YEBEH-04358; No of Pages 3 Epilepsy & Behavior xxx (2015) xxx–xxx
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Hyperglycemia associated with seizure control in status epilepticus Piyawan Chiewthanakul a, Parinya Noppaklao a,b, Kittisak Sawanyawisuth b,c, Somsak Tiamkao b,d,⁎ a
Department of Medicine, Khon Kaen Hospital, Khon Kaen, Thailand Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand c Research Center in Back, Neck, Other Joint Pain and Human Performance (BNOJPH), Khon Kaen University, Khon Kaen, Thailand d Integrated Epilepsy Research Group, Khon Kaen University, Khon Kaen, Thailand b
a r t i c l e
i n f o
Article history: Revised 23 April 2015 Accepted 25 April 2015 Available online xxxx Keywords: Status epilepticus Outcomes Prognosis Risk factors Hyperglycemia
a b s t r a c t Background: Status epilepticus (SE) is a serious neurological condition and has a high mortality rate. Factors associated with seizure control measures in nonneurointensive care units (non-NICU) are limited. Methods: Adult patients diagnosed with SE at Khon Kaen hospital, Thailand from October 1st, 2010 to September 30th, 2012 were enrolled. Patients were categorized as having controlled seizures and having uncontrolled seizures. Controlled seizures were defined as seizures that were aborted without any recurrence, while uncontrolled seizures were defined as unstoppable or recurrent seizures. Clinical factors were analyzed to find factors associated with uncontrolled SE. Results: During the study period, there were 211 patients diagnosed with SE. Of those, 57 patients (27.01%) were in the group with controlled SE. Plasma glucose and serum albumin were two significant factors with adjusted ORs (95% CI) of 1.008 (1.001, 1.027) and 0.166 (0.059, 0.466) that differentiated patients with controlled seizures from patients with uncontrolled seizures. Central nervous system infections and cardiac arrests were also completely associated with the uncontrolled SE in the multivariate logistic analysis. Conclusions: In the etiology of SE, high plasma glucose and low serum albumin levels were associated with uncontrolled seizures in patients with SE in the non-NICU setting. This article is part of a Special Issue entitled “Status Epilepticus”. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Status epilepticus (SE) is an emergency neurological condition that leads to high morbidity and mortality particularly if seizures are uncontrolled or recurrent [1]. At 3 months after the development of SE, 87 out of 224 patients with SE (38.8%) had severe functional status problems with the Glasgow Coma Scale of 2–4 [2]. The mortality rate may be as high as 61% at discharge if seizures were uncontrolled [1]. The incidence of SE may be varied among continents [3,4]. Factors associated with seizure control in SE are still debated. There is no large sample size study of factors associated with predictors of refractory SE from the neurological intensive care units (NICU). A study from the United States–Switzerland, conducted with 302 patients with SE, found that etiology, coma state, and serum albumin were significant predictors for refractory SE [5]. A study from Indian NICUs had central nervous system infections as a predictor for uncontrolled SE in 126 patients [6], which was similar to a study from Germany [7]. This
study aimed to add knowledge of factors associated with seizure control in patients with SE in a non-NICU, tertiary care setting. 2. Materials and methods This study retrospectively reviewed charts of adult patients aged more than 15 years, diagnosed with SE at Khon Kaen Hospital from October 1st, 2010 to September 30th, 2012. Patients were identified by using the ICD code G41. Khon Kaen Hospital is the tertiary care hospital located in the northeastern part of Thailand. Characteristics of all patients are described elsewhere [8]. Patients were categorized into two groups by seizure control: patients with controlled seizures or patients with uncontrolled seizures. A controlled seizure was defined as a seizure that was stopped after clinical treatment and has no evidence of recurrence. An uncontrolled seizure was defined as a seizure that was never stopped or was recurrent. 3. Statistical analysis
⁎ Corresponding author at: 123 Mitraparp Road, Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand. Tel.: + 66 43 363664; fax: +66 43 348399. E-mail address: [email protected] (S. Tiamkao).
Descriptive statistics were used to detect significant differences between patients with controlled and uncontrolled seizures. Univariate logistic regression analysis was applied to calculate the crude odds ratios (ORs) of individual variables for having poor outcomes. All variables
http://dx.doi.org/10.1016/j.yebeh.2015.04.061 1525-5050/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Chiewthanakul P, et al, Hyperglycemia associated with seizure control in status epilepticus, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.04.061
2
P. Chiewthanakul et al. / Epilepsy & Behavior xxx (2015) xxx–xxx
with P b 0.20 in the univariate analysis were included in the subsequent multivariate logistic regression analysis. The final model was composed of factors associated with poor outcomes. Analytical results are presented as adjusted ORs and 95% confidence intervals (CIs). The study protocol was approved by the institutional review committee, Khon Kaen University (HE 561217).
4. Results During the study period, there were 211 patients who met the study criteria. Of those, 57 patients (27.01%) were in the group with controlled SE; 46 patients (80.70%) had recurrent seizures, and 11 patients (19.30%) had unstoppable SE. The mean recurrent seizure time was 11.18 (SD 16.06) minutes. Most factors between the group with controlled SE and the group with uncontrolled SE were not different (Table 1). The group with uncontrolled SE had a significantly higher proportion of patients with more central nervous system (CNS) infections (21.05% vs 4.55%), more uremia (5.26% vs 0.65%), and fewer cardiac arrests (1.75% vs 11.04%) than the group with controlled SE (Table 1). Physical signs were not different between both groups (Table 2). The mean levels of blood urea nitrogen and creatinine were significantly higher in the group with uncontrolled SE (32.70 vs 16.25 mg/dL; 2.21 vs 1.23 mg/dL), but the mean serum albumin levels were significantly lower in the group with uncontrolled seizures compared with the group with controlled seizures (2.59 vs 3.49 g/dL). The univariate logistic analyses showed that serum creatinine and serum albumin were two significant factors associated with the uncontrolled SE with unadjusted ORs (95% CI) of 1.565 (1.132, 2.163) and 0.237 (0.121, 0.461). For the multivariate logistic analysis, plasma glucose and serum albumin were two significant factors with adjusted ORs (95% CI) of 1.008 (1.001, 1.027) and 0.166 (0.059, 0.466) as shown in Table 3. The CNS infections and cardiac arrests were also completely associated with the uncontrolled SE in the multivariate logistic analysis.
Table 1 Baseline characteristics and initial presentations of patients with status epilepticus categorized by seizure control. Factors
Controlled n = 154
Uncontrolled n = 57
Age, years Male gender, n Duration of symptoms, minutes Comorbid diseases Epilepsy, n Hypertension, n Diabetes, n Stroke, n Renal failure, n Liver cirrhosis, n Alcoholism, n Head injury, n Causes of status Acute stroke, n Alcohol related, n Cardiac arrest, n Sepsis, n AEDs withdrawal, n AEDs subtherapeutic level, n CNS infection, n Hyper/hypoglycemia, n Uremia, n Types of seizure GTCs, n Nonconvulsive, n Others, n On endotracheal tube, n
53.64 (19.27) 91 (59.09) 154.60 (267.98)
52.32 (18.60) 39 (68.42) 158.18 (404.32)
P value 0.654 0.216 0.942
36 (23.38) 35 (22.73) 29 (18.83) 35 (22.73) 8 (5.19) 4 (2.60) 15 (9.74) 2 (1.30)
16 (28.07) 14 (24.56) 10 (17.54) 12 (21.05) 5 (8.77) 2 (3.51) 5 (8.77) 1 (1.75)
0.482 0.779 0.831 0.854 0.831 0.724 0.831 0.804
26 (16.88) 21 (13.64) 17 (11.04) 15 (9.74) 14 (9.09) 8 (5.19) 7 (4.55) 4 (2.60) 1 (0.65)
7 (12.28) 9 (15.79) 1 (1.75) 9 (15.79) 5 (8.77) 3 (5.26) 12 (21.05) 1 (1.75) 3 (5.26)
0.414 0.691 0.032 0.219 0.943 0.984 b0.001 0.721 0.029 0.745
132 (94.29) 2 (1.43) 6 (4.29) 93 (62.84)
47 (95.92) 1 (2.04) 1 (2.04) 32 (57.14)
0.520
Note. AEDs: antiepileptic drugs, CNS: central nervous system, GTCs: generalized tonic– clonic seizures; data presented as mean (SD) or number (percentage).
Table 2 Physical signs and laboratory results of patients with status epilepticus categorized by seizure control. Factors
Survived n = 154
Died n = 57
Body temperature, °C Pulse rate, bpm Systolic blood pressure, mm Hg Glasgow Coma Scale Hematocrit, % White blood cell, cells/mm3 Neutrophils, % Plasma glucose, mg/dL Blood urea nitrogen, mg/dL Creatinine, mg/dL ALT, U/L AST, U/L Total bilirubin, mg/dL Albumin, g/dL
37.31 (1.14) 99.59 (24.01) 139.05 (31.57) 9.06 (3.61) 25.73 (17.73) 8759.10 (7269.76) 49.81 (37.37) 169.36 (107.19) 16.25 (20.02) 1.23 (1.05) 75.11 (118.66) 121.45 (176.95) 1.23 (1.01) 3.49 (0.71)
37.27 (1.08) 0.874 101.85 (24.12) 0.557 135.94 (26.29) 0.522 8.84 (4.41) 0.719 23.34 (17.37) 0.371 7642.98 (6949.63) 0.318 48.71 (39.18) 0.851 202.80 (93.34) 0.064 32.70 (36.66) b0.001 2.21 (2.28) b0.001 135.63 (299.98) 0.264 109.31 (83.54) 0.794 1.74 (1.54) 0.177 2.59 (0.86) b0.001
119 (77.27) 31 (20.13) 4 (2.60)
41 (71.93) 16 (28.07) 0
118 (100) 0
50 (98.04) 1 (1.96)
Treatment First-line medications Diazepam, n Phenytoin, n Sodium valproate, n Second-line medications Phenytoin, n Sodium valproate, n
P value
0.245
0.127
Note. Data presented as mean (SD) or number (percentage); AST: aspartate aminotransferase, ALT: alanine transaminase.
5. Discussion There were four factors associated with seizure control in patients with SE at the non-NICU setting including CNS infection, cardiac arrest, baseline plasma glucose, and baseline serum albumin. Etiology of SE was previously shown to be associated with seizure outcome [9]. The present results confirmed that CNS infection was strongly associated with seizure control in patients with SE as in two studies conducted in the NICU setting [6,7]. Cardiac arrest, another cause of SE, was also an independent factor in the multivariate logistic analysis. This finding indicated that early cardiopulmonary resuscitation not only saved lives, but also had a preferable outcome if SE occurred. Those patients with SE rescued from cardiac arrest with a good outcome may be associated with no or low epileptic activities [10]. Acute etiologies of SE have been previously shown to be associated with poor outcomes or mortality [5,7,11,12]. Central nervous system infection is one of these acute etiologies that have been shown to be related with SE mortality [7,11]. Central nervous system infection, particularly encephalitis, is known to be epileptogenic and resistant to treatment [7]. If the infection affects the temporal area, a low seizure threshold area, SE may be more refractory [7]. Stroke was previously reported to be another bad prognostic factor for SE but was not one of the significant factors in this study [13]. A small study population may explain these findings. Only 47 patients with stroke with SE were included
Table 3 Factors associated with uncontrolled seizures in patients with status epilepticus. Model and factors
Unadjusted odds ratio (95% confidence interval)
Adjusted odds ratio (95% confidence interval)
Age Male gender Duration of symptoms Sepsis First AED medication Plasma glucose Serum creatinine Serum albumin
0.996 (0.981, 1.012) 1.500 (0.788, 2.857) 1.000 (0.999, 1.001) 1.738 (0.714, 4.227) 1.124 (0.604, 2.091) 1.002 (0.999, 1.005) 1.565 (1.132, 2.163) 0.237 (0.121, 0.461)
1.016 (0.978, 1.056) 0.627 (0.159, 2.475) 1.000 (0.999, 1.001) 4.230 (0.556, 32.167) 0.941 (0.159, 5.575) 1.008 (1.001, 1.027) 0.754 (0.485, 1.174) 0.166 (0.059, 0.466)
Note. AED: antiepileptic drug.
Please cite this article as: Chiewthanakul P, et al, Hyperglycemia associated with seizure control in status epilepticus, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.04.061
P. Chiewthanakul et al. / Epilepsy & Behavior xxx (2015) xxx–xxx
in this study, while a study from the US enrolled 1415 patients with acute stroke with SE out of 718,531 hospitalizations that showed significant poor outcomes [13]. Hyperglycemia has been found to be associated with poor SE outcome as in this study [14]. Every 1 mg of increased plasma glucose increased the chance of having uncontrolled SE by 1% (adjusted ORs 1.008) as shown in Table 3. Even though plasma glucose levels were not significantly different in the univariate analysis, they were significantly different in the multivariate analysis. This finding indicated that it was an independent factor for seizure control. The multivariate analysis is more robust and can control confounding factors. The clear mechanisms of glycemic levels and SE are still unclear. In animal models, hyperglycemia causes hippocampal damage and also aggravates seizures [15,16]. Therefore, glucose control may be important in patients with SE, particularly in Asian populations. Further studies should be performed to evaluate the effect of plasma glucose and SE in other ethnic regions. Hypoalbuminemia was another independent factor for uncontrolled SE with adjusted ORs of 0.166 (Table 3). The increasing of serum albumin by 1 g/dL can reduce the risk of uncontrolled SE by approximately 84%. This finding was similar to the study from two countries (US and Switzerland) [5]. Initial low serum albumin increases the risk of uncontrolled SE by 2.45 times [5]. Low serum albumin is an indicator for inflammatory processes during SE. It is negatively associated with inflammatory cytokines such as interleukin-1, interleukin-6, or tumor necrosis factor [5]. The low serum albumin level in patients with SE may suggest severe inflammatory processes or refractory SE leading to high mortality or uncontrolled SE. There are some limitations in this study. Retrospective data collection may not have complete data, particularly laboratory findings such as HbA1c levels or history of previous medications, such as steroid use that may affect plasma glucose levels. Further prospective studies are needed to confirm the results of this study. Clinical implications: physicians should keep in mind that initial high plasma glucose and low serum albumin levels in patients with SE may be factors in uncontrolled seizures. More aggressive treatment and monitoring are needed. Novel antiepileptic medications or anesthetic agents may be a treatment of choice including alternative treatments such as hypothermia, immunosuppression, surgical intervention, or electrical stimulation therapies [9].
6. Conclusions The etiologies of SE, high plasma glucose, and low serum albumin levels were associated with uncontrolled seizures in patients with SE in the non-NICU setting.
3
Acknowledgment The authors would like to thank Ms. Kanokwan Boonpracheon (medical student) for her assistance in data management. Disclosures All authors report no disclosures with regard to the present study. Conflicts of interest None declared. References [1] Brophy GM, Bell R, Claassen J, Alldredge B, Bleck TP, Glauser T, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012;17:3–23. [2] Legriel S, Azoulay E, Resche-Rigon M, Lemiale V, Mourvillier B, Kouatchet A, et al. Functional outcome after convulsive status epilepticus. Crit Care Med 2010;38:2295–303. [3] Knake S, Rosenow F, Vescovi M, Oertel WH, Mueller HH, Wirbatz A, et al. Incidence of status epilepticus in adults in Germany: a prospective, population-based study. Epilepsia 2001;42:714–8. [4] DeLorenzo RJ, Hauser WA, Towne AR, Boggs JG, Pellock JM, Penberthy L, et al. A prospective, population-based epidemiologic study of status epilepticus in Richmond, Virginia. Neurology 1996;46:1029–35. [5] Sutter R, Kaplan PW, Marsch S, Hammel EM, Rüegg S, Ziai WC. Early predictors of refractory status epilepticus: an international two-center study. Eur J Neurol 2015;22: 79–85. [6] Vooturi S, Jayalakshmi S, Sahu S, Mohandas S. Prognosis and predictors of outcome of refractory generalized convulsive status epilepticus in adults treated in neurointensive care unit. Clin Neurol Neurosurg 2014;126:7–10. [7] 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. [8] Chiewthanakul P, Noppaklao P, Sawanyawisuth K, Tiamkao S. Factors associated with poor discharge status in patients with status epilepticus at Khon Kaen Hospital. Neuropsychiatr Dis Treat 2015;11:1097-101. [9] Hocker SE, Britton JW, Mandrekar JN, Wijdicks EF, Rabinstein AA. Predictors of outcome in refractory status epilepticus. JAMA Neurol 2013;70:72–7. [10] Seder DB, Sunde K, Rubertsson S, Mooney M, Stammet P, Riker RR, et al. Neurologic outcomes and postresuscitation care of patients with myoclonus following cardiac arrest. Crit Care Med 2015;43:965–72. [11] Agan K, Afsar N, Midi I, Us O, Aktan S, Aykut-Bingol C. Predictors of refractoriness in a Turkish status epilepticus data bank. Epilepsy Behav 2009;14:651–4. [12] Chin RF, Neville BG, Scott RC. A systematic review of the epidemiology of status epilepticus. Eur J Neurol 2004;11:800–10. [13] Bateman BT, Claassen J, Willey JZ, Hirsch LJ, Mayer SA, Sacco RL, et al. Convulsive status epilepticus after ischemic stroke and intracerebral hemorrhage: frequency, predictors, and impact on outcome in a large administrative dataset. Neurocrit Care 2007;7:187–93. [14] Rathakrishnan R, Sidik NP, Huak CY, Wilder-Smith EP. Generalised convulsive status epilepticus in Singapore: clinical outcomes and potential prognostic markers. Seizure 2009;18:202–5. [15] Huang CW, Cheng JT, Tsai JJ, Wu SN, Huang CC. Diabetic hyperglycemia aggravates seizures and status epilepticus-induced hippocampal damage. Neurotox Res 2009; 15:71–81. [16] Schauwecker PE. The effects of glycemic control on seizures and seizure-induced excitotoxic cell death. BMC Neurosci 2012;13:94.
Please cite this article as: Chiewthanakul P, et al, Hyperglycemia associated with seizure control in status epilepticus, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.04.061
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Hyperglycemia associated with seizure control in status epilepticus Piyawan Chiewthanakul a, Parinya Noppaklao a,b, Kittisak Sawanyawisuth b,c, Somsak Tiamkao b,d,⁎ a
Department of Medicine, Khon Kaen Hospital, Khon Kaen, Thailand Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand c Research Center in Back, Neck, Other Joint Pain and Human Performance (BNOJPH), Khon Kaen University, Khon Kaen, Thailand d Integrated Epilepsy Research Group, Khon Kaen University, Khon Kaen, Thailand b
a r t i c l e
i n f o
Article history: Revised 23 April 2015 Accepted 25 April 2015 Available online xxxx Keywords: Status epilepticus Outcomes Prognosis Risk factors Hyperglycemia
a b s t r a c t Background: Status epilepticus (SE) is a serious neurological condition and has a high mortality rate. Factors associated with seizure control measures in nonneurointensive care units (non-NICU) are limited. Methods: Adult patients diagnosed with SE at Khon Kaen hospital, Thailand from October 1st, 2010 to September 30th, 2012 were enrolled. Patients were categorized as having controlled seizures and having uncontrolled seizures. Controlled seizures were defined as seizures that were aborted without any recurrence, while uncontrolled seizures were defined as unstoppable or recurrent seizures. Clinical factors were analyzed to find factors associated with uncontrolled SE. Results: During the study period, there were 211 patients diagnosed with SE. Of those, 57 patients (27.01%) were in the group with controlled SE. Plasma glucose and serum albumin were two significant factors with adjusted ORs (95% CI) of 1.008 (1.001, 1.027) and 0.166 (0.059, 0.466) that differentiated patients with controlled seizures from patients with uncontrolled seizures. Central nervous system infections and cardiac arrests were also completely associated with the uncontrolled SE in the multivariate logistic analysis. Conclusions: In the etiology of SE, high plasma glucose and low serum albumin levels were associated with uncontrolled seizures in patients with SE in the non-NICU setting. This article is part of a Special Issue entitled “Status Epilepticus”. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Status epilepticus (SE) is an emergency neurological condition that leads to high morbidity and mortality particularly if seizures are uncontrolled or recurrent [1]. At 3 months after the development of SE, 87 out of 224 patients with SE (38.8%) had severe functional status problems with the Glasgow Coma Scale of 2–4 [2]. The mortality rate may be as high as 61% at discharge if seizures were uncontrolled [1]. The incidence of SE may be varied among continents [3,4]. Factors associated with seizure control in SE are still debated. There is no large sample size study of factors associated with predictors of refractory SE from the neurological intensive care units (NICU). A study from the United States–Switzerland, conducted with 302 patients with SE, found that etiology, coma state, and serum albumin were significant predictors for refractory SE [5]. A study from Indian NICUs had central nervous system infections as a predictor for uncontrolled SE in 126 patients [6], which was similar to a study from Germany [7]. This
study aimed to add knowledge of factors associated with seizure control in patients with SE in a non-NICU, tertiary care setting. 2. Materials and methods This study retrospectively reviewed charts of adult patients aged more than 15 years, diagnosed with SE at Khon Kaen Hospital from October 1st, 2010 to September 30th, 2012. Patients were identified by using the ICD code G41. Khon Kaen Hospital is the tertiary care hospital located in the northeastern part of Thailand. Characteristics of all patients are described elsewhere [8]. Patients were categorized into two groups by seizure control: patients with controlled seizures or patients with uncontrolled seizures. A controlled seizure was defined as a seizure that was stopped after clinical treatment and has no evidence of recurrence. An uncontrolled seizure was defined as a seizure that was never stopped or was recurrent. 3. Statistical analysis
⁎ Corresponding author at: 123 Mitraparp Road, Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand. Tel.: + 66 43 363664; fax: +66 43 348399. E-mail address: [email protected] (S. Tiamkao).
Descriptive statistics were used to detect significant differences between patients with controlled and uncontrolled seizures. Univariate logistic regression analysis was applied to calculate the crude odds ratios (ORs) of individual variables for having poor outcomes. All variables
http://dx.doi.org/10.1016/j.yebeh.2015.04.061 1525-5050/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Chiewthanakul P, et al, Hyperglycemia associated with seizure control in status epilepticus, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.04.061
2
P. Chiewthanakul et al. / Epilepsy & Behavior xxx (2015) xxx–xxx
with P b 0.20 in the univariate analysis were included in the subsequent multivariate logistic regression analysis. The final model was composed of factors associated with poor outcomes. Analytical results are presented as adjusted ORs and 95% confidence intervals (CIs). The study protocol was approved by the institutional review committee, Khon Kaen University (HE 561217).
4. Results During the study period, there were 211 patients who met the study criteria. Of those, 57 patients (27.01%) were in the group with controlled SE; 46 patients (80.70%) had recurrent seizures, and 11 patients (19.30%) had unstoppable SE. The mean recurrent seizure time was 11.18 (SD 16.06) minutes. Most factors between the group with controlled SE and the group with uncontrolled SE were not different (Table 1). The group with uncontrolled SE had a significantly higher proportion of patients with more central nervous system (CNS) infections (21.05% vs 4.55%), more uremia (5.26% vs 0.65%), and fewer cardiac arrests (1.75% vs 11.04%) than the group with controlled SE (Table 1). Physical signs were not different between both groups (Table 2). The mean levels of blood urea nitrogen and creatinine were significantly higher in the group with uncontrolled SE (32.70 vs 16.25 mg/dL; 2.21 vs 1.23 mg/dL), but the mean serum albumin levels were significantly lower in the group with uncontrolled seizures compared with the group with controlled seizures (2.59 vs 3.49 g/dL). The univariate logistic analyses showed that serum creatinine and serum albumin were two significant factors associated with the uncontrolled SE with unadjusted ORs (95% CI) of 1.565 (1.132, 2.163) and 0.237 (0.121, 0.461). For the multivariate logistic analysis, plasma glucose and serum albumin were two significant factors with adjusted ORs (95% CI) of 1.008 (1.001, 1.027) and 0.166 (0.059, 0.466) as shown in Table 3. The CNS infections and cardiac arrests were also completely associated with the uncontrolled SE in the multivariate logistic analysis.
Table 1 Baseline characteristics and initial presentations of patients with status epilepticus categorized by seizure control. Factors
Controlled n = 154
Uncontrolled n = 57
Age, years Male gender, n Duration of symptoms, minutes Comorbid diseases Epilepsy, n Hypertension, n Diabetes, n Stroke, n Renal failure, n Liver cirrhosis, n Alcoholism, n Head injury, n Causes of status Acute stroke, n Alcohol related, n Cardiac arrest, n Sepsis, n AEDs withdrawal, n AEDs subtherapeutic level, n CNS infection, n Hyper/hypoglycemia, n Uremia, n Types of seizure GTCs, n Nonconvulsive, n Others, n On endotracheal tube, n
53.64 (19.27) 91 (59.09) 154.60 (267.98)
52.32 (18.60) 39 (68.42) 158.18 (404.32)
P value 0.654 0.216 0.942
36 (23.38) 35 (22.73) 29 (18.83) 35 (22.73) 8 (5.19) 4 (2.60) 15 (9.74) 2 (1.30)
16 (28.07) 14 (24.56) 10 (17.54) 12 (21.05) 5 (8.77) 2 (3.51) 5 (8.77) 1 (1.75)
0.482 0.779 0.831 0.854 0.831 0.724 0.831 0.804
26 (16.88) 21 (13.64) 17 (11.04) 15 (9.74) 14 (9.09) 8 (5.19) 7 (4.55) 4 (2.60) 1 (0.65)
7 (12.28) 9 (15.79) 1 (1.75) 9 (15.79) 5 (8.77) 3 (5.26) 12 (21.05) 1 (1.75) 3 (5.26)
0.414 0.691 0.032 0.219 0.943 0.984 b0.001 0.721 0.029 0.745
132 (94.29) 2 (1.43) 6 (4.29) 93 (62.84)
47 (95.92) 1 (2.04) 1 (2.04) 32 (57.14)
0.520
Note. AEDs: antiepileptic drugs, CNS: central nervous system, GTCs: generalized tonic– clonic seizures; data presented as mean (SD) or number (percentage).
Table 2 Physical signs and laboratory results of patients with status epilepticus categorized by seizure control. Factors
Survived n = 154
Died n = 57
Body temperature, °C Pulse rate, bpm Systolic blood pressure, mm Hg Glasgow Coma Scale Hematocrit, % White blood cell, cells/mm3 Neutrophils, % Plasma glucose, mg/dL Blood urea nitrogen, mg/dL Creatinine, mg/dL ALT, U/L AST, U/L Total bilirubin, mg/dL Albumin, g/dL
37.31 (1.14) 99.59 (24.01) 139.05 (31.57) 9.06 (3.61) 25.73 (17.73) 8759.10 (7269.76) 49.81 (37.37) 169.36 (107.19) 16.25 (20.02) 1.23 (1.05) 75.11 (118.66) 121.45 (176.95) 1.23 (1.01) 3.49 (0.71)
37.27 (1.08) 0.874 101.85 (24.12) 0.557 135.94 (26.29) 0.522 8.84 (4.41) 0.719 23.34 (17.37) 0.371 7642.98 (6949.63) 0.318 48.71 (39.18) 0.851 202.80 (93.34) 0.064 32.70 (36.66) b0.001 2.21 (2.28) b0.001 135.63 (299.98) 0.264 109.31 (83.54) 0.794 1.74 (1.54) 0.177 2.59 (0.86) b0.001
119 (77.27) 31 (20.13) 4 (2.60)
41 (71.93) 16 (28.07) 0
118 (100) 0
50 (98.04) 1 (1.96)
Treatment First-line medications Diazepam, n Phenytoin, n Sodium valproate, n Second-line medications Phenytoin, n Sodium valproate, n
P value
0.245
0.127
Note. Data presented as mean (SD) or number (percentage); AST: aspartate aminotransferase, ALT: alanine transaminase.
5. Discussion There were four factors associated with seizure control in patients with SE at the non-NICU setting including CNS infection, cardiac arrest, baseline plasma glucose, and baseline serum albumin. Etiology of SE was previously shown to be associated with seizure outcome [9]. The present results confirmed that CNS infection was strongly associated with seizure control in patients with SE as in two studies conducted in the NICU setting [6,7]. Cardiac arrest, another cause of SE, was also an independent factor in the multivariate logistic analysis. This finding indicated that early cardiopulmonary resuscitation not only saved lives, but also had a preferable outcome if SE occurred. Those patients with SE rescued from cardiac arrest with a good outcome may be associated with no or low epileptic activities [10]. Acute etiologies of SE have been previously shown to be associated with poor outcomes or mortality [5,7,11,12]. Central nervous system infection is one of these acute etiologies that have been shown to be related with SE mortality [7,11]. Central nervous system infection, particularly encephalitis, is known to be epileptogenic and resistant to treatment [7]. If the infection affects the temporal area, a low seizure threshold area, SE may be more refractory [7]. Stroke was previously reported to be another bad prognostic factor for SE but was not one of the significant factors in this study [13]. A small study population may explain these findings. Only 47 patients with stroke with SE were included
Table 3 Factors associated with uncontrolled seizures in patients with status epilepticus. Model and factors
Unadjusted odds ratio (95% confidence interval)
Adjusted odds ratio (95% confidence interval)
Age Male gender Duration of symptoms Sepsis First AED medication Plasma glucose Serum creatinine Serum albumin
0.996 (0.981, 1.012) 1.500 (0.788, 2.857) 1.000 (0.999, 1.001) 1.738 (0.714, 4.227) 1.124 (0.604, 2.091) 1.002 (0.999, 1.005) 1.565 (1.132, 2.163) 0.237 (0.121, 0.461)
1.016 (0.978, 1.056) 0.627 (0.159, 2.475) 1.000 (0.999, 1.001) 4.230 (0.556, 32.167) 0.941 (0.159, 5.575) 1.008 (1.001, 1.027) 0.754 (0.485, 1.174) 0.166 (0.059, 0.466)
Note. AED: antiepileptic drug.
Please cite this article as: Chiewthanakul P, et al, Hyperglycemia associated with seizure control in status epilepticus, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.04.061
P. Chiewthanakul et al. / Epilepsy & Behavior xxx (2015) xxx–xxx
in this study, while a study from the US enrolled 1415 patients with acute stroke with SE out of 718,531 hospitalizations that showed significant poor outcomes [13]. Hyperglycemia has been found to be associated with poor SE outcome as in this study [14]. Every 1 mg of increased plasma glucose increased the chance of having uncontrolled SE by 1% (adjusted ORs 1.008) as shown in Table 3. Even though plasma glucose levels were not significantly different in the univariate analysis, they were significantly different in the multivariate analysis. This finding indicated that it was an independent factor for seizure control. The multivariate analysis is more robust and can control confounding factors. The clear mechanisms of glycemic levels and SE are still unclear. In animal models, hyperglycemia causes hippocampal damage and also aggravates seizures [15,16]. Therefore, glucose control may be important in patients with SE, particularly in Asian populations. Further studies should be performed to evaluate the effect of plasma glucose and SE in other ethnic regions. Hypoalbuminemia was another independent factor for uncontrolled SE with adjusted ORs of 0.166 (Table 3). The increasing of serum albumin by 1 g/dL can reduce the risk of uncontrolled SE by approximately 84%. This finding was similar to the study from two countries (US and Switzerland) [5]. Initial low serum albumin increases the risk of uncontrolled SE by 2.45 times [5]. Low serum albumin is an indicator for inflammatory processes during SE. It is negatively associated with inflammatory cytokines such as interleukin-1, interleukin-6, or tumor necrosis factor [5]. The low serum albumin level in patients with SE may suggest severe inflammatory processes or refractory SE leading to high mortality or uncontrolled SE. There are some limitations in this study. Retrospective data collection may not have complete data, particularly laboratory findings such as HbA1c levels or history of previous medications, such as steroid use that may affect plasma glucose levels. Further prospective studies are needed to confirm the results of this study. Clinical implications: physicians should keep in mind that initial high plasma glucose and low serum albumin levels in patients with SE may be factors in uncontrolled seizures. More aggressive treatment and monitoring are needed. Novel antiepileptic medications or anesthetic agents may be a treatment of choice including alternative treatments such as hypothermia, immunosuppression, surgical intervention, or electrical stimulation therapies [9].
6. Conclusions The etiologies of SE, high plasma glucose, and low serum albumin levels were associated with uncontrolled seizures in patients with SE in the non-NICU setting.
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Acknowledgment The authors would like to thank Ms. Kanokwan Boonpracheon (medical student) for her assistance in data management. Disclosures All authors report no disclosures with regard to the present study. Conflicts of interest None declared. References [1] Brophy GM, Bell R, Claassen J, Alldredge B, Bleck TP, Glauser T, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012;17:3–23. [2] Legriel S, Azoulay E, Resche-Rigon M, Lemiale V, Mourvillier B, Kouatchet A, et al. Functional outcome after convulsive status epilepticus. Crit Care Med 2010;38:2295–303. [3] Knake S, Rosenow F, Vescovi M, Oertel WH, Mueller HH, Wirbatz A, et al. Incidence of status epilepticus in adults in Germany: a prospective, population-based study. Epilepsia 2001;42:714–8. [4] DeLorenzo RJ, Hauser WA, Towne AR, Boggs JG, Pellock JM, Penberthy L, et al. A prospective, population-based epidemiologic study of status epilepticus in Richmond, Virginia. Neurology 1996;46:1029–35. [5] Sutter R, Kaplan PW, Marsch S, Hammel EM, Rüegg S, Ziai WC. Early predictors of refractory status epilepticus: an international two-center study. Eur J Neurol 2015;22: 79–85. [6] Vooturi S, Jayalakshmi S, Sahu S, Mohandas S. Prognosis and predictors of outcome of refractory generalized convulsive status epilepticus in adults treated in neurointensive care unit. Clin Neurol Neurosurg 2014;126:7–10. [7] 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. [8] Chiewthanakul P, Noppaklao P, Sawanyawisuth K, Tiamkao S. Factors associated with poor discharge status in patients with status epilepticus at Khon Kaen Hospital. Neuropsychiatr Dis Treat 2015;11:1097-101. [9] Hocker SE, Britton JW, Mandrekar JN, Wijdicks EF, Rabinstein AA. Predictors of outcome in refractory status epilepticus. JAMA Neurol 2013;70:72–7. [10] Seder DB, Sunde K, Rubertsson S, Mooney M, Stammet P, Riker RR, et al. Neurologic outcomes and postresuscitation care of patients with myoclonus following cardiac arrest. Crit Care Med 2015;43:965–72. [11] Agan K, Afsar N, Midi I, Us O, Aktan S, Aykut-Bingol C. Predictors of refractoriness in a Turkish status epilepticus data bank. Epilepsy Behav 2009;14:651–4. [12] Chin RF, Neville BG, Scott RC. A systematic review of the epidemiology of status epilepticus. Eur J Neurol 2004;11:800–10. [13] Bateman BT, Claassen J, Willey JZ, Hirsch LJ, Mayer SA, Sacco RL, et al. Convulsive status epilepticus after ischemic stroke and intracerebral hemorrhage: frequency, predictors, and impact on outcome in a large administrative dataset. Neurocrit Care 2007;7:187–93. [14] Rathakrishnan R, Sidik NP, Huak CY, Wilder-Smith EP. Generalised convulsive status epilepticus in Singapore: clinical outcomes and potential prognostic markers. Seizure 2009;18:202–5. [15] Huang CW, Cheng JT, Tsai JJ, Wu SN, Huang CC. Diabetic hyperglycemia aggravates seizures and status epilepticus-induced hippocampal damage. Neurotox Res 2009; 15:71–81. [16] Schauwecker PE. The effects of glycemic control on seizures and seizure-induced excitotoxic cell death. BMC Neurosci 2012;13:94.
Please cite this article as: Chiewthanakul P, et al, Hyperglycemia associated with seizure control in status epilepticus, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.04.061
