Survival of the Ischemic Brain:A Progress Report

PERITZ SCHEINBERG, M.D.

SUMMARY The number of patients with cerebral infarctions increases as the population ages, despite cam-paigns against hypertension, the greatest risk factor. Cerebral ischemia initiates events that are presumed todefer the stage of irreversible injury. These events cause an increase of perfusion around the central ischemiczone and trigger the Bohr effect, both of which preserve tissue viability. Almost simultaneously, mitochondrialfunction fails, resulting in insufficient energy for the enzyme systems to control Na and K ion equilibrium. Atthe same time, protein synthesis slows and cellular respiratory enzymes decrease their activity, initiating anirreversible state of tissue change. Tissue fatty acids increase as a result of dissolution of cell membranelipoprotein structure. Barbiturates reduce the extent of experimental infarction. Resperine and aminophyllineare also effective, but there are no corroborative clinical trials. That ischemic brain damage may be the resultof toxic substances in the ischemic tissue represents a new concept.

THE PAST 25 YEARS has witnessed an enthusiasticawakening of interest in the problem of cerebralvascular diseases. The demonstration that arterio-sclerotic lesions of the extracranial arteries were fre-quently responsible for strokes1-3 led directly to an ap-preciation of the significance of certain symptoms andsigns in diagnosis, as well as to a more dynamicclassification of stroke, which focused upon path-ogenesis and management (transient ischemic at-tack, progressing stroke and completed stroke) and tocarotid endarterectomy as a means of preventingcerebral infarction.4-7 Simultaneously, medical pro-phylaxis of cerebral infarction by anticoagulation wasdescribed.8"- This form of therapy remains contro-versial despite many published studies."1-23 Evaluationof therapy required studies on the natural history ofthe various types of occlusive and hemorrhagic cere-bral vascular diseases; though difficult to interpret,these studies sharpened our understanding of theclinical and pathologic problem.24 33 Epidemiologicstudies gradually identified a few obvious risk factorsin cerebral vascular disease34-36 similar to those inarteriosclerotic heart disease that eventually resultedin a modestly successful campaign against hyperten-sion, which is clearly the most important risk fac-tor,34-38 as well as an endorsement of dietary weightcontrol and increased physical activity.

There now appears to be evidence that modest in-roads have been made in reducing the number ofcerebral infractions by means of the variousmodalities described above, as well as by the use ofdrugs that inhibit platelet agglutination.39-47 Despitethese hard-won achievements, the number of patientswith cerebral infarction continues to increase with theage of the population. It is now apparent that, short offinding a means of eliminating atherosclerosis,hypertension and valvular heart disease, the number

From the Department of Neurology, University of Miami Schoolof Medicine, Miami, Florida.

Address for correspondence: Peritz Scheinberg, M.D., Depart-ment of Neurology, University of Miami School of Medicine, P.O.Box 016960, Miami, Florida 33101.

Circulation 60, No. 7, 1979.

of patients with symptomatic cerebral vascular dis-eases will continue to increase. It is also clear that ourability to treat the patient who has already had a"stroke" has not improved measurably in the past 25years, although there have been benefits of better nurs-ing care, more sophisticated life-system monitoringtechniques and improved medical management of thevarious systemic disorders that frequently coexist inthe patient with stroke. The true clinical problem isproper management of cerebral ischemia to preventischemia from becoming infarction.

Insight into the biology of cerebral ischemia hasbeen acquired from studies of patients with strokesand from animal models of cerebral ischemia.Progressively more definitive means of studyingcerebral blood flow, biochemical measurements onischemic brain tissue, histochemical and immuno-fluorescent staining techniques, electron microscopyand electrophysiologic measurements have resulted ina better understanding of the biology of cerebralischemia. Studies using these techniques have begun topermit some insight into the sequence of events incerebral ischemia, and have afforded an opportunityto devise pharmacologic techniques to influence thoseevents. This has been achieved together with an enor-mously improved understanding of normal cerebralcirculatory and metabolic functions, their controls andhow they are affected by disease.48The circulatory physiologic events in cerebral

ischemia have been well documented and can bereviewed briefly:

1) Cerebral blood flow (CBF) is reduced in thecenter of the infarct and increased in the surroundingischemic zone. The hyperemia (sometimes termed"'luxury perfusion") is secondary to increased H+ ionconcentration in brain parenchyma from lactic acidand CO.49-65

2) Autoregulation is impaired, resulting in predict-able clinical consequences."2 66"75

3) There is an inconsistent alteration in vascularresponsivity to Paco2 changes. "Intracerebral steal" isobserved in patients with middle cerebral arteryocclusion.7"-82 Prolonged hypocapnia does not in-fluence the clinical course.76' 77, 83

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4) CBF is decreased in noninfarcted areas of thesame hemisphere and intact hemisphere (diaschi-Sis?)52' 58, 60, 61, 75, 84, 85

5) There is a significant impairment of cerebralrecirculation after ischemia (no-reflow phenomenon)due to swelling of capillary endothelium, swelling ofperivascular glia and increased blood viscosity due tocoagulopathy.86-94

6) Tissue survival during total ischemia is enhancedby washing out residual blood in cerebral vessels at theonset of ischemia.9' 102 Though the mechanism for thisis not understood, it suggests that one deleteriouseffect of ischemia may be an accumulation of "toxic"substance rather than substrate deficiency alone.The sequence of many biochemical and histologic

events in ischemia has also been established from ex-perimental stroke models. Experimental limitationsrelate specifically to the necessity of immobilizing allcerebral metabolic and enzymatic activity instan-taneously. A perfect model does not yet exist, andmodalities for stopping tissue metabolic activity areunder intensive study. A solution will provide a quan-tum leap in stroke research.The evidence suggests that cerebral ischemia ini-

tiates events that defer the stage of irreversible injury.Vascular occlusion is followed by the circulatoryevents previously described, i.e., immediate reductionor loss of substrate (02 and glucose) delivery and in-crease in "waste" products. 02 storage is insignificantso that anaerobic glycolysis is almost instantaneouslyinitiated, even though neuronal mitochondria maycontinue to function until tissue Po2 is about 5torr.'03-106 The consequent increase in tissue lactatealso increases tissue Pco2. The latter is liberated fromthe -HCOS buffer system by lactate and is alsoderived from retained tissue CO2.107-1i These eventsare responsible for the increased perfusion around thecentral ischemia zone; in addition, they stimulate theBohr effect.112- 15 Both mechanisms preserve tissueviability.Almost simultaneously, three other events are

known to occur: Tissue cAMP increases pre-cipitately,"6 119 tissue norepinephrine falls"l9-124 andthe level of ATP, the ATP/ADP ratio and the energycharge of the 5'-adenosine Po4 system and of othercerebral high-energy compounds, such as guaninenucleotides, all decrease simultaneously, reflectingfailure of mitochondrial function.'25-'34 The first twochanges may well provoke other events inimical to cellsurvival. cAMP is a protein kinase activator that mayalter the integrity and survivability of the cell mem-brane.135, 136 The adrenergic discharge may alsoadversely affect cell metabolic activity or constrictcollateral arteries. 117 137, 138 The decrease in tissueenergy charge and alteration of the tissue redox stateresults in insufficient energy for the enzyme systems tocontrol cellular ionic equilibrium so that, in effect,power failure occurs. K+ ions leak out of cells and arereplaced by NA+ ions, and tissue HOH in-creases. 134 135-142 Edema of this type is reversible if theenergy state can be improved.134

Almost simultaneously, there is a decrease in pro-tein synthesis,'30' 143-146 with alteration in tissue aminoacids and an increase in tissue NH3.'32 147-149 Cellularrespiratory enzymes show decreased activity,'50 152 andthe tissue moves into a stage of irreversible change,reflected by an increase in tissue fatty acids associatedwith dissolution of the lipoprotein structure of the cellmembrane. 153-155

The above observations have stimulated the devel-opment of strategies aimed at enhancing tissue survi-val by decreasing those metabolic activities involved incell function so that sufficient energy potential will re-main to preserve cell membrane integrity and preventcell autolysis.

Evidence demonstrates that barbiturates reduce theextent of experimental infarction, an effect that mayhave direct clinical applicability.'16-158 The mecha-nisms responsible for this protective effect have beenthe subject of much interest and study. Several ex-planations have been suggested: 1) improvement ofCBF and brain glucose use in stage of recirculation;1592) no relation to reduced energy requirements of thetissues;'60 and 3) prevention of the initiation of thechain-spreading, free-radical reactions.'61' 162 Otherdrugs, such as reserpine, which depletes tissue storesof monoamines, and aminophylline, which inhibits theischemia-induced rise of cAMP, are also effective infavorably altering the biochemical evidences ofprogressing ischemia,163 but there have been no cor-roborative clinical trials.

Interest has been focused on the concept thatischemic brain damage is not so much a function ofsubstrate deprivation as it is an effect of "toxic sub-stances" in the ischemic tissue. It has been suggestedthat the central nervous system is particularly suscep-tible to free-radical degenerative processes,'61 162, 64 165because membrane lipids undergo pathologic free-radical reactions in the presence of oxygen. The lipiddamage is catalyzed by derivatives from mitochon-drial and endoplasmic reticulum electron transportsystems and extravasated red blood cells. Thesehypotheses, which represent a radical departure fromthe traditional view of the mechanism of tissuedamage in ischemia, await experimental confirmation.

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134. Kogure K, Busto R, Scheinberg P: Energy metabolites andwater content in rat brain during early stage of development ofcerebral infarction. Brain 97: 103, 1974

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Research Related to Validation of TreatmentModalities by Large-scale Clinical Trials

RICHARD D. REMINGTON, M.P.H., PH.D.

SUMMARY The history of randomized, controlled, clinical trials is reviewed. Cooperative clinical trials arereviewed and summarized, and specific needs for future trials are identified. Improved policy on resource

allocation decisions for clinical trials vs other forms of research is necessary, particularly as such trials beginto translate improved therapeutic knowledge into community level disease control.

IN 1949 Sir George Pickering, in his presidential ad-dress to the Section of Experimental Medicine andTherapeutics of the Royal Society of Medicine, said:

Therapeutics is the branch of medicine that, by its very nature,should be experimental. For if we take a patient afflicted with amalady, and we alter his conditions of life, either by dieting him, orby putting him to bed, or by administering to him a drug, or by per-forming on him an operation, we are performing an experiment.And if we are scientifically minded we should record the results.Before concluding that the change for better or for worse in thepatient is due to the specific treatment employed, we must ascertainwhether the result can be repeated a significant number of times insimilar patients, whether the result was merely due to the naturalhistory of the disease or in other words to the lapse of time, orwhether it was due to some other factor which was necessarilyassociated with the therapeutic measure in question. And if, as aresult of these procedures, we learn that the therapeutic measureemployed produces a significant, though not very pronounced, im-provement, we would experiment with the method altering dosageor other detail to see if it can be improved. This would seem theprocedure to be expected of men with six years of scientific trainingbehind them. But it has not been followed. Had it been done, weshould have gained a fairly precise knowledge of the place of in-dividual methods of therapy in disease, and our efficiency as doctorswould have been enormously enhanced.'

From the University of Michigan School of Public Health, AnnArbor, Michigan.

Address for correspondence: Richard D. Remington, M.P.H.,Ph.D., Dean, University of Michigan School of Public Health, AnnArbor, Michigan 48109.

Circulation 60, No. 7, 1979.

Treatment of atherosclerosis and hypertension haschanged dramatically since Sir George made thatstatement. Therapeutic evaluation has improved sincethen, but much improvement lies ahead, and the at-titudes against systematic assessment of therapeuticsafety and efficacy still persist, though they are not asstrong as in the 1940s.The history of clinical trials is temporally parallel to

the history of the National Heart, Lung, and BloodInstitute (NHLBI) and the American Heart Associa-tion (AHA). The first paper that fully describedmethodologic standards for the clinical trial waspublished by Sir Austin Bradford Hill in 1951.2 In1959, Professor Greenberg published his importantmethodologic advice on the conduct of cooperativefield and clinical trials.3 By the mid-1960s, the HeartSpecial Projects Committee, a primary review groupof the National Heart Institute, had prepared stan-dardized recommendations for use by staff membersof the Institute in planning and administeringcooperative clinical trials in the cardiovascular field.

Throughout the history of large-scale trials, theethical basis of the methods has been debated and dis-cussed. In 1951, Bradford Hill said:The first step in such a trial is to decide precisely what it hopes toprove, and secondly to consider whether these aims can be ethicallyfulfilled. It need hardly be said that the latter consideration isparamount and must never, on any scientific grounds whatever, belost sight of. If a treatment cannot ethically be withheld then clearly

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P ScheinbergSurvival of the ischemic brain: a progress report.

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1979 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation doi: 10.1161/01.CIR.60.7.1600

1979;60:1600-1605Circulation. 

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