Use of mild intraischemic hypothermia versus mannitol to reduce infarct size after temporary middle cerebral artery occlusion in rats

Restricted access

✓ To determine which of two treatments for reducing ischemic injury after temporal focal ischemia is more effective, the effects of mild (33°C) intraischemic hypothermia were compared with those of mannitol, the most commonly used neuroprotective agent. Four groups of Sprague-Dawley rats underwent 1 hour of endovascular middle cerebral artery occlusion followed by 23 hours of normothermic reperfusion. The four experimental groups were as follows: Group A, saline control; Group B, mannitol (25%, 1 g/kg); Group C, hypothermia; and Group D, hypothermia plus man-nitol.

Laser-Doppler estimates of cortical blood flow showed that hypothermia did not affect blood flow during ischemia or reperfusion. Mannitol increased cortical blood flow during ischemia and reperfusion under both normothermic and hypothermic conditions (p < 0.05). Neurological deficit was significantly less severe in treated rats (Group B, p < 0.05; Group C or D, p < 0.01) than in controls (Group A). Infarct volume, measured on semiserial Nissl-stained sections, was significantly smaller in treated rats (p < 0.01) than in controls. Infarct volume was also significantly smaller in rats treated with hypothermia than in those treated with mannitol (Group C vs. Group B, p < 0.05); there was no difference between rats treated with mannitol and those treated with mannitol and hypothermia. All three treatments reduced infarct area in the ischemic penumbra; hypothermia with or without mannitol also reduced infarct area in the ischemic core.

These results demonstrate that both mild intraischemic hypothermia and mannitol reduce infarct size and neurological deficit: hypothermia reduces infarct size more effectively than mannitol, and mannitol adds no significant protection to hypothermia, whereas hypothermia adds significant protection beyond that afforded by mannitol after brief focal ischemia followed by reperfusion in rats. The results suggest that mild intraischemic hypothermia alone, or in combination with mannitol, may be useful in avoiding ischemic injury from temporary vessel occlusion during cerebrovascular surgery.

Article Information

Contributor Notes

Address reprint requests to: Hiroshi Karibe, M.D., Department of Neurological Surgery, The Editorial Office, 1360 Ninth Avenue, Suite 210, San Francisco, California 94122.
Headings
References
  • 1.

    Benveniste HDrejer JSchousboe Aet al: Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. J Neurochem 43:136913741984Benveniste H Drejer J Schousboe A et al: Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. J Neurochem 43:1369–1374 1984

    • Search Google Scholar
    • Export Citation
  • 2.

    Botterell EHLougheed WMScott JWet al: Hypothermia, and interruption of carotid, or carotid and vertebral circulation, in the surgical management of intracranial aneurysms. J Neurosurg 13:1421956Botterell EH Lougheed WM Scott JW et al: Hypothermia and interruption of carotid or carotid and vertebral circulation in the surgical management of intracranial aneurysms. J Neurosurg 13:1–42 1956

    • Search Google Scholar
    • Export Citation
  • 3.

    Burke AMQuest DOChien Set al: The effects of mannitol on blood viscosity. J Neurosurg 55:5505531981Burke AM Quest DO Chien S et al: The effects of mannitol on blood viscosity. J Neurosurg 55:550–553 1981

    • Search Google Scholar
    • Export Citation
  • 4.

    Busto RDietrich WDGlobus MYTet al: Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury. J Cereb Blood Flow Metab 7:7297381987Busto R Dietrich WD Globus MYT et al: Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury. J Cereb Blood Flow Metab 7:729–738 1987

    • Search Google Scholar
    • Export Citation
  • 5.

    Busto RGlobus MYTDietrich WDet al: Effect of mild hypothermia on ischemia-induced release of neurotransmitters and free fatty acids in rat brain. Stroke 20:9049101989Busto R Globus MYT Dietrich WD et al: Effect of mild hypothermia on ischemia-induced release of neurotransmitters and free fatty acids in rat brain. Stroke 20:904–910 1989

    • Search Google Scholar
    • Export Citation
  • 6.

    Cardell MBoris-Möller FWieloch T: Hypothermia prevents the ischemia-induced translocation and inhibition of protein kinase C in the rat striatum. J Neurochem 57:181418171991Cardell M Boris-Möller F Wieloch T: Hypothermia prevents the ischemia-induced translocation and inhibition of protein kinase C in the rat striatum. J Neurochem 57:1814–1817 1991

    • Search Google Scholar
    • Export Citation
  • 7.

    Chen JGraham SHSimon RPet al: Extracellular glutamate and glucose utilization in caudate and cortex following focal ischemia and reperfusion. Stroke 24:1771993 (Abstract)Chen J Graham SH Simon RP et al: Extracellular glutamate and glucose utilization in caudate and cortex following focal ischemia and reperfusion. Stroke 24:177 1993 (Abstract)

    • Search Google Scholar
    • Export Citation
  • 8.

    Choi DW: Glutamate neurotoxicity and diseases of the nervous system. Neuron 1:6236341988Choi DW: Glutamate neurotoxicity and diseases of the nervous system. Neuron 1:623–634 1988

    • Search Google Scholar
    • Export Citation
  • 9.

    Choi DW: Possible mechanisms limiting N-methyl-d-aspartate receptor overactivation and the therapeutic efficacy of Nmethyl-d-aspartate antagonists. Stroke 21 (Suppl):20221990Choi DW: Possible mechanisms limiting N-methyl-d-aspartate receptor overactivation and the therapeutic efficacy of Nmethyl-d-aspartate antagonists. Stroke 21 (Suppl):20–22 1990

    • Search Google Scholar
    • Export Citation
  • 10.

    Dirnagl UKaplan BJacewicz Met al: Continuous measurement of cerebral cortical blood flow by laser-Doppler flowmetry in a rat stroke model. J Cereb Blood Flow Metab 9:5895961989Dirnagl U Kaplan B Jacewicz M et al: Continuous measurement of cerebral cortical blood flow by laser-Doppler flowmetry in a rat stroke model. J Cereb Blood Flow Metab 9:589–596 1989

    • Search Google Scholar
    • Export Citation
  • 11.

    Drake CGBarr HWKColes JCet al: The use of extracorporeal circulation and profound hypothermia in the treatment of ruptured intracranial aneurysm. J Neurosurg 21:5755811964Drake CG Barr HWK Coles JC et al: The use of extracorporeal circulation and profound hypothermia in the treatment of ruptured intracranial aneurysm. J Neurosurg 21:575–581 1964

    • Search Google Scholar
    • Export Citation
  • 12.

    Ginsberg MDSternau LLGlobus MYTet al: Therapeutic modulation to brain temperature: relevance to ischemic brain injury. Cerebrovasc Brain Metab Rev 4:1892251992Ginsberg MD Sternau LL Globus MYT et al: Therapeutic modulation to brain temperature: relevance to ischemic brain injury. Cerebrovasc Brain Metab Rev 4:189–225 1992

    • Search Google Scholar
    • Export Citation
  • 13.

    Graham SHChen JSimon RP: A dose-response study of dextrorphan in permanent focal ischemia. Neurosci Lett 160:21231993Graham SH Chen J Simon RP: A dose-response study of dextrorphan in permanent focal ischemia. Neurosci Lett 160:21–23 1993

    • Search Google Scholar
    • Export Citation
  • 14.

    Hossmann KA: Hemodynamics of postischemic reperfusion of the brain in Weinstein PRFaden AI (eds): Protection of the Brain from Ischemia. Baltimore: Williams & Wilkins1990 pp 2136Hossmann KA: Hemodynamics of postischemic reperfusion of the brain in Weinstein PR Faden AI (eds): Protection of the Brain from Ischemia. Baltimore: Williams & Wilkins 1990 pp 21–36

    • Search Google Scholar
    • Export Citation
  • 15.

    Kader ABrisman MHMaraire Net al: The effect of mild hypothermia on permanent focal ischemia in the rat. Neurosurgery 31:105610611992Kader A Brisman MH Maraire N et al: The effect of mild hypothermia on permanent focal ischemia in the rat. Neurosurgery 31:1056–1061 1992

    • Search Google Scholar
    • Export Citation
  • 16.

    Kaplan BBrint STanabe Jet al: Temporal thresholds for neocortical infarction in rats subjected to reversible focal cerebral ischemia. Stroke 22:103210391991Kaplan B Brint S Tanabe J et al: Temporal thresholds for neocortical infarction in rats subjected to reversible focal cerebral ischemia. Stroke 22:1032–1039 1991

    • Search Google Scholar
    • Export Citation
  • 17.

    Karibe HChen JZarow GJet al: Delayed induction of mild hypothermia to reduce infarct after temporary middle cerebral artery occlusion in rats. J Neurosurg 80:1121191994Karibe H Chen J Zarow GJ et al: Delayed induction of mild hypothermia to reduce infarct after temporary middle cerebral artery occlusion in rats. J Neurosurg 80:112–119 1994

    • Search Google Scholar
    • Export Citation
  • 18.

    Karibe HChen SFZarow GJet al: Mild intraischemic hypothermia suppresses consumption of endogenous antioxidants after temporary focal ischemia in rats. Brain Res 649:12181994Karibe H Chen SF Zarow GJ et al: Mild intraischemic hypothermia suppresses consumption of endogenous antioxidants after temporary focal ischemia in rats. Brain Res 649:12–18 1994

    • Search Google Scholar
    • Export Citation
  • 19.

    Kramer RSSanders APLesage AMet al: The effect of profound hypothermia on preservation of cerebral ATP content during circulatory arrest. J Thorac Cardiovasc Surg 56:6997091968Kramer RS Sanders AP Lesage AM et al: The effect of profound hypothermia on preservation of cerebral ATP content during circulatory arrest. J Thorac Cardiovasc Surg 56:699–709 1968

    • Search Google Scholar
    • Export Citation
  • 20.

    Kuroiwa TTing PMartinez THet al: The biphasic opening of the blood-brain barrier to proteins following temporary middle cerebral artery occlusion. Acta Neuropathol 68:1221291985Kuroiwa T Ting P Martinez TH et al: The biphasic opening of the blood-brain barrier to proteins following temporary middle cerebral artery occlusion. Acta Neuropathol 68:122–129 1985

    • Search Google Scholar
    • Export Citation
  • 21.

    Kwak ROkudaira YSuzuki Jet al: [Problems in hypothermic anesthesia for direct surgical treatment of intracranial aneurysms, with special reference to ventilated fibrillation.] No To Shinkei 24:4034101972 (Jpn)Kwak R Okudaira Y Suzuki J et al: [Problems in hypothermic anesthesia for direct surgical treatment of intracranial aneurysms with special reference to ventilated fibrillation.] No To Shinkei 24:403–410 1972 (Jpn)

    • Search Google Scholar
    • Export Citation
  • 22.

    Ljunggren BSäveland HBrandt Let al: Temporary clipping during early operation for ruptured aneurysm: preliminary report. Neurosurgery 12:5255301983Ljunggren B Säveland H Brandt L et al: Temporary clipping during early operation for ruptured aneurysm: preliminary report. Neurosurgery 12:525–530 1983

    • Search Google Scholar
    • Export Citation
  • 23.

    Longa EZWeinstein PRCarlson Set al: Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20:84911989Longa EZ Weinstein PR Carlson S et al: Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20:84–91 1989

    • Search Google Scholar
    • Export Citation
  • 24.

    Lundberg NNielsen KCNilsson E: Deep hypothermia in intracranial surgery. J Neurosurg 13:2352471956Lundberg N Nielsen KC Nilsson E: Deep hypothermia in intracranial surgery. J Neurosurg 13:235–247 1956

    • Search Google Scholar
    • Export Citation
  • 25.

    Marshall LFSmith RWShapiro HM: The outcome with aggressive treatment in severe head injuries. Part II: acute and chronic barbiturate administration in the management of head injury. J Neurosurg 50:26301979Marshall LF Smith RW Shapiro HM: The outcome with aggressive treatment in severe head injuries. Part II: acute and chronic barbiturate administration in the management of head injury. J Neurosurg 50:26–30 1979

    • Search Google Scholar
    • Export Citation
  • 26.

    Meyer FBAnderson RESundt TM Jret al: Treatment of experimental focal cerebral ischemia with mannitol. Assessment by intracellular brain pH, cortical blood flow, and electroencephalography. J Neurosurg 66:1091151987Meyer FB Anderson RE Sundt TM Jr et al: Treatment of experimental focal cerebral ischemia with mannitol. Assessment by intracellular brain pH cortical blood flow and electroencephalography. J Neurosurg 66:109–115 1987

    • Search Google Scholar
    • Export Citation
  • 27.

    Michenfelder JDMilde JH: Failure of prolonged hypocapnia, hypothermia, or hypertension to favorably alter acute stroke in primates. Stroke 8:87911977Michenfelder JD Milde JH: Failure of prolonged hypocapnia hypothermia or hypertension to favorably alter acute stroke in primates. Stroke 8:87–91 1977

    • Search Google Scholar
    • Export Citation
  • 28.

    Michenfelder JDTheye RA: The effect of anesthesia and hypothermia on canine cerebral ATP and lactate during anoxia produced by decapitation. Anesthesiology 33:4304391970Michenfelder JD Theye RA: The effect of anesthesia and hypothermia on canine cerebral ATP and lactate during anoxia produced by decapitation. Anesthesiology 33:430–439 1970

    • Search Google Scholar
    • Export Citation
  • 29.

    Michenfelder JDTheye RA: Hypothermia: effect on canine brain and whole-body metabolism. Anesthesiology 29:110711121968Michenfelder JD Theye RA: Hypothermia: effect on canine brain and whole-body metabolism. Anesthesiology 29:1107–1112 1968

    • Search Google Scholar
    • Export Citation
  • 30.

    Mizoi KSuzuki JImaizumi Set al: Development of new cerebral protective agents: the free radical scavengers. Neurol Res:75801986Mizoi K Suzuki J Imaizumi S et al: Development of new cerebral protective agents: the free radical scavengers. Neurol Res:75–80 1986

    • Search Google Scholar
    • Export Citation
  • 31.

    Morikawa EGinsberg MDDietrich WDet al: The significance of brain temperature in focal cerebral ischemia: histopathological consequences of middle cerebral artery occlusion in the rat. J Cereb Blood Flow Metab 12:3803891992Morikawa E Ginsberg MD Dietrich WD et al: The significance of brain temperature in focal cerebral ischemia: histopathological consequences of middle cerebral artery occlusion in the rat. J Cereb Blood Flow Metab 12:380–389 1992

    • Search Google Scholar
    • Export Citation
  • 32.

    Nagasawa HKogure K: Correlation between cerebral blood flow and histologic changes in a new rat model of middle cerebral artery occlusion. Stroke 20:103710431989Nagasawa H Kogure K: Correlation between cerebral blood flow and histologic changes in a new rat model of middle cerebral artery occlusion. Stroke 20:1037–1043 1989

    • Search Google Scholar
    • Export Citation
  • 33.

    Nemoto EMShiu GKBleyaert AL: Efficacy of therapies and attenuation of brain free fatty acid liberation during global ischemia. Crit Care Med 9:3973981981Nemoto EM Shiu GK Bleyaert AL: Efficacy of therapies and attenuation of brain free fatty acid liberation during global ischemia. Crit Care Med 9:397–398 1981

    • Search Google Scholar
    • Export Citation
  • 34.

    Pool JL: Aneurysms of the anterior communicating artery. Bifrontal craniotomy and routine use of temporary clips. J Neurosurg 18:981111961Pool JL: Aneurysms of the anterior communicating artery. Bifrontal craniotomy and routine use of temporary clips. J Neurosurg 18:98–111 1961

    • Search Google Scholar
    • Export Citation
  • 35.

    Rosomoff HLHoladay DA: Cerebral blood flow and cerebral oxygen consumption during hypothermia. Am J Physiol 179:85881954Rosomoff HL Holaday DA: Cerebral blood flow and cerebral oxygen consumption during hypothermia. Am J Physiol 179:85–88 1954

    • Search Google Scholar
    • Export Citation
  • 36.

    Seki HYoshimoto YOgawa Aet al: Effect of mannitol on rCBF in canine thalamic ischemia—an experimental study. Stroke 14:46501983Seki H Yoshimoto Y Ogawa A et al: Effect of mannitol on rCBF in canine thalamic ischemia—an experimental study. Stroke 14:46–50 1983

    • Search Google Scholar
    • Export Citation
  • 37.

    Shirane RWeinstein PR: Effect of mannitol on local cerebral blood flow after temporary complete cerebral ischemia in rats. J Neurosurg 76:4864921992Shirane R Weinstein PR: Effect of mannitol on local cerebral blood flow after temporary complete cerebral ischemia in rats. J Neurosurg 76:486–492 1992

    • Search Google Scholar
    • Export Citation
  • 38.

    Siesjö BK: Pathophysiology and treatment of focal cerebral ischemia. Part I: pathophysiology. J Neurosurg 77:1691841992Siesjö BK: Pathophysiology and treatment of focal cerebral ischemia. Part I: pathophysiology. J Neurosurg 77:169–184 1992

    • Search Google Scholar
    • Export Citation
  • 39.

    Siesjö BK: Pathophysiology and treatment of focal cerebral ischemia. Part II: mechanisms of damage and treatment. J Neurosurg 77:3373541992Siesjö BK: Pathophysiology and treatment of focal cerebral ischemia. Part II: mechanisms of damage and treatment. J Neurosurg 77:337–354 1992

    • Search Google Scholar
    • Export Citation
  • 40.

    Simon RShiraishi K: N-methyl-d-aspartate antagonist reduces stroke size and regional glucose metabolism. Ann Neurol 27:6066111990Simon R Shiraishi K: N-methyl-d-aspartate antagonist reduces stroke size and regional glucose metabolism. Ann Neurol 27:606–611 1990

    • Search Google Scholar
    • Export Citation
  • 41.

    Steen PASoule EHMichenfelder JD: Detrimental effect of prolonged hypothermia in cats and monkeys with and without regional cerebral ischemia. Stroke 10:5225291979Steen PA Soule EH Michenfelder JD: Detrimental effect of prolonged hypothermia in cats and monkeys with and without regional cerebral ischemia. Stroke 10:522–529 1979

    • Search Google Scholar
    • Export Citation
  • 42.

    Suzuki JKwak ROkudaira Y: [The safety time limit of temporary clamping of cerebral arteries in the direct surgical treatment of the intracranial aneurysm under moderate hypothermia.] No To Shinkei 25:4074161973 (Jpn)Suzuki J Kwak R Okudaira Y: [The safety time limit of temporary clamping of cerebral arteries in the direct surgical treatment of the intracranial aneurysm under moderate hypothermia.] No To Shinkei 25:407–416 1973 (Jpn)

    • Search Google Scholar
    • Export Citation
  • 43.

    Suzuki JMizoi KYoshimoto T: Bifrontal interhemispheric approach to aneurysms of the anterior communicating artery. J Neurosurg 64:1831901986Suzuki J Mizoi K Yoshimoto T: Bifrontal interhemispheric approach to aneurysms of the anterior communicating artery. J Neurosurg 64:183–190 1986

    • Search Google Scholar
    • Export Citation
  • 44.

    Suzuki JYoshimoto TKayama T: Surgical treatment of middle cerebral artery aneurysms. J Neurosurg 61:17231984Suzuki J Yoshimoto T Kayama T: Surgical treatment of middle cerebral artery aneurysms. J Neurosurg 61:17–23 1984

    • Search Google Scholar
    • Export Citation
  • 45.

    Swanson RAMorton MTTsao-Wu Get al: A semiautomated method for measuring brain infarct volume. J Cereb Blood Flow Metab 10:2902931990Swanson RA Morton MT Tsao-Wu G et al: A semiautomated method for measuring brain infarct volume. J Cereb Blood Flow Metab 10:290–293 1990

    • Search Google Scholar
    • Export Citation
  • 46.

    Tominaga TOhnishi ST: Interrelationship of brain edema, motor deficits, and memory impairment in rats exposed to focal ischemia. Stroke 20:5135181989Tominaga T Ohnishi ST: Interrelationship of brain edema motor deficits and memory impairment in rats exposed to focal ischemia. Stroke 20:513–518 1989

    • Search Google Scholar
    • Export Citation
TrendMD
Metrics

Metrics

All Time Past Year Past 30 Days
Abstract Views 255 245 22
Full Text Views 144 60 1
PDF Downloads 84 28 1
EPUB Downloads 0 0 0
PubMed
Google Scholar