Therapy

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Clearly, the first priority in the treatment of cerebral ischemia is the reestablishment of blood flow. Trials of thrombolytics have shown tissue plasminogen activator to be of some benefit in select subgroups of stroke patients, but it must be administered within a 3-h window.15 Methods of restoring spontaneous circulation in cardiac arrest are described in Chap 8, Chap 10, and Chap..20.

Because the ultimate extent of injury observed following ischemia largely reflects damage incurred during reperfusion (reperfusion injury), effective therapy must not only limit ongoing mechanisms of damage but also facilitate repair of the damage that has already occurred. Optimum therapy to obviate continuing injury and salvage viable brain tissue is unknown.16 Most therapeutic studies use animal models, use pretreatment, or contain small numbers of patients. However, a few general principles can be stated. Perfusion should be maintained at normal levels. It does not appear that intracranial pressure is increased in the postresuscitation period, and therefore therapies directed at increased intracranial pressure (hyperventilation and osmotic agents) are unnecessary. Hypotension should be avoided for obvious reasons. Oxygenation should be maintained at or near normal levels. Hyperoxia should be avoided, since it is toxic to the lungs and may increase brain damage. Prearrest hyperglycemia is associated with poor neurologic outcome, and although glucose administered postinsult has not been adequately studied, hyperglycemia should probably be avoided.17 As mentioned above, several other therapies have been advocated, but human studies have failed to show efficacy. These therapies include pentobarbital coma, calcium antagonists, and glucocorticoids.1 l9

Ischemic injury of the brain is complex, and this complexity indicates that single-drug therapeutic approaches will continue to fail. The pattern of ATP and ionic recovery and DNA transcription during reperfusion shows that several cellular systems are intact following prolonged ischemia and reperfusion. Future investigation of therapeutic approaches may combine calpain antagonists, iron chelators, lipid peroxidation chain reaction terminators, and growth factors to forestall further lipid peroxidation and to stimulate repair mechanisms. Effective therapeutic protocols will be identified only by continued studies.

CHAPTER REFERENCES

1. Brain Resuscitation Clinical Trial I Study Group: Study of thiopental loading in comatose survivors of cardiac arrest. N Engl J Med 314:397-401, 1986.

2. Brain Resuscitation Clinical Trial II Study Group: A randomized clinical study of a calcium-entry blocker (lidoflazine) in the treatment of comatose survivors of cardiac arrest. N Engl J Med 324:1225-1231, 1991.

3. RANITAS investigators: A randomized trial of trilazad mesylate in patients with acute stroke. Stroke 27:1453-1458, 1996.

4. Nellgard B, Gustafson I, Wieloch T: Lack of protection by the N-methyl-D-aspartate receptor blocker dizocilpine (MK-801) after transient cerebral ischemia in the rat. Anesthesiology 75:279-287, 1991.

5. O'Neil BJ, Krause GS, Grossman LI, et al: Global brain ischemia and reperfusion by cardiac arrest and resuscitation: Mechanisms leading to death of vulnerable neurons and a fundamental basis for therapeutic approaches, in Paradis NA, Halperin HR, Nowak RM (eds): Cardiac Arrest: The Science and Practice of Resuscitation Medicine. Baltimore, Williams & Wilkins, 1996, pp 84-112.

6. White B, Grossman L, Krause G: Membrane damage and repair in brain injury by ischemia and reperfusion. Neurology 43:1656-1665, 1993.

7. Siesjo BK, Bengtsson F, Grampp W, et al: Calcium, excitotoxins, and neuronal death in the brain. Ann N Y Acad Sci 568:234-251, 1989.

8. Krause GS, Tiffany BR: Protein synthesis in the reperfused brain. Stroke 24:747-756, 1993.

9. Krause GS, DeGracia DJ, Neumar RW, et al: elF4E degradation during brain ischemia. J Neurochem 63:1391-1394, 1995.

10. Neumar RW, DeGracia DJ, Konkoly LL, et al: Calpain I mediates eukaryotic initiation factor 4G degradation during global brain ischemia. J Cereb Blood Flow Metab 18:876-881, 1998.

11. DeGracia DJ, Neumar RW, White BC, Krause GS: Global brain ischemia and reperfusion: Modifications in eukaryotic initiation factors are associated with inhibition of translation initiation. J Neurochem 67:2005-2012, 1996.

12. Neumar RW, Hagle SM, DeGracia DJ, et al: Brain calpain autolysis during global cerebral ischemia. J Neurochem 66:421-424, 1996.

13. DeGracia DJ, Sullivan JM, Neumar RW, et al: Effect of brain ischemia and reperfusion on the localization of phosphorylated eukaryotic initiation factor 2a. J Cereb Blood Flow Metab 17:1291-1302, 1997.

14. White BC, Daya A, DeGracia DJ, et al: Flourescent histochemical localization of lipid peroxidation during brain reperfusion following cardiac arrest. Acta Neuropathol (Berlin) 86:1-9, 1993.

15. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group: Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 333:1581-1587, 1995.

16. del Zoppo GJ, Wagner S, Tagaya M: Trends and future developments in the pharmacological treatment of acute ischemic stroke. Drugs 54:9-38, 1997.

17. Wass CT, Lanier WL: Glucose modulation of ischemic brain injury: Review and clinical recommendations. Mayo Clin Proc 71:801-812, 1996.

18. Grafton ST, Longstreth WT Jr: Steroids after cardiac arrest: A retrospective study with concurrent, nonrandomized controls. Neurology 38:1315-1316, 1988.

19. Jastremski M, Sutton-Tyrrell K, Vaagenes P, et al: Glucocorticoid treatment does not improve neurological recovery following cardiac arrest: Brain Resuscitation Clinical Trial I Study Group. JAMA 262:3427-3430, 1989.

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