Glucose Control and Risk of TPA-Related Symptomatic Intracerebral Hemorrhage in Patients With Hyperglycemic Acute Ischemic Stroke: Preplanned Analysis From the SHINE Trial

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Introduction: In acute ischemic stroke (AIS), hyperglycemia promotes enhanced blood brain barrier permeability, tissue acidosis, and oxygen free radicals, and may increase risk of post-tPA symptomatic intracerebral hemorrhage (sICH). We performed a pre-planned analysis from the SHINE trial (NCT01369069) to examine the effects of blood glucose (BG) control on post-thrombolysis ICH.

Hypothesis: In AIS, (1) post-tPA BG measures are associated with sICH, and (2) intensive insulin therapy can reduce the risk of sICH.

Methods: Hyperglycemic AIS patients <12 hours onset were randomized to intensive insulin (target range 80-130 mg/dL) vs standard BG control (80-179 mg/dL) over a 72-hour period. Randomization was stratified by tPA treatment. Three independent vascular neurologists reviewed all sICH events occurring within 7 days, defined by neurologic deterioration of ≥4 points on the NIHSS. Associations between BG control and sICH were analyzed using a logistic regression model accounting for NIHSS, age, systolic blood pressure, onset to tPA time, and endovascular therapy. Associations were reported as odds ratios (95% CI). Categorical variables and outcomes were compared using the chi-square test (p < 0.05).

Results: Of the 1151 SHINE participants, 725 (63%) received IV tPA (median age 65, 46% women, 29% Black, 18% Hispanic). Median NIHSS was 7, baseline BG 187 (IQR 153-247) mg/dL, and onset to tPA was 2.2 hrs (1.6-2.9). Post-tPA sICH occurred in 3.6% (3% intensive vs. 4.3% standard, OR 1.10, 95% CI 0.60-2.01, p=0.697). There was a consistent association between post-tPA BG measures and sICH. In the first 12 hours, every 10 mg/dL increase in median BG increased odds of sICH by ~8% (OR 1.08, 95% CI 1.03-1.14, p=0.004), and a greater percentage of BG measures 80-130 mg/dL decreased odds of sICH by ~11% (0.89, 95% CI 0.80-0.99, p=0.030).

Conclusion: In this pre-planned analysis, intensive insulin therapy was not associated with a reduced risk of post-tPA sICH. However, post-tPA hyperglycemia was associated with a higher risk of sICH overall, particularly in the early post-treatment period. These data provide class IIa, level B-R evidence that post-tPA glucose levels between 80-130 mg/dL are associated with decreased risk of sICH. Acknowledgments: NIH-NINDS U01 NS069498.