Prognostic Value of Admission Hyperglycemia on Outcomes of Thrombolysis in Ischemic Stroke Patients with or Without Diabetes
Thrombolytic therapy within 4.5 hours from symptom onset is a recognized effective and standard treatment for acute ischemic stroke (AIS). However, despite its efficacy, some patients still experience poor clinical outcomes. Identifying and controlling predictors of poor outcomes in AIS is crucial for optimizing treatment strategies. Among these predictors, admission blood glucose (ABG) has been a topic of debate, as its prognostic value remains unclear. This study aimed to investigate the prognostic value of ABG on clinical outcomes of AIS after thrombolysis, particularly in relation to diabetes mellitus (DM) status, in a Chinese population.
The study utilized data from the Thrombolysis Implementation and Monitor of Acute Ischemic Stroke in China (TIMS-China) study, a prospective, multicenter, open-label, observational study conducted from January 2000 to November 2008 across 67 investigative sites in China. Patients who received intravenous recombinant tissue-type plasminogen activator (rtPA) within 4.5 hours after ischemic stroke onset were included. All patients underwent a standard investigation protocol, including blood tests, electrocardiography, magnetic resonance imaging, and cranial computed tomography (CT). Ethics committees at participating hospitals approved the study, and all patients or their legal representatives provided written informed consent.
ABG was measured in all patients at the emergency department before intravenous thrombolysis. Metabolic parameters and stroke risk factors were recorded in a computer-based laboratory system. DM was defined as a history of DM or the use of insulin and/or oral hypoglycemic agents. According to the American Diabetes Association guidelines, hyperglycemia was defined as ABG ≥7.8 mmol/L, and severe hyperglycemia was defined as ABG ≥11.1 mmol/L.
Primary outcomes included 90-day functional outcome and 90-day mortality. Functional dependence was assessed using the modified Rankin Scale (mRS) score at 3 months, categorized as favorable (mRS score 0–2) or poor (mRS score 3–6). Secondary outcomes included early neurological deterioration (END) and 7-day mortality. END was defined as an increase of ≥4 points on the National Institutes of Health Stroke Scale score between admission and 24 hours. Mortality included deaths from all causes. Safety evaluation was based on the incidence of symptomatic intracranial hemorrhage (sICH) at 36 hours, defined according to the modified Safe Implementation of Treatment in Stroke-Monitoring Study (SITS-MOST) criteria.
Out of 1440 patients in the TIMS-China registry, 1128 received intravenous rtPA within 4.5 hours after onset. After excluding 44 patients due to missing information on DM history or ABG levels, 1084 patients were analyzed. Among these, 191 (17.62%) had a history of DM. In total, 726 (66.97%) patients had ABG <7.8 mmol/L, 257 (23.71%) had ABG between 7.8 and 11.1 mmol/L, and 101 (9.32%) had ABG ≥11.1 mmol/L.
Univariate and multivariate analyses revealed that a history of DM was associated with an increased risk of sICH, occurring in 3.66% of patients with DM compared to 1.46% of those without DM (P = 0.016). A history of DM was also associated with elevated risks of END, 7-day mortality, 90-day functional outcome, and 90-day mortality, although these associations were not statistically significant. When ABG levels were stratified, the risk of poor outcomes increased in a graded fashion as ABG levels rose. The severe hyperglycemia group (ABG ≥11.1 mmol/L) had significantly higher risks of poor outcomes, including END (adjusted odds ratio [OR], 2.23; 95% confidence interval [CI], 1.13–4.41; P = 0.020) and mRS >2 (adjusted OR, 1.55; 95% CI, 1.00–2.41; P = 0.049). Similar results were observed for mortality, with higher risks in the severe hyperglycemia group (7-day mortality-adjusted OR, 2.70; 95% CI, 1.32–5.54; P = 0.007; and 90-day mortality-adjusted OR, 2.31; 95% CI, 1.31–4.07; P = 0.004). ABG levels were not significantly associated with sICH.
Elevated ABG was an independent predictor of poor outcomes only among patients without DM. In non-diabetic patients, severe hyperglycemia was associated with significantly greater risks of poor clinical outcomes, including END (adjusted OR, 4.082; 95% CI, 1.625–10.254; P = 0.0028) and mortality (7-day mortality-adjusted OR, 4.250; 95% CI, 1.591–11.352, P = 0.0038; and 90-day mortality-adjusted OR, 3.704; 95% CI, 1.647–8.326; P = 0.0015). sICH and 90-day functional outcomes were not associated with ABG in patients without DM. In patients with DM, ABG was not significantly related to poor outcomes or sICH.
The study’s findings align with previous research on the prognostic value of ABG in conditions such as intracerebral hemorrhage and myocardial infarction. Higher ABG in non-diabetic patients, often defined as stress hyperglycemia, is typically associated with critical illness. In contrast, diabetic patients with long-term exposure to elevated glucose levels may have reduced adverse effects of hyperglycemia on metabolism. Additionally, diabetic patients often have better control of other cardiovascular risk factors, such as blood pressure and lipid levels, which may mitigate the impact of hyperglycemia on outcomes.
The study also highlighted differences in ABG cut-off values for predicting poor outcomes in AIS patients with and without DM. Previous research has shown that the ABG cut-off value for mortality prediction in non-diabetic AIS patients is lower than in diabetic patients. For example, one study found that the ABG cut-off value for mortality prediction in non-diabetic patients was >113.5 mg/dL, compared to >210.5 mg/dL in diabetic patients. Another study showed that a mean blood glucose level >6.3 mmol/L predicted 30-day mortality in non-diabetic patients, while the corresponding value in diabetic patients was 10.3 mmol/L. These differences in cut-off values may explain why diabetic patients with ABG ≥11.1 mmol/L had elevated risks of mortality and neurological dysfunction in this study, although the associations were not statistically significant.
sICH following thrombolytic therapy for AIS is a potentially devastating complication with high mortality. While ABG has been recognized as an independent risk factor for sICH after intravenous rtPA in ischemic stroke patients, the specific links between elevated ABG and sICH remain inconsistent. Some studies have demonstrated that sICH is related to ABG in patients treated with rtPA, while others have not found this association. In this study, a history of DM, rather than ABG, was a predictor of sICH in AIS patients. This finding may be explained by the hypothesis that chronic microvascular injury, rather than acute stress-induced hyperglycemia, results in an increased risk of sICH. Chronic exposure to elevated blood glucose levels can cause metabolic and structural derangements, leading to cerebral microvascular and macrovascular damage.
The study had several limitations, including the use of retrospective data. For example, only ABG was measured, with no data on fasting blood glucose, postprandial blood glucose, or hemoglobin A1c levels. Additionally, the diagnosis of DM was based on patient medical records, which may have resulted in missed diagnoses, particularly for new patients with previously undiagnosed diabetes. The study also lacked data on the duration of diabetes or the type of treatment received. Larger prospective trials are needed to investigate these blood glucose parameters more thoroughly.
In summary, elevated ABG (≥11.1 mmol/L) was an independent predictor of poor clinical outcomes after thrombolysis for AIS in non-diabetic patients but not in diabetic patients. A history of DM independently correlated with an increased risk of thrombolysis-related sICH. These findings underscore the importance of glycemic control in primary prevention and suggest that attention should be paid to controlling sICH when thrombolysis is administered to diabetic patients.
doi.org/10.1097/CM9.0000000000001005
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