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Non-pharmacologic (physiologic) neuroprotection in the treatment of brain ischemia
1Departments of Pathology & Clinical Neurosciences, University of Calgary, 3330 Hospital Drive N.W., Calgary, Alberta, Canada T2N 4N1. rauer@ucalgary.ca
Abstract:
Clinical trials for ischemic stroke have been characterized by a disappointing series of negative results, using a panoply of pharmacologic agents. This paper emphasizes five physiologic measures that can be taken to mitigate ischemic brain damage. These are (1) hypothermia, (2) insulin, (3) arterial hyperoxemia, (4) blood pressure control and (5) magnesium. Hypothermia is protective in both focal and global ischemia, even postischemically protecting against selective neuronal necrosis and infarction. The total equation for protection includes the (i) postischemic delay, (ii) depth, and (iii) duration of hypothermia. Insulin operates by lowering glucose levels to the normal range in focal ischemia. It is possible that very low glucose levels are detrimental in focal ischemia with paradoxical augmentation of the infarct size, and that spreading depression plays a role in this. Controlled arterial hyperoxemia seems effective experimentally in reducing infarct size, operating mechanistically by either a direct effect of oxygen, or vasoconstriction causing shunting of blood into the infarct, or both. Blood pressure is a critical determinant of infarct size, and raising blood pressure improves collateral blood flow and reduces stroke size. To be used clinically, however, hemorrhage must be ruled out. The most dramatic clinical effects of blood pressure are seen in aneurysm patients with vasospasm, where minor increases in blood pressure reverse temporary hemiparesis by reducing ischemia. Magnesium is likely the safest NMDA antagonist, with a long history of safe administration to pregnant women with eclampsia. There is potential interaction with insulin, in that magnesium causes hyperglycemia, which requires insulin to counteract it. Magnesium and insulin together have been shown effective in experimental brain ischemia. In the absence of safe and effective pharmacologic neuroprotection agents, clinical trials should be designed and launched to test these physiologic measures, singly and in combination, to reduce brain damage after ischemia.
Insights
Clinical trials for ischemic stroke have yielded negative results. This paper highlights five physiologic measures: hypothermia, insulin, arterial hyperoxemia, blood pressure control, and magnesium, to mitigate brain damage.
Area of Science:
- Neuroscience
- Neurology
- Emergency Medicine
Background:
- Clinical trials for ischemic stroke have largely failed to identify effective pharmacologic neuroprotective agents.
- There is a critical need for alternative strategies to reduce ischemic brain damage.
Purpose of the Study:
- To review and emphasize five physiologic measures that show promise in mitigating ischemic brain damage.
- To advocate for clinical trials investigating these physiologic interventions.
Main Methods:
- Review of experimental and clinical data on hypothermia, insulin, arterial hyperoxemia, blood pressure control, and magnesium.
- Analysis of proposed mechanisms of action for each intervention.
- Discussion of potential clinical applications and trial designs.
Main Results:
- Hypothermia demonstrates protective effects in both focal and global ischemia, with protection dependent on delay, depth, and duration.
- Insulin normalizes glucose levels in focal ischemia, potentially preventing infarcts.
- Arterial hyperoxemia and controlled blood pressure elevation show promise in reducing infarct size by improving collateral flow.
- Magnesium, a safe NMDA antagonist, may be effective, especially in combination with insulin, to counteract hyperglycemia.
Conclusions:
- Physiologic measures offer a promising alternative to pharmacologic agents for reducing ischemic brain damage.
- Further clinical trials are warranted to evaluate the efficacy of these measures, individually and in combination.