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Cerebral Injury following Cardiac Operations
89
LEADING ARTICLES
brain.3-7 Three of BRIERLEY’S cases did in fact show such focal damage, which was easily distinguished from the commoner and larger " geographical " lesions. The use of antifoaming agents, therefore, remains a hazard; and HELMSWORTH et al.report its presence in the tissues in each of thirty-three cases where patients died for various reasons after cardiac surgery. LONDON 11 JANUARY 1964 Other sorts of emboli have been implicated in small infarcts. Fat and marrow emboli may result from splitting the sternum during the surgical approach,9 or from Cerebral Injury following Cardiac Operations dislodging mediastinal fat which may be taken up by a in the pericardial sac.10 Fat THE strides that have been made in cardiovascular coronary aspirator lying also in globules may appear stored transfused blood from surgery have been achieved by a combination of new if it is recirculated anxsthetic methods, careful control of electrolyte non-fasting donors, especially a screen membrane oxygenator; oxygenators balance, hypothermia, the use of pump-oxygenators to through seem not to have this effect.10 Microthrombi are sometake over the functions of heart and lungs, and improvetimes produced also by changes in the blood resulting ments in surgical technique. But, on the debit side, from its passage through the oxygenating machine: patients who survive a successful cardiac repair some- larger thrombi may break away from the endocardium times show evidence of damage to the brain and of a diseased heart or from the site of the recent surgical occasionally die of this. wound itself. The hazards to the nervous system during cessation of By closely scrutinising the focal ischxmic lesions, cardiac and pulmonary activity are clearly not entirely BRIERLEY was able to exclude these types of emboli as a dispelled by the methods used to replace these organs, cause of the large lesions, and he suggests that most of even with the help of hypothermia to reduce the the damage is due to air-embolism. Such a diagnosis metabolic demands of the brain. It is important that cannot be made with any certainty from postmortem the nature of the damage to nervous tissue should be of the brain several days postoperatively; and in established quickly by postmortem study of fatal cases study one of his cases was such a diagnosis suspected in order that its causes may be identified. Six cardiac only during the operation. SLOANE et al.,11 reporting seventysurgery units have contributed to a neuropathological deaths following cardiac surgery in a series of 600 investigation of this problem by BRIERLEY.1 He carefully eight no account of the cerebral lesions in the fatal examined the brains from eleven patients who died cases, gave but believed that air-embolism might be between six hours and eleven days after operation, and cases, for the neurological disorders manifested in each case he found ischaemic damage. The cerebral responsible that careful lesions resulting from the anoxic episodes associated with by many surviving patients. They suggested evacuation of air from the left side of the heart at the circulatory collapse at normal temperature, or from end of the operation is essential. In the absence of asphyxia, carbon-monoxide poisoning, or hypoglycxmia, visible emboli, vasospasm of the smaller cerebral arteries have a characteristic symmetrical pattern affecting possibly be responsible-a suggestion also made notably the cerebellar Purkinje cells, Sommer’s sector might some reservations) in explanation of somewhat of the Ammon’s horn, the globus pallidus, and diffusely (with similar " geographical " lesions in cases of subarachnoid the third and fourth layers of the cortex. Although haemorrhage.12 eight cases, reported by BJÖRK and HULTQUIST,2 in It is unfortunate that in BRIERLEY’S cases only the which death followed cardiac surgery and hypothermia, brains were received for examination, for it is difficult to did show something like this pathological picture, at least one of their cases and ten of BRIERLEY’S suggest a interpret obscure ischaemic lesions of the brain without different aetiology. In these cases the damage was focal knowing the state of the extracranial cerebral arteries. and " geographical " in distribution-that is to say, the Moreover, one of the easiest places to discover small lesions had the irregular outlines of the territories of circulating emboli is the renal glomerulus. Whether small arteries. They were predominantly in the posterior air-embolism arises via the pump-oxygenator or from half of the brain and were usually asymmetrical, affecting the operative site can only really be decided by careful the grey matter of one hemisphere more than the other. observation during the operation. ElectroencephaloP. O., Cassie, A. B., Dark, J. F., Jack, G. D., Riddell, A. G. The distribution and size of these lesions undoubtedly 3. Yates, Lancet, 1959, i, 130. 4. Cassie, A. B., Riddell, A. G., Yates, P. O. Thorax, 1960, 15, 22. indicate a local arterial cause rather than general 5. Smith, W. T. J. Path. Bact. 1960, 80, 9. 6. Lindberg, D. A. B., Lucas, F. V., Sheagren, J., Malm, J. R. Amer. J. failure of the circulation. The problem is, therefore, not Path. 1961, 39, 129. R. W., Howbert, J. P., Winn, D. F., Thompson, S. W. simply one of inefficiency of the pump-oxygenator. In 7. Thomassen, J. thorac. cardiovasc. Surg. 1961, 41, 611. earlier machines the process of oxygenation of the blood 8. Helmsworth, J. A., Gall, E. A., Perrin, E. V., Braley, S. A., Flege, J. B., Kaplan, S., Keirle, A. M., De Forest, D. Surgery, 1963, 53, 177. created a considerable amount of bubbling, and the 9. Miller, J. A., Fonkalsrud, E. W., Latta, H. L., Maloney, J. V. ibid. 1962, 51, 448. silicone antifoaming agent which had to be added to the 10. Wright, E. S., Sarkozy, E., Dobell, A. R. C., Murphy, D. R. ibid. 1963, 53, 500. blood was responsible for small embolic infarcts in the 11.
THE LANCET
1. 2.
Brierley, J. B. Thorax, 1963, 18, 291. Björk, V. O., Hultquist, G. ibid. 1960, 15,
Sloane, H., Morris, J. D., Mackenzie, J., Stern,
A.
Thorax, 1962, 17,
128.
284.
12.
Logue, V., Smith, B. J. Neurol. Neurosurg. Psychiat. 1962, 25, 393.
90
should at least inform the surgeon accident has occurred. Apparently some of these cerebral lesions are nearly always detectable when death has followed cardiac surgery, even if the death is not attributable to cerebral damage. Accordingly, many patients who survive these operations will have some cerebral impairment. In modern surgery, even when all known dangers have been investigated experimentally, difficulties commonly appear when the new treatment is applied to man. This is an unavoidable concomitant of progress; but the surgical innovator has the same duty promptly to assess, and, if possible eradicate, an unexpected hazard as has a physician who suspects a new drug of dangerous
graphic monitoring
material; and (4) autophagic vacuoles containing partially
when such
degraded mitochondria and other cell constituents. Recognition that some of these bodies belong to the class of lysosomes has been hastened by adaptation of histochemical techniques for acid phosphatase to electron micrographs. HOLT has also shown that esterases can be demonstrated in lysosomes by histochemical methods applicable to electron micrography. One of the obvious functions of lysosomal enzymes is the digestion of material taken into cells by engulfment. There is a basic similarity between the various engulfing processes known as phagocytosis, pinocytosis, micropinocytosis (as well as athrocytosis, rhopheocytosis, colloidopexy, &c.), and DE DUvE suggests that these should be grouped together under the term endocytosis. MuLLER and his colleagues review evidence that lysosomal
an
toxicity.
Lysosomes IN 1955 DE DUVE and his colleagues1 found that five distinct cellular hydrolytic enzymes with acidic pH
optima (phosphatase, ribonuclease, deoxyribonuclease, protease, and
3-glucuronidase)
were
associated with
a
" group of cytoplasmic particles-namely, lysosomes ". They suggested that these enzymes were normally held in an inactive form within the lysosomes, from which they could be released by any of several treatments either in vitro or in vivo. These ideas have attracted much attention and have helped to explain a wide range of natural processes-from digestion in the food vacuoles of protozoans to the degenerative processes accompanying certain pathological conditions in mammals. Much of the information that has accumulated in the past eight years was discussed at a symposium held last year by the Ciba Foundation, the proceedings of which have just appeared.22 DE DUvE concludes that subsequent work has greatly strengthened the original concept. Rat-liver lysosomes are now known to contain at least twelve separate hydrolytic enzymes, capable of breaking down many different constituents of living things. All these become active only when the lipoprotein membranes surrounding the lysosomes are damaged-for example, by exposure to
special
enzymes are released into food vacuoles of protozoa, and CoHN and his colleagues show that this happens in an orderly way when bacteria are ingested by neutrophil
The phase-contrast cine-photomicrographs of HIRSCH have shown that, when the neutrophil granules (lysosomes) collide with vacuoles containing ingested bacteria, they burst and discharge their contents into the vacuoles. Lysosomal enzymes also play a part in differentiation where breakdown and resorption of tissue are taking place. Thus, these enzymes are activated in the tails of amphibian larvse undergoing metamorphosis (WEBER), in the mullerian ducts during sexual differentiation of the male chick embryo (SCHEIB), and in the involuting mammary gland (SLATER et al.). Activation of lysosomal enzymes also takes place in the liver after exposure to poisons and non-ionic detergents (DIANZANI, SLATER et al., W ATTIAUX et al.), but whether these biochemical lesions are primary or secondary is not yet certain. BITENSKY has found that when the Gomori technique for acid phosphatase is used on unfixed cells, very little or no staining results, presumably because the lysosomal membranes are impermeable to the phosphatase substrate. The first change, which is found in traumatic shock and various other conditions, is an increase in lysosomal " fragility " manifested by permeability of the membrane to the substrate so that staining of lysosomes occurs in unfixed cells. The second, irreversible, change is characterised by release of the
leucocytes.
detergents, lipid solvents, phospholipases, or proteases, by freezing and thawing. When cell homogenates are analysed, lysosomes appear in the " light " mitochondrial fraction, and the electron micrographs of NoviKOFF, of lysosomal enzymes into the cytoplasm. This change, HoLT, and of others show them to be quite different from which is seen in cells exposed to antibody and complemitochondria. They vary greatly in structure from cell ment, may contribute to immune cytolysis. THOMAS to cell and even in the same cell, apparently being describes evidence that purified lysosomes of polymorph equivalent to the " pericanalicular dense bodies " in leucocytes exposed to endotoxin can produce in skin a liver cells, neutrophil granules of polymorph leucocytes, type of necrosis similar to that in the local Shwartzman reabsorption droplets " of the kidney tubules, dense reaction. bodies " of the thymus, and so forth. In fact, the lysoIn 1952 FELL and MELLANBY3 found that, when somes now appear to consist of a group of different cell cartilage was grown in a medium containing organelles, including (1) storage granules in which newly embryonic vitamin excess A, metachromatic material was lost from synthesised hydrolytic enzymes are kept ready for use; (2) pinocytosis vacuoles at various stages of evolution; the matrix, which rapidly disintegrated. It now seems are due to release of lysosomal (3) residual bodies containing the remnants of digested that theseandchanges DINGLE has shown that the a or
"
"
1. de Duve, C., Pressman, B. C., Gianetto, R., Wattiaux, R., Appelmans, F. Biochem J. 1955, 60, 604. 2. Ciba Foundation Symposium on Lysosomes (edited by A. V. S. de Reuck and M. P. Cameron). London: Churchill. 1963. (This work is
reviewed on p. 88.) Subsequent references this volume unless otherwise listed.
are to
contributions in
vitamin has enzymes, direct effect on lysosomal particles. In rabbits the breakdown of cartilage following injection of papain 3.
Fell,
H.
B., Mellanby,
E.
J. Physiol. 1952, 116,
320.
LEADING ARTICLES
brain.3-7 Three of BRIERLEY’S cases did in fact show such focal damage, which was easily distinguished from the commoner and larger " geographical " lesions. The use of antifoaming agents, therefore, remains a hazard; and HELMSWORTH et al.report its presence in the tissues in each of thirty-three cases where patients died for various reasons after cardiac surgery. LONDON 11 JANUARY 1964 Other sorts of emboli have been implicated in small infarcts. Fat and marrow emboli may result from splitting the sternum during the surgical approach,9 or from Cerebral Injury following Cardiac Operations dislodging mediastinal fat which may be taken up by a in the pericardial sac.10 Fat THE strides that have been made in cardiovascular coronary aspirator lying also in globules may appear stored transfused blood from surgery have been achieved by a combination of new if it is recirculated anxsthetic methods, careful control of electrolyte non-fasting donors, especially a screen membrane oxygenator; oxygenators balance, hypothermia, the use of pump-oxygenators to through seem not to have this effect.10 Microthrombi are sometake over the functions of heart and lungs, and improvetimes produced also by changes in the blood resulting ments in surgical technique. But, on the debit side, from its passage through the oxygenating machine: patients who survive a successful cardiac repair some- larger thrombi may break away from the endocardium times show evidence of damage to the brain and of a diseased heart or from the site of the recent surgical occasionally die of this. wound itself. The hazards to the nervous system during cessation of By closely scrutinising the focal ischxmic lesions, cardiac and pulmonary activity are clearly not entirely BRIERLEY was able to exclude these types of emboli as a dispelled by the methods used to replace these organs, cause of the large lesions, and he suggests that most of even with the help of hypothermia to reduce the the damage is due to air-embolism. Such a diagnosis metabolic demands of the brain. It is important that cannot be made with any certainty from postmortem the nature of the damage to nervous tissue should be of the brain several days postoperatively; and in established quickly by postmortem study of fatal cases study one of his cases was such a diagnosis suspected in order that its causes may be identified. Six cardiac only during the operation. SLOANE et al.,11 reporting seventysurgery units have contributed to a neuropathological deaths following cardiac surgery in a series of 600 investigation of this problem by BRIERLEY.1 He carefully eight no account of the cerebral lesions in the fatal examined the brains from eleven patients who died cases, gave but believed that air-embolism might be between six hours and eleven days after operation, and cases, for the neurological disorders manifested in each case he found ischaemic damage. The cerebral responsible that careful lesions resulting from the anoxic episodes associated with by many surviving patients. They suggested evacuation of air from the left side of the heart at the circulatory collapse at normal temperature, or from end of the operation is essential. In the absence of asphyxia, carbon-monoxide poisoning, or hypoglycxmia, visible emboli, vasospasm of the smaller cerebral arteries have a characteristic symmetrical pattern affecting possibly be responsible-a suggestion also made notably the cerebellar Purkinje cells, Sommer’s sector might some reservations) in explanation of somewhat of the Ammon’s horn, the globus pallidus, and diffusely (with similar " geographical " lesions in cases of subarachnoid the third and fourth layers of the cortex. Although haemorrhage.12 eight cases, reported by BJÖRK and HULTQUIST,2 in It is unfortunate that in BRIERLEY’S cases only the which death followed cardiac surgery and hypothermia, brains were received for examination, for it is difficult to did show something like this pathological picture, at least one of their cases and ten of BRIERLEY’S suggest a interpret obscure ischaemic lesions of the brain without different aetiology. In these cases the damage was focal knowing the state of the extracranial cerebral arteries. and " geographical " in distribution-that is to say, the Moreover, one of the easiest places to discover small lesions had the irregular outlines of the territories of circulating emboli is the renal glomerulus. Whether small arteries. They were predominantly in the posterior air-embolism arises via the pump-oxygenator or from half of the brain and were usually asymmetrical, affecting the operative site can only really be decided by careful the grey matter of one hemisphere more than the other. observation during the operation. ElectroencephaloP. O., Cassie, A. B., Dark, J. F., Jack, G. D., Riddell, A. G. The distribution and size of these lesions undoubtedly 3. Yates, Lancet, 1959, i, 130. 4. Cassie, A. B., Riddell, A. G., Yates, P. O. Thorax, 1960, 15, 22. indicate a local arterial cause rather than general 5. Smith, W. T. J. Path. Bact. 1960, 80, 9. 6. Lindberg, D. A. B., Lucas, F. V., Sheagren, J., Malm, J. R. Amer. J. failure of the circulation. The problem is, therefore, not Path. 1961, 39, 129. R. W., Howbert, J. P., Winn, D. F., Thompson, S. W. simply one of inefficiency of the pump-oxygenator. In 7. Thomassen, J. thorac. cardiovasc. Surg. 1961, 41, 611. earlier machines the process of oxygenation of the blood 8. Helmsworth, J. A., Gall, E. A., Perrin, E. V., Braley, S. A., Flege, J. B., Kaplan, S., Keirle, A. M., De Forest, D. Surgery, 1963, 53, 177. created a considerable amount of bubbling, and the 9. Miller, J. A., Fonkalsrud, E. W., Latta, H. L., Maloney, J. V. ibid. 1962, 51, 448. silicone antifoaming agent which had to be added to the 10. Wright, E. S., Sarkozy, E., Dobell, A. R. C., Murphy, D. R. ibid. 1963, 53, 500. blood was responsible for small embolic infarcts in the 11.
THE LANCET
1. 2.
Brierley, J. B. Thorax, 1963, 18, 291. Björk, V. O., Hultquist, G. ibid. 1960, 15,
Sloane, H., Morris, J. D., Mackenzie, J., Stern,
A.
Thorax, 1962, 17,
128.
284.
12.
Logue, V., Smith, B. J. Neurol. Neurosurg. Psychiat. 1962, 25, 393.
90
should at least inform the surgeon accident has occurred. Apparently some of these cerebral lesions are nearly always detectable when death has followed cardiac surgery, even if the death is not attributable to cerebral damage. Accordingly, many patients who survive these operations will have some cerebral impairment. In modern surgery, even when all known dangers have been investigated experimentally, difficulties commonly appear when the new treatment is applied to man. This is an unavoidable concomitant of progress; but the surgical innovator has the same duty promptly to assess, and, if possible eradicate, an unexpected hazard as has a physician who suspects a new drug of dangerous
graphic monitoring
material; and (4) autophagic vacuoles containing partially
when such
degraded mitochondria and other cell constituents. Recognition that some of these bodies belong to the class of lysosomes has been hastened by adaptation of histochemical techniques for acid phosphatase to electron micrographs. HOLT has also shown that esterases can be demonstrated in lysosomes by histochemical methods applicable to electron micrography. One of the obvious functions of lysosomal enzymes is the digestion of material taken into cells by engulfment. There is a basic similarity between the various engulfing processes known as phagocytosis, pinocytosis, micropinocytosis (as well as athrocytosis, rhopheocytosis, colloidopexy, &c.), and DE DUvE suggests that these should be grouped together under the term endocytosis. MuLLER and his colleagues review evidence that lysosomal
an
toxicity.
Lysosomes IN 1955 DE DUVE and his colleagues1 found that five distinct cellular hydrolytic enzymes with acidic pH
optima (phosphatase, ribonuclease, deoxyribonuclease, protease, and
3-glucuronidase)
were
associated with
a
" group of cytoplasmic particles-namely, lysosomes ". They suggested that these enzymes were normally held in an inactive form within the lysosomes, from which they could be released by any of several treatments either in vitro or in vivo. These ideas have attracted much attention and have helped to explain a wide range of natural processes-from digestion in the food vacuoles of protozoans to the degenerative processes accompanying certain pathological conditions in mammals. Much of the information that has accumulated in the past eight years was discussed at a symposium held last year by the Ciba Foundation, the proceedings of which have just appeared.22 DE DUvE concludes that subsequent work has greatly strengthened the original concept. Rat-liver lysosomes are now known to contain at least twelve separate hydrolytic enzymes, capable of breaking down many different constituents of living things. All these become active only when the lipoprotein membranes surrounding the lysosomes are damaged-for example, by exposure to
special
enzymes are released into food vacuoles of protozoa, and CoHN and his colleagues show that this happens in an orderly way when bacteria are ingested by neutrophil
The phase-contrast cine-photomicrographs of HIRSCH have shown that, when the neutrophil granules (lysosomes) collide with vacuoles containing ingested bacteria, they burst and discharge their contents into the vacuoles. Lysosomal enzymes also play a part in differentiation where breakdown and resorption of tissue are taking place. Thus, these enzymes are activated in the tails of amphibian larvse undergoing metamorphosis (WEBER), in the mullerian ducts during sexual differentiation of the male chick embryo (SCHEIB), and in the involuting mammary gland (SLATER et al.). Activation of lysosomal enzymes also takes place in the liver after exposure to poisons and non-ionic detergents (DIANZANI, SLATER et al., W ATTIAUX et al.), but whether these biochemical lesions are primary or secondary is not yet certain. BITENSKY has found that when the Gomori technique for acid phosphatase is used on unfixed cells, very little or no staining results, presumably because the lysosomal membranes are impermeable to the phosphatase substrate. The first change, which is found in traumatic shock and various other conditions, is an increase in lysosomal " fragility " manifested by permeability of the membrane to the substrate so that staining of lysosomes occurs in unfixed cells. The second, irreversible, change is characterised by release of the
leucocytes.
detergents, lipid solvents, phospholipases, or proteases, by freezing and thawing. When cell homogenates are analysed, lysosomes appear in the " light " mitochondrial fraction, and the electron micrographs of NoviKOFF, of lysosomal enzymes into the cytoplasm. This change, HoLT, and of others show them to be quite different from which is seen in cells exposed to antibody and complemitochondria. They vary greatly in structure from cell ment, may contribute to immune cytolysis. THOMAS to cell and even in the same cell, apparently being describes evidence that purified lysosomes of polymorph equivalent to the " pericanalicular dense bodies " in leucocytes exposed to endotoxin can produce in skin a liver cells, neutrophil granules of polymorph leucocytes, type of necrosis similar to that in the local Shwartzman reabsorption droplets " of the kidney tubules, dense reaction. bodies " of the thymus, and so forth. In fact, the lysoIn 1952 FELL and MELLANBY3 found that, when somes now appear to consist of a group of different cell cartilage was grown in a medium containing organelles, including (1) storage granules in which newly embryonic vitamin excess A, metachromatic material was lost from synthesised hydrolytic enzymes are kept ready for use; (2) pinocytosis vacuoles at various stages of evolution; the matrix, which rapidly disintegrated. It now seems are due to release of lysosomal (3) residual bodies containing the remnants of digested that theseandchanges DINGLE has shown that the a or
"
"
1. de Duve, C., Pressman, B. C., Gianetto, R., Wattiaux, R., Appelmans, F. Biochem J. 1955, 60, 604. 2. Ciba Foundation Symposium on Lysosomes (edited by A. V. S. de Reuck and M. P. Cameron). London: Churchill. 1963. (This work is
reviewed on p. 88.) Subsequent references this volume unless otherwise listed.
are to
contributions in
vitamin has enzymes, direct effect on lysosomal particles. In rabbits the breakdown of cartilage following injection of papain 3.
Fell,
H.
B., Mellanby,
E.
J. Physiol. 1952, 116,
320.