Therapeutic hypothermia for acute stroke

International Journal of Stroke

Volumn 1, Issue 1, 2006, Pages 9-19

  Lyden, Patrick D ^a,f   Krieger, Derk ^b   Yenari, Midori ^c,d   Dietrich, W Dalton ^e  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b LERNER RESEARCH INSTITUTE   (United States)

^c UNIVERSITY OF CALIFORNIA   (United States)

^d SAN FRANCISCO VETERANS AFFAIRS MEDICAL CENTER   (United States)

^e UNIVERSITY OF MIAMI MILLER SCHOOL OF MEDICINE   (United States)

^f UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BUSPIRONE; DEXMEDETOMIDINE; OPIATE; PETHIDINE; PROPOFOL; TISSUE PLASMINOGEN ACTIVATOR;

CLINICAL STUDY; CONSCIOUSNESS DISORDER; CORE TEMPERATURE; DRUG MECHANISM; DRUG POTENTIATION; HEART ARREST; HOMEOSTASIS; HUMAN; HYPOTENSION; HYPOTHESIS; INDUCED HYPOTHERMIA; INTRAVASCULAR CATHETER; LUNG DISEASE; MEDICAL TECHNOLOGY; NEUROPROTECTION; NONHUMAN; PATIENT SAFETY; PRIORITY JOURNAL; PROCESS DEVELOPMENT; PROTECTIVE EQUIPMENT; RESPIRATION DEPRESSION; REVIEW; STROKE; THERMOREGULATION; TREATMENT FAILURE; TREATMENT INDICATION;

BODY TEMPERATURE REGULATION; CLINICAL TRIALS AS TOPIC; HUMANS; HYPOTHERMIA, INDUCED; STROKE; TIME FACTORS;

EID: 33646703742     PISSN: 17474930     EISSN: 17474949     Source Type: Journal    
DOI: 10.1111/j.1747-4949.2005.00011.x     Document Type: Review

References (119)

1. Siebke H, Rotd T, Breivik H et al. Survival after 40 minutes submersion without cerebral sequel. Lancet 1975; 1: 1275-7.
2. Young RSK, Zalneraitis EL, Dooling EC: Neurological outcome in cold water drowning. JAMA 1980; 244: 1233-5.
3. Huckabee HC, Craig PL, WiAliams JM: Near drowning in frigid water: a case study of a 31 year old woman. J Int Neuropsychol Soc 1996; 2: 256-60.
4. Clifton GL, Christensen ML: Use of moderate hypothermia during elective craniotomy. Tex Med 1992; 88: 66-9.
5. Christakis GT, Abel JG, Lichtenstein SV: Neurological outcomes and cardiopulmonary temperature: A clinical review. J Card Surg 1995; 10: 475-80.
6. Krieger DW, Yenari MA: Therapeutic hypothermia for acute ischemic stroke: What do laboratory studies teach us? Stroke 2004; 35: 1482-9.
7. Hallenbeck JM, Frerichs KU: Stroke therapy. It may be time for an integrated approach. Arch Neurol 1993; 50: 768-70.
8. Grotta J: The current status of neuronal protWctive therapy: why have all neuronal protective drugs worked in animals but none so far in stroke patients? Cerebrovasc Dis 1994; 4: 115-20.
9. Shackelford RT, Hegedus SA: Factors affecting cerebral blood flow -experimental review. Ann Surg 1966; 163: 771-7.
10. Michenfelder JD, Theye R: The effects of anesthesia and hypothermia on canine cerebral ATP and lactate during anoxia produced by decapitation. Anesthesiology 1970; 33: 430-9.
11. Chopp M, Knight R, Tidwell CD et al. The metabolic effects of mild hypothermia in global cerebral ischemia and recirculation in the cat: comparison to normothermia and hyperthermia. J Cereb Blood Flow Metab 1989; 9: 141-8.
12. Erecinska M, Thoresen M, Silver IA: Effects of hypothermia on energy metabolism in mammalian central nervous system. J Cereb Blood Flow Metab 2003; 23: 513-30.
13. Hagerdal M, Harp J, Nilsson L et al. The effect of induced hypothermia upon oxygen consumption in the rat brain. J Neurochem 1975; 24: 311-6.
14. Ehrlich MP, McCullough JN, Zhang N et al. Effect of hypothermia on cerebral blood flow and metabolism in the pig. Ann Thorac Surg 2002; 73: 191-7.
15. Natale JE, D'Alecy LG: Protection from cerebral ischemia by brain cooling without reduced lactate accumulation in dogs. Stroke 1989; 20: 770-7.
16. Busto R, Globus MYT, Dietrich WD: Effect of mild hypothermia on ischemia induced release of neurotransmitters and free fatty acids in rat brain. Stroke 1989; 20: 904-10.
17. Matsumoto M, Scheller MS, Zornow MH et al. Effects of s -emopamil, nimodipine, and mild hypothermia on hippocampal glutamate concentrations after repeated cerebral ischemia in rabbits. Stroke 1993; 24: 1228-34.
18. Mitani A, Kataoka K: Critical levels of extracellular glutamate mediating gerbil hippocampal delayed neuronal death during hypothermia: brain microdialysis study. Neuroscience 1991; 42: 661-70.
19. Colbourne F, Grooms SY, Zukin RS et al. Hypothermia rescues hippocampal CA1 neurons and attenuates down-regulation of the AMPA receptor glur2 subunit after forebrain ischemia. Proc Natl Acad Sci USA 2003; 100: 2906-10.
20. Nakashima K, Todd MM: Effects of hypothermia on the rate of excitatory amino acid release after ischemic depolarization. Stroke 1996; 27: 913-8.
21. Yamamoto H, Mitani A, Cui Y et al. Neuroprotective effect of mild hypothermia cannot be explained in terms of a reduction of glutamate release during ischemia. Neuroscience 1999; 91: 501-9.
22. Taylor CP, Weber ML, Gaughan CL et al. Oxygen/glucose deprivation in hippocampal slices: Altered intraneuronal elemental composition predicts structural and functional damage. J Neurosci 1999; 19: 619-2.
23. 2+]i accumulation and ATP levels during oxygen and/or glucose deprivation in hippocampal slices of guinea pigs. Neurosci Lett 1997; 227: 41-4.
24. 2+/ calmodulin-dependent protein kinase II and its messenger RNA in the rat hippocampus following normo- and hypothermic ischemia Neuroscience 1995; 68: 1003-16.
25. Kawai N, Okauchi M, Nagao S: Effects of delayed intraischemic and postischemic hypothermia on a focal model of transient cerebral ischemia in rats. Stroke 2000; 31: 1982-9.
26. Inamasu J, Suga S, Sato S et al. Intra-ischemic hypothermia attenuates intercellular molecule-1 (ICAM-1) and migration of neutrophil. Neurol Res 2001; 1: 105-11.
27. Wang GJ, Deng HY, Maier CM et al. Mild hypothermia reduces ICAM-1 expression, neutrophil infiltration and microglia/monocyte accumulation following experimental stroke. Neuroscience 2002; 114: 1081-90.
28. Han HS, Qiao Y, Giffard RG et al. Influence of mild hypothermia on inducible nitric oxide synthase expression and reactive nitrogen production in experimental stroke and inflammation. Neuroscience 2002; 22: 3921-8.
29. Globus MY-T, Busto R, Lin B et al. Detection of free radical activity during transient global ischemia amd recirculation. J Neurochem 1995; 65: 1250-6.
30. Inamasu J, Suga S, Horiguchi T et al. Post-ischemic hypothermia delayed neutrophil accumulation and microglial activation following transient focal ischemia in rats. J Neuroimmunol 2000; 109: 66-74.
31. Corbett D, Hamilton M, Colbourne F: Persistent neuroprotection with prolonged postischemic hypothermia in adult rats subjected to transient middle cerebral artery occlusion. Exp Neurol 2000; 163: 200-6.
32. Dietrich W, Busto R, Halley M et al. The importance of brain temperature in alterations of the blood/brain barrier following cerebral ischemia. J Neuropathol Exp Neurol 1990; 49: 486-97.
33. Meden P, Overgaard K, Pedersen H et al. Effect of hypothermia and delayed thrombolysis in a rat embolic stroke model. Acta Neurol Scand 1994; 90: 91-8.
34. Horstmann S, Kalb P, Koziol J et al. Profiles of matrix metalloproteinases, their inhibitors, and laminin in stroke patients: influence of different therapies. Stroke 2003; 34: 2165-70.
35. Zhang ZJ, Sobel RA, Cheng DY et al. Mild hypothermia increases Bcl-2 protein expression following global cerebral ischemia. Mol Brain Res 2001; 95: 75-85.
36. Xu LJ, Yenari MA, Steinberg GK et al. Mild hypothermia reduces apoptosis of mouse neurons in vitro early in the cascade. J Cereb Blood Flow Metab 2002; 22: 21-8.
37. Maier CM, Ahern K, Cheng ML et al. Optimal depth and duration of mild hypothermia in a focal model of transient cerebral ischemia: Effects on neurologic outcome, infarct size, apoptosis, and inflammation. Stroke 1998; 29: 2171-80.
38. Ferrand-Drake M, Wieloch T: The time-course of DNA fragmentation in the choroid plexus and the CA1 region following transient global ischemia in the rat brain. The effect of intra-ischemic hypothermia. Neuroscience 1999; 93: 537-49.
39. Yenari MA, Iwayama S, Cheng D et al. Mild hypothermia attenuates cytochrome c release but does not alter Bcl-2 expression or caspase activation after experimental stroke. J Cereb Blood Flow Metab 2002; 22: 29-38.
40. Eberspacher E, Werner C, Engelhard K et al. Long-term effects of hypothermia on neuronal cell death and the concentration of apoptotic proteins after incomplete cerebral ischemia and reperfusion in rats. Acta Anaesthesiol Scand 2005; 49: 477-8.
41. Wang LM, Yan Y, Zou LJ et al. Moderate hypothermia prevents neural cell apoptosis following spinal cord ischemia in rabbits. Cell Res 2005; 15: 387-93.
42. Lopez M, Sessler DI, Walter K et al. Rate and gender dependence of the sweating, vasoconstriction, and shivering thresholds in humans. Anesthesiology 1994; 80: 780-8.
43. Vassilieff N, Rosencher N, Sessler DI et al. The shivering threshold during spinal anesthesia is reduced in the elderly. Anesthesiology 1995; 83: 1162-6.
44. Hales JRS, Jessen C, Fawcett AA: Skin AVA and capillary dilatation and constriction induced by local skin heating. Pflugers Arch 1985; 404: 203-7.
45. Jessen K: An assessment of human regulatory nonshivering thermogenesis. Acta Anaesthesiol Scand 1980; 24: 138-43.
46. Hynson JM, Sessler DI, Moayeri A: Absence of nonshivering thermogenesis in anesthetized humans. Anesthesiology 1993; 79: 695-703.
47. Doufas AG, Lin CM, Suleman MI et al. Dexmedetomidine and meperidine additively reduce the shivering threshold in humans. Stroke 2003; 34: 1218-23.
48. Kurz A, Ikeda T, Sessler DI: Meperidine decreases the shivering threshold twice as much as the vasoconstriction threshold. Anesthesiology 1997; 86: 1046-54.
49. Kurz M, Belani K, Sessler DI: Naloxone, medeprine, and shivering. Anesthesiology 1993; 79: 1193-201.
50. Burks L, Aisner J, Fortner CL: Meperidine for the treatment of shaking chills and fever. Arch Intern Med 1980; 140: 483-4.
51. Alfonsi P, Sessler DI, Du Manoir B: The effects of meperidine and sufentanil on the shivering threshold in postoperative patients. Anesthesiology 1998; 89: 43-8.
52. Mokhtarani M, Mahgoub AN, Morioka M et al. Buspirone and mederidine synergistically reduce the shivering threshold. Anesth Analg 2001; 93: 1233-9.
53. Ginefri-Gayet M, Gayet J: Hypothermia induced by infusion of methionine sulfoximine into the dorsal raphe nucleus of the rat: Involvement of 5-HT 1A and GABA-B receptors. Eur J Pharmacol 1993; 235: 189-96.
54. Lee HS, Meltzer H: Buspirone does not produce a 5-HT1A-mediated decrease in temperature in man. J Neural Transm Gen Sect 1991; 86: 71-6.
55. Feldberg W, Myers RD: Effects on temperature of amines injected into the cerebral ventricles: A new concept of temperature regulation. J Physiol 1964; 173: 226-37.
56. Gordon CJ: Temperature Regulation in Laboratory Rodents. Cambridge: Cambridge University Press, 1993.
57. Venn RM, Hell J, Grounds RM: Respiratory effects of dexmedetomidine in the surgical patient requiring intensive care. Crit Care 2000; 4: 302-8.
58. Baker C, Onesti S, Barth K et al. Hypothermic protection following middle cerebral artery occlusion in the rat. Surg Neurol 1991; 36: 175-80.
59. Onesti S, Baker C, Sun P et al. Transient hypothermia reduces focal ischemic brain injury in the rat. Neurosurgery 1991; 29: 369-73.
60. Baker C, Onesti S, Solomon R: Reduction by delayed hypothermia of cerebral infarction following middle cerebral artery occlusion in the rat: A time-course study. J Neurosurg 1992; 77: 438-44.
61. Morikawa 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 1992; 12: 380-9.
62. Ridenour TR, Warner DS, Todd MM et al. Mild hypothermia reduces infarct size resulting from temporary but not permanent focal ischemia in rats. Stroke 1992; 23: 733-8.
63. Barone FC, Feuerstein GZ, White RF: Brain cooling during transient focal ischemia provides complete neuroprotection. Neurosc Biobehav Rev 1997; 21: 31-44.
64. Chen H, Chopp M, Welch KMA: Effect of mild hyperthermia on the ischemic infarct volume after middle cerebral artery occlusion in the rat. Neurology 1991; 41: 1133-5.
65. Zhang R-L, Chopp M, Chen H et al. Postischemic (1 hour) hypothermia significantly reduces ischemic cell damage in rats subjected to 2 hours of middle cerebral artery occlusion. Stroke 1993; 24: 1235-40.
66. Yanamoto H, Nagata I, Nakahara I et al. Combination of intraischemic and postischemic hypothermia provides potent and persistent neuroprotection against temporary focal ischemia in rats. Stroke 1999; 30: 2720-6.
67. Yamamoto H, Nagata I, Niitsu Y et al. Prolonged mild hypothermia therapy protects the brain against permanent ischemia. Stroke 2001; 32: 232-9.
68. Yenari MA, Onley D, Hedehus M et al. Diffusion- and perfusion-weighted magnetic resonance imaging of focal cerebral ischemia and cortical spreading depression under conditions of mild hypothermia. Brain Res 2000; 885: 208-19.
69. Mancuso A, Derugin N, Hara K et al. Mild hypothermia decreases the incidence of transient ADC reduction detected with diffusion MRI and expression of c-fos and hsp70 mRNA acute focal ischemia in rats. Brain Res 2000; 887: 34-45.
70. Zausinger S, Hungerhuber E, Baethmann A et al. Neurological impairment in rats after transient middle cerebral artery occlusion: A comparative study undre various treatment paradigms. Brain Res 2000; 863: 94-105.
71. Maier CM, Sun GH, Kunis D et al. Delayed induction and long-term effects of mild hypothermia in a focal model of transient cerebral ischemia: neurological outcome and infarct size. J Neurosurg 2001; 94: 90-6.
72. Huh PW, Belayev L, Zhao W et al. Comparative neuroprotective efficacy of prolonged moderate intraischemic and postischemic hypothermia in focal cerebral ischemia. J Neurosurg 2000; 92: 91-9.
73. Colbourne F, Corbett D, Zhao Z et al. Prolonged but delayed postischemic hypothermia: A long term outcome study in the rat middle cerebral artery occlusion model. J Cereb Blood Flow Metab 2000; 20: 1702-8.
74. Busto R, Dietrich W, Globus M: Small differences in intraischemic brain temperature critically determines the extent of neuronal injury. J Cereb Blood Flow Metab 1987; 7: 729-38.
75. Chopp M, Chen H, Dereski MO et al. Mild hypothermic intervention after graded ischemic stress in rats. Stroke 1991; 22: 37-43.
76. Minamisawa H, Smith ML, Siesjo BK: The effect of mild hyperthermia and hypothermia on brain damage following 5, 10, and 15 minutes of forebrain ischemia. Ann Neurol 1990; 28: 26-33.
77. Sano T, Drummond JC, Patel PM et al. A comparison of the cerebral protective effects of isoflurane and mild hypothermia in a model of incomplete forebrain ischemia in the rat. Anesthesiology 1992; 76: 221-8.
78. Kader A, Brisman MH, Maraire N et al. The effect of mild hypothermia on permanent focal ischemia in the rat. Neurosurgery 1992; 31: 1056-60.
79. Ikonomidou C, Mosinger JL, Olney JW: Hypothermia enhances protective effect of MK-801 against hypoxic/ischemic brain damage in infant rats. Brain Res 1989; 487: 184-7.
80. Buchan A, Pulsinelli WA: Hypothermia but not the N-methyl-d-aspartate antagonist, MK-801, attenuates neuronal damage in gerbils subjected to transient global ischemia. J Neurosci 1990; 10: 311-6.
81. Welsh FA, Sims RE, Harris VA: Mild hypothermia prevents ischemic injury in gerbil hippocampus. J Cereb Blood Flow Metab 1990; 10: 557-63.
82. Welsh FA, Harris VA: Postischemic hypothermia fails to reduce ischemic injury in gerbil hippocampus. J Cereb Blood Flow Metab 1991; 11: 617-20.
83. Green EJ, Dietrich WD, van Dijk F et al. Protective effects of brain hypothermia on behavior and histopathology following global cerebral ischemia in rats. Brain Res 1992; 580: 197-204.
84. Carroll M, Beek O: Protection against hippocampal CA1 cell loss by post-ischemic hypothermia is dependent on delay of initiation and duration. Metab Brain Dis 1992; 7: 45-50.
85. Dietrich WD, Busto R, Alonso O et al. Intraischemic but not postischemic brain hypothermia protects chronically following global forebrain ischemia in rats. J Cereb Blood Flow Metab 1993; 13: 541-9.
86. Colbourne F, Corbett D: DelaAed postischemic hypothermia: a six month survival study using behavioral and histological assessments of neuroprotection. J Neurosci 1995; 15: 7250-6.
87. Colbourne F, Li H, Buchan A: Indefatigable CA1 sector neuroprotection with mild hypothermia induced 6 hours after severe forebrain ischemia in rats. J Cereb Blood Flow Metab 1999; 19: 742-9.
88. Shiozaki T, Sugimoto H, Taneda M et al. Selection of severely head injured patients for mild hypothermia therapy. J Neurosurg 1999; 90: 607-8.
89. Marion D, Penrod L, Kelsey S et al. Treatment of traumatic brain injury with moderate hypothermia. N Engl J Med 1997; 336: 540-6.
90. Clifton GL, Miller ER, Choi S et al. Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med 2001; 344: 556-63.
91. Yanagawa YIS, Norio H: Preliminary clinical outcome study of mild resuscitative hypothermia after out-of-hospital cardiopulomonary arrest. Resuscitation 1998; 39: 61-6.
92. Bernard SA GT, Buist MD, Jones BM et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002; 346: 557-63.
93. Felberg RA, Krieger D, Chuang R et al. Hypothermic neurologic protection after cardiac arrest: A pilot feasibility study. Circulation 2001; 104: 1799-804.
94. The Hypothermia After Cardiac Arrest Study Group: Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002; 346: 549-56.
95. Zeiner AHM, Sterz F: Mild resuscitative hypothermia to improve neurological outcome after cardiac arrest: A clinical feasibility trial. Stroke 2000; 31: 86-94.
96. Schwab S, Schwarz S, Spranger M et al. Moderate hypothermia in the treatment of patients with severe middle cerebral artery infarction. Stroke 1998; 29: 2461-6.
97. Schwab S, Georgiadis D, Berrouschot J et al. Feasibility and safety of moderate hypothermia after massive hemispheric infarction. Stroke 2001; 32: 2033-5.
98. Kammersgaard L, Rasmussen BH, Jorgensen HS et al. Feasibility and safety of inducing modest hypothermia in awake patients with acute stroke through surface cooling: A case-control study. Stroke 2000; 31: 2251-6.
99. Krieger D, De Georgia M, Abou-Chebl A et al. COOLing for Acute Ischemic brain Damage (COOL AID). Stroke 2001; 32: 1847-54.
100. De Georgia MA, Krieger DW, Abou-Chebl A et al. Cooling for Acute Ischemic Brain Damage (COOL AID): A feasibility trial of endovascular cooling. Neurology 2004; 63: 312-7.
101. Lyden P, Allgren R, Ng K et al. Intravascular cooling in the treatment of stroke (ICTuS): Early clinical experience. J Stroke Cerebrovasc Dis 2005; 14: 107-14.
102. Zweifler R, Voorhees ME, Mahmood MA et al. Induction and maintenance of mild hypothermia by surface cooling in non-intubated subjects. J Stroke Cerebrovasc Dis 2003; 12: 237-43.
103. Mayer SA, Kowalski RG, Presciutti M et al. Clinical trial of a novel surface cooling system for fever control in neurocritical care patients. Crit Care Med 2004; 32: 2508-15.
104. Bristow GK, Biesbrecht GG, Sessler DI: Leg temperature and heat content in humans during immerson hypothermia and rewarming. Aviat Space Environ Med 1994; 65: 220 -6.
105. Georgiadis D, Schwarz S, Kollmar R et al. Endovascular cooling for moderate hypothermia in patients with acute stroke: First results of a novel approach. Stroke 2001; 32: 2550-3.
106. Baumgardner J, Baranov D, Smith DS et al. The effectiveness of rapidly infused intravenous fluids for inducing moderate hypothermia in neurosurgical patients. Anesth Analg 1999; 89: 163-9.
107. Inderbitzen B, Yon S, Lasheras J et al. Safety and performance of a novel intravascular catheter for induction and reversal of hypothermia in a porcine model. Neurosurgery 2002; 50: 364-70.
108. Mack WJ, Huang J, Winfree C et al. Ultrarapid, convection-enhanced intravascular hypothermia; a feasability study in nonhuman primate stroke. Stroke 2003; 34: 1994-9.
109. Yenari MA, Palmer JT, Bracci PM et al. Thrombolysis with tissue plasminogen activator (TPA) is temperature dependent. Thromb Res 1995; 77: 475-81.
110. Schwarzenberg H, Muller-Hulsbeck S, Brossman J et al. Hyperthermic fibrinolysis with rt-PA: In vitro results. Cardiovasc Intervent Radiol 1998; 21: 142-5.
111. Dae MW, Gao DW, Ursell PC et al. Safety and efficacy of endovascular cooling and rewarming for induction and reversal of hypothermia in human-sized pigs. Stroke 2003; 34: 734-8.
112. Watts DD, Trask A, Soeken K et al. Hypothermic coagulopathy in trauma: effect of varying levels of hypothermia on enzyme speed, platelet function, and fibrinolytic activity. J Trauma 1998; 44: 846-54.
113. Resnick DK, Marion D, Darby J: The effect of hypothermia on the incidence of delayed traumatic intracerebral hemorrhage. Neurosurgery 1994; 34: 252-6.
114. Lapchak PA, Chapman DF, Zivin JA: Metalloproteinase inhibition reduces thrombolytic (tissue plasminogen activator)-induced hemorrhage after thromboembolic stroke. Stroke 2000; 31: 3034-40.
115. Sumii T, Lo EH: Involvement of matrix metalloproteinase in thrombolysis-associated hemorrhagic transformation after embolic focal ischemia in rats. Stroke 2002; 33: 831-6.
116. Christou I, Burgin WS, Alexandrov AV et al. Arterial status after intravenous TPA therapy for ischaemic stroke. A need for further interventions. Int Angiol 2001; 20: 208-13.
117. Alexandrov AV, Grotta JC: Arterial reocclusion in stroke patients treated with intravenous tissue plasminogen activator. Neurology 2002; 59: 862-7.
118. Iaizzo PA, Jeon YM, Sigg DC: Facial warming increases the threshold for shivering. J Neurosurg Anesthesiol 1999; 11: 231-9.
119. Lyden P, Jackson-Friedman C, Shin C et al. Synergistic combinatorial stroke therapy: A quantal bioassay of a GABA agonist and a glutamate antagonist. Exp Neurol 2000; 163: 477 -89.