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March 23, 1984, Vol 251, No. 12 >
ARTICLE | March 23, 1984

Brain Ischemic Anoxia: Title and subTitle BreakMechanisms of Injury FREE

Blaine C. White, MD; John G. Wiegenstein, MD; Carl D. Winegar, MD
[+] Author Affiliations

Reprint requests to Section of Emergency Medicine, Department of Medicine, Room A-206, East Fee Hall, Michigan State University, East Lansing, MI 48824 (Dr White).


JAMA. 1984;251(12):1586-1590. doi:10.1001/jama.1984.03340360052029
Text Size: A A A
Published online
Article
References

THE DEVELOPMENT of effective therapy to preserve normal neurological function in patients surviving a cardiac arrest hinges on our growing understanding of the pathophysiology of ischemic anoxia. It is worthwhile, then, to review our new understanding of these mechanisms, as well as the laboratory search for therapies to protect neurons injured by cardiac arrest.

The early doctrine that four to six minutes of ischemic anoxia leads to irreversible brain injury was based on work done in the 1940s with dogs subjected to breathing 100% nitrogen.1,2 However, it became apparent from work by Ames and Guarian3 and Hossman and Kleihues4 that the neurons themselves have substantial intrinsic resistance to complete ischemic anoxia. The evidence suggests that CNS neurons can tolerate between 20 and 60 minutes of complete ischemic anoxia without irreversible injury. Following these severe insults, neurons regain the ability to synthesize protein, produce adenosine triphosphate (ATP), and

REFERENCES

1 +
Heymans C:  Survival and revival of nervous tissue after arrest of circulation . Physiol Rev 1950;;30:375-382.
2 +
Weinberger LM, Gibbon MH, Gibbon JH:  Temporary arrest of the circulation to the central nervous system: I. Physiologic effects . Arch Neurol 1940;;43:615-621.
3 +
Ames A III, Guarian BS:  Effects of glucose deprivation on function of isolated mammalian retina . J Neurophysiol 1963;;26:617-634.
4 +
Hossman KA, Kleihues P:  Reversibility of ischemic brain damage . Arch Neurol 1973;;29:375-384.
5 +
Ames A III, Wright RL, Kowada M, et al:  Cerebral ischemia: II. The no reflow phenomenon . Am J Pathol 1968;;52:437-453.
6 +
Drewes LR, Gilboe DD, Betz AL:  Metabolic alterations in brain during anoxic-anoxia and subsequent recovery . Arch Neurol 1973;;29:385-390.
7 +
Rehncrona S, Abdul-Rahman A, Siesjo BK:  Local cerebral blood flow in the post ischemic period . Acta Neurol Scand 1979;;60( (suppl) ):294-295.
8 +
Snyder JV, Nemoto EM, Carrol RG, et al:  Global ischemia in dogs: Intracranial pressure, brain blood flow, and metabolism . Stroke 1975;; 6:21-27.
9 +
Gadzinski DS, White BC, Hoehner PJ, et al:  Alterations in canine cerebral cortical blood flow and vascular resistance post cardiac arrest . Ann Emerg Med 1982;;11:58-63.
10 +
Chiang J, Kowada M, Ames A III, et al:  Cerebral ischemia: III. Vascular changes . Am J Pathol 1968;;52:455-476.
11 +
Ljunggren B, Schultz H, Siesjo BK:  Changes in energy state and acid-base parameters of the rat brain during complete compression ischemia . Brain Res 1974;;73:277-289.
12 +
Seimkowicz E, Hansen AJ:  Brain extracellular ion composition and EEG activity following ten minutes ischemia in normo- and hyperglycemic rats . Stroke 1981;;12:236-240.
13 +
Hossman KA:  Neuronal survival and revival during and after cerebral ischemia . Am J Emerg Med 1983;;1:191-197.
14 +
Nemoto EM, Sjiu GK, Nemmer JP, et al:  Free fatty acid accumulation in the pathogenesis of cerebral ischemic-anoxic injury . Am J Emerg Med 1983;;1:175-179.
15 +
Siesjo BK:  Cell damage in the brain: A speculative synthesis . J Cereb Blood Flow Metab 1981;;1:155-185.
16 +
Aveldaño MI, Bazán NG:  Rapid production of diacylglycerols enriched in arachidonate and stearate during early brain ischemia . J Neurochem 1975;;25:919-920.
17 +
Gaudet RJ, Levine L:  Transient cerebral ischemia and brain prostaglandins . Biochem Biophys Res Commun 1979;;86:893-901.
18 +
Chan PH, Fishman RA:  Transient formation of superoxide radicals in polyunsaturated fatty acid induced brain swelling . J Neurochem 1978;;35:1004-1007.
19 +
Raichle ME:  The pathophysiology of brain ischemia . Ann Neurol 1983;;13:2-10.
20 +
Hallenbeck JM, Furlow TW:  Prostaglandin 12 and indomethacin prevent impairment of post-ischemic brain reperfusion in the dog . Stroke 1979;;10:629-637.
21 +
Thomas MJ, Mehl KS, Pryor WA:  The role of the superoxide anion in the xanthine oxidase induced autoxidation of linoleic acid . Biochem Biophys Res Commun 1978;;83:927-932.
22 +
Brawn K, Fridovich I:  Superoxide radical and superoxide dismutases: Threat and defence . Acta Physiol Scand 1980;;492( (suppl) ):9-18.
23 +
Del Maestro RF, Thaw HH, Bjork J, et al:  Free radicals as mediators of tissue injury . Acta Physiol Scand 1980;;492( (suppl) ):43-58.
24 +
Demopoulos HB, Flamm ES, Pictronigro DD, et al:  The free radical pathology and the microcirculation in the major CNS disorders . Acta Physiol Scand 1980;;492( (suppl) ):91-118.
25 +
Cooper AJ, Pulsineli WA, Duffy TF:  Glutathione and ascorbate during ischemia and postischemic reperfusion in the rat brain . J Neurochem 1980;;35:1242-1245.
26 +
Katz AM, Reuter H:  Cellular calcium and cardiac cell death . Am J Cardiol 1979;;44:188-190.
27 +
Dipolo R:  Ca2+ pump driven by ATP in squid axons . Nature 1978;;274:390-392.
28 +
Blaustein MP:  The interrelationship between sodium and calcium fluxes across cell membranes . Rev Physiol Biochem Pharmacol 1974;;70:33-82.
29 +
Mitchell P:  Chemiosmotic hypothesis of oxidative phosphorylation . Nature 1967;;213:137-139.
30 +
Lehninger AL:  Role of phosphate and other proton donating cations in respiration coupled transport of Ca2+ by mitochondria . Proc Natl Acad Sci USA 1974;;71:1520-1524.
31 +
Madeira VMC:  Proton movements across the membranes of sarcoplasmic reticulum during the uptake of Ca2+ . Arch Biochem Biophys 1980;;200:319-325.
32 +
Winegar CP, White BC:  Physiology of resuscitation . Emerg Med Clin 1983;;1:5-17.
33 +
Vykocil F, Kritz N, Bures J:  Potassium selective microelectrodes used for measuring the extracellular brain K+ during spreading depression and anoxic depolarization in rats . Brain Res 1972;;39:255-259.
34 +
Van Neuten JM, Vanhoutte PM:  Improvement of tissue perfusion with inhibitors of Ca2+ influx . Biochem Pharmacol 1980;;29:479-481.
35 +
Hass WK:  Beyond cerebral blood flow, metabolism, and ischemic thresholds: An examination of the role of Ca2+ in the initiation of cerebral infarction , in Cerebral Vascular Disease: Proceedings of the Saltzburg Conference on Cerebral Vascular Disease. Amsterdam, Excerpta Medica, 1981 , vol 3, pp 3-17.
36 +
Stueven H, Thompson BM, Aprahamian C, et al:  Use of calcium in prehospital cardiac arrest . Ann Emerg Med 1983;;12:136-139.
37 +
Steen PA, Michenfelder JD, Milde JH:  Incomplete versus complete cerebral ischemia: Improved outcome with a minimal blood flow . Ann Neurol 1979;;6:389-394.
38 +
Rehncrona S, Kagstrom E:  Tissue lactic acidosis and ischemic brain damage . Am J Emerg Med 1983;;1:168-174.
39 +
Rehncrona S, Mela L, Siesjo BK:  Recovery of brain mitochondrial function in the rat after complete and incomplete cerebral ischemia . Stroke 1979;;10:437.
40 +
Nordstrom CH, Rehncrona S, Siesjo BK:  Restitution of cerebral energy state after 30 minutes of complete ischemia in rats . J Neurochem 1978;;30:479-486.
41 +
White BC, Winegar CP, Jackson RE, et al:  Cerebral cortical perfusion during and following resuscitation from cardiac arrest in dogs . Am J Emerg Med 1983;;1:128-138.
42 +
Koehler RC, Chandra N, Guerci AD, et al:  Augmentation of cerebral perfusion by simultaneous chest compression and lung inflation with abdominal binding after cardiac arrest in dogs . Circulation 1983;;67:266-275.
43 +
Luce JM, Ross BK, O'Quin RJ, et al:  Regional blood flow during cardiopulmonary resuscitation in dogs using simultaneous and nonsimultaneous compression and ventilation . Circulation 1983;;67:258-265.
44 +
Bircher NG, Safar P:  Cerebral preservation during cardiopulmonary resuscitation (CPR) in dogs . Anesthesiology 1983;;59:A93.
45 +
Bergner L, Eisenberg MS, Hallstrom A, et al: Evaluation of Paramedic Services for Cardiac Arrest . US Dept of Health and Human Services, HS 02456. National Center for Health Services Research Report, (December) 1981;.
46 +
Mirick MJ, Mahoney BD, Sherman R, et al:  Refractory prehospital cardiac arrest: A contrast from previously reported prognostic indicators . Presented at the University Association for Emergency Medicine-Scientific Assembly, Salt Lake City, April 16, 1982 .
47 +
Eisenberg MS, Copass MK, Hallstrom A, et al:  Management of out-of-hospital cardiac arrest: Failure of basic emergency medical technician services . JAMA 1980;;243:1049.
48 +
Babbs CF:  Regional blood flow during interposed abdominal counterpulsation CPR . Am J Emerg Med , in press.
49 +
Walker JW, Bruestle JC, White BC, et al:  Perfusion of the cerebral cortex using abdominal counterpulsation during CPR . Am J Emerg Med , in press.
50 +
Jackson RE, Joyce K, Danosi S, et al:  Cerebral cortical perfusion during cardiac resuscitation in dogs . Ann Emerg Med 1983;;12:257.
51 +
Hoffmeister F, Kazda S, Krause HP:  Influence of nimodipine on the post ischemic changes of brain function . Acta Neurol Scand 1979;; 60( (suppl 72) ):358-359.
52 +
Steen PA, Newburg LA, Milde JH, et al:  Nimodipine improves cerebral blood flow and neurologic recovery after complete cerebral ischemia in the dog . J Cereb Blood Flow Metab 1983;;3:38-42.
53 +
White BC, Winegar CD, Wilson RF, et al:  Calcium blockers in cerebral resuscitation . J Trauma 1983;;23:788-793.
54 +
Hong SCL, Levine L:  Inhibition of arachidonic acid release from cells as the biochemical action of steroids . Proc Natl Acad Sci USA 1976;;73:1730-1734.
55 +
Aragno R, Doni MG:  The exclusion of the cerebral circulation: Effect on the in vivo platelet aggregation . Thromb Res 1976;;9:319-325.
56 +
Winegar CP, Henderson O, White BC, et al:  Early amelioration of neurologic deficit by lidoflazine after 15 minutes of cardiopulmonary arrest in dogs . Ann Emerg Med 1983;;12:470-476.
57 +
Wauquier A, Ashton D, Hermans C, et al:  Pharmacological effects in protective and resuscitative models of brain hypoxia , in Hoyer S, Wiedmann K (eds): Workshop on Problems and Perspectives of Brain Protection . New York, Springer Publishing Co Inc, 1982;.
58 +
Schwartz AC:  Calcium blockers: Status post cardiac arrest . Ann Emerg Med 1983;; 12:137.
59 +
Weishaar RE, Bing RJ:  The beneficial effect of a calcium channel blocker, diltiazem, on the ischemic-reperfused heart . Mol Cell Cardiol 1980;;12:993-998.
60 +
Borle AB:  Control, modulation, and regulation of cell calcium . Rev Physiol Biochem Pharmacol 1981;;90:13-153.
61 +
Flaim SF, Irwin JM, Ratz PH, et al:  Differential effects of calcium channel blocking agents on oxygen consumption rate in vascular smooth muscle . Am J Cardiol 1982;;49:511-520.

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Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
Heymans C:  Survival and revival of nervous tissue after arrest of circulation . Physiol Rev 1950;;30:375-382.
2 +
Weinberger LM, Gibbon MH, Gibbon JH:  Temporary arrest of the circulation to the central nervous system: I. Physiologic effects . Arch Neurol 1940;;43:615-621.
3 +
Ames A III, Guarian BS:  Effects of glucose deprivation on function of isolated mammalian retina . J Neurophysiol 1963;;26:617-634.
4 +
Hossman KA, Kleihues P:  Reversibility of ischemic brain damage . Arch Neurol 1973;;29:375-384.
5 +
Ames A III, Wright RL, Kowada M, et al:  Cerebral ischemia: II. The no reflow phenomenon . Am J Pathol 1968;;52:437-453.
6 +
Drewes LR, Gilboe DD, Betz AL:  Metabolic alterations in brain during anoxic-anoxia and subsequent recovery . Arch Neurol 1973;;29:385-390.
7 +
Rehncrona S, Abdul-Rahman A, Siesjo BK:  Local cerebral blood flow in the post ischemic period . Acta Neurol Scand 1979;;60( (suppl) ):294-295.
8 +
Snyder JV, Nemoto EM, Carrol RG, et al:  Global ischemia in dogs: Intracranial pressure, brain blood flow, and metabolism . Stroke 1975;; 6:21-27.
9 +
Gadzinski DS, White BC, Hoehner PJ, et al:  Alterations in canine cerebral cortical blood flow and vascular resistance post cardiac arrest . Ann Emerg Med 1982;;11:58-63.
10 +
Chiang J, Kowada M, Ames A III, et al:  Cerebral ischemia: III. Vascular changes . Am J Pathol 1968;;52:455-476.
11 +
Ljunggren B, Schultz H, Siesjo BK:  Changes in energy state and acid-base parameters of the rat brain during complete compression ischemia . Brain Res 1974;;73:277-289.
12 +
Seimkowicz E, Hansen AJ:  Brain extracellular ion composition and EEG activity following ten minutes ischemia in normo- and hyperglycemic rats . Stroke 1981;;12:236-240.
13 +
Hossman KA:  Neuronal survival and revival during and after cerebral ischemia . Am J Emerg Med 1983;;1:191-197.
14 +
Nemoto EM, Sjiu GK, Nemmer JP, et al:  Free fatty acid accumulation in the pathogenesis of cerebral ischemic-anoxic injury . Am J Emerg Med 1983;;1:175-179.
15 +
Siesjo BK:  Cell damage in the brain: A speculative synthesis . J Cereb Blood Flow Metab 1981;;1:155-185.
16 +
Aveldaño MI, Bazán NG:  Rapid production of diacylglycerols enriched in arachidonate and stearate during early brain ischemia . J Neurochem 1975;;25:919-920.
17 +
Gaudet RJ, Levine L:  Transient cerebral ischemia and brain prostaglandins . Biochem Biophys Res Commun 1979;;86:893-901.
18 +
Chan PH, Fishman RA:  Transient formation of superoxide radicals in polyunsaturated fatty acid induced brain swelling . J Neurochem 1978;;35:1004-1007.
19 +
Raichle ME:  The pathophysiology of brain ischemia . Ann Neurol 1983;;13:2-10.
20 +
Hallenbeck JM, Furlow TW:  Prostaglandin 12 and indomethacin prevent impairment of post-ischemic brain reperfusion in the dog . Stroke 1979;;10:629-637.
21 +
Thomas MJ, Mehl KS, Pryor WA:  The role of the superoxide anion in the xanthine oxidase induced autoxidation of linoleic acid . Biochem Biophys Res Commun 1978;;83:927-932.
22 +
Brawn K, Fridovich I:  Superoxide radical and superoxide dismutases: Threat and defence . Acta Physiol Scand 1980;;492( (suppl) ):9-18.
23 +
Del Maestro RF, Thaw HH, Bjork J, et al:  Free radicals as mediators of tissue injury . Acta Physiol Scand 1980;;492( (suppl) ):43-58.
24 +
Demopoulos HB, Flamm ES, Pictronigro DD, et al:  The free radical pathology and the microcirculation in the major CNS disorders . Acta Physiol Scand 1980;;492( (suppl) ):91-118.
25 +
Cooper AJ, Pulsineli WA, Duffy TF:  Glutathione and ascorbate during ischemia and postischemic reperfusion in the rat brain . J Neurochem 1980;;35:1242-1245.
26 +
Katz AM, Reuter H:  Cellular calcium and cardiac cell death . Am J Cardiol 1979;;44:188-190.
27 +
Dipolo R:  Ca2+ pump driven by ATP in squid axons . Nature 1978;;274:390-392.
28 +
Blaustein MP:  The interrelationship between sodium and calcium fluxes across cell membranes . Rev Physiol Biochem Pharmacol 1974;;70:33-82.
29 +
Mitchell P:  Chemiosmotic hypothesis of oxidative phosphorylation . Nature 1967;;213:137-139.
30 +
Lehninger AL:  Role of phosphate and other proton donating cations in respiration coupled transport of Ca2+ by mitochondria . Proc Natl Acad Sci USA 1974;;71:1520-1524.
31 +
Madeira VMC:  Proton movements across the membranes of sarcoplasmic reticulum during the uptake of Ca2+ . Arch Biochem Biophys 1980;;200:319-325.
32 +
Winegar CP, White BC:  Physiology of resuscitation . Emerg Med Clin 1983;;1:5-17.
33 +
Vykocil F, Kritz N, Bures J:  Potassium selective microelectrodes used for measuring the extracellular brain K+ during spreading depression and anoxic depolarization in rats . Brain Res 1972;;39:255-259.
34 +
Van Neuten JM, Vanhoutte PM:  Improvement of tissue perfusion with inhibitors of Ca2+ influx . Biochem Pharmacol 1980;;29:479-481.
35 +
Hass WK:  Beyond cerebral blood flow, metabolism, and ischemic thresholds: An examination of the role of Ca2+ in the initiation of cerebral infarction , in Cerebral Vascular Disease: Proceedings of the Saltzburg Conference on Cerebral Vascular Disease. Amsterdam, Excerpta Medica, 1981 , vol 3, pp 3-17.
36 +
Stueven H, Thompson BM, Aprahamian C, et al:  Use of calcium in prehospital cardiac arrest . Ann Emerg Med 1983;;12:136-139.
37 +
Steen PA, Michenfelder JD, Milde JH:  Incomplete versus complete cerebral ischemia: Improved outcome with a minimal blood flow . Ann Neurol 1979;;6:389-394.
38 +
Rehncrona S, Kagstrom E:  Tissue lactic acidosis and ischemic brain damage . Am J Emerg Med 1983;;1:168-174.
39 +
Rehncrona S, Mela L, Siesjo BK:  Recovery of brain mitochondrial function in the rat after complete and incomplete cerebral ischemia . Stroke 1979;;10:437.
40 +
Nordstrom CH, Rehncrona S, Siesjo BK:  Restitution of cerebral energy state after 30 minutes of complete ischemia in rats . J Neurochem 1978;;30:479-486.
41 +
White BC, Winegar CP, Jackson RE, et al:  Cerebral cortical perfusion during and following resuscitation from cardiac arrest in dogs . Am J Emerg Med 1983;;1:128-138.
42 +
Koehler RC, Chandra N, Guerci AD, et al:  Augmentation of cerebral perfusion by simultaneous chest compression and lung inflation with abdominal binding after cardiac arrest in dogs . Circulation 1983;;67:266-275.
43 +
Luce JM, Ross BK, O'Quin RJ, et al:  Regional blood flow during cardiopulmonary resuscitation in dogs using simultaneous and nonsimultaneous compression and ventilation . Circulation 1983;;67:258-265.
44 +
Bircher NG, Safar P:  Cerebral preservation during cardiopulmonary resuscitation (CPR) in dogs . Anesthesiology 1983;;59:A93.
45 +
Bergner L, Eisenberg MS, Hallstrom A, et al: Evaluation of Paramedic Services for Cardiac Arrest . US Dept of Health and Human Services, HS 02456. National Center for Health Services Research Report, (December) 1981;.
46 +
Mirick MJ, Mahoney BD, Sherman R, et al:  Refractory prehospital cardiac arrest: A contrast from previously reported prognostic indicators . Presented at the University Association for Emergency Medicine-Scientific Assembly, Salt Lake City, April 16, 1982 .
47 +
Eisenberg MS, Copass MK, Hallstrom A, et al:  Management of out-of-hospital cardiac arrest: Failure of basic emergency medical technician services . JAMA 1980;;243:1049.
48 +
Babbs CF:  Regional blood flow during interposed abdominal counterpulsation CPR . Am J Emerg Med , in press.
49 +
Walker JW, Bruestle JC, White BC, et al:  Perfusion of the cerebral cortex using abdominal counterpulsation during CPR . Am J Emerg Med , in press.
50 +
Jackson RE, Joyce K, Danosi S, et al:  Cerebral cortical perfusion during cardiac resuscitation in dogs . Ann Emerg Med 1983;;12:257.
51 +
Hoffmeister F, Kazda S, Krause HP:  Influence of nimodipine on the post ischemic changes of brain function . Acta Neurol Scand 1979;; 60( (suppl 72) ):358-359.
52 +
Steen PA, Newburg LA, Milde JH, et al:  Nimodipine improves cerebral blood flow and neurologic recovery after complete cerebral ischemia in the dog . J Cereb Blood Flow Metab 1983;;3:38-42.
53 +
White BC, Winegar CD, Wilson RF, et al:  Calcium blockers in cerebral resuscitation . J Trauma 1983;;23:788-793.
54 +
Hong SCL, Levine L:  Inhibition of arachidonic acid release from cells as the biochemical action of steroids . Proc Natl Acad Sci USA 1976;;73:1730-1734.
55 +
Aragno R, Doni MG:  The exclusion of the cerebral circulation: Effect on the in vivo platelet aggregation . Thromb Res 1976;;9:319-325.
56 +
Winegar CP, Henderson O, White BC, et al:  Early amelioration of neurologic deficit by lidoflazine after 15 minutes of cardiopulmonary arrest in dogs . Ann Emerg Med 1983;;12:470-476.
57 +
Wauquier A, Ashton D, Hermans C, et al:  Pharmacological effects in protective and resuscitative models of brain hypoxia , in Hoyer S, Wiedmann K (eds): Workshop on Problems and Perspectives of Brain Protection . New York, Springer Publishing Co Inc, 1982;.
58 +
Schwartz AC:  Calcium blockers: Status post cardiac arrest . Ann Emerg Med 1983;; 12:137.
59 +
Weishaar RE, Bing RJ:  The beneficial effect of a calcium channel blocker, diltiazem, on the ischemic-reperfused heart . Mol Cell Cardiol 1980;;12:993-998.
60 +
Borle AB:  Control, modulation, and regulation of cell calcium . Rev Physiol Biochem Pharmacol 1981;;90:13-153.
61 +
Flaim SF, Irwin JM, Ratz PH, et al:  Differential effects of calcium channel blocking agents on oxygen consumption rate in vascular smooth muscle . Am J Cardiol 1982;;49:511-520.

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