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Influence of glibenclamide on outcome in patients with type 2 diabetes and traumatic brain injury
Clinical Neurology and Neurosurgery 115 (2013) 2166–2169
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Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Influence of glibenclamide on outcome in patients with type 2 diabetes and traumatic brain injury Jun Ding, Fang Yuan, Jian-Yi Guo, Hao Chen, Heng-Li Tian ∗ Department of Neurosurgery, Shanghai Sixth People Hospital, Shanghai Jiaotong University, Shanghai 200233, China
a r t i c l e
i n f o
Article history: Received 3 February 2013 Received in revised form 6 August 2013 Accepted 11 August 2013 Available online 17 August 2013 Keywords: Traumatic brain injury Glibenclamide Outcome Progressive secondary hemorrhage
a b s t r a c t Background and purpose: The influence of sulfonylurea receptor 1 (SUR1) and its inhibitor glibenclamide on progressive secondary hemorrhage (PSH), progressive hemorrhagic necrosis (PHN), and brain edema has been studied in rat models of traumatic brain injury (TBI) and ischemia. These studies indicate that blocking SUR1 may exert protective effects in terms of outcome. Methods: We discuss the effects of glibenclamide on outcome in patients with type 2 diabetes mellitus and TBI. We collected demographic, clinical, and imaging data from the clinical records of TBI patients with type 2 diabetes who were admitted to the neurosurgery department at Shanghai 6th People’s Hospital between 2001 and 2012. Data from patients who met the inclusion criteria were analyzed. Patients were divided into glibenclamide group and insulin group. Results: Of 70 patients fit criteria for inclusion, no significant difference was observed except for age and fasting plasma glucose between the two groups. Outcome indicators, including GCS discharge, GOS discharge, length of study in hospital (LOS-H), and the presence of PSH showed no significant difference too (p > 0.05), except for length of stay in neuro-intensive care unit (LOS-NICU) (p < 0.05). Age, hours between the initial CT scan and the injury (HCT1) and GCS at admission were observed as factors associated with PSH after logistic regression. Conclusions: In general, the use of glibenclamide to control plasma glucose after TBI had no significant effect on patient outcome at discharge but it could reduce the LOS-NICU (p < 0.05). Glibenclamide also had no apparent effect on the presence of PSH in TBI patients with type 2 diabetes mellitus. © 2013 Elsevier B.V. All rights reserved.
1. Introduction Traumatic brain injury (TBI) is one of the most disabling types of traumatic injury; nearly half of hospitalized survivors of TBI experience long-term disabilities [1,2]. TBI encompasses numerous types of insults to the brain, including brain contusion, subdural hemorrhage (SDH), epidural hemorrhage (EDH), and subarachnoid hemorrhage (SAH). In recent years, studies have focused on secondary brain injury in TBI, including progressive hemorrhagic injury (PHI) [3]. Of these, one of the most important is progressive secondary hemorrhage (PSH), defined by Simard [4]; it shows a higher mortality rate and unfavorable outcome. PSH implies that intraparenchymal hemorrhagic lesion volume increases when comparing two successive CT scans. There is no general agreement on the volume of lesion increase which can be considered as PSH.
∗ Corresponding author at: Department of Neurosurgery, Shanghai 6th People’s Hospital, Shanghai Jiaotong University, Shanghai 200233, China. Tel.: +86 21 24058405; fax: +86 21 64369181. E-mail address: [email protected] (H.-L. Tian). 0303-8467/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.clineuro.2013.08.010
In this study, a 25% increase or more vs the first post injury CT scan in size was considered as PSH according to previous studies [5,6]. Many mechanisms are involved in the development of PSH, including molecular cascades and inflammation, excitotoxicity, metabolic derangements, apoptosis/necrosis/autophagy, and coagulopathy. Recently, a novel mechanism was identified, which can lead to delayed hemorrhagic progression in rat models of spinal cord injury and TBI [4,7]. Sulfonylurea receptor 1 (SUR1) was shown to be up-regulated after spinal and brain contusion in rats and was associated with PSH. Thus, SUR1 may be a novel biomarker of PSH in TBI patients. The blockade of SUR1 using low-dose glibenclamide largely eliminated PSH and capillary fragmentation, and was associated with a significant reduction in necrotic lesion size and in the preservation of neurobehavioral function [4]. Glibenclamide, which is commonly used to control blood glucose in patients with type 2 diabetes, causes few adverse effects. In China, glibenclamide has been used since 1987. Given that Simard [4] used a continuous infusion of glibenclamide post-TBI, we hypothesized that patients who were on glibenclamide both pre- and post-TBI would have improved outcomes compared with patients not on glibenclamide. Kunte [8] discussed the effect of sulfonylureas on outcome retrospectively in patients with type 2
J. Ding et al. / Clinical Neurology and Neurosurgery 115 (2013) 2166–2169
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Table 1 Characteristics of patients in glibenclamide group and insulin group, PSH group and non-PSH group.
Gender (male/female) Age (year) Volume (ml) Fasting plasma glucose (mmol/L) HCT1 (h) GCS admission GCS discharge GOS discharge LOS-NICU (days) LOS-H (days) PSH (yes/no)
Glibenclamide group
Insulin group
p
PSH
Non-PSH
p
19/13 56.75 ± 10.21 23.0 ± 3.09 6.05 ± 0.89 5.64 ± 1.97 10 [8,12] 13 [11,15] 4 [3,4] 6 [5,8] 14 [12,17] 8/24
26/12 62.55 ± 7.86 22.05 ± 2.83 5.62 ± 0.82 5.16 ± 2.30 11 [8,12] 13 [10,15] 4 [3,4] 8 [6,12] 13 [11,18] 11/27
0.463 0.009 0.186 0.042 0.360 0.340 0.899 0.761 0.023 0.995 0.791
11/8 63.32 ± 9.57 23.95 ± 2.59 5.93 ± 0.71 4.32 ± 1.81 9[8,11] 12 [10,12] 3 [3,3] 11 [9,13] 17 [14,18] –
34/17 56.63 ± 9.14 18.69 ± 3.10 5.58 ± 0.93 6.40 ± 2.29 12 [9,13] 14 [12,15] 4 [3,4] 7 [5,8] 12 [11,17] –
0.579 0.033 0.041 0.526 0.012 0.007 0.000 0.001 0.000 0.006 –
Glibenclamide group: in this group, patients took glibenclamide to control blood glucose. Insulin group: in this group, patients took insulin to control blood glucose. HCT1: hours between the initial CT scan and the injury. LOS-NICU: length of stay in neuro-intensive care unit. LOS-H: length of study in hospital.
diabetes and acute ischemic stroke. They found that sulfonylureas may be beneficial for diabetic patients with acute ischemic stroke. To the best of our knowledge, no reported study has discussed the effect of sulfonylureas on outcome in TBI patients with type 2 diabetes mellitus. Glibenclimide is the most used sulfonylurea used in PSH studies before, so we focused on the effect of glibenclimide on outcome of TBI in this study. The aim of this study was to identify whether the use of glibenclamide at the time of TBI and during hospitalization would result in better neurological and functional outcomes in patients with type 2 diabetes and to examine its association with PSH. The primary outcome was defined as an improved GCS score at discharge. GCS scores are commonly used to assess short-term outcomes. Other outcome indicators, including the length of stay in the neurointensive care unit and in the hospital (LOS-NICU and LOS-H, respectively), GOS score at discharge (GOS discharge), and development of PSH, were also analyzed.
2. Methods
2.2. Data collection Patient demographic data (gender and age), clinical characteristics (GCS scores at admission and discharge, fasting plasma glucose, GOS at discharge, presence of PSH, LOS-NICU and LOS-H), and computed tomography (CT) characteristics including hours between the initial CT scan and the injury (HCT1) and injury volume of the initial CT scan [Lesion volume determination was carried out using an ImageJ software (National Institutes of Health)], were collected from clinical records.
2.3. Statistics To analyze the differences between groups 1 and 2, a 2 test was used for numerical data, while the t-test was used to analyze Gaussian distributed data; all results are presented as means ± SD. A non-parametric test was use to analyze non-normally distributed data; the results are presented as inter-quartile ranges in bracket listed in the following tables. To determine the effect of glibenclamide on PSH, a logistic regression analysis was used.
2.1. Patients The TBI patients involved in this study were admitted to the neurosurgery department of Shanghai 6th People’s Hospital (Shanghai, China) between January 1, 2001, and April 30, 2012. Of all of the patients admitted during this period (n = 3453), only 32 TBI patients who suffered from type 2 diabetes were treated with glibenclamide at admission through discharge to control blood glucose and were treated without surgery (glibenclamide group). A second group of TBI patients (n = 38) were used as controls; these 38 patients suffered from type 2 diabetes mellitus, were treated conservatively, and received insulin to control their blood glucose (insulin group). Patients who were treated surgically (n = 2063), died within 3 days (n = 162), experienced severe multiple injuries (ISS ≥ 16; n = 295), had a diffuse axonal injury or brain stem injury (n = 273), had an epidural hematoma (EDH) or a subdural hematoma (SDH) merely (n = 202), suffered coagulopathy or used anticoagulant drugs (n = 103), were older than 80 (n = 119), arrived at admission more than 24 h after the injury (n = 68), and patients who were taken off glibenclamide or changed from glibenclamide to insulin after TBI (n = 98) were excluded from the study. After admission, all patients were taken to the neuro-ICU, where they were evaluated and treated according to the guidelines for the Management of Severe Head Injury [9].
3. Results 3.1. Differences between glibenclamide group and insulin group We found no statistically significant difference between the groups except for age and fasting plasma glucose. The age of the patients was lower in group 1 than in group 2 (p = 0.009), and the fasting plasma glucose levels were higher in group 1 than in group 2 (p = 0.042). Outcome indicators, including GCS discharge (p = 0.899), GOS discharge (0.761), and LOS-H (0.995), showed no significant difference between the groups except for LOS-NICU (p = 0.023). Importantly, presence of PSH also showed no significant difference between the two groups (p = 0.791) (Table 1).
3.2. Difference between PSH patients and non-PSH patients As shown in Table 1, patients suffered a PSH had a higher age (p = 0.033) and injury volume (p = 0.041); they also had a longer LOS-NICU (p = 0.000) and LOS-H (p = 0.006). But they had a shorter HCT1 (p = 0.012), a lower GCS at admission (p = 0.007), a lower GCS at discharge (p = 0.000) and a lower GOS at discharge (p = 0.001). Gender and fasting plasma glucose showed no significant difference between the two groups (p = 0.579 and p = 0.526).
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Table 2 Factors associated with PSH.
Glibenclamide vs insulin Age (≤50 years vs >50 years) Gender (male vs female) GCS admission HCT1 Volume Fasting plasma glucose
OR
95% CI
p
0.747 1.25 0.611 0.722 0.801 1.108 0.673
0.241, 2.312 1.03, 2.81 0.200, 1.865 0.434, 0.958 0.751, 0.970 0.912, 1.347 0.345, 1.312
0.613 0.037 0.387 0.015 0.033 0.303 0.245
HCT1: hours between the initial CT scan and the injury.
3.3. Factors associated with PSH To determine the effect of glibenclamide on PSH, we used a logistic regression analysis. After adjusting for other factors, including age, sex, and GCS admission, we found that glibenclamide was not an independent influencing factor for PSH (OR = 0.747, 95% CI 0.241–2.312, p = 0.613), as well as gender (OR = 0.611, 95% CI 0.200–1.865, p = 0.387), volume (OR = 1.108, 95% CI 0.912, 1.347, p = 0.303) and fasting plasma glucose (OR = 0.673, 95% CI 0.345, 1.312, p = 0.245). But age (OR = 1.25, 95% CI 1.03–2.81, p = 0.037), GCS at admission (OR = 0.722, 95% CI 0.434–0.958, p = 0.015) and HCT1 (OR = 0.801, 95% CI 0.751–0.970, p = 0.033) were influencing factors for PSH (Table 2). 4. Discussion In this study, we focused on the effects of glibenclamide, an inhibitor of SUR1, on development of PSH and the outcome of patients who suffered from both TBI and type 2 diabetes mellitus. We found significant differences in patient age, fasting plasma glucose, and GCS at admission between these two groups (p < 0.05). However, there was no significant difference in gender, HCT1 and volume between the groups (p > 0.05). After logistic regression, we found that glibenclamide was not a influencing factor of PSH (OR = 0.747, 95% CI 0.241–2.312, p = 0.613) and had no significant effect on outcome of TBI patients [GCS at discharge, GOS at discharge and LOS-H had no significant difference between glibenclamide group and insulin group (p > 0.05) except for LOS-NICU (p < 005)]. More and more authors discussed PSH or progressive hemorrhagic injury (PHI) these years: focus on influencing factors of PSH or PHI; predicting outcome of TBI. In our previous studies, we studied factors associated with progressive brain hemorrhage (PBH) [10], established prognostic models of TBI [11] and found a method to predict PHI [12]. In this study, we found that patients’ age, GCS at admission and HCT1 are influencing factors of PSH but glibenclamide was not associated with PSH. These factors are classic factors of PHI we found before [10]. SUR1, a member of the ATP-binding cassette superfamily, is best known for its role in KATP channel formation [13,14]. However, SUR1 has also come to be recognized for its role in the formation of SUR1-regulated NCCa-ATP channels as a regulatory subunit [15,16]. Drugs such as glibenclamide and repaglinide are potent inhibitors of SUR1-regulated channel activity. SUR1-regulated NCCa-ATP channels are cation channels that conduct inorganic monovalent cations (Na+ , K+ , Cs+ , Li+ , and Rb+ ), but are impermeable to Ca2+ and Mg2+ [17]. Channel opening requires nanomolar concentrations of Ca2+ on the cytoplasmic side. Channel opening is blocked by ATP. SUR1-regulated NCCa-ATP channels are not expressed constitutively; they are up-regulated in the CNS under conditions of hypoxia or injury. SUR1-regulated NCCa-ATP channels have been identified in neurons from the core of ischemic stroke and TBI [4,16].
In recent years, the role of SUR1 has been studied in patients and animals suffering from ischemic and traumatic brain injuries. Authors studied the effects of SUR1-regulated NCCa-ATP channels on cerebral edema after ischemic stroke in animal models [16]. They found that SUR1 was expressed significantly above background levels 2–3 h after MCAO and that the brain water content was reduced significantly after treatment with glibenclamide when SUR1 was blocked. Thus, the NCCa-ATP channel regulatory subunit SUR1 is crucially involved in the development of cerebral edema. Blocking SUR1 may reduce brain edema after ischemic stroke and improve outcomes. Studies also indicated that glibenclamide improved several neurological parameters at 3 weeks after hypoxia–ischemia (HI) in neonatal rats, indicating that glibenclamide provides a long-term neuroprotective effect after neonatal HI [18]. Abdallah found that glibenclamide decreased lipid peroxides, myeloperoxidase activity, TNF-␣, and PGE2 , but increased glutathione, total antioxidant capacity, nitric oxide, and IL-10 levels in the hippocampus [19]. Authors retrospectively studied patients who suffered from acute ischemic stroke and type 2 diabetes mellitus and found that patients who were on sulfonylureas were significantly more likely to have a better neurological outcome and a better functional outcome at the time of discharge [8]. Together, these studies indicate that sulfonylureas may have a protective effect after ischemic brain injury. Similarly to Kunte’s study, we retrospectively studied patients who suffered from traumatic brain injury and type 2 diabetes mellitus. There are also many studies of the effects of glibenclamide or SUR1 on outcomes in TBI or spinal cord injury (SCI). A number of studies have used rat models of SCI to study the effects of endothelial SUR1-regulated NCCa-ATP channels in progressive hemorrhagic necrosis (PHN) [7,20,21]. Without the blockade of SUR1, they reported lesion expansion, capillary fragmentation, tissue necrosis, and severe neurological dysfunction. This indicates that SUR1-regulated NCCa-ATP channels in the capillary endothelium are important in the development of PHN. Other studies have used rat models of TBI to study the effects of glibenclamide or SUR1 on PSH or inflammation and vasogenic edema [4,22]. In those studies, it was found that the blockade of SUR1 with glibenclamide largely eliminated PSH and capillary fragmentation, and was associated with a significant reduction in the size of the necrotic lesion and in the preservation of neurobehavioral function. Blocking SUR1 could also reduce inflammation, vasogenic edema, and caspase-3 activation after SAH, indicating that glibenclamide may ameliorate several pathological effects associated with inflammation that lead to cortical dysfunction after SAH. The studies cited here indicate that blocking SUR1 using sulfonylureas may also produce a protective effect after TBI. This study has some limitations. First, it was a retrospective study with a long time course (from 2001 to 2012). Past treatment protocols may be very different from those used today. Differences between the groups were identified in age and fasting plasma glucose. These may influence the outcome in patients, in combination with other factors. Thus, prospective studies are necessary focus on this topic. Second, the patient sample size was small. Future studies should include a larger sample size with mild, moderate, and severe TBI patients. Third, outcomes were recorded at the time of discharge, and long-term follow-up was not considered. Thus, we cannot determine glibenclamide’s impact on long-term outcomes of the patients. In future studies, followup should be done for at least 6 months. Finally, all of the TBI patients involved in this study suffered from type 2 diabetes mellitus. The effect of glibenclamide on outcome in these patients does not represent the effects in TBI patients without type 2 diabetes mellitus. The effects of blocking SUR1 using glibenclamide or another SUR1 blocker in other TBI patients should therefore be studied.
J. Ding et al. / Clinical Neurology and Neurosurgery 115 (2013) 2166–2169
In conclusion, the use of glibenclamide to control plasma glucose after TBI had no significant effect on patient outcome at discharge, but it could reduce the LOS-NICU. Glibenclamide also had no apparent effect on the presence of PSH in TBI patients with type 2 diabetes mellitus.
[8]
[9]
Conflicts of interest [10]
The authors report no conflicts of interest. [11]
Acknowledgements We thank Yaping Hao for her assistance in statistic analysis. Grant support was provided by National Nature and Science Foundation of China (grant no. 81271383) and the Shanghai Science and Technique Committee (grant no. 13411951400, 13411951401 and 10JC1412500). References [1] Selassie AW, Zaloshnja E, Langlois JA, Miller T, Jones P, Steiner C. Incidence of long-term disability following traumatic brain injury hospitalization, United States, 2003. J Head Trauma Rehabil 2008;23: 123–31. [2] Zaloshnja E, Miller T, Langlois JA, Selassie AW. Prevalence of long-term disability from traumatic brain injury in the civilian population of the United States, 2005. J Head Trauma Rehabil 2008;23:394–400. [3] Tian HL, Chen H, Wu BS, Cao HL, Xu T, Hu J, et al. D-dimer as a predictor of progressive hemorrhagic injury in patients with traumatic brain injury: analysis of 194 cases. Neurosurg Rev 2010;33:359–65. [4] Simard JM, Kilbourne M, Tsymbalyuk O, Tosun C, Caridi J, Ivanova S, et al. Key role of sulfonylurea receptor 1 in progressive secondary hemorrhage after brain contusion. J Neurotrauma 2009;26:2257–67. [5] Oertel M, Kelly DF, Mcarthur D, Boscardin WJ, Glenn TC, Lee JH. Progressive hemorrhage after head trauma: predictors and consequences of the evolving injury. J Neurosurg 2002;96:109–16. [6] Sanus GZ, Taner T, Ilker A, Sabri A, Mustafa U. Evolving traumatic brain lesions: predictors and results of ninety-eight head-injured patients. Neurosurg Q 2004;14:97–104. [7] Simard JM, Tsymbalyuk O, Ivanov A, Ivanova S, Bhatta S, Geng Z, et al. Endothelial sulfonylurea receptor 1-regulated NCCa-ATP channels mediate
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Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Influence of glibenclamide on outcome in patients with type 2 diabetes and traumatic brain injury Jun Ding, Fang Yuan, Jian-Yi Guo, Hao Chen, Heng-Li Tian ∗ Department of Neurosurgery, Shanghai Sixth People Hospital, Shanghai Jiaotong University, Shanghai 200233, China
a r t i c l e
i n f o
Article history: Received 3 February 2013 Received in revised form 6 August 2013 Accepted 11 August 2013 Available online 17 August 2013 Keywords: Traumatic brain injury Glibenclamide Outcome Progressive secondary hemorrhage
a b s t r a c t Background and purpose: The influence of sulfonylurea receptor 1 (SUR1) and its inhibitor glibenclamide on progressive secondary hemorrhage (PSH), progressive hemorrhagic necrosis (PHN), and brain edema has been studied in rat models of traumatic brain injury (TBI) and ischemia. These studies indicate that blocking SUR1 may exert protective effects in terms of outcome. Methods: We discuss the effects of glibenclamide on outcome in patients with type 2 diabetes mellitus and TBI. We collected demographic, clinical, and imaging data from the clinical records of TBI patients with type 2 diabetes who were admitted to the neurosurgery department at Shanghai 6th People’s Hospital between 2001 and 2012. Data from patients who met the inclusion criteria were analyzed. Patients were divided into glibenclamide group and insulin group. Results: Of 70 patients fit criteria for inclusion, no significant difference was observed except for age and fasting plasma glucose between the two groups. Outcome indicators, including GCS discharge, GOS discharge, length of study in hospital (LOS-H), and the presence of PSH showed no significant difference too (p > 0.05), except for length of stay in neuro-intensive care unit (LOS-NICU) (p < 0.05). Age, hours between the initial CT scan and the injury (HCT1) and GCS at admission were observed as factors associated with PSH after logistic regression. Conclusions: In general, the use of glibenclamide to control plasma glucose after TBI had no significant effect on patient outcome at discharge but it could reduce the LOS-NICU (p < 0.05). Glibenclamide also had no apparent effect on the presence of PSH in TBI patients with type 2 diabetes mellitus. © 2013 Elsevier B.V. All rights reserved.
1. Introduction Traumatic brain injury (TBI) is one of the most disabling types of traumatic injury; nearly half of hospitalized survivors of TBI experience long-term disabilities [1,2]. TBI encompasses numerous types of insults to the brain, including brain contusion, subdural hemorrhage (SDH), epidural hemorrhage (EDH), and subarachnoid hemorrhage (SAH). In recent years, studies have focused on secondary brain injury in TBI, including progressive hemorrhagic injury (PHI) [3]. Of these, one of the most important is progressive secondary hemorrhage (PSH), defined by Simard [4]; it shows a higher mortality rate and unfavorable outcome. PSH implies that intraparenchymal hemorrhagic lesion volume increases when comparing two successive CT scans. There is no general agreement on the volume of lesion increase which can be considered as PSH.
∗ Corresponding author at: Department of Neurosurgery, Shanghai 6th People’s Hospital, Shanghai Jiaotong University, Shanghai 200233, China. Tel.: +86 21 24058405; fax: +86 21 64369181. E-mail address: [email protected] (H.-L. Tian). 0303-8467/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.clineuro.2013.08.010
In this study, a 25% increase or more vs the first post injury CT scan in size was considered as PSH according to previous studies [5,6]. Many mechanisms are involved in the development of PSH, including molecular cascades and inflammation, excitotoxicity, metabolic derangements, apoptosis/necrosis/autophagy, and coagulopathy. Recently, a novel mechanism was identified, which can lead to delayed hemorrhagic progression in rat models of spinal cord injury and TBI [4,7]. Sulfonylurea receptor 1 (SUR1) was shown to be up-regulated after spinal and brain contusion in rats and was associated with PSH. Thus, SUR1 may be a novel biomarker of PSH in TBI patients. The blockade of SUR1 using low-dose glibenclamide largely eliminated PSH and capillary fragmentation, and was associated with a significant reduction in necrotic lesion size and in the preservation of neurobehavioral function [4]. Glibenclamide, which is commonly used to control blood glucose in patients with type 2 diabetes, causes few adverse effects. In China, glibenclamide has been used since 1987. Given that Simard [4] used a continuous infusion of glibenclamide post-TBI, we hypothesized that patients who were on glibenclamide both pre- and post-TBI would have improved outcomes compared with patients not on glibenclamide. Kunte [8] discussed the effect of sulfonylureas on outcome retrospectively in patients with type 2
J. Ding et al. / Clinical Neurology and Neurosurgery 115 (2013) 2166–2169
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Table 1 Characteristics of patients in glibenclamide group and insulin group, PSH group and non-PSH group.
Gender (male/female) Age (year) Volume (ml) Fasting plasma glucose (mmol/L) HCT1 (h) GCS admission GCS discharge GOS discharge LOS-NICU (days) LOS-H (days) PSH (yes/no)
Glibenclamide group
Insulin group
p
PSH
Non-PSH
p
19/13 56.75 ± 10.21 23.0 ± 3.09 6.05 ± 0.89 5.64 ± 1.97 10 [8,12] 13 [11,15] 4 [3,4] 6 [5,8] 14 [12,17] 8/24
26/12 62.55 ± 7.86 22.05 ± 2.83 5.62 ± 0.82 5.16 ± 2.30 11 [8,12] 13 [10,15] 4 [3,4] 8 [6,12] 13 [11,18] 11/27
0.463 0.009 0.186 0.042 0.360 0.340 0.899 0.761 0.023 0.995 0.791
11/8 63.32 ± 9.57 23.95 ± 2.59 5.93 ± 0.71 4.32 ± 1.81 9[8,11] 12 [10,12] 3 [3,3] 11 [9,13] 17 [14,18] –
34/17 56.63 ± 9.14 18.69 ± 3.10 5.58 ± 0.93 6.40 ± 2.29 12 [9,13] 14 [12,15] 4 [3,4] 7 [5,8] 12 [11,17] –
0.579 0.033 0.041 0.526 0.012 0.007 0.000 0.001 0.000 0.006 –
Glibenclamide group: in this group, patients took glibenclamide to control blood glucose. Insulin group: in this group, patients took insulin to control blood glucose. HCT1: hours between the initial CT scan and the injury. LOS-NICU: length of stay in neuro-intensive care unit. LOS-H: length of study in hospital.
diabetes and acute ischemic stroke. They found that sulfonylureas may be beneficial for diabetic patients with acute ischemic stroke. To the best of our knowledge, no reported study has discussed the effect of sulfonylureas on outcome in TBI patients with type 2 diabetes mellitus. Glibenclimide is the most used sulfonylurea used in PSH studies before, so we focused on the effect of glibenclimide on outcome of TBI in this study. The aim of this study was to identify whether the use of glibenclamide at the time of TBI and during hospitalization would result in better neurological and functional outcomes in patients with type 2 diabetes and to examine its association with PSH. The primary outcome was defined as an improved GCS score at discharge. GCS scores are commonly used to assess short-term outcomes. Other outcome indicators, including the length of stay in the neurointensive care unit and in the hospital (LOS-NICU and LOS-H, respectively), GOS score at discharge (GOS discharge), and development of PSH, were also analyzed.
2. Methods
2.2. Data collection Patient demographic data (gender and age), clinical characteristics (GCS scores at admission and discharge, fasting plasma glucose, GOS at discharge, presence of PSH, LOS-NICU and LOS-H), and computed tomography (CT) characteristics including hours between the initial CT scan and the injury (HCT1) and injury volume of the initial CT scan [Lesion volume determination was carried out using an ImageJ software (National Institutes of Health)], were collected from clinical records.
2.3. Statistics To analyze the differences between groups 1 and 2, a 2 test was used for numerical data, while the t-test was used to analyze Gaussian distributed data; all results are presented as means ± SD. A non-parametric test was use to analyze non-normally distributed data; the results are presented as inter-quartile ranges in bracket listed in the following tables. To determine the effect of glibenclamide on PSH, a logistic regression analysis was used.
2.1. Patients The TBI patients involved in this study were admitted to the neurosurgery department of Shanghai 6th People’s Hospital (Shanghai, China) between January 1, 2001, and April 30, 2012. Of all of the patients admitted during this period (n = 3453), only 32 TBI patients who suffered from type 2 diabetes were treated with glibenclamide at admission through discharge to control blood glucose and were treated without surgery (glibenclamide group). A second group of TBI patients (n = 38) were used as controls; these 38 patients suffered from type 2 diabetes mellitus, were treated conservatively, and received insulin to control their blood glucose (insulin group). Patients who were treated surgically (n = 2063), died within 3 days (n = 162), experienced severe multiple injuries (ISS ≥ 16; n = 295), had a diffuse axonal injury or brain stem injury (n = 273), had an epidural hematoma (EDH) or a subdural hematoma (SDH) merely (n = 202), suffered coagulopathy or used anticoagulant drugs (n = 103), were older than 80 (n = 119), arrived at admission more than 24 h after the injury (n = 68), and patients who were taken off glibenclamide or changed from glibenclamide to insulin after TBI (n = 98) were excluded from the study. After admission, all patients were taken to the neuro-ICU, where they were evaluated and treated according to the guidelines for the Management of Severe Head Injury [9].
3. Results 3.1. Differences between glibenclamide group and insulin group We found no statistically significant difference between the groups except for age and fasting plasma glucose. The age of the patients was lower in group 1 than in group 2 (p = 0.009), and the fasting plasma glucose levels were higher in group 1 than in group 2 (p = 0.042). Outcome indicators, including GCS discharge (p = 0.899), GOS discharge (0.761), and LOS-H (0.995), showed no significant difference between the groups except for LOS-NICU (p = 0.023). Importantly, presence of PSH also showed no significant difference between the two groups (p = 0.791) (Table 1).
3.2. Difference between PSH patients and non-PSH patients As shown in Table 1, patients suffered a PSH had a higher age (p = 0.033) and injury volume (p = 0.041); they also had a longer LOS-NICU (p = 0.000) and LOS-H (p = 0.006). But they had a shorter HCT1 (p = 0.012), a lower GCS at admission (p = 0.007), a lower GCS at discharge (p = 0.000) and a lower GOS at discharge (p = 0.001). Gender and fasting plasma glucose showed no significant difference between the two groups (p = 0.579 and p = 0.526).
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Table 2 Factors associated with PSH.
Glibenclamide vs insulin Age (≤50 years vs >50 years) Gender (male vs female) GCS admission HCT1 Volume Fasting plasma glucose
OR
95% CI
p
0.747 1.25 0.611 0.722 0.801 1.108 0.673
0.241, 2.312 1.03, 2.81 0.200, 1.865 0.434, 0.958 0.751, 0.970 0.912, 1.347 0.345, 1.312
0.613 0.037 0.387 0.015 0.033 0.303 0.245
HCT1: hours between the initial CT scan and the injury.
3.3. Factors associated with PSH To determine the effect of glibenclamide on PSH, we used a logistic regression analysis. After adjusting for other factors, including age, sex, and GCS admission, we found that glibenclamide was not an independent influencing factor for PSH (OR = 0.747, 95% CI 0.241–2.312, p = 0.613), as well as gender (OR = 0.611, 95% CI 0.200–1.865, p = 0.387), volume (OR = 1.108, 95% CI 0.912, 1.347, p = 0.303) and fasting plasma glucose (OR = 0.673, 95% CI 0.345, 1.312, p = 0.245). But age (OR = 1.25, 95% CI 1.03–2.81, p = 0.037), GCS at admission (OR = 0.722, 95% CI 0.434–0.958, p = 0.015) and HCT1 (OR = 0.801, 95% CI 0.751–0.970, p = 0.033) were influencing factors for PSH (Table 2). 4. Discussion In this study, we focused on the effects of glibenclamide, an inhibitor of SUR1, on development of PSH and the outcome of patients who suffered from both TBI and type 2 diabetes mellitus. We found significant differences in patient age, fasting plasma glucose, and GCS at admission between these two groups (p < 0.05). However, there was no significant difference in gender, HCT1 and volume between the groups (p > 0.05). After logistic regression, we found that glibenclamide was not a influencing factor of PSH (OR = 0.747, 95% CI 0.241–2.312, p = 0.613) and had no significant effect on outcome of TBI patients [GCS at discharge, GOS at discharge and LOS-H had no significant difference between glibenclamide group and insulin group (p > 0.05) except for LOS-NICU (p < 005)]. More and more authors discussed PSH or progressive hemorrhagic injury (PHI) these years: focus on influencing factors of PSH or PHI; predicting outcome of TBI. In our previous studies, we studied factors associated with progressive brain hemorrhage (PBH) [10], established prognostic models of TBI [11] and found a method to predict PHI [12]. In this study, we found that patients’ age, GCS at admission and HCT1 are influencing factors of PSH but glibenclamide was not associated with PSH. These factors are classic factors of PHI we found before [10]. SUR1, a member of the ATP-binding cassette superfamily, is best known for its role in KATP channel formation [13,14]. However, SUR1 has also come to be recognized for its role in the formation of SUR1-regulated NCCa-ATP channels as a regulatory subunit [15,16]. Drugs such as glibenclamide and repaglinide are potent inhibitors of SUR1-regulated channel activity. SUR1-regulated NCCa-ATP channels are cation channels that conduct inorganic monovalent cations (Na+ , K+ , Cs+ , Li+ , and Rb+ ), but are impermeable to Ca2+ and Mg2+ [17]. Channel opening requires nanomolar concentrations of Ca2+ on the cytoplasmic side. Channel opening is blocked by ATP. SUR1-regulated NCCa-ATP channels are not expressed constitutively; they are up-regulated in the CNS under conditions of hypoxia or injury. SUR1-regulated NCCa-ATP channels have been identified in neurons from the core of ischemic stroke and TBI [4,16].
In recent years, the role of SUR1 has been studied in patients and animals suffering from ischemic and traumatic brain injuries. Authors studied the effects of SUR1-regulated NCCa-ATP channels on cerebral edema after ischemic stroke in animal models [16]. They found that SUR1 was expressed significantly above background levels 2–3 h after MCAO and that the brain water content was reduced significantly after treatment with glibenclamide when SUR1 was blocked. Thus, the NCCa-ATP channel regulatory subunit SUR1 is crucially involved in the development of cerebral edema. Blocking SUR1 may reduce brain edema after ischemic stroke and improve outcomes. Studies also indicated that glibenclamide improved several neurological parameters at 3 weeks after hypoxia–ischemia (HI) in neonatal rats, indicating that glibenclamide provides a long-term neuroprotective effect after neonatal HI [18]. Abdallah found that glibenclamide decreased lipid peroxides, myeloperoxidase activity, TNF-␣, and PGE2 , but increased glutathione, total antioxidant capacity, nitric oxide, and IL-10 levels in the hippocampus [19]. Authors retrospectively studied patients who suffered from acute ischemic stroke and type 2 diabetes mellitus and found that patients who were on sulfonylureas were significantly more likely to have a better neurological outcome and a better functional outcome at the time of discharge [8]. Together, these studies indicate that sulfonylureas may have a protective effect after ischemic brain injury. Similarly to Kunte’s study, we retrospectively studied patients who suffered from traumatic brain injury and type 2 diabetes mellitus. There are also many studies of the effects of glibenclamide or SUR1 on outcomes in TBI or spinal cord injury (SCI). A number of studies have used rat models of SCI to study the effects of endothelial SUR1-regulated NCCa-ATP channels in progressive hemorrhagic necrosis (PHN) [7,20,21]. Without the blockade of SUR1, they reported lesion expansion, capillary fragmentation, tissue necrosis, and severe neurological dysfunction. This indicates that SUR1-regulated NCCa-ATP channels in the capillary endothelium are important in the development of PHN. Other studies have used rat models of TBI to study the effects of glibenclamide or SUR1 on PSH or inflammation and vasogenic edema [4,22]. In those studies, it was found that the blockade of SUR1 with glibenclamide largely eliminated PSH and capillary fragmentation, and was associated with a significant reduction in the size of the necrotic lesion and in the preservation of neurobehavioral function. Blocking SUR1 could also reduce inflammation, vasogenic edema, and caspase-3 activation after SAH, indicating that glibenclamide may ameliorate several pathological effects associated with inflammation that lead to cortical dysfunction after SAH. The studies cited here indicate that blocking SUR1 using sulfonylureas may also produce a protective effect after TBI. This study has some limitations. First, it was a retrospective study with a long time course (from 2001 to 2012). Past treatment protocols may be very different from those used today. Differences between the groups were identified in age and fasting plasma glucose. These may influence the outcome in patients, in combination with other factors. Thus, prospective studies are necessary focus on this topic. Second, the patient sample size was small. Future studies should include a larger sample size with mild, moderate, and severe TBI patients. Third, outcomes were recorded at the time of discharge, and long-term follow-up was not considered. Thus, we cannot determine glibenclamide’s impact on long-term outcomes of the patients. In future studies, followup should be done for at least 6 months. Finally, all of the TBI patients involved in this study suffered from type 2 diabetes mellitus. The effect of glibenclamide on outcome in these patients does not represent the effects in TBI patients without type 2 diabetes mellitus. The effects of blocking SUR1 using glibenclamide or another SUR1 blocker in other TBI patients should therefore be studied.
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In conclusion, the use of glibenclamide to control plasma glucose after TBI had no significant effect on patient outcome at discharge, but it could reduce the LOS-NICU. Glibenclamide also had no apparent effect on the presence of PSH in TBI patients with type 2 diabetes mellitus.
[8]
[9]
Conflicts of interest [10]
The authors report no conflicts of interest. [11]
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