG performed before the first intravenous anesthetic treatment was started in the ICU,
Please cite this article as: Kantanen A-M, et al, Incidence and mortality of super-refractory status epilepticus in adults, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.04.065
A.-M. Kantanen et al. / Epilepsy & Behavior xxx (2015) xxx–xxx
3
Data available Data missing University Hospital Central Hospital
Fig. 1. The catchment area of the study. All five university hospitals and 10 out of 15 central hospitals participated in this study. The total adult referral population is 3.9 million inhabitants, representing 91% of the total adult population of Finland. Finland's total area is 337,030 km2.
(IVAs). Seizure activity was resolved in 81% of the cases with SRSE in the ICU. The length of treatment in the ICU (median: 9 days) was long compared to Finnish ICU patients in general (median: 1.6 days) [9].
Table 2 Short- and long-term outcome of super-refractory status epilepticus (SRSE) and refractory status epilepticus (RSE) in the intensive care unit (ICU).
Table 1 Diagnosis and treatment of super-refractory status epilepticus (N = 87). Diagnostic EEG, N (%) cEEG monitoring, N (%) Posttreatment EEG, N (%) Number of anesthesia ≥ 2 Seizure activity resolved, N (%) First IVA, propofol, N (%) LOS ICU, days, median (IQR) LOS hospital, days, median (IQR)
63 (72%) 74 (85%) 84 (96%) 84 (96%) 70 (81%) 84 (96%) 9 (6.4–11.9) 21 (14–32)
cEEG = continuous EEG, IVA = intravenous anesthetic, LOS = length of stay, ICU = intensive care unit, and IQR = interquartile range.
ICU mortality (95% CI) Hospital mortality (95% CI) 1-year mortality (95% CI) 1-year mortality age b75 years N75 years Hospital discharge Home To specialist level care To primary care Death
SRSE (N = 87)
RSE (N = 304)
2% (0–5%) 10% (4%–16%) 36% (26%–46%)
0.3% (0–0.9%) 6% (3%–9%) 22% (17%–27%)
33% 63%
21% 37%
17% 17% 55% 10%
26% 23% 44% 6%
Please cite this article as: Kantanen A-M, et al, Incidence and mortality of super-refractory status epilepticus in adults, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.04.065
4
A.-M. Kantanen et al. / Epilepsy & Behavior xxx (2015) xxx–xxx
4.3. Strengths and limitations
Conflict of interest
This is the first population-based analysis of SRSE showing the incidence and mortality of SRSE in Finland. The current definitions of RSE and SRSE were used. Continuous EEG monitoring was available for the majority of the patients. The limitations include missing information about the etiology, detailed medications, and the cognitive and longterm neurological outcome of these patients. We were also able to only include patients treated in ICUs.
Anne-Mari Kantanen has received funding from Kuopio University Hospital and the Finnish Epilepsy Research Foundation. Matti Reinikainen, Ilkka Parviainen, Esko Ruokonen, Marika Ala-Peijari, and Tom Bäcklund have no disclosures. Juha Koskenkari has received congress expense support from Orion Pharma and Ruut Laitio from Octapharma. Reetta Kälviäinen has received speaker's honoraria from Eisai, UCB, and Orion; honoraria for participation in advisory boards from Eisai, Fennomedical, Pfizer, Sage, and UCB; and research support for her institute from the Academy of Finland, UCB, and Eisai.
5. Conclusion Super-refractory status epilepticus is a rare medical emergency with high mortality rate, especially in the elderly population. More population-based prospective studies of SE are needed not only to understand this entity but also to improve the long-term outcome of patients with SRSE. Acknowledgments We would like to thank all the participating ICU physicians in central hospitals: Central Finland Central Hospital: Raili Laru-Sompa, East Savo Central Hospital: Pekka Saastamoinen, Helsinki University Hospital: Johanna Wennevirta, Lapland Central Hospital: Outi Kiviniemi, Middle Ostrobothnia Central Hospital: Tadeusz Kaminski, Päijät-Häme Central Hospital: Antti-Pekka Loisa, Satakunta Hospital District: Atte Koskinen, South Karelia Central Hospital: Sari Melto and Kirsi Anne, South Savo Central Hospital: Heikki Laine, South Ostrobothnia Central Hospital: Kari Saarinen, Tampere University Hospital: Sari Karlsson, and Vaasa Central Hospital: Simo-Pekka Koivisto. Funding This study was supported by grants from the Kuopio University Hospital VTR and Finnish Epilepsy Research Foundation. Human and animal rights This is a retrospective observational study based on a national ICU registry. The Finnish Intensive Care Consortium board granted us access to its database. These registry data are anonymous. Local hospital registry permissions were obtained. This study does not contain any experimentation with human or animal subjects.
References [1] Shorvon SD, Ferlisi M. The treatment of super-refractory status epilepticus: a critical review of available therapies and clinical treatment protocol. Brain 2011;134:2802–18. [2] Novy J, Logroscino G, Rossetti AO. Refractory status epilepticus: a prospective observational study. Epilepsia 2010;51(2):251–6. [3] Hocker S, Tatum WO, LaRoche S, Freeman WD. Refractory and super-refractory status epilepticus — an update. Curr Neurol Neurosci Rep 2014;14(6):452. [4] Shorvon SD, Ferlisi M. The outcome of therapies in refractory and super-refractory convulsive status epilepticus and recommendations for therapy. Brain 2012;135: 2314–28. [5] Pugin D, Foreman B, De Marchis GM, Fernandez A, Schmidt JM, Czeisler BM, et al. Is pentoparbital safe and efficacious in the treatment of super-refractory status epilepticus: a cohort study. Crit Care 2014;18:R103. [6] Holtkamp M, Othman J, Buchheim K, Meierkord H. Predictors and prognosis of refractory status epilepticus treated in a neurological intensive care unit. J Neurol Neurosurg Psychiatry 2005;76:534–9. [7] Towne AR. Epidemiology and outcomes of status epilepticus in the elderly. Int Rev Neurobiol 2007;81:111–27. [8] Kälviäinen R, Eriksson K, Häppölä O, Keränen T, Kurola J, Kuusela AL, et al. Update on current care guidelines. The treatment of status epilepticus. Duodecim 2009; 125(22):2469–71. [9] Reinikainen M, Mussalo P, Hovilehto S, Uusaro A, Varpula T, Kari A, et al. Association of automated data collection and data completeness with outcomes of intensive care. A new customised model for outcome prediction. Acta Anaesthesiol Scand 2012;56:1114–22. [10] Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med 1985;13:818–29. [11] Neligan A, Shorvon SD. Frequency and prognosis of convulsive status epilepticus of different causes: a systematic review. Arch Neurol 2010;67(8):931–40. [12] Marchi NA, Novy J, Faouzi M, Stähli C, Burnand B, Rossetti AO. Status epilepticus: impact of therapeutic coma on outcome. Crit Care Med 2015. [13] Sutter R, Kaplan PW, Marsch S, Hammel EM, Rüegg S, Zial WC. Early predictors of refractory status epilepticus: an international two-center study. Eur J Neurol 2015; 22(1):79–85. [14] Sutter R, Marsch S, Fuhr P, Rüegg S. Mortality and recovery from refractory status epilepticus in the ICU: a 7-year observational study. Epilepsia 2013;54:502–11. [15] Patel M, Bagary M, McCorry D. The management of convulsive refractory status epilepticus in adults in UK: no consistency in practice and little access to continuous EEG monitoring. Seizure 2015;24:33–7.
Please cite this article as: Kantanen A-M, et al, Incidence and mortality of super-refractory status epilepticus in adults, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.04.065
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Incidence and mortality of super-refractory status epilepticus in adults Anne-Mari Kantanen a,⁎, Matti Reinikainen b, Ilkka Parviainen c, Esko Ruokonen d, Marika Ala-Peijari e, Tom Bäcklund f, Juha Koskenkari g, Ruut Laitio h, Reetta Kälviäinen i a
Neurocenter, Kuopio University Hospital, University of Eastern Finland, Kuopio, Finland Intensive Care Unit, North Karelia Central Hospital, Joensuu, Finland Intensive Care Unit, Kuopio University Hospital, Kuopio, Finland d Intensive Care Unit, Kuopio University Hospital, University of Eastern Finland, Kuopio, Finland e Division of Intensive Care, Tampere University Hospital, Tampere, Finland f Department of Internal Medicine, Helsinki University Hospital, Helsinki, Finland g Department of Anesthesiology, Division of Intensive Care, Oulu University Hospital, Oulu, Finland h Department of Perioperative Services, Intensive Care and Pain Medicine, Turku University Hospital, Turku, Finland i Epilepsy Center/Neurocenter, Kuopio University Hospital, University of Eastern Finland, Kuopio, Finland b c
a r t i c l e
i n f o
Article history: Revised 26 April 2015 Accepted 28 April 2015 Available online xxxx Keywords: Mortality Status epilepticus Superrefractory ICU Incidence
a b s t r a c t Objectives: Super-refractory status epilepticus (SRSE) is defined as status epilepticus (SE) that continues or recurs 24 h or more after the onset of anesthetic therapy. We defined the incidence and outcome of SRSE in adults in Finland. Methods: We analyzed retrospectively the Finnish Intensive Care Consortium database in order to identify adult patients with SRSE treated in ICUs in Finland during a three-year period (2010–2012). The database consists of admissions to all 20 Finnish hospitals treating refractory SE (RSE) with general anesthesia in the intensive care unit (ICU). We included consecutive adult (16 years or older) patients with RSE and identified those who had SRSE. Patients with postanoxic etiologies were excluded. Results: All five university hospitals and 10/15 of the central hospitals participated. The adult referral population of the study hospitals is 3.9 million, representing 91% of the total adult population of Finland. We identified 395 patients with ICU-treated RSE, 87 (22%) of whom were classified as having SRSE. This corresponds to an annual incidence of SRSE of 0.7/100,000 (95% confidence interval [CI]: 0.6–0.9). The one-year mortality rates were 36% (95% CI: 26–46%) for patients with SRSE and 22% (95% CI: 17–27%) for patients with RSE. Mortality was highest (63%) in patients with SRSE aged over 75 years. Conclusions: Approximately 20% of patients with RSE treated in Finnish ICUs progressed to having SRSE. The incidence of SRSE, 0.7/100,000, is about 5–10% of the incidence of SE. The mortality of patients with SRSE, 36%, was comparable to earlier studies and twofold higher than the mortality of patients with RSE. This article is part of a Special Issue entitled “Status Epilepticus”. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Status epilepticus (SE) is an important neurological emergency associated with significant mortality and morbidity. Status epilepticus is considered refractory (RSE) if the first- and second-line treatments with antiepileptic drugs fail and the patient is treated with general anesthesia in the intensive care unit (ICU). Status epilepticus is defined as super-refractory (SRSE) if it continues 24 h or more after the onset of anesthesia, including those cases in which the SE recurs on the reduction or withdrawal of anesthesia [1]. Approximately 12–43% of all those ⁎ Corresponding author at: Acute Neurology, Kuopio University Hospital, Neurocenter, P.O. Box 100, 70029 Kuopio, Finland. Tel.: +358 447174860. E-mail address: anne-mari.kantanen@kuh.fi (A.-M. Kantanen).
presenting to the hospital with SE progress to having RSE and 10–15% to SRSE [1,2]. In most studies assessing SE, persistence or recurrence of seizures beyond 24 h of anesthetic treatment is not documented. The incidence of SRSE is not known [3]. The prognosis of SRSE is rather poor, and long-term mortality rates between 30 and 50% have been reported [4]. A recent hospital-based series of SRSE reported a one-year mortality of 58% [5]. Most previous SRSE studies are hospital-based case series. There are no population-based studies of SRSE [4]. Based on previous data, the three main prognostic factors of SE are the duration of SE, the patient's age, and the underlying cause [1,6]. According to a review about the outcome of patients with RSE, including those with SRSE, roughly one-third of patients die, one-third survive with mild or severe neurological deficits, and one-third recover to their baseline health [4]. Elderly patients
http://dx.doi.org/10.1016/j.yebeh.2015.04.065 1525-5050/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Kantanen A-M, et al, Incidence and mortality of super-refractory status epilepticus in adults, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.04.065
2
A.-M. Kantanen et al. / Epilepsy & Behavior xxx (2015) xxx–xxx
seem to have a worse prognosis. In addition, elderly patients are more sensitive to the harmful side effects of antiepileptic drugs (AEDs) and anesthetics used [7]. The etiology spectrum of SRSE differs from the etiologies of SE. Refractory seizures are more likely to develop as a result of severe brain injury due to trauma, infection, immunological disease, or stroke or as new-onset refractory epilepsy. The seizure types vary from convulsive to nonconvulsive [3]. The aim of the treatment is to prevent damage to the cerebral cortex by controlling the epileptic activity while treating the cause of SRSE at the same time [1,3]. This study was conducted to assess the incidence and mortality of SRSE in the adult population in Finland. We wanted also to determine how well the Finnish current care guidelines [8], recommendations on diagnostic EEG, and continuous EEG monitoring in RSE are being followed.
whereas in 28% of the patients, the diagnosis was based on clinical judgment alone. Seventy-four (85%) patients had continuous EEG monitoring during the treatment. Eighty-four (96%) patients had EEG and clinical evaluation combined when weaning from the anesthesia. Results for treatment characteristics are shown in Table 1. 3.3. Mortality and long-term outcome In the group with SRSE, the one-year mortality was 36% (95% CI: 26– 46%). When discharged from the hospital, 55% of the patients with SRSE went to primary care, 17% to specialist level care, and 17% home. Detailed outcome data are shown in Table 2. 4. Discussion
2. Material and methods We analyzed retrospectively the Finnish Intensive Care Consortium database in order to identify patients with RSE and SRSE treated in ICUs in Finland during a three-year period (2010–2012). Finland is divided into 20 hospital districts that have 15 central hospitals and 5 university hospitals that provide all the secondary and tertiary care, ICUs, and neurological services for their referral population. The Finnish Intensive Care Consortium is a body coordinating a national benchmarking program in intensive care. The Consortium database collects data from every ICU admission from all general adult ICUs in Finnish hospitals. The information on clinical characteristics, severity of illness, and outcome is validated in each ICU by local physicians [9]. We searched the database by using the ICD-10 codes for epilepsy, SE, and convulsions (G40.X, G41.X, R56.8) as well as the Acute Physiology and Chronic Health Evaluation (APACHE) II [10] diagnostic group “seizure” to identify all patients treated in an ICU for seizure disorders and included the patients that had been treated in the ICU for at least 48 h (minimum duration of treatment for patients treated with general anesthesia in ICUs). Intensive care unit physicians in each participating hospital reevaluated the patient charts to identify patients with RSE and SRSE according to the criteria. We included consecutive adult (16 years or older) patients with RSE that had seizures that failed to improve with the first- and second-line treatments with AEDs and were treated with general anesthesia in the ICU, and among this population with RSE, we identified the patients meeting the criteria for SRSE (SE continuing or recurring 24 h after the onset of the first general anesthesia). Patients with postanoxic etiologies were excluded. The statistical analyses were made with SPSS 21.0. We conducted a retrospective observational study based on a national ICU registry. The Finnish Intensive Care Consortium board granted us access to its database. These registry data are anonymous. Local hospital registry permissions were obtained.
This study reveals the relatively low incidence and high mortality of SRSE in a population-based setting. Diagnostic EEG and continuous EEG monitoring were widely used in this group of patients. 4.1. Incidence and mortality
3. Results
To our knowledge, this is the first population-based study describing the incidence and long-term mortality of SRSE. The incidence of SRSE was 0.7/100,000. The annual incidence of SE was estimated earlier at about 10–20/100,000 [11]. A rough approximation has shown that 10–15% of all SE becomes super-refractory [1–3]. In a recent hospitalbased study from Switzerland by Marchi et al., 50/467 (11%) of patients with SE needed general anesthesia, but the duration of the therapy was not indicated [12]. We may estimate that 1–3 patients per 100,000 annually need ICU treatment and anesthesia because of their RSE, but not all of them have seizures that progress into SRSE. Approximately one in every five of our patients with RSE had seizures that became super-refractory. We do not have the exact incidence of SE from our area from the same time point, but we can estimate that 5–10% of all SE becomes SRSE. The hospital mortality (10%) of patients with SRSE in our study is low compared to other studies that have reported hospital mortalities of up to 42% [4,5,13,14]. However, the hospital mortality of patients with SRSE was markedly higher than that of patients with RSE. Likewise, mortality at one year was much higher in the patients with SRSE than in the patients with RSE (36% vs. 22%). Compared to earlier studies, the long-term mortality of SRSE in our study was comparable or lower [4, 5,13,14]. The exact definitions of RSE and SRSE seem to vary between different studies, making the comparisons difficult. Also in some of the older studies, cases of postanoxic etiologies were included, resulting in higher RSE mortality. In our study, after being treated in the hospital, over 50% of the patients with SRSE were discharged to primary care and only 17% to home. This implies that the short-term neurological outcome was poor.
3.1. Study population and incidence
4.2. Diagnostics and treatment
All five university hospitals and 10 out of the 15 central hospitals participated in this study (Fig. 1). The total adult referral population of these hospitals is 3.9 million inhabitants, representing 91% of the total adult population of Finland. During the study period, altogether 56,427 patients were treated in the study ICUs. We identified 395 patients with RSE, and 87 (22%) of them were classified as having SRSE. This corresponds to an annual incidence of SRSE of 0.7/100,000 (95% CI: 0.6–0.9). The median age of patients with SRSE was 57 years (range: 17–84 years). There were 44 males (51%) and 43 females (49%).
In Finland, the national current care guidelines for SE were updated in 2009 [8]. According to the protocol, patients receive prehospital treatment with buccal midazolam or rectal diazepam; first-line benzodiazepines such as intravenous diazepam or lorazepam; and second-line medications with chosen AEDs such as fosphenytoin, valproic acid, or levetiracetam. The recommended third-line treatment is suppressive general anesthesia, monitored by continuous EEG. Neurologists and ICU physicians collaborate in the treatment of RSE. In this study, eighty-five percent of the patients had continuous EEG monitoring for evaluation of the depth of coma and burst suppression during anesthesia. Compared to a recent article on this subject in the UK, where only 33% of the trusts had continuous EEG monitoring available [15], patients with SRSE in Finland had greater access to EEG. Ninety-six percent of the patients with SRSE received two or more intravenous anesthetics
3.2. Diagnosis and treatment Sixty-three (72%) patients had a diagnostic EEG performed before the first intravenous anesthetic treatment was started in the ICU,
Please cite this article as: Kantanen A-M, et al, Incidence and mortality of super-refractory status epilepticus in adults, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.04.065
A.-M. Kantanen et al. / Epilepsy & Behavior xxx (2015) xxx–xxx
3
Data available Data missing University Hospital Central Hospital
Fig. 1. The catchment area of the study. All five university hospitals and 10 out of 15 central hospitals participated in this study. The total adult referral population is 3.9 million inhabitants, representing 91% of the total adult population of Finland. Finland's total area is 337,030 km2.
(IVAs). Seizure activity was resolved in 81% of the cases with SRSE in the ICU. The length of treatment in the ICU (median: 9 days) was long compared to Finnish ICU patients in general (median: 1.6 days) [9].
Table 2 Short- and long-term outcome of super-refractory status epilepticus (SRSE) and refractory status epilepticus (RSE) in the intensive care unit (ICU).
Table 1 Diagnosis and treatment of super-refractory status epilepticus (N = 87). Diagnostic EEG, N (%) cEEG monitoring, N (%) Posttreatment EEG, N (%) Number of anesthesia ≥ 2 Seizure activity resolved, N (%) First IVA, propofol, N (%) LOS ICU, days, median (IQR) LOS hospital, days, median (IQR)
63 (72%) 74 (85%) 84 (96%) 84 (96%) 70 (81%) 84 (96%) 9 (6.4–11.9) 21 (14–32)
cEEG = continuous EEG, IVA = intravenous anesthetic, LOS = length of stay, ICU = intensive care unit, and IQR = interquartile range.
ICU mortality (95% CI) Hospital mortality (95% CI) 1-year mortality (95% CI) 1-year mortality age b75 years N75 years Hospital discharge Home To specialist level care To primary care Death
SRSE (N = 87)
RSE (N = 304)
2% (0–5%) 10% (4%–16%) 36% (26%–46%)
0.3% (0–0.9%) 6% (3%–9%) 22% (17%–27%)
33% 63%
21% 37%
17% 17% 55% 10%
26% 23% 44% 6%
Please cite this article as: Kantanen A-M, et al, Incidence and mortality of super-refractory status epilepticus in adults, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.04.065
4
A.-M. Kantanen et al. / Epilepsy & Behavior xxx (2015) xxx–xxx
4.3. Strengths and limitations
Conflict of interest
This is the first population-based analysis of SRSE showing the incidence and mortality of SRSE in Finland. The current definitions of RSE and SRSE were used. Continuous EEG monitoring was available for the majority of the patients. The limitations include missing information about the etiology, detailed medications, and the cognitive and longterm neurological outcome of these patients. We were also able to only include patients treated in ICUs.
Anne-Mari Kantanen has received funding from Kuopio University Hospital and the Finnish Epilepsy Research Foundation. Matti Reinikainen, Ilkka Parviainen, Esko Ruokonen, Marika Ala-Peijari, and Tom Bäcklund have no disclosures. Juha Koskenkari has received congress expense support from Orion Pharma and Ruut Laitio from Octapharma. Reetta Kälviäinen has received speaker's honoraria from Eisai, UCB, and Orion; honoraria for participation in advisory boards from Eisai, Fennomedical, Pfizer, Sage, and UCB; and research support for her institute from the Academy of Finland, UCB, and Eisai.
5. Conclusion Super-refractory status epilepticus is a rare medical emergency with high mortality rate, especially in the elderly population. More population-based prospective studies of SE are needed not only to understand this entity but also to improve the long-term outcome of patients with SRSE. Acknowledgments We would like to thank all the participating ICU physicians in central hospitals: Central Finland Central Hospital: Raili Laru-Sompa, East Savo Central Hospital: Pekka Saastamoinen, Helsinki University Hospital: Johanna Wennevirta, Lapland Central Hospital: Outi Kiviniemi, Middle Ostrobothnia Central Hospital: Tadeusz Kaminski, Päijät-Häme Central Hospital: Antti-Pekka Loisa, Satakunta Hospital District: Atte Koskinen, South Karelia Central Hospital: Sari Melto and Kirsi Anne, South Savo Central Hospital: Heikki Laine, South Ostrobothnia Central Hospital: Kari Saarinen, Tampere University Hospital: Sari Karlsson, and Vaasa Central Hospital: Simo-Pekka Koivisto. Funding This study was supported by grants from the Kuopio University Hospital VTR and Finnish Epilepsy Research Foundation. Human and animal rights This is a retrospective observational study based on a national ICU registry. The Finnish Intensive Care Consortium board granted us access to its database. These registry data are anonymous. Local hospital registry permissions were obtained. This study does not contain any experimentation with human or animal subjects.
References [1] Shorvon SD, Ferlisi M. The treatment of super-refractory status epilepticus: a critical review of available therapies and clinical treatment protocol. Brain 2011;134:2802–18. [2] Novy J, Logroscino G, Rossetti AO. Refractory status epilepticus: a prospective observational study. Epilepsia 2010;51(2):251–6. [3] Hocker S, Tatum WO, LaRoche S, Freeman WD. Refractory and super-refractory status epilepticus — an update. Curr Neurol Neurosci Rep 2014;14(6):452. [4] Shorvon SD, Ferlisi M. The outcome of therapies in refractory and super-refractory convulsive status epilepticus and recommendations for therapy. Brain 2012;135: 2314–28. [5] Pugin D, Foreman B, De Marchis GM, Fernandez A, Schmidt JM, Czeisler BM, et al. Is pentoparbital safe and efficacious in the treatment of super-refractory status epilepticus: a cohort study. Crit Care 2014;18:R103. [6] Holtkamp M, Othman J, Buchheim K, Meierkord H. Predictors and prognosis of refractory status epilepticus treated in a neurological intensive care unit. J Neurol Neurosurg Psychiatry 2005;76:534–9. [7] Towne AR. Epidemiology and outcomes of status epilepticus in the elderly. Int Rev Neurobiol 2007;81:111–27. [8] Kälviäinen R, Eriksson K, Häppölä O, Keränen T, Kurola J, Kuusela AL, et al. Update on current care guidelines. The treatment of status epilepticus. Duodecim 2009; 125(22):2469–71. [9] Reinikainen M, Mussalo P, Hovilehto S, Uusaro A, Varpula T, Kari A, et al. Association of automated data collection and data completeness with outcomes of intensive care. A new customised model for outcome prediction. Acta Anaesthesiol Scand 2012;56:1114–22. [10] Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med 1985;13:818–29. [11] Neligan A, Shorvon SD. Frequency and prognosis of convulsive status epilepticus of different causes: a systematic review. Arch Neurol 2010;67(8):931–40. [12] Marchi NA, Novy J, Faouzi M, Stähli C, Burnand B, Rossetti AO. Status epilepticus: impact of therapeutic coma on outcome. Crit Care Med 2015. [13] Sutter R, Kaplan PW, Marsch S, Hammel EM, Rüegg S, Zial WC. Early predictors of refractory status epilepticus: an international two-center study. Eur J Neurol 2015; 22(1):79–85. [14] Sutter R, Marsch S, Fuhr P, Rüegg S. Mortality and recovery from refractory status epilepticus in the ICU: a 7-year observational study. Epilepsia 2013;54:502–11. [15] Patel M, Bagary M, McCorry D. The management of convulsive refractory status epilepticus in adults in UK: no consistency in practice and little access to continuous EEG monitoring. Seizure 2015;24:33–7.
Please cite this article as: Kantanen A-M, et al, Incidence and mortality of super-refractory status epilepticus in adults, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.04.065
