PROPRANOLOL IN MYOCARDIAL INFARCTION

788 Calculated values for this hyperventilation are shown for three masks in fig. 2. With any mask a balance must be struck between the possible benefits of forced hyperventilation and the harmful effects of increasing the work of breathing. If high oxygen concentrations are required then either a valved mask with a reservoir bag or an M.C. mask used with high oxygen flows may be more satisfactory. Departments of Anæsthesia and Medical Electronics, St. Bartholomew’s Hospital, London E.C.1.

J. M. COLLIS D. W. BETHUNE.

PROPRANOLOL IN MYOCARDIAL INFARCTION SIR,-Recently you have published several papers and letters discussing the actions of propranolol. It seems to me that unjustified conclusions about the effects of propranolol on the coronary circulation and on cardiac function in patients have been drawn from observations in anaesthetised dogs.1-4 Several points deserve consideration. So-called " coronary vasodilator drugs " which increase coronary blood-flow in anaesthetised animals do not do so in patients with angina.56 Although Parratt and Grayson1 have found that propranolol reduced myocardial blood-flow in anaesthetised dogs, there is no evidence that this occurs in patients. Propranolol is effective in the treatment of angina; it has never been suggested that it increases coronary bloodflow in man. It may act in angina by reducing the work and demands of the heart for oxygen. In dogs adrenaline and noradrenaline increase coronary blood-flow owing to stimulation of adrenergic j3 receptors in the coronary vessels and to the direct action on vessels of " metabolites " formed during the increase in cardiac work.5 After propranolol the effect of these amines on p receptors in the coronary vessels and on cardiac work is abolished, and as a result the amines reduce coronary flow owing to " unmasking " of their effect on adrenergic a receptors in the vessels.7 It is unjustified to suggest that propranolol influences the responses of the coronary vessels to adrenaline and noradrenaline in patients with arteriosclerosis in the same way as it alters their responses in anaesthetised dogs. In patients with angina, an attack of pain can be produced by the administration of adrenaline, since the increase in coronary blood-flow in response to adrenaline is not sufficient to meet the increased demands of the heart for oxygen.8 9 In these patients, propranolol will reduce the increase in work and oxygendemand of the heart in response to adrenaline, and this action of propranolol appears to outweigh any effect it may have on the coronary circulation. Folle and Aviado 10 showed in anaesthetised dogs that a -receptor-blocking agent abolished the coronary vasodilatation produced in response to systemic anoxaemia but not that produced by perfusion of the coronary vascular bed with blood from the external jugular vein. These results have been cited2 to indicate that propranolol may have deleterious effects on the coronary vascular response to hypoxia, but these experimental procedures are not comparable with the effects of exercise or with the action of catecholamines on the coronary circulation in patients with arteriosclerosis. In normal man propranolol reduces heart-rate and cardiac contractility by blockade of the sympathetic drive to the heart.11 This is a normal pharmacological action of the drug 1. 2. 3. 4. 5. 6. 7.

Parratt, J. R., Grayson, J. Lancet, 1966, i, 338. Parratt, J. R., Grayson, J. ibid. p. 819. Redding, V. J., Rees, J. R. ibid. p. 548. Ross, G. ibid. Feb. 18, 1967, p. 396. Rowe, G. G. Am. Heart J. 1964, 68, 691. Winbury, M. M. Adv. Pharmac. 1964, 3, 1. Gaal, P. G., Kattus, A. A., Kolin, A., Ross, G. Br. J. Pharmac. Chemother. 1966, 26, 713. 8. Levine, S. A., Ernstene, A. C., Jacobson, B. Archs intern. Med. 1930, 45, 191. 9. Raab, W. Am. J. Cardiol. 1962 9, 576. 10. Folle, L. E., Aviado, D. M. J. Pharmac. exp. Ther. 1965, 149, 79. 11. Sowton, E., Hamer, J. Am. J. Cardiol. 1966, 18, 317.

and does not seriously impair cardiac function. The situation would be very different in patients who were dependent on increased sympathetic drive for the maintenance of cardiac efficiency. This situation probably exists in patients who are in cardiac failure 12; it is not yet clear to what extent it exists in acute myocardial infarction. In patients in cardiac failure propranolol may produce a striking deterioration in their condition. In my opinion this is due to removal of the sympathetic drive to the heart in these patients; again this is a predictable action of the drug and is better considered as such rather than as a negative inotropic action.4 Since ill-effects occur more often after the intravenous administration of propranolol, it seems safer to use a small dose (the 1 mg. ampoule now available) for intravenous administration. Because propranolol is a potent drug and its effects sometimes difficult to predict in severely ill patients care must be taken when it is given intravenously. Department of Therapeutics and Pharmacology, Queens University, R. G. SHANKS. Belfast 12.

SIR,-The overwhelming mass of evidence indicates that, clinically, propranolol is ineffective in the treatment of infarction.13-15 It is, however, a most potent P blocker, unmasking the action of oc receptors and, in consequence, producing coronary vasoconstriction and decreasing the blood-flow to the myocardium. There is also general agreement that propranolol diminishes cardiac oxygen consumption, heat production is not greatly altered, and blood-pressure is unchanged, although the heart-rate declines. All this suggests a substantial increase in cardiac efficiency. There is some argument whether the drop in flow is matched by the decrease in local demands for oxygen. Most patients, however, do not die after receiving propranolol, and infarcted patients are probably none the worse for propranolol treatment; this must mean that the blood-flow after propranolol is adequate for normal purposes. The danger of propranolol, in my view, lies in its action in potentiating the vasoconstrictor effects of adrenaline and noradrenaline ; Dr. Ross (Feb. 18, p. 396) also cites evidence on this point. In normal animals the net effect of adrenaline on the coronary vascular bed is to produce vasodilatation; once the receptors which mediate vasodilatation are blocked, adrenaline, through its simultaneous action on cc receptors, becomes a most powerful vasoconstrictor agent-and noradrenaline even more so. Propranolol should therefore be used with the greatest care. It is essential to avoid any situation which might increase the endogenous secretion of adrenaline. The administration of adrenaline or noradrenaline to propranolol-treated patients is strongly contraindicated. Despite its lack of clinical success, in our own experiments pretreatment with propranolol strikingly reduced the 6-hour infarction-rate in 10 deeply anaesthetised dogs in which the left descending coronary arteries were suddenly ligated. (In 98% of untreated dogs this procedure produces, after 6 hours, very clear macroscopic or microscopic evidence of infarction.) The purpose of the deep anxsthesia was to lessen endogenous adrenaline production, and the relative failure of propranolol in man may be due to local or systemic production of adrenaline in the manner suggested by Naimi and Proger.16 Infarction of course is complex. It is no longer sufficient to regard it as cell death following end-artery occlusion. There is an ample collateral circulation even in man. 17 In the dog, acute occlusion does not produce a fall in myocardial flow to anything approaching zero 1’-this comes later. In the arterial stump beyond the ligature I have demonstrated a persistently high pulsatile pressure, further evidence of patent collaterals. Braunwald, E., Chidsey, C. A. Proc. R. Soc. Med. 1965, 58, 1063. Balcon, R., Jewitt, D. E., Davies, J. P. H., Oram, S. Lancet, 1966, ii, 917. Clausen, J., Felsby, M., Jørgensen, F. S., Nielsen, B. L., Roin, J., Strange, B. ibid. p. 920. 15. ibid. p. 1435. 16. Naimi, S., Proger, S. Lancet, 1966, ii, 1465. 17. Baroldi, G. Am. J. Cardiol. 1965, 16, 859. 12. 13. 14.

789

question then becomes: why does infarction ever occur ? My experiments suggest that the factor which triggers the infarction process is a relative anoxia which might be local. This can result from an acute occlusion of a coronary vessel, but it is probable that more often it is the result of a myocardium which through excitement, unwise physical effort, or other similar cause, asks too much of a blood-supply already depleted by atheroma. In any case, the effect is a spreading and slowly intensifying ischxmia arising from intense vasoconstriction in the myocardium. One factor in this spreading vasospasm is sympathetically mediated activation of the oc receptors. As reported earlier 18 Lapin and I have been able to control the vasospastic element in the infarction process by combining deep anaesthesia with an adrenergic blocking agent (bethanidine sulphate or bretylium tosylate). These blockers alone are not likely to be of any immediate clinical value, since, even after effective blockade, endogenous secretion of adrenaline can precipitate florid infarction after acute ligation of the coronary vessels-and few situations are more likely to cause endogenous

The

adrenaline release than one’s first coronary attack. In my hands, a blockers (such as phentolamine [’ Rogitine ’]) have also been ineffective. The answer is not easy to see. Perhaps a combined a and p blockade might offer one approach. Meanwhile the demonstration that an effective collateral circulation exists, and that a physiological error contributes to the anatomical disturbance, offers hope that a useful pharmacological approach to the treatment of the developing infarct may yet be possible. Department of Physiology, J. GRAYSON. University of Ibadan, Nigeria.

GASTRIC FUNCTION IN GASTRIC CARCINOMA

SIR,-I should like to add some observations to those of Dr. Shearman and his colleagues (Feb. 18, p. 343). At this department the secretion of intrinsic factor (l.F.) has been studied in 18 patients with gastric carcinoma (see accompanying table). Our results suggest that patients with SECRETORY VALUES AND LOCALISATION OF TUMOUR IN 18 PATIENTS WITH GASTRIC CARCINOMA

I thank surgeons-in-chief K. H. Kaster, F. Zachariae, A. Zacho, and K. Fischermann, of surgical department A, Bispebjerg Hospital, and the surgical department, Finsen Institute, Copenhagen, for permission to examine gastric juices from patients under their care. This study was aided by a grant from Daell Fonden, Denmark. Medical Department F,

Glostrup Hospital, Copenhagen.

COFFEE AND GLUCOSE TOLERANCE

SIR,-Dr. Jankelson and his colleagues (March 11, p. 527) claim to have found that coffee significantly lowers glucose tolerance in maturity-onset diabetes. However, difficulties in their method and interpretation bring this conclusion into question. Because all the tests done after coffee ingestion took

place the week before the hot-water control series the possibility both of influence by some experience in common of the volunteer outpatients and of contamination by a systematic laboratory error cannot be excluded. The blood-glucose level in those subjects seemingly affected by coffee tended to be higher to start with in the trial with coffee. One could therefore predict that subsequent bloodglucose values would be higher without postulating any rise due to the coffee. Because of this interdependence of bloodglucose levels within runs, random temporal fluctuations in the glucose tolerance of an individual, and the relatively slight differences found between runs, the only applicable nonparametric test of significance assumes a binary distribution with P=0.5 and n=9. Since in no more than seven of nine trials did the " coffee " glucose values exceed the " water " results, the null hypothesis may be rejected at no"less than the 18% level. A two-tailed test is necessary, not a one-sided " one as suggested by Dr. Jankelson and his colleagues, because advance prediction of an adverse rather than a favourable effect of coffee drinking was not made. It would appear helpful in further research to randomise the order of trials, to report results in more subjects, to perform more trials in each subject, and perhaps to use parenteral caffeine to circumvent the vagaries of the various digestive tracts. More powerful parametric statistics would then be available. As they now stand, the data do not support the inference that coffee may influence carbohydrate metabolism. Hillside Hospital, MYRON PULIER. Glen Oaks, New York 11004.

’*’ ’*’ ’*’ This letter has been shown reply follows.-ED. L.

*

In ng. vitamin-B’2 units per hour.19 t Free acid titrated to pH 3-3; criteria of hypochlorhydria and achlorhydria

according

to

Callender

et

al.2.

region may have normal I.F. secretion, and secretion is lowest in patients with diffusely infiltrating gastric carcinoma. 2 achlorhydric patients only, both in the latter group, were with certainty in the pernicious-anoemia range of Of. secretion.19 I regret that our previous article 19 on this topic was misunderstood by Dr. Shearman and his colleagues: all the patients we studied had their Of. secretion measured before any operations were performed. The relatively low Of. concentration then reported in patients with gastric cancer seems consistent with the recent suggestions of Dr. Shearman and his colleagues.

cancer

that

in the cardiac

Of.

18. Grayson, J., Lapin B. A. Lancet, 1966, i, 1284. 19. Rødbro P., Christiansen, P. M., Schwartz, M. Lancet, 20. Callender, S. T., Retief, F. P., Witts, L. J. Gut, 1960,

1965, ii, 1, 326.

1200.

PAUL RØDBRO.

to

Professor

Mayer, whose

SIR,-My colleagues and I should obviously have made it clearer that the glucose-tolerance tests following water and following coffee were done over a period of several months. While it is true that the coffee tests were done first (we wanted to be sure to have the results of the glucose-tolerance and insulin tests following coffee even if the patients did not return), the facts that no more than two patients at the most were tested or their glucose and insulin run on a given week, and that the study period extended over a long period, make it unlikely that the values were influenced by some common experience of the volunteer outpatients or by a systematic laboratory

error.

As for the other considerations raised by Dr. Pulier, we readily agree that additional studies with much larger numbers of subjects are needed before any sort of definitive statement can be made. Our conclusion emphasised this particular point, and we believe was properly tentative in tone. Previous work in our laboratory has demonstrated a dramatic effect of coffee and caffeine in exacerbating hyperglycaemia in the hereditary obese hyperglycaemic syndrome of mice. Furthermore, black coffee is often consumed in very large amounts by patients with maturity-onset diabetes told to reduce their weight in an attempt to restore their carbohydrate metabolism to normal. We felt that under these conditions it was important to report our preliminary work, hoping that it would lead to work on a