Hemorrhagic transformation of ischemic stroke in diabetics on sulfonylureas

Abstract

Objective: Disability or death occurs more frequently in patients with hemorrhagic transformation (HT) after ischemic stroke. In rat models of stroke, sulfonylurea (SU) drugs such as glibenclamide (adopted US name, glyburide) confer protection against swelling and HT through actions on the novel SUR1-regulated NC(Ca-ATP) channel. Here, we sought to determine whether the use of SU drugs in patients with diabetes mellitus (DM) presenting with acute ischemic stroke might influence the incidence of HT.

Methods: We retrospectively analyzed data on 220 patients with DM who presented with acute ischemic stroke, 43 of whom were managed with and continued to receive SU drugs, and 177 of whom were managed without (controls).

Results: During a median length of stay in hospital of 11 days, 20 control patients (11%) experienced symptomatic HT (sHT), whereas no patient in the SU group experienced sHT (p = 0.016). No patient in the SU group died, compared to 18 (10%) in the control group (p = 0.027). Similarly favorable outcomes were observed after matching for baseline imbalances and excluding outliers. In support of the proposed mechanism, we present a case of sHT in which an analysis of brain tissues obtained intraoperatively showed prominent upregulation of SUR1, the target of SU drugs, in microvessels and neurons.

Interpretation: We conclude that, in diabetic patients with acute ischemic stroke, prior and continued use of SU drugs is associated with reduced sHT compared to those whose treatment regimen does not include SU drugs.

Figure 1. Diabetic patients taking sulfonylurea drugs are more likely to survive during hospitalization for stroke

Risk of in-hospital death in diabetic patients treated with sulfonylurea (SU) drugs versus those managed without SU drugs; Kaplan-Meier survival estimates; log rank test, χ²= 4.89; P=0.03.

Figure 2. Sulfonylurea receptor 1 (SUR1) is upregulated in a patient with symptomatic hemorrhagic transformation (sHT)

A–C: Sections of cortex obtained at operation from the ipsilateral cerebral cortex of a patient who underwent decompressive craniectomy for malignant cerebral edema complicated by sHT (A), or at autopsy from the ipsilateral (B) and contralateral (C) cerebral cortex of a patient who had suffered a recent non-fatal embolic stroke (control), double immunolabeled for SUR1 (red) and for the endothelial cell marker, PECAM-1 (CD31; green); merged images of the double labelling are shown in (C), and in the panels on the right in (A) and (B), with co-localization indicated by the yellow colour. In (A), note the extravasated erythrocytes that autofluoresce in the green channel (arrow), and the extravasated neutrophils (asterisk) which are believed to express SUR1-K_ATP channels surrounding the SUR1-positive vessel (yellow). In (B) and (C), note the swollen SUR1-positive endothelium (B, arrow), compared to the thin, SUR1-negative endothelium in the control tissues (C, arrow). D–F: Sections of cortex from the patient with sHT (D,F) and from the control tissues (E), double immunolabeled for SUR1 (red) and for the neuronal marker, NeuN (green); merged images of the double labelling are shown in (E), and in the panel on the right in (D), with co-localization indicated by the yellow colour. Note the SUR1-positive cortical neurons with blebbing in (D,F), compared to the SUR1-negative cortical neurons in the control tissues (E); in (F), blebs are observed in the perikaryon and in large processes (arrows).