Hyperglycemia is common in acute ischemic stroke, with an incidence of 30-50% in patients without a history of diabetes mellitus. Increased glucose levels have been associated with larger final infarct volume and worse clinical outcome, also in patients who underwent intravenous thrombolysis with rtPA or endovascular therapy. Additionally, patients with acute ischemic stroke due to large vessel occlusion of the anterior circulation with hyperglycemia on admission had a significantly larger ischemic core volume at six hours after symptom onset than patients without hyperglycemia. Proposed underlying pathomechanisms of hyperglycemia include activation of coagulation, reduction of the fibrinolytic activity of alteplase, increased post-ischemic inflammatory response, and altered blood-brain barrier permeability resulting in brain edema formation.
Hyperglycemia might be an effective therapeutic target in acute ischemic stroke patients. However, active glucose-lowering had no effect on infarct size or functional outcome in various studies. None of the previous studies focused on patients who underwent recanalization treatment and only one study assessed the effects of glucose reduction in the very early phase of acute stroke. This study was hampered by the heterogeneity of the population and failure to realize target recruitment and target glucose levels in the intervention group.
Little is known about the effects of hyperglycemia in combination with hypoxia at the cellular level. In an in-vitro model of the system of the penumbra, consisting of networks of cultured cortical neurons, it has been shown that hypoxia reduces spontaneous neuronal network activity. Subsequent recovery depended on the depth and duration of hypoxia, with complete reversibility if oxygen supply was restored within six hours and progression towards irreversible neuronal damage on the time scales of 24-48 hours. In human neuronal networks exposed to hypoxia, significant changes in firing activity and synchronicity were present already one hour after the onset of hypoxia. The neuronal networks completely lost synchronicity within 24 hours of hypoxia and a longer duration of hypoxia was associated with an increased number of apoptotic cells. In these experiments, glucose levels were not adjusted.
A better understanding of interactions between glucose levels and network recovery at the cellular level might provide input in future clinical studies on glucose management in ischemic stroke patients. The aim of this study is to assess whether hyperglycemia interacts with neuronal responses to hypoxia and restoration at the neuronal network and cellular level, including dose-dependency. We will assess whether the degree of spontaneous neuronal network activity and apoptosis during and after hypoxia vary with varying glucose levels. Our hypothesis is that hyperglycemia is associated with less functional recovery and more apoptosis after hypoxia and reoxygenation.