Αρθρογραφία

Keywords

• Stress hyperglycemia
• Type 2 diabetes mellitus
• Ischemic stroke
• Outcome

Introduction

Ischemic stroke is a leading cause of death and long-term disability worldwide [1,2]. The presence of type 2 diabetes mellitus (T2DM) more than doubles the risk of ischemic stroke [3-6]. Furthermore, ischemic stroke is more severe in patients with T2DM and is also associated with poorer functional outcome and higher risk of death [7-9]. Moreover, preliminary data suggest that antidiabetic treatment might ameliorate stroke severity and improve the outcome of acute ischemic stroke [10-13]. In contrast with the established adverse effects of T2DM on stroke severity and outcome, it is unclear whether acute elevations in glucose levels during acute ischemic stroke adversely affect the outcome of non-diabetic patients. During acute ischemic stroke, stress stimulates the hypothalamus–pituitary-adrenal axis and the sympathetic nervous system leading to release of stress hormones, including cortisol and catecholamines, which increase glucose levels [4]. This phenomenon, coined stress hyperglycemia, is present in approximately 8-35% of non-diabetic patients withacute ischemic stroke [4,14,15]. Several studies reported worse outcomes in patients with acute ischemic stroke who exhibit stress hyperglycemia [15-17]. However, stress hyperglycemia is more frequent in patients with more severe stroke [18-21]. Therefore, it is unclear whether the association between stress hyperglycemia and stroke outcome is causal or due to a greater stroke severity in patients with stress hyperglycemia. Moreover, many studies did not differentiate between patients withstress hyperglycemia and those with established T2DM [22-25]. The aim of the present study was to evaluate whether stress hyperglycemia is associated with the functional outcome at discharge and the in-hospital mortality of non-diabetic patients with acute ischemic stroke.

Patients and methods

We prospectively studied all patients who were admitted in our Department with acute ischemic stroke between September 2010 and March 2015 (n = 790; 41.0% males, age 79.4±6.8 years). At admission, demographic data (age, sex), history of cardiovascular risk factors [hypertension, T2DM, atrial fibrillation (AF), smoking, alcohol consumption, family history of cardiovascular disease (CVD)], history of concomitant CVD (coronary heart disease (CHD), previous ischemic stroke, heart failure) and pharmacological treatment were recorded. Smoking status and alcohol consumption were self-reported. Systolic and diastolic blood pressure (DBP) was measured at the Emergency Department. Anthropometric parameters (weight, height, waist and hipcircumference) were also measured. The severity of stroke was assessed at admission with the National Institutes of Health Stroke Scale (NIHSS).Routine laboratory investigations were performed after overnight fasting at the first day after admission and included serum levels of glucose, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), creatinine and uric acid. Low-density lipoprotein cholesterol (LDL-C) levels were calculated using Friedewald’s formula [26]. Glomerular filtration rate (GFR) was estimated using the Modification of Diet in Renal Disease (MDRD) equation [27]. Chronic kidney disease was defined as estimated GFR (eGFR) < 60 ml/min/1.73m2. T2DM was defined as a history of physician-diagnosed T2DM or treatment with antidiabetic agents. Stress hyperglycemia was defined as fasting serum glucose levels at the first day after admission ≥ 126 mg/dl in patients without T2DM. All patients underwent brain computed tomography at admission and a second brain computed tomography was performed if clinically indicated. The outcome was assessed with adverse outcome rates at discharge and with in-hospital mortality. Adverse outcome was defined as a modified Rankin scale at discharge between 2 and 6. Outcome data were collected during hospitalization.

Statistical analysis

All data were analyzed with the statistical package SPSS (version 17.0; SPSS, Chicago, IL, USA). Data are presented as percentages for categorical variables and as mean and standard deviation for continuous variables. Serum TG levels were logtransformed to normalize their distribution. Differences in categorical variables between groups were assessed with the chi-square test. Differences in continuous variables between groups were assessed with one-way analysis of variance and pairwise post-hoc comparisons between groups were performed with the Holm-Sidak test. Binary logistic regression analysis was used to identify independent predictors of adverse outcome at discharge and of in-hospital mortality. In all cases, a two-tailed p < 0.05 was considered significant.

Results

At admission, 32.0% of the total study population had T2DM. At the second day after admission, 8.6% of the total study population had stress hyperglycemia (i.e. 12.7% of the non-diabetic patients). Characteristics of patients with stress hyperglycemia, T2DM and neither stress hyperglycemia nor T2DM are shown in Table 1. Patients with stress hyperglycemia were older than patients with T2DM, had higher HDL-C levels, were less likely to receive statins and antiplatelet agents prior to stroke and had more severe stroke. Patients with stress hyperglycemia also had higher prevalence of AF, higher heart rate and more severe stroke than patients with neither stress hyperglycemia nor T2DM. On the other hand, patients with T2DM had higher body mass index and waist circumference, higher prevalence of CHD and heartfailure, lower HDL-C levels and higher TG levels than patients with neither stress hyperglycemia nor T2DM, but had lower LDL-C levels, were more likely to receive statins, antiplatelet and antihypertensive agents prior to stroke and had similar stroke severity compared with the former. At discharge, 64.3% of patients had adverse outcome. Average discharge time was 6.5±3.9 days. Patients with stress hyperglycemia had higher rates of adverse outcome than patients with T2DM and patients with neither stress hyperglycemia nor T2DM (80.9, 65.6 and 60.8%, respectively; p < 0.005). Other significant differences between patients with adverse outcome at discharge and those with favorable outcome are shown in Table 2. The former were older than those who had favorable outcome (p < 0.001), had higher prevalence of AF and prior ischemic stroke (p < 0.001 for both comparisons), were less likely to receive statins prior to stroke (p < 0.001) and had higher heart rate (p < 0.05), lower serum TC and log-TG levels (p < 0.05 and p < 0.005, respectively), lower eGFR (p < 0.05) and higher NIHSS at admission (p < 0.001). In binary logistic regression analysis, independent predictors of adverse outcome at discharge were age (relative risk (RR) 1.08, 95% confidence interval (CI) 1.04-1.12, p < 0.001), history of ischemic stroke (RR 1.91, 95% CI 1.17-3.11, p < 0.01) and NIHSS at admission (RR 1.51, 95% CI 1.38-1.64, p < 0.001), whereas treatment with statins prior to stroke negatively correlated with adverse outcome (RR 0.39, 95% CI 0.23-0.66, p < 0.001). When the NIHSS at admission was removed from the multivariate model, independent predictors of adverse outcome at discharge were age (RR 1.08, 95% CI 1.05-1.11, p < 0.001), heart rate at admission (RR 1.02, 95% CI 1.01-1.03, p < 0.01), history of ischemic stroke (RR 1.82, 95% CI 1.26-2.61, p < 0.001) and stress hyperglycemia (patients with stress hyperglycemia vs. patients with neither stress hyperglycemia nor T2DM: RR 2.42, 95% CI 1.16-5.07, p < 0.05; patients with T2DM vs. patients with neither stress hyperglycemia nor T2DM: RR 1.44, 95% CI 0.97-2.13, p = NS) whereas log-TG levels (RR 0.28, 95% CI 0.10-0.79, p < 0.05) and treatment with statins prior to stroke negatively correlated with adverse outcome (RR 0.41, 95% CI 0.28-0.59, p < 0.001). During hospitalization, 9.2% of patients died. Average lethal outcome time was 8.0±5.4 days. Patients with stress hyperglycemia had higher in-hospital mortality rates than patients with T2DM and patients with neither stress hyperglycemia nor T2DM (30.9, 9.1 and 6.2%, respectively; p < 0.001). Other significant differences between patients who died during hospitalization and those who were discharged are shown in Table 3. The former were older than patients who were discharged (p < 0.001) and had higher prevalence of AF (p < 0.001), higher DBP (p < 0.001), higher heart rate (p < 0.001), lower serum log-TG levels (p < 0.005) and higher NIHSS at admission (p < 0.001). In binary logistic regression analysis, independent predictors of in-hospital mortality were AF, DBP, serum log-TG levels and NIHSS at admission (Table 4). When the NIHSS at admission was removed from the multivariate model, independent predictors of in-hospital mortality were age, AF, DBP, serum log-TG levels and stress hyperglycemia (Table 4). We performed a secondary analysis using HbA1c levels to identify patients with T2DM among patients with stress hyperglycemia or normoglycemia. Among patients with stress hyperglycemia, 11.8% had HbA1c levels ≥ 6.5% and were reclassified as patients with T2DM. Among patients with normoglycemia, 1.9% had HbA1c levels ≥ 6.5% and were reclassified as patients with T2DM. When all analyses were repeated according to this alternative classification of the study population, the results did not change substantially.

Discussion

The main finding of the present study is that stress hyperglycemia during acute ischemic stroke in non-diabetic patients does not appear to be directly associated with the risk of adverse outcome. Indeed, the association between stress hyperglycemia and adverse functional outcome and increased in-hospital mortality appears to be due to the greater stroke severity in patients with stress hyperglycemia. Patients with stress hyperglycemia had more severe stroke at admission than patients with T2DM and patients with neither stress hyperglycemia nor T2DM. These findings are in agreement with 2 previous small studies [16,28]. Others also reported that more severe stroke is associated with stress hyperglycemia in non-diabetic patients [18-21]. The size of infarct also correlates with serum glucose levels at admission [16,29]. These associations are probably due to the more pronounced stress response in patients with more severe stroke [4,30]. Indeed, cortisol levels are the main determinant of glucose levels during acute stroke [30]. In the present study, patients with stress hyperglycemia had worse functional outcome than both patients with T2DM and patients with neither stress hyperglycemia nor T2DM. However, in multivariate analysis, stress hyperglycemia was not an independent predictor of adverse outcome. When stroke severity was removed from the multivariate model, stress hyperglycemia was associated with higher risk for adverse outcome, suggesting that the relationship between stress hyperglycemia and outcome is due to the more severe stroke in these patients. Indeed, in patients with acute stroke, cortisol, but not glucose levels, predicted the outcome, further supporting the notion that glucose is a marker of stress response and is not directly associated with adverse outcome [30]. Notably, an early meta-analysis reported that non-diabetic patients with stress hyperglycemia had higher risk for poor functional recovery up to 6 months after stroke [15]. However, only unadjusted associations between stresshyperglycemia and functional outcome were reported and stroke severity was not considered in the analyses [135]. Other studies reported worse functional outcome at 30 days in patients with hyperglycemia at admission but did not differentiate between patients with stress hyperglycemia and patients with T2DM [22-25]. On the other hand, a post-hoc analysis of the second European Cooperative Acute Stroke Study (ECASS-II) showed that non-diabetic patients with serum glucose levels > 140 mg/dl at 24h after admission for acute ischemic stroke have worse functional outcome at 90 days independently of stroke severity at admission [31]. However, these findings have the inherent limitations of a post-hoc analysis; moreover, patients with minor strokes were excluded from ECASS-II, limiting the generalizability of these results [31]. Patients with stress hyperglycemia had higher in-hospital mortality rates than patients with T2DM and patients with neither stress hyperglycemia nor T2DM. However, these differences did not persist in multivariate analysis adjusting for stroke severity, again suggesting that stress hyperglycemia is not directly associated with the outcome of acute ischemic stroke. Previous studies reported higher in-hospital mortality in non-diabetic patients with ischemic stroke and stress hyperglycemia but did not adjust for differences in stroke severity [15-17]. In studies with longer followup, stress hyperglycemia did not predict mortality at 1 year in non-diabetic patients when stroke severity was included in multivariate analyses [28]. In contrast, a retrospective study (n = 447) reported higher mortality at 90 days in non-diabetic patients with non-fasting glucose levels > 130 mg/dl at admission, independently of stroke severity [20]. However, stroke severity was evaluated retrospectively in this study, on the basis of the neurological evaluation performed at admission [20]. The afore-mentioned post-hoc analysis of the ECASS-II also reported higher mortality at 90 days in patients with serum glucose levels > 140 mg/dl at 24h after admission, independently of stroke severity, but the same limitations of a post-hoc analysis apply to these findings [31]. On the other hand, it should be emphasized that patients with stress hyperglycemia in our study had more severe cardiovascular risk factors and less aggressive preventive treatment as compared to patients with T2DM, and were more likely to die, which may have clinical implications. Our study has a number of limitations. First, we have no data on history of acute hyperglycemia during prior admissions of the study population. Furthermore, we did not measure markers of insulin resistance and we did not evaluate glucose tolerance in our study and therefore we cannot assess the prevalence of insulin resistance or impaired glucose tolerance among patients with stress hyperglycemia or normoglycemia. In addition, we did not systemically record the occurrence of hypoglycemia. Finally, due to financial limitations, we did not perform brainmagnetic resonance imaging, echocardiography or carotid imaging studies in all patients and therefore we are not able to classify the population into ischemic stroke subtypes. Therefore, we are not able to evaluate the association between stroke subtypes and stress hyperglycemia. On the other hand, the strengths of our study include the prospective design, the differentiation between patients with stress hyperglycemia and patients with T2DM, as well as the inclusion of stroke severity in the analysis of the association between stress hyperglycemia and outcome, which suggests that stress hyperglycemia is not directly associated with adverse outcome but is only a marker of stroke severity. In conclusion, stress hyperglycemia is associated with more severe acute ischemic stroke. Patients with stress hyperglycemia have more adverse functional outcome at discharge and higher in-hospital mortality, but this association does not persist after adjustment for stroke severity. Therefore, stress hyperglycemia appears toreflect stroke severity and does not appear to be directly associated with more adverse outcome. Indeed, tight glycemic control with insulin did not improve the functional outcome and did not reduce the mortality of patients with acute ischemic stroke but increased the risk of hypoglycemia [32]. Accordingly, stress hyperglycemia might be useful as an index of stroke severity but it is doubtful whether glucose-lowering treatments will improve the outcome of patients with acute ischemic stroke. On the other hand, given that patients with stress hyperglycemia had higher prevalence of cardiovascular risk factors than patients with normoglycemia and that glucose tolerance was not evaluated, more studies are needed to validate our findings.