Robbins NM and Swanson RA. Opposing Effects of Glucose on Stroke and Reperfusion Injury: Acidosis, Oxidative Stress, and Energy Metabolism. Stroke. 2014
Hyperglycemia can contribute to infarct expansion and reperfusion injury post-stroke. Aggressive blood sugar management, however, shows no clear benefit in early human trials. This review by Robbins & Swanson breaks down the biochemical processes associated with brain glucose metabolism in the setting of stroke. The authors bring great clarity to the complex processes involved and provide hope that at least a subset of hyperglycemic stroke patients may benefit from aggressive glycemic control.
Rat models teach us a great deal about the effects of hyperglycemia post-stroke. Most of these experiments suggest that hyperglycemia increases morbidity and mortality. Interestingly, hyperglycemia does not worsen outcome and may actually benefit those animals with a core lesion and no penumbra. Robbins & Swanson suggest this is because cerebral blood flow is so low in the core that tissue is damaged beyond repair regardless of circulating glucose levels. Lacunar infarcts may behave similarly since they reflect areas of no collateral flow. Correction of hyperglycemia in animals with penumbra does seem to be beneficial. A key difference between rat and human hyperglycemia post-stroke is that hyperglycemia in rat models is almost always iatrogenic. In humans, the elevated blood sugar probably reflects more of a stress response. The authors highlight that this may hinder translational efforts.
Despite concerns about translation to human trials, there are reasons to remain optimistic. Clinically, humans react largely the same as rats to post-stroke hyperglycemia. There is strong evidence to suggest that hyperglycemia causes worse outcomes in humans. In addition, humans lacking evidence of ischemic penumbra (i.e. little diffusion/perfusion mismatch) are not affected by circulating blood glucose levels.
Perhaps a study of tight glycemic control in subjects selected for diffusion/perfusion mismatch is called for. The authors conclude with a discussion of the association between hyperglycemia and reperfusion injury, suggesting we may want to exclude more hyperglycemic patients from IV-TPA. To my knowledge the hemorrhage rate increases linearly with blood sugar level, so the presence of hyperglycemia alone, if mild-moderate, is not a good reason to withhold IV-TPA. The ongoing SHINE trial, which compares aggressive glucose control to standard care in hyperglycemic patients stratified by treatment with IV-TPA, should shed some light on this topic.