Experimental Hypoxic Brain Damage

J Clin Pathol: first published as 10.1136/jcp.s3-11.1.181 on 1 January 1977. Downloaded from J. clin. Path., 30, Suppl. (Roy. Coll. Path.), 11, 181-187 Experimental hypoxic brain damage J. B. BRIERLEY From the Medical Research Council Laboratories, Carshalton, Surrey The majority of hypoxic episodes that result in the light of subsequent information from human and histologically proven damage in the human brain experimental animals sources as follows: cannot be adequately defined in physiological terms. They are usually accidents so that basic information 1 ISCHAEMIC such as the precise duration of a cardiac arrest or the Blood flow is arrested in the brain as a whole or in blood pressure and heart rate during a period of the territory of a single artery. severe hypotension is very rarely available. In such cases, neuropathological descriptions, however ex- 2 OLIGAEMIC haustive, may well explain the final neuropsychiatric A reduction in blood flow in the brain as a whole or status of the patient but can at best indicate only within the territory of a single artery may occur tentatively the nature of the episode itself. as a result of a greatly reduced cardiac output or The experimental approach is justified if it can major systemic hypotension from any cause. indicate whether damage of a particular type in neurones and in white matter is or is not a direct 3 ANOXIC consequence ofa particular hypoxic stress adequately The arterial oxygen tension is 0 mm Hg. It occurs if copyright. delineated in physiological terms. inert gases are inhaled, if there is total obstruction of At the outset it must be recalled that the energy the upper respiratory tract or in the event of sudden for the normal functioning of the central nervous exposure to an altitude greater than 50 000 ft (the system is derived from the oxidative metabolism of combined tensions of water vapour and carbon glucose. A deficiency of oxygen or glucose will dioxide within the pulmonary alveoli then exceed the impair function and if severe and protracted enough ambient pressure and no oxygen can enter the lungs). will lead to irreversible brain damage. Interruption http://jcp.bmj.com/ of the oxygen supply produces the most rapid 4 HYPOXIC impairment of brain function. Thus consciousness is There is some reduction in a p02 short ofanoxaemia. lost about 10 sec after circulatory arrest. Abrupt This occurs in chronic pulmonary disease and in anoxia exemplified by inhalation of an inert gas or congestive heart disease; when the inspired oxygen sudden decompression to an altitude above 50 000 is diluted by an inert gas (as in some anaesthetic ft leads to loss of consciousnessafter aslightlylonger accidents) and also in exposures to altitudes less than interval (17-20 sec). This rapid loss of consciousness 50000 ft. in instances of profound hypoxia may well be on September 30, 2021 by guest. Protected responsible for the widely held view that enduring 5 ANAEMIC brain damage may begin soon after consciousness is There is some reduction in the amount of circulating lost. haemoglobin available for combination with oxygen. It can occur after severe haemorrhage, in severe Types of hypoxia hypochromic anaemia but the commonest apparent cause of anaemic brain damage is carbon monoxide Before considering the relationships between the intoxication. known neuropathological patterns in the human brain that are ascribed to hypoxia and their apparent 6 HISTOTOXIC counterparts in the brains ofexperimental animals, it This implies the poisoning of oxidative enzymes will be useful to classify the several types ofhypoxia. within neuronal mitochondria. Cyanide and azide However, it will be shown that there is no justifica- are examples. tion for the assumption that each type of hypoxia can, per se, give rise to brain damage. The original 7 HYPOGLYCAEMIA classification of Barcroft (1925) must be modffied in A deficiency of the principal substrate, glucose, per 181 J Clin Pathol: first published as 10.1136/jcp.s3-11.1.181 on 1 January 1977. Downloaded from 182 J. B. Brierley se can also give rise to ischaemic cell change even if primate are sharp reminders that such 'models' can- the level of arterial oxygenation is normal. not provide two of the most important factors in the The previous contributors to this section of the aetiology of 'stroke' in man. These are some impair- Symposium have defined the nature and time course ment in cardiac function (leading to some reduction of ischaemic cell change and have pointed out that it in cerebral blood flow) and some degree of occlusive is the principal neuronal response to all types of vascular disease. These factors, singly or together, hypoxia in the brains of rodents as well as in those of account for the extension of the infarct into the primates including man. In this survey of the brain centrum semi-ovale and even into the whole of the damage attributable to hypoxia in all its forms, only anatomical cortical territory. It follows, that in the the patterns of distribution of ischaemic cell change human brain, ischaemic necrosis in some portion of will be considered with emphasis on the contributions an arterial territory can seldom be explained from experimental studies. satisfactorily without careful examination of the myocardium, the coronary arteries and the major 1 Ischaemic arteries of the neck and brain. Overall or global arrest of the brain circulation Arrest of circulation within a single brain artery leads to a loss of consciousness in eight to 10 sec and results in an infarct which can range in size from the the EEG is isoelectric a few seconds later. Respira- 'total territory' in an anatomical sense to a small tion fails at about the same time while the heart may volume of tissue close to the point of arterial continue to beat for a matter of minutes. Neuro- occlusion. Where the cortex of cerebrum or cerebel- pathological descriptions of the consequences of lum is concerned the extent of infarction is deter- circulatory arrest (including 35 personal cases) pro- mined by the level of systemic blood pressure at and vide the best examples of the involvement of the after the instant of occlusion and, in particular, by 'selectively vulnerable' regions of the brain in the functional efficiency of the leptomeningeal ves- hypoxia. Frequently, little of the cerebral cortex is sels that anastomose with the cortical branches of normal but damage is usually greater in the posterior neighbouring arteries. If these anastomotic systems half of each cerebral hemisphere, in the floors copyright. of and the major arteries in the neck and the circle of sulci rather than over the crests of gyri and in the Willis are normal, the cortical infarct will be small. If third, fifth and sixth layers rather than in the second one or both are the site of occlusive vascular disease, and fourth. Certain portions of the hippocampus the infarct will be larger. (zones h.1-Sommer sector-and h.3-5,-endfolium) It must be borne in mind that the basal ganglia and are vulnerable as are the Purkinje cells of the the internal capsule, in particular, are supplied by cerebellum. Many sensory nuclei in the brain stem end-arteries (penetrating organglionicbranchesofthe are vulnerable in the infant and young child (Ranck http://jcp.bmj.com/ major cerebral arteries). Occlusion of an arterial and Windle, 1959; Brierley, 1965, 1976). trunk proximal to the ganglionic branches produces Where circulatory arrest has been studied in the an infarct in these deeply placed regions of grey and experimental animal, it is important to recognize white matter even in the healthy experimental that earlier studies were concerned to define the primate. Evidently the retrograde flow of blood from maximum period of arrest of the cerebral circulation leptomeningeal anastomoses into the arterial stem beyond which some degree of irreversible brain a may never enter all its ganglionic branches or, if it damage would occur. Attempts to define such on September 30, 2021 by guest. Protected does so, it may be too little and too late to avert 'threshold' have been reviewed by Hoff et al (1945), irreversible tissue damage. Thus, for example, Meyer (1963) and Brierley (1976). The general division of the middle cerebral artery close to its conclusion from these studies has been stated by origin from the internal carotid artery in the baboon Schneider (1963) as follows: 'A complete revival leaves the sensory and motor cortex intact and without neurological or histological damage cannot cortical infarction is confined to some portion of the be brought about after a complete stop of brain insula. A variable hemiparesis involves only the circulation of more than four to five min duration'. contralateral face and upper limb and its neuro- In contrast to the experiments summarized above, pathological basis has been shown to lie entirely certain recent studies have attempted to define a within white matter, ie, in the genu and supra- much greater period of circulatory arrest after which lentiform portions of the internal capsule, where after there can be some evidence of recovery in at least a a survival of three years there is a sharply circum- neurophysiological sense andhistologicalexamination scribed cystic infarct (Symon and Brierley, 1976). can show that some parts of the brain are normal. The limited neurological deficit and the small, Thus Hossmann and Sato (1970) claimed that deeply placed infarct that follow division of the .... unequivocal signs of neuronal recovery can be middle cerebral artery in a healthy experimental detected after complete ischaemia of more than one J Clin Pathol: first published as 10.1136/jcp.s3-11.1.181 on 1 January 1977. Downloaded from Experimental hypoxic brain damage 183 hour's duration'.

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