808 of administration required to maintain an adequate level of anaesthesia. This is an important finding because the management of total intravenous anaesthesia by increments or infusion is very difficult compared with the breath-by-breath control of inhalation anaesthesia. Despite the difficulties, there is much to be said for persevering with development of total intravenous anaesthesia because with this technique no agents escape into the air of the operating-theatre. Continuous recording of trends of cerebral activity will also give a clue when the patient is becoming too light. The plight of the patient who is conscious whilst fully paralysed may not be clinically obvious to the anaesthetist, and any device which helps to avert this chilling experience for the patient deserves close attention. Piped gases and modern anxsthetic circuits have introduced a new set of hazards into anaesthesia; and this method of monitoring may in addition give early
warning of potentially disastrous incidents involving cerebral hypoxia.
partly for the clinical efficacy of antidepressant drugs and, as a corollary, that some disturbance of histaminergic neurons may contribute to the aetiology of endogenous depression. Before the hypothesis becomes wholly acceptable, two major questions have to be answered. Firstly, how do the "monoamine-oxidase inhibitors" (pargyline, isocarboxazid, tranylcypromine) work? They apparently form the only major class of antidepressants which do not block histamine-sensitive cyclase. Kanof and Greengard do not feel that this represents a serious challenge to their hypothesis since the monoamine-oxidase inhibitors produce a spectrum of clinical effects different from that of the tricyclic antidepressants. Secondly, why do antidepressant drugs take ten or more days to work in man? The answer may simply be that this time is required to overcome compensatory feedback changes, but the point needs investigation in terms of the new hypothesis. Whatever the drawbacks, the histamine hypothesis will generate much interest, and we can expect to hear much more about histaminergic neurons and their pharma-
cology. ANTIDEPRESSANTS AND HISTAMINE OF the various substances proposed as synaptic transmitters in the central nervous system, histamine is one of the less well investigated, although it fulfils many of the classic criteria for a neurotransmitter.’ This is partly because there seems to be no well-defined and therefore experimentally accessible histaminergic tract in the brain. An ascending pathway has been described traversing the medial forebrain bundle,’ but this pathway distributes terminals diffusely throughout the telencephalon, and no specific behavioural changes have been identified after electrical or pharmacological manipulation of this histaminergic tract. Like other biogenic amines histamine is believed to exert some of its actions as a neurotransmitter by activating adenylate cyclase and thus increasing the neuronal levels of cyclic A.M.P.2 Kanof and Greengard3 have developed an in-vitro system for examining this activation of adenylate cyclase by histamine, and have uncovered a remarkable correlation between the ability of drugs to inhibit the activation, and their clinical usage as antidepressants. Many of the current antidepressants inhibit the reuptake of noradrenaline or 5-hydroxytryptamine into nerve terminals or varicosities, and this effect was for many years believed to be the basis of their clinical action.4 There then appeared several effective antidepressant compounds which do not block amine reuptake processes-for instance, iprindole and mianserin. The particular interest of Kanof and Greengard’s work lies in the fact that these newer compounds share with the established antidepressants the ability to block the histamine-sensitive adenylate cyclase. Several other drugs, such as chlorpromazine, thioridazine, and thiothixene, which have antidepressant activity in man but are not as frequently used for this effect, were also found to be antagonists of the histamine-sensitive cyclase. The hypothesis which now emerges is that a blockade of histamine-sensitive adenylate cyclase may account at least Schwartz, J.-C. A. Rev. Pharmac. 1977, 17, 325. Bloom, F. E. Rev. Physiol. Biochem. Pharmac. 1975, 74, 1. 3. Kanof, P. D., Greengard, P. Nature, 1978, 272, 329. 4. Goodman, L. S., Gilman, A. The Pharmacological Basis of Therapeutics. New York, 1975. 1. 2.
COLLATERAL VENTILATION IN MAN IN the
early 1930s Van Allen, Lindskog, and their colleaguesl-4 showed that obstruction to a lobar bronchus of the dog was followed by absorption collapse of the lung distal to the occlusion, but that such collapse did not result if a more peripheral bronchus, at segmental level, was obstructed. They concluded that ventilation of the segment could continue by channels which bypassed the
obstruction, the so-called collateral ventilation. This phenomenon attracted only sporadic interest until some 10 years ago, when Hogg et a1.s found that aidlowed through such collateral channels communicating between the lobes of human lungs, in vitro, much more easily in lungs taken from patients with emphysema than in lungs from normal adults. Terry et al.6 have now confirmed these deductions by in-vivo measurements of the resistance to collateral ventilation in seven young normal subjects, three normal subjects aged around 59 years, and five patients with "emphysema" (as judged by a low F.E.V.1, hyperinflation, and a low carbon-monoxide transfer factor). Resistance to collateral flow, measured from a fibreoptic bronchoscope wedged to occlude a segmental or subsegmental bronchus, was higher in the younger normal subjects than in the older, but the pathways involved in this collateral ventilation tended to close sporadically both in the older subjects and in the patients with emphysema. However, in the emphysematous patients the pressure at the tip of the wedged bronchoscope usually fell abruptly at first when airflow into the obstructed segment was stopped, with a subsequent slow decline of pressure, which could imply that although collateral channels between air spaces might be widely patent in these cases, 1. Van Allen, C. M. Surgery, Gynec. Obstet. 1932, 55, 303. 2. Van Allen, C. M., Lindskog, G. E. ibid. 1931, 53, 16. 3. Van Allen, C. M., Lindskog, G. E., Richter, H. G. J. clin. Invest. 1941, 10, 599. 4. Lindskog, G. E., Bradshaw, H. H. Am. J. Physiol. 1934, 108, 581. 5. Hogg, J. C., Macklem, P. T., Thurlbeck, W. M. J. clin. Invest. 1969, 48, 421. 6. Terry, P. Traystman, R. J., Newball, H. H., et al. New Engl. J. Med.
B.,
1978, 298, 10.
809
nonetheless the peripheral airways leading from such air were
severely narrowed.
spaces The anatomical basis of collateral ventilation remains somewhat uncertain, but most observers allocate a major role to the pores of Kohn, which are holes of some 3-13 p.m diameter, communicating between gasexchanging alveoli. In the dog, where such pores are numerous, there may be up to 10 per alveolus,7.8 or even more. However, in excised human lungs, polystyrene spheres of up to 64 p.m in diameter can be passed through collateral channels, implying that other communications than the pores of Kohn can be involved in collateral ventilation.9,lO Transfer af oxygen and carbon dioxide between blood and gas in such collaterally ventilated spaces can be remarkably efficient. In the dog, where the poorly lobulated lung seems to allow extensive collateral ventilation between adjacent air spaces,ll,12 expiratory sampling of gas from a catheter obstructing a subsegmental bronchus revealed a P02 well above mixed-venous levels, and calculated values of ventilation/perfusion ratios in the collaterally ventilated air spaces were close to those calculated conventionally for the lungs as a whole." Furthermore, extrapolation of these studies from dog to man suggests that a high overall ventilation/perfusion ratio-as for example in an asthmatic attack, where the arterial PC02 is characteristically low"’"—would optimise efficient collateral ventilation, which might be very important if some small airways are severely narrowed or even closed by the asthmatic attack. However, in the pig, where the extensive fibrous septa lobulating the lung probably account for the scarcity of collateral channels for ventilation," obstruction of subsegmental airways does severely hamper gas exchange. 12 What messages do these physiological studies bear for the clinician? In normal young subjects collateral ventilation probably contributes little to the distribution of ventilation, but the contribution may increase as the lungs lose elasticity with advancing years and become more prone to closure of some basal airways (as shown by an increase in closing volume with age16,17). Even in subjects with previously normal lungs, collateral ventilation from neighbouring segments may save the distal lung segment from collapse after occlusion of a subsegmental or smaller-sized bronchus.4 The role of collateral ventilation in patients with chronic bronchitis and emphysema is less clear. Mucus production is increased in chronic bronchitis, with also an increase in numbers and extension of goblet cells into the lining epithelium of small-diameter bronchioles,l8 and narrowing of small airways.19 Nonetheless, although patchy distal atelec7. Martin, H. B. Am. Rev. resp. Dis. 1963, 88, 773. 8. Martin, H. B. J. appl. Physiol. 1966, 21, 1443. 9. Henderson, R., Horsfield, K., Cumming, G. Respiration Physiol. 1968, 6, 128. 10. Macklem, P. T. Physiol. Rev. 1971, 51, 368. 11. Brown, R., Woolcock, A. J., Vincent, N. J., Macklem, P. T. J. appl. Physiol.
1969, 27, 328. 12. Flenley, D. C., Picken, J., Welchel, L., Ruff, F., Corry, P. M., Macklem, P.T. Respiration Physiol. 1972, 15, 39. 13. Flenley, D. C., Welchel, L., Macklem, P. T. ibid. 1972, 15, 52. 14. Tai, E., Read, J. Lancet, 1967, i, 644. 15. McFadden, E. R., Lyons, H. A. New Engl. J. Med. 1968, 278, 1027. 16. Leblanc, P., Ruff, F., Milic-Emili, J.J. appl. Physiol. 1970, 28, 448. 17. McCarthy, D. S., Spencer, R., Greene, R., Milic-Emili, J. Am. J. Med. 1972,
52, 747. 18. Bignon, J., Depierre, A., Andre-Bougaran, J., Hem, B. Proc. R. Soc. Med. 1976, 69, 128. 19. Matsuba, K., Thurlbeck, W. M. Am. Rev. resp. Dis. 1973, 107, 552.
tasis does occur in bronchitis,2O major segmental collapse is not a dominant feature, suggesting that the apparent increase in patency of collateral channels may also play some similar role in preventing widespread atelectasis. Terry et awl. suggest that collateral ventilation of such air spaces is responsible for the near-normality of arterial blood-gas tensions in patients with the "pink-andpuffing" type of chronic bronchitis and emphysema, in contrast to the hypoxaemia and CO2 retention of the "blue-and-bloated" type of bronchitic, where they seem to propose only a minor role for collateral ventilation. Not everyone will accept this. The pathological basis for this clinical distinction has proved elusive,21 and other
explanations are possible. 22 BRAIN
ON April 5, the Editors and Guarantors of Brain celebrated the centenary of their journal in a meeting at the Royal College of Physicians of London (see p. 836). Brain emerged as a development of Crichton-Browne’s West Riding Lunatic Asylum Reports, which contained perceptive and scientific neurological observations. These publications soon attracted wide interest and contributions arrived from many other parts of the country. The need for a journal to cover all aspects of neurology was served by the issue of the first number of Brain in April, 1878; and the device of using the name of the main organ as the title of the journal has been widely copied. Since that first issue Brain has maintained a very high standard of scientific presentation of mature works, expressed in the personal styles of authorities who were often not only professionally skilled but also masters of language. It has reflected the historical developments of many branches of science, at first in Britain but now very much on an international scale. It has survived two world wars which created formidable problems for the editors of those times. The original circulation (at 3s 6d a copy, post free) is not known, but the figure is now prospering at 5000, despite the later appearance of many other neurological journals. The need for Guarantors has, happily, long been an anachronism. The success of this journal has been entirely due to the personal talents and exceptional industry of a small number of variously gifted men who, in spite of formidable commitments in clinical practice, in academic work, in literary output, in medical administration, and in politics, have kept the journal alive and flourishing. Though there has long been an editorial board of great distinction, with editorial assistance of modest proportions but high efficiency, the final product has always been the direct reflection of the wisdom and experience of the Editors. Maintaining the right balance between the neurology of the highest cerebral functions and that of more peripheral mechanisms is still an exacting task, but it is as ably achieved now as it was in the earlier issues. The modern neurologist cannot be sufficiently grateful to the line of great figures who have arduously, modestly, and effectively preserved this journal over its first hundred years. 20. 21.
Reid, L. Lancet, 1954, i, 275. Thurlbeck, W. M. in Chronic Airflow Obstruction in Lung Disease: Major Problems in Pathology V (edited by J. C. Bennington). Philadelphia,
22.
Flenley, D.
1976. C. Lancet, 1978, i, 542.
warning of potentially disastrous incidents involving cerebral hypoxia.
partly for the clinical efficacy of antidepressant drugs and, as a corollary, that some disturbance of histaminergic neurons may contribute to the aetiology of endogenous depression. Before the hypothesis becomes wholly acceptable, two major questions have to be answered. Firstly, how do the "monoamine-oxidase inhibitors" (pargyline, isocarboxazid, tranylcypromine) work? They apparently form the only major class of antidepressants which do not block histamine-sensitive cyclase. Kanof and Greengard do not feel that this represents a serious challenge to their hypothesis since the monoamine-oxidase inhibitors produce a spectrum of clinical effects different from that of the tricyclic antidepressants. Secondly, why do antidepressant drugs take ten or more days to work in man? The answer may simply be that this time is required to overcome compensatory feedback changes, but the point needs investigation in terms of the new hypothesis. Whatever the drawbacks, the histamine hypothesis will generate much interest, and we can expect to hear much more about histaminergic neurons and their pharma-
cology. ANTIDEPRESSANTS AND HISTAMINE OF the various substances proposed as synaptic transmitters in the central nervous system, histamine is one of the less well investigated, although it fulfils many of the classic criteria for a neurotransmitter.’ This is partly because there seems to be no well-defined and therefore experimentally accessible histaminergic tract in the brain. An ascending pathway has been described traversing the medial forebrain bundle,’ but this pathway distributes terminals diffusely throughout the telencephalon, and no specific behavioural changes have been identified after electrical or pharmacological manipulation of this histaminergic tract. Like other biogenic amines histamine is believed to exert some of its actions as a neurotransmitter by activating adenylate cyclase and thus increasing the neuronal levels of cyclic A.M.P.2 Kanof and Greengard3 have developed an in-vitro system for examining this activation of adenylate cyclase by histamine, and have uncovered a remarkable correlation between the ability of drugs to inhibit the activation, and their clinical usage as antidepressants. Many of the current antidepressants inhibit the reuptake of noradrenaline or 5-hydroxytryptamine into nerve terminals or varicosities, and this effect was for many years believed to be the basis of their clinical action.4 There then appeared several effective antidepressant compounds which do not block amine reuptake processes-for instance, iprindole and mianserin. The particular interest of Kanof and Greengard’s work lies in the fact that these newer compounds share with the established antidepressants the ability to block the histamine-sensitive adenylate cyclase. Several other drugs, such as chlorpromazine, thioridazine, and thiothixene, which have antidepressant activity in man but are not as frequently used for this effect, were also found to be antagonists of the histamine-sensitive cyclase. The hypothesis which now emerges is that a blockade of histamine-sensitive adenylate cyclase may account at least Schwartz, J.-C. A. Rev. Pharmac. 1977, 17, 325. Bloom, F. E. Rev. Physiol. Biochem. Pharmac. 1975, 74, 1. 3. Kanof, P. D., Greengard, P. Nature, 1978, 272, 329. 4. Goodman, L. S., Gilman, A. The Pharmacological Basis of Therapeutics. New York, 1975. 1. 2.
COLLATERAL VENTILATION IN MAN IN the
early 1930s Van Allen, Lindskog, and their colleaguesl-4 showed that obstruction to a lobar bronchus of the dog was followed by absorption collapse of the lung distal to the occlusion, but that such collapse did not result if a more peripheral bronchus, at segmental level, was obstructed. They concluded that ventilation of the segment could continue by channels which bypassed the
obstruction, the so-called collateral ventilation. This phenomenon attracted only sporadic interest until some 10 years ago, when Hogg et a1.s found that aidlowed through such collateral channels communicating between the lobes of human lungs, in vitro, much more easily in lungs taken from patients with emphysema than in lungs from normal adults. Terry et al.6 have now confirmed these deductions by in-vivo measurements of the resistance to collateral ventilation in seven young normal subjects, three normal subjects aged around 59 years, and five patients with "emphysema" (as judged by a low F.E.V.1, hyperinflation, and a low carbon-monoxide transfer factor). Resistance to collateral flow, measured from a fibreoptic bronchoscope wedged to occlude a segmental or subsegmental bronchus, was higher in the younger normal subjects than in the older, but the pathways involved in this collateral ventilation tended to close sporadically both in the older subjects and in the patients with emphysema. However, in the emphysematous patients the pressure at the tip of the wedged bronchoscope usually fell abruptly at first when airflow into the obstructed segment was stopped, with a subsequent slow decline of pressure, which could imply that although collateral channels between air spaces might be widely patent in these cases, 1. Van Allen, C. M. Surgery, Gynec. Obstet. 1932, 55, 303. 2. Van Allen, C. M., Lindskog, G. E. ibid. 1931, 53, 16. 3. Van Allen, C. M., Lindskog, G. E., Richter, H. G. J. clin. Invest. 1941, 10, 599. 4. Lindskog, G. E., Bradshaw, H. H. Am. J. Physiol. 1934, 108, 581. 5. Hogg, J. C., Macklem, P. T., Thurlbeck, W. M. J. clin. Invest. 1969, 48, 421. 6. Terry, P. Traystman, R. J., Newball, H. H., et al. New Engl. J. Med.
B.,
1978, 298, 10.
809
nonetheless the peripheral airways leading from such air were
severely narrowed.
spaces The anatomical basis of collateral ventilation remains somewhat uncertain, but most observers allocate a major role to the pores of Kohn, which are holes of some 3-13 p.m diameter, communicating between gasexchanging alveoli. In the dog, where such pores are numerous, there may be up to 10 per alveolus,7.8 or even more. However, in excised human lungs, polystyrene spheres of up to 64 p.m in diameter can be passed through collateral channels, implying that other communications than the pores of Kohn can be involved in collateral ventilation.9,lO Transfer af oxygen and carbon dioxide between blood and gas in such collaterally ventilated spaces can be remarkably efficient. In the dog, where the poorly lobulated lung seems to allow extensive collateral ventilation between adjacent air spaces,ll,12 expiratory sampling of gas from a catheter obstructing a subsegmental bronchus revealed a P02 well above mixed-venous levels, and calculated values of ventilation/perfusion ratios in the collaterally ventilated air spaces were close to those calculated conventionally for the lungs as a whole." Furthermore, extrapolation of these studies from dog to man suggests that a high overall ventilation/perfusion ratio-as for example in an asthmatic attack, where the arterial PC02 is characteristically low"’"—would optimise efficient collateral ventilation, which might be very important if some small airways are severely narrowed or even closed by the asthmatic attack. However, in the pig, where the extensive fibrous septa lobulating the lung probably account for the scarcity of collateral channels for ventilation," obstruction of subsegmental airways does severely hamper gas exchange. 12 What messages do these physiological studies bear for the clinician? In normal young subjects collateral ventilation probably contributes little to the distribution of ventilation, but the contribution may increase as the lungs lose elasticity with advancing years and become more prone to closure of some basal airways (as shown by an increase in closing volume with age16,17). Even in subjects with previously normal lungs, collateral ventilation from neighbouring segments may save the distal lung segment from collapse after occlusion of a subsegmental or smaller-sized bronchus.4 The role of collateral ventilation in patients with chronic bronchitis and emphysema is less clear. Mucus production is increased in chronic bronchitis, with also an increase in numbers and extension of goblet cells into the lining epithelium of small-diameter bronchioles,l8 and narrowing of small airways.19 Nonetheless, although patchy distal atelec7. Martin, H. B. Am. Rev. resp. Dis. 1963, 88, 773. 8. Martin, H. B. J. appl. Physiol. 1966, 21, 1443. 9. Henderson, R., Horsfield, K., Cumming, G. Respiration Physiol. 1968, 6, 128. 10. Macklem, P. T. Physiol. Rev. 1971, 51, 368. 11. Brown, R., Woolcock, A. J., Vincent, N. J., Macklem, P. T. J. appl. Physiol.
1969, 27, 328. 12. Flenley, D. C., Picken, J., Welchel, L., Ruff, F., Corry, P. M., Macklem, P.T. Respiration Physiol. 1972, 15, 39. 13. Flenley, D. C., Welchel, L., Macklem, P. T. ibid. 1972, 15, 52. 14. Tai, E., Read, J. Lancet, 1967, i, 644. 15. McFadden, E. R., Lyons, H. A. New Engl. J. Med. 1968, 278, 1027. 16. Leblanc, P., Ruff, F., Milic-Emili, J.J. appl. Physiol. 1970, 28, 448. 17. McCarthy, D. S., Spencer, R., Greene, R., Milic-Emili, J. Am. J. Med. 1972,
52, 747. 18. Bignon, J., Depierre, A., Andre-Bougaran, J., Hem, B. Proc. R. Soc. Med. 1976, 69, 128. 19. Matsuba, K., Thurlbeck, W. M. Am. Rev. resp. Dis. 1973, 107, 552.
tasis does occur in bronchitis,2O major segmental collapse is not a dominant feature, suggesting that the apparent increase in patency of collateral channels may also play some similar role in preventing widespread atelectasis. Terry et awl. suggest that collateral ventilation of such air spaces is responsible for the near-normality of arterial blood-gas tensions in patients with the "pink-andpuffing" type of chronic bronchitis and emphysema, in contrast to the hypoxaemia and CO2 retention of the "blue-and-bloated" type of bronchitic, where they seem to propose only a minor role for collateral ventilation. Not everyone will accept this. The pathological basis for this clinical distinction has proved elusive,21 and other
explanations are possible. 22 BRAIN
ON April 5, the Editors and Guarantors of Brain celebrated the centenary of their journal in a meeting at the Royal College of Physicians of London (see p. 836). Brain emerged as a development of Crichton-Browne’s West Riding Lunatic Asylum Reports, which contained perceptive and scientific neurological observations. These publications soon attracted wide interest and contributions arrived from many other parts of the country. The need for a journal to cover all aspects of neurology was served by the issue of the first number of Brain in April, 1878; and the device of using the name of the main organ as the title of the journal has been widely copied. Since that first issue Brain has maintained a very high standard of scientific presentation of mature works, expressed in the personal styles of authorities who were often not only professionally skilled but also masters of language. It has reflected the historical developments of many branches of science, at first in Britain but now very much on an international scale. It has survived two world wars which created formidable problems for the editors of those times. The original circulation (at 3s 6d a copy, post free) is not known, but the figure is now prospering at 5000, despite the later appearance of many other neurological journals. The need for Guarantors has, happily, long been an anachronism. The success of this journal has been entirely due to the personal talents and exceptional industry of a small number of variously gifted men who, in spite of formidable commitments in clinical practice, in academic work, in literary output, in medical administration, and in politics, have kept the journal alive and flourishing. Though there has long been an editorial board of great distinction, with editorial assistance of modest proportions but high efficiency, the final product has always been the direct reflection of the wisdom and experience of the Editors. Maintaining the right balance between the neurology of the highest cerebral functions and that of more peripheral mechanisms is still an exacting task, but it is as ably achieved now as it was in the earlier issues. The modern neurologist cannot be sufficiently grateful to the line of great figures who have arduously, modestly, and effectively preserved this journal over its first hundred years. 20. 21.
Reid, L. Lancet, 1954, i, 275. Thurlbeck, W. M. in Chronic Airflow Obstruction in Lung Disease: Major Problems in Pathology V (edited by J. C. Bennington). Philadelphia,
22.
Flenley, D.
1976. C. Lancet, 1978, i, 542.
