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PHENTOLAMINE FOR VASODILATOR TREATMENT OF SEVERE HEART-FAILURE
Saturday 2 October
PHENTOLAMINE FOR VASODILATOR TREATMENT OF SEVERE HEART-FAILURE B. SHARMA
P. A. MAJID S. H. TAYLOR
Cardiovascular Unit, University Department of Medicine, General Infirmary, Leeds LS1 3EX
Phentolamine,
adrenergic alphareceptor-blocking drug, was administwelve patients with severe progressive left
Summary
an
tered to ventricular failure due to ischæmic heart-disease. The drug was infused intravenously in a dose of 1-2 mg. per minute, sufficient to lower the systemic arterial blood-pressure by 20-30 mm. Hg. This resulted in a rapid relief of symptoms simultaneously with a substantial reduction in the left ventricular end-diastolic and pulmonary-artery mean pressures, and a significant increase in stroke volume and cardiac output; these changes were maintained throughout the 3-hour infusion. Patients who were able to exercise also reported a significant reduction in breathlessness, an increase in the cardiac output, and a decrease in the left ventricular end-diastolic Chest radiographs pressure response to exercise. showed a conspicuous clearing of pulmonary œdema and reduction in cardiac size after the drug. The benefits of this treatment are probably due to the effects of the drug in lowering the raised systemic vascular resistance and thus reducing cardiac pressure-
load, and to its positive inotropic action increasing the strength of myocardial contraction. The drug may also directly support the metabolism of the failing heart by release of the suppression of insulin secretion frequently associated with severe heart-failure, and its bronchodilator action may also contribute
to the relief in with cardiac asthma. This of symptoms patients the of severe to treatment heart-failure approach may usefully complement conventional treatment with digitalis and diuretics and may be of particular value where digitalis is contraindicated.
Introduction ’
.
DIGITALis and diuretics are the mainstay of the conventional treatment of heart-failure. Although the clinical usefulness of these drugs is beyond question, their limitations in the treatment of severe heartfailure are frequently encountered. This is due to the circulatory adaptations that occur when severe pumping failure develops; these are characterised by reflex vasoconstriction in most of the regional vascular territories so that the central aortic pressure is maintained and cerebral and coronary blood-flow sustained. These 7727
1971
predominantly brought about by vasoconstriction mediated through the sympathetic adrenergic alpha-receptors in the peripheral systemic bloodvessels. However, this increase in peripheral resistance results not only in a redistribution of blood volume
changes
are
towards the heart but also in considerable increase in the pressure component of the work of the heart, thus aggravating further the pumping failure of the dilated left ventricle. In these circumstances the increased strength of myocardial contraction afforded by digitalis and the decrease in cardiac volume resulting from diuretics are logical methods of treatment. However, it is equally logical and possibly of more immediate physiological importance to reduce the pressure-work of the failing dilated ventricle by lowering systemic vascular resistance. Phentolamine, a specific alphareceptor-blocking drug, lowers systemic vascular resistance and increases cardiac output in man 1-3 and in the dog.4 If these haemodynamic responses were equally applicable to the patient in heart-failure, significant clinical benefit could be expected. The following investigation was undertaken to examine this possibility. Patients and Methods
Patients were made in twelve male patients, average (range 38-59), in severe heart-failure. All had a distinct history of ischxmic heart-disease, and four had had a myocardial infarction within the previous 2 weeks. All were in clinically severe acute or subacute left ventricular failure, in six of whom it had progressed to congestive cardiac failure with raised jugular venous pressure and peripheral oedema. All were in sinus rhythm. None had evidence of valvular heart-disease, hypertension, or diabetes. All had been treated with digoxin and diuretics, despite which the heart-failure was clinically progressive. The electrocardiogram showed T-wave inversion with or without sT-segment depression in chest leads V 4-6 in eight patients, with additional evidence of recent myocardial infarction in four. The chest radiographs in all patients showed conspicuous cardiac enlargement, predominantly due to left ventricular dilatation, with pulmonary venous hypertension and oedema.
The studies
age 49 years
The nature and purpose of the treatment and the associated studies was explained to each patient and their relatives.5,66 In all instances verbal and written consent was given without inducement.
Design of Investigation The investigation was designed in two parts to take account of the severity of the clinical disability of each
patient. Group A.-The six patients in this group were so incapacitated that studies were carried out only at rest.
720 Observations began 15 minutes after insertion of the intravascular catheters. Electrocardiogram and intravascular pressures were recorded continuously throughout the study. Cardiac output was measured by the direct oxygen Fick method over 4-minute periods at mean times of 15 and 5 minutes before and 5, 30, 60, 90, 120, 150, and 180 minutes after the start of an intravenous infusion of phentolamine. Phentolamine in a concentration of 20 mg. per ml. was given by a motor-driven pump in an initial dose of 5 mg. per minute for 1 minute followed by a dose of 1-2 mg. per minute, the dose being adjusted in each patient to reduce the supine mean systemic arterial pressure by approximately 25 mm. Hg. The infusion was stopped after 3 hours; the systemic arterial pressure returned gradually to preinfusion levels during the subsequent 12-24 hours.
Group B.-The six patients in perform light supine leg exercise.
this group were able to 15 minutes after insertion of the intravascular catheters, tests began with a 6-minute period of light supine leg exercise at a work-load just sufficient to double the resting oxygen uptake. Cardiac output was measured during the last 2 minutes of exercise. The patient then rested quietly for 20 minutes; the resting cardiac output was measured during the final 4 minutes of this period. An intravenous infusion of phentolamine was then started in a concentration and dose similar to that in the patients in group A so as to reduce the mean systemic arterial pressure by 25 mm. Hg. The infusion was continued for 1 hour, after which the resting cardiac output was again measured over 4 minutes followed by a second 6-minute period of exercise with a further cardiac output
during the final 2 minutes of exercise, electrocardiogram and intravascular pressures were again recorded continuously throughout. measurement
made
The
Laboratory Techniques The aortic and left ventricular pressures were measured means of nylon catheters (75 cm. x0-l cm.) introduced percutaneously from the brachial arteries. Pressures and mixed-venous blood-samples were obtained from the pulmonary artery through a double-lumen 9F catheter introduced under radiological screening control from an antebrachial vein. The common zero reference level for all pressures was set at 10 cm. below the sternal angle with the patient supine. Pressures were transduced by Statham P23D6 strain-gauges. Using this method of measurement of the cardiac output by the direct oxygen Fick method, its reproducibility both at rest and during supine leg exercise is 7%.7 Blood-gas tensions were measured by a direct polargraphic method (E.I. Laboratories) calibrated by gases analysed on a Lloyd-Haldane apparatus. The electrocardiogram and intravascular pressures were recorded on an ultraviolet light recorder (S.E. Laboratories model 3012).
by
Measurements, Calculations, and Statistical Methods Mean pressures were measured from electronically intePhasic pressure measurements were grated records. averaged over two whole respiratory cycles. The mean systolic and mean diastolic pressures were measured by planimetric integration of the left ventricular and aortic pressure
pulse components
over
one
respiratory cycle.8
Left ventricular work was calculated as the product of cardiac output and mean systolic pressure.9° The systemic and pulmonary vascular resistances were calculated with respect to surface area.1o Statistical analyses were based on orthodox methods 11; the significance of differences between groups relates to the comparison of means.
Results
Clinical Effects All patients spontaneously reported conspicuous reduction in breathlessness at rest immediately after the phentolamine infusion, and those who a
exercised also noted much reduced breathlessness during exertion after Fig. 1-Chest radiographs of infusion of phentolamine (1
a
patient: (a) before, and (b) 12 hours after minute).
a
3-hour
mg. per
phentolamine. The electrocardiogram was continuously monitored and did not reveal any dysrhythmias or any other change during or after the phentolamine infusion. Chest radiographs before and after the infusion revealed conspicuous clearing in pulmonary oedema (fig. 1) and reduction in heart size (fig. 2). No side-effects of the drug were observed apart from mild nausea in three patients and diarrhoea in two patients; these side-effects were mild, undistressing, and of short duration in all instances; they did not require
symptomatic patient: (a) before, and (b) 12 hours after phentolamine (1 mg. per minute).
Fig. 2-Chest radiographs of intravenous infusion of
a
a
3-hour
treatment.
Haemodynamic Effects Group A (table i, fig. 3).-The indi-
721 I.4BU I—CIRCULATORY STUDIES IN PATIENTS WITH SEVERE HEART-FAILURE BEFORE AND AFTER INTRAVENOUS INFUSION OF PHENTOLAMINE: A GROUP
expressed as meanj:s.E.M. A-V = Systemic-pulmonary arterial blood-oxygen content difference. s.A.= Systemic arterial pressure. P.v.R.= Pulmonary vascular resistance. S.v.R.=Systemic vascular resistance. a-APo. = Alveolar-air/systemic-artena!-blood-oxygen tension gradient. * p < 0-05. t P < 0-02. 1p< 0-01. § P < 0-001. Probabilities relate to comparison of group means.
Data
vidual haemodynamic characteristics in this group of patients were similar. Before phentolamine, the resting cardiac output was severely reduced, the heart-rate raised, and the left ventricular end-diastolic and pulmonary-artery mean pressures significantly increased above the normal range. The response to intravenous phentolamine was similar in all patients. The reduction in the systemic arterial mean pressure was immediately followed by a significant increase in stroke volume and cardiac output, and a consistent fall in left ventricular end-diastolic pressure, with a concomitant reduction in the pulmonary-artery mean pressure. The averaged reduction in pulmonary vascular resistance was not
statistically significant. These changes were maintained throughout the 3-hour period of the phentolamine infusion. TABLE II-CIRCULATORY STUDIES IN PATIENTS WITH SEVERE HEARTAND FAILURE BEFORE AFTER INTRAVENOUS INFUSION OF PHENTOLAMINE : GROUP B
Data
expressed as mean::!:s.E.M. Systemic-pulmonary arterial blood-oxygen s.A. = Systemic arterial pressure. S.V.R. Systemic vascular resistance. P. V.R. =Pulmonary vascular resistance.
A-V
Fig. 3-Changes
=
content
difference.
=
at rest
during infusion of phentolamine in six
patients with severe heart-failure. Results as means.B.M. LV,E.D,P. =Left ventricular end-diastolic pressure.
a—Apo = Alveolar-air/systemic-arterial-blood-oxygen-tension gradient. *P<0-05. P < 0-001. fp<0’02. tP<0’01. Probabilities relate to comparison of group means.
722 out the infusion. A similar significant shift to the left in the left ventricular function curve after phentol. amine was observed in the six patients in group B, again without statistically significant changes in heart. rate.
Fig. 4-Changes during exercise during infusion of phentolamine in six patients with severe heart-failure. Results as mean-S.E.M. with probability of significance of
grouped
differences.
Group B (table n, fig. 4).-The hxmodynamic findings in these patients and their response to exercise before and after phentolamine were again remarkably consistent. In the control study the resting cardiac output and stroke volume were reduced and their response to exercise severely impaired. The left ventricular enddiastolic pressure was considerably raised at rest and further increased significantly during exercise; the
pulmonary-artery
mean
pressure
was
concomitantly
increased. After 1 hour of phentolamine infusion, during which time the resting systemic arterial mean pressure was reduced by 20 mm. Hg, the resting cardiac output response to exercise was raised to within nearly The resting left ventricular endnormal limits. diastolic pressure was significantly reduced after phentolamine, and the increase during exercise significantly less than that in the control study. The pulmonary-artery mean pressure was concomitantly reduced both at rest and during exercise after phentolamine.
Left Ventricular Function (fig. 5) The relationship between left ventricular stroke work and end-diastolic pressure before and after phentolamine infusion is illustrated in fig. 5. In the six patients in group A studied at rest, the infusion of phentolamine was immediately followed by a large
Effects
on
reduction in end-diastolic pressure and an increase in stroke work output by the ventricle without change in heart-rate. These changes were maintained through-
Fig. 5-Mean changes in left ventricular function induced by phentolamine at rest and during exercise in patients with severe
heart-failure.
=Left ventricular stroke work index. Numbers next to graph points represent time in minutes before or after start of phentolamine infusion. L.V.S.W.I.
Respiratory Effects (tables I and II) Group A.-In the six patients studied at rest in this group there was no significant change in respira. tory-rate or minute-ventilation throughout the phen. tolamine infusion. A small but statistically significant increase in oxygen uptake began 1 hour after the start of the infusion. There was no significant change in the alveolar-air/systemic-arterial oxygen-tension gradient (a-A gradient) and no significant change in the systemic arterial blood-gas tensions or pH throughout the infusion. Group B.-In the six patients studied at rest and during exercise in this group there were no statistically significant changes in respiratory-rate, minute-ventilation, oxygen uptake, a-A gradient, or systemic arterial blood-gas tensions or pH at rest or during exercise. Discussion
These studies clearly demonstrate the therapeutic value of reducing the systemic vascular resistance with the vasodilator drug phentolamine in patients with severe left ventricular failure. The rationale for the use of this drug in this situation was based on the following physiological considerations. The onset of pumping failure of the left ventricle is accompanied by reflex vasoconstriction in most of the regional vascular territories, the raised systemic resistance serving to maintain the aortic blood pressure and flow to the cerebral and coronary circulations. However, if maintained, this increase in resistance has two important aggravating effects on left ventricular function in the failing heart: widespread peripheral vasoconstriction redistributes the blood volume towards the heart and lungs, further dilating the failing ventricle, and since myocardial oxygen consumption is directly related both to ventricular volume and the pressure component of left ventricular work, the reflex increase in systemic resistance can be expected to increase progressively oxygen usage by the dilated ventricle. This chain of events may be interrupted by reduction of systemic resistance. The reflex constriction of arterioles and veins accompanying heart-failure is accomplished nearly entirely through the activity of sympathetic adrenergic alpha-receptors in the peripheral vascular territories, especially those of the skin, renal, and splanchnic circulations. Phentolamine, a specific alpha-receptor antagonist, blocks this vasoconstriction.1,12,13Thus, phentolamine could be expected to prove efficacious in heart-failure for two reasons: by increasing the capacity of the peripheral vessels, particularly the veins, the drug will act in a similar manner to a venous tourniquet or bleeding, acutely reducing the volume of blood in the dilated heart; by reducing the pressure component of the work of the left ventricle, myocardial oxygen consumption will be directly reduced.14 Although these studies afford no clueas to the proportionate importance of these two mechanisms in the relief of left ventricular failure in these
723
patients, they confirm the immediate symptomatic and hsemodynamic benefits of phentolamine in severe heart-failure if given in sufficient dose to reduce the systemic vascular resistance to a level of blood-pressure that affords no hazard to the cerebral and coronary circulations. Some of the beneficial effects of the drug on cardiac performance may have been due to a reflex increase in sympathetic activity secondary to the fall in systemic blood-pressure. An increase in sympathetic drive to the ventricle (inotropic effect) cannot be entirely discounted from our findings, but the fact that there was no increase in heart-rate (chronotropic effect) probably indicates that any reflex increase in inotropic
activity was relatively small. It has also been suggested that the drug may directly stimulate the myocardium.15 Gould et a1.,3on the basis of evidence derived from strain-gauges on the right ventricle of the anxsthetised dog and from measurements of left ventricular dp/dt (max) in intact normal subjects and patients recovered from heart-failure, concluded that the drug had a significant positive inotropic effect. Although the validity of this conclusion is questionable, since the increases in myocardial force and speed of contraction were accompanied by conspicuous changes
,
in heart-rate and arterial pressure in many of the animals and patients, experiments in our laboratory have confirmed that the drug has a positive inotropic effect in the denervated dog heart in which arterial e pressure and heart-rate were closely controlled. 16 Dairman et al." found that intravenous phentolamine (5 mg. per kg.) resulted in a threefold increase in conversion of tyrosine- 14C to noradrenaline in the heart, brain, and adrenal glands of the rat. This evidence suggests that phentolamine may increase
myocardial contractility by two mechanisms-indirectly, by reflex sympathetic stimulation secondary to the reduction in systemic blood-pressure, and directly, probably by stimulation of the cardiac beta-receptors in the myocardium on the left ventricle. 16 e We should also mention the possible role of phentolamine in the relief of the insulin suppression observed in patients with severe heart-failure. Insulin and glucose are vital for the maintenance of pumping function of the failing heart. 18- 22 Severe pumping failure of the heart is associated with suppression of insulin secretion whatever the aetiology of the heartfailure. 23-27 Phentolamine produces an immediate and significant reversal of this insulin suppression. 28 It may be that, although the vasodilator actions of phentolamine in unloading the failing left ventricle may play the predominant role in the relief of heartfailure, the effects of the drug in supporting myocardial metabolism by release of insulin suppression may also play an important if subordinate role in these circumstances.
Despite the apparent simplicity of this therapeutic application of phentolamine, it seems to have received little previous clinical or experimental attention. After investigating the haemodynamic effects of the drug on the systemic and pulmonary circulations, Taylor et al." suggested that phentolamine might benefit patients in severe left heart-failure. Weil and Bradley 12a
observed that the drug increased the cardiac output and skin and renal blood-flows in patients in circulatory shock, but concluded that the associated fall in blood-pressure limited its use in this situation. Gould et al. found that the drug significantly increased both cardiac output and systemic arterial pressure in hsemorrhagic shock in dogs; the same group also reported the conspicuous clinical effects of the drug in patients with pulmonary oedema, but haemodynamic data were given for only one patient. 29 Our results seem to be the first to describe the haemodynamic benefits that accrue from the use of the drug in patients with severe left ventricular-failure. The mechanisms involved in the relief of symptoms of breathlessness afforded by phentolamine in these patients are obscure. Although the relief of dyspnoea was closely correlated in time and extent with the fall in left ventricular end-diastolic and pulmonary arterial pressures, and presumably a reduction in the pulmonary blood volume,13,3o the amelioration in symptoms was unaccompanied by any change in the respiratory-rate or ventilatory volumes in any patient. However, some of the relief in breathlessness following phentolamine may have been due to its bronchodilator effects. The drug is completely effective in preventing experimental histaminic and allergic bronchoconstriction both in the guineapig 31 and in man. 32 This action of the drug may have played a subordinate
mean
role in the relief of the bronchoconstrictor symptoms associated with pulmonary oedema. Although digitalis and diuretics remain the mainstay of treatment of severe heart-failure they are often of limited usefulness, especially in severe left ventricular failure after myocardial infarction or ischsemic heartdisease. Indeed, in these circumstances, the administration of agents that directly enhance the inotropic state of the myocardium, such as digitalis, may exert paradoxical effects in that they may increase oxygen demand and, since oxygen supply is critically limited, further ischsemic damage and functional impairment may ensue. In these situations intravenous phentolamine may afford a means of rapidly reversing left ventricular failure, especially if it is used in conjunction with digitalis and diuretics. This approach may also offer advantages in the long-term treatment of heart-failure. Although present treatments are with the support of the concerned nearly entirely the digitalis glycosides heart either with failing directly or by reduction of the plasma volume with diuretics, these results suggest that treatment also directed towards relief of the increased work-load of the heart in failure may afford significant clinical benefit when other methods have been unsuccessful. Oral preparations of the adrenergic alpha-receptor-blocking drugs deserve further investigation in this respect. We thank Sister F. Ellis, Sister R. Cox, and the nursing staff of the medical professorial unit, Mr. R. Stafford and the technicians and nursing staff of the Cardiovascular Unit for their help and cooperation throughout these studies. P. A. M. is a senior Wellcome Foundation research fellow, B. S. is a senior Ciba research fellow. The work was supported by grants from the Wellcome Foundation and the Leeds and West Riding Medical Research Trust.
Requests
for
reprints should be addressed
to
S. H. T.
724
INDICATIONS FOR ORAL GLUCOSE-TOLERANCE TESTS DURING PREGNANCY
J. M. MALINS Diabetic Clinic, General Hospital, Birmingham B4 6NH N. G. SOLER
Diabetes was uncommon amongst women referred by obstetricians for 50 g. oral glucose tolerance test (G.T.T.) during the third trimester of pregnancy; it was found in only 8 out of 200 women investigated. Of these 8 diabetics 1 had a history of a stillbirth, 2 had glucosuria in pregnancy, and 5 had first-degree diabetic relatives. The indications for oral G.T.T.S during pregnancy have been reviewed. In urines collected after meals a single finding of glucosuria can be ignored in the absence of a family history of diabetes or of a history of previous abnormal G.T.T.S, stillbirths, or large babies, but two or more tests showing glucosuria in excess of " light " ’Clinistix’ or "trace" ’ Clinitest’ call for investigation even when there are no other pointers to the diagnosis of diabetes.
Summary
Introduction
" FLORID " diabetes with symptoms may be first discovered during pregnancy. It is managed in the same way and carries a similar prognosis to pregnancy in known diabetics.1 The main purpose of oral glucose-tolerance tests (G.T.T.) during pregnancy is to detect women with a milder degree of diabetic abnormality. In most cases this mild abnormality disappears when the pregnancy is over,and it is for these cases that the term " gestational diabetes"" should be reserved.3 Gestational diabetics have increased fetal wastage compared with women with normal carbohydrate tolerance,4 and their infants are at risk of neonatal complications such as large birthweight, hypoglycaemia, and respiratory distress.5 We have recorded the frequency of diabetes and other minor G.T.T. abnormalities amongst glucosuric pregnant women and women referred for investigation because of various " other " indications. A comparison is also made with the G.T.T. results in unselected healthy pregnant women attending a general practice. Patients and Methods
1.
2.
Taylor, S. H., Sutherland, G. R., MacKenzie, G. J., Staunton, H. P., Donald, K. W. Circulation, 1965, 31, 741. Evans, G. L., Smulyan, H., Eich, R. H. Am. J. Cardiol. 1967, 20, 216.
Gould, L., Zahir, M., Ettinger, S. Br. Heart J. 1969, 31, 154. Gould, L., Ettinger, S., Carmichael, A., Lord, P., Hofstra, P. Angiology, 1970, 21, 330. 5. Medical Research Council statement on Responsibility in Investigations on Human Subjects. Br. med. J. 1964, ii, 178. 6. Ormrod, R. ibid. 1968, ii, 7. 7. Taylor, S. H., Pakrashi, B. C., Galvin, M., Sharma, B., Majid, P. A. Unpublished. 8. Taylor, S. H., MacDonald, H. R., Robinson, M. C., Sapru, R. P. Br. Heart J. 1967, 29, 352. 9. Dexter, L., Whittenberger, J. L., Haynes, F. W., Goodale, W. T., Gorlin, R., Sawyer, C. G. J. appl. Physiol. 1951, 3, 439. 10. Taylor, S. H., Sutherland, G. R., Hutchison, D. C. S., Kidd, B. S. L., Robertson, P. C., Kennelly, B. M., Donald, K. W. Am. Heart J. 1962, 63, 239. 11. Fisher, R. A. Statistical Methods for Research Workers. Edinburgh, 1946. 12. Weil, M. H., Bradley, E. C. J. clin. Invest. 1965, 44, 1030. 13. Taylor, S. H., MacKenzie, G. J., George, M., McDonald, A. Br. Heart J. 1965, 27, 627. 14. Sarnoff, S. J., Braunwald, E., Welch, G. H., Case, R. B., Stainsby, W. N., Macruz, R. Am. J. Physiol. 1958, 192, 148. 15. Goodman, L. S., Gilman, A. The Pharmacological Basis of Therapeutics; p. 557. New York, 1965. 16. Taylor, S. H., Snow, M., Linden, R. J. Unpublished. 17. Dairman, W., Gordon, R., Spector, S., Sjoerdsma, A., Udenfriend, S. Fedn Proc. 1968, 27, 240. 18. Scheuer, J. Am. J. Cardiol. 1967, 19, 385. 19. Cascarano, J., Chick, W. L., Seidman, L. Proc. Soc. exp. Biol. Med. 1968, 127, 25. 20. Weissler, A., Kruger, F. A., Baba, N., Scarpelli, D. C., Leighton, R. F., Gallimore, J. K. J. clin. Invest. 1968, 47, 403. 21. Owen, P., Thomas, M., Opie, L. Lancet, 1969, i, 1187. 22. Taylor, S. H. Br. Heart J. 1971, 33, 329. 23. Taylor, S. H., Saxton, C., Majid, P. A., Dykes, J. R. W., Ghosh, P., Stoker, J. B. Lancet, 1969, ii, 396. 24. Allison, S. P., Chamberlain, M. J., Hinton, P. Br. med. J. 1969, iv, 3. 4.
776.
Sharma, B., Majid, P. A., Pakrashi, B. C., Dykes, J. R. W., Taylor, S. H. Br. med. J. 1970, ii, 396. 26. Majid, P. A., Ghosh, P., Pakrashi, B. C., Ionescu, M., Dykes, J. R. W., Taylor, S. H. Br. Heart J. 1971, 33, 329. 27. Taylor, S. H., Majid, P. A. J. mol. cell. Cardiol. 1971, 2, 293. 28. Majid, P. A., Saxton, C., Dykes, J. R. W., Galvin, M. C., Taylor, S. H. Br. med. J. 1970, iv, 328. 29. Gould, L., Zahir, M., Shariff, M., Guiliani, M. Jap. Heart J. 1970, 11, 141. 30. Murphy, G. W., Schreiner, B. F., Yu, P. N. Circulation, 1971, 43, 145. 31. Gould, L. Am. Heart J. 1969, 78, 276. 32. Kerr, J. W., Govindaraj, M., Patel, K. R. Br. med. J. 1970, ii, 139. 25.
The the
referred for oral G.T.T.s by obstetricians Birmingham Maternity Hospital between January, 1968, and December, 1969. At the antenatal clinics of this hospital urines are tested for glucose withQinistix’ and ’Clinitest’ (Ames) at every attendance, and 100 women had G.T.T.s because of the single indication of glucosuria in pregnancy. Another 100 pregnant women had G.T.T.S for other indications such as family history of diabetes, a history of having borne 10 Ib. (4500 g.) babies or stillbirths, abnormal G.T.T.s during past pregnancies, hydramnios, and obesity. Only 38 of these women with other indications were known to have glucosuria. No mothers of congenitally deformed babies were studied, whilst abortions and infertility were not considered as at
women were
individual indications. 50 consecutive unselected women attending a general practice during the same period were used as controls and also had G.T.T.S in the third trimester. Details of age and parity of all the women studied are shown in table I. TABLE I-AGE AND PARITY OF WOMEN STUDIED
done on an outpatient basis between the and twenty-eighth thirty-second weeks of pregnancy, The women were advised to continue their normal diet and physical activities in the days preceding the test. They fasted for twelve hours before attending hospital at 9 A.M. on the morning of the investigation and the test started half an hour later. A 50 g. glucose load dissolved in 250 ml. of orange or lemon flavoured water was used throughout the series. Nausea was not commonly encountered at this late stage of pregnancy, but when it occurred the test was repeated. The Hoffman method6 on a Technicon‘ AutoAnalyzer ’was used for the determination of capillary blood-sugars fasting and half-hourly after the 50 g. glucose loads. G.T.T. diabetes was defined according G.T.T.s were
PHENTOLAMINE FOR VASODILATOR TREATMENT OF SEVERE HEART-FAILURE B. SHARMA
P. A. MAJID S. H. TAYLOR
Cardiovascular Unit, University Department of Medicine, General Infirmary, Leeds LS1 3EX
Phentolamine,
adrenergic alphareceptor-blocking drug, was administwelve patients with severe progressive left
Summary
an
tered to ventricular failure due to ischæmic heart-disease. The drug was infused intravenously in a dose of 1-2 mg. per minute, sufficient to lower the systemic arterial blood-pressure by 20-30 mm. Hg. This resulted in a rapid relief of symptoms simultaneously with a substantial reduction in the left ventricular end-diastolic and pulmonary-artery mean pressures, and a significant increase in stroke volume and cardiac output; these changes were maintained throughout the 3-hour infusion. Patients who were able to exercise also reported a significant reduction in breathlessness, an increase in the cardiac output, and a decrease in the left ventricular end-diastolic Chest radiographs pressure response to exercise. showed a conspicuous clearing of pulmonary œdema and reduction in cardiac size after the drug. The benefits of this treatment are probably due to the effects of the drug in lowering the raised systemic vascular resistance and thus reducing cardiac pressure-
load, and to its positive inotropic action increasing the strength of myocardial contraction. The drug may also directly support the metabolism of the failing heart by release of the suppression of insulin secretion frequently associated with severe heart-failure, and its bronchodilator action may also contribute
to the relief in with cardiac asthma. This of symptoms patients the of severe to treatment heart-failure approach may usefully complement conventional treatment with digitalis and diuretics and may be of particular value where digitalis is contraindicated.
Introduction ’
.
DIGITALis and diuretics are the mainstay of the conventional treatment of heart-failure. Although the clinical usefulness of these drugs is beyond question, their limitations in the treatment of severe heartfailure are frequently encountered. This is due to the circulatory adaptations that occur when severe pumping failure develops; these are characterised by reflex vasoconstriction in most of the regional vascular territories so that the central aortic pressure is maintained and cerebral and coronary blood-flow sustained. These 7727
1971
predominantly brought about by vasoconstriction mediated through the sympathetic adrenergic alpha-receptors in the peripheral systemic bloodvessels. However, this increase in peripheral resistance results not only in a redistribution of blood volume
changes
are
towards the heart but also in considerable increase in the pressure component of the work of the heart, thus aggravating further the pumping failure of the dilated left ventricle. In these circumstances the increased strength of myocardial contraction afforded by digitalis and the decrease in cardiac volume resulting from diuretics are logical methods of treatment. However, it is equally logical and possibly of more immediate physiological importance to reduce the pressure-work of the failing dilated ventricle by lowering systemic vascular resistance. Phentolamine, a specific alphareceptor-blocking drug, lowers systemic vascular resistance and increases cardiac output in man 1-3 and in the dog.4 If these haemodynamic responses were equally applicable to the patient in heart-failure, significant clinical benefit could be expected. The following investigation was undertaken to examine this possibility. Patients and Methods
Patients were made in twelve male patients, average (range 38-59), in severe heart-failure. All had a distinct history of ischxmic heart-disease, and four had had a myocardial infarction within the previous 2 weeks. All were in clinically severe acute or subacute left ventricular failure, in six of whom it had progressed to congestive cardiac failure with raised jugular venous pressure and peripheral oedema. All were in sinus rhythm. None had evidence of valvular heart-disease, hypertension, or diabetes. All had been treated with digoxin and diuretics, despite which the heart-failure was clinically progressive. The electrocardiogram showed T-wave inversion with or without sT-segment depression in chest leads V 4-6 in eight patients, with additional evidence of recent myocardial infarction in four. The chest radiographs in all patients showed conspicuous cardiac enlargement, predominantly due to left ventricular dilatation, with pulmonary venous hypertension and oedema.
The studies
age 49 years
The nature and purpose of the treatment and the associated studies was explained to each patient and their relatives.5,66 In all instances verbal and written consent was given without inducement.
Design of Investigation The investigation was designed in two parts to take account of the severity of the clinical disability of each
patient. Group A.-The six patients in this group were so incapacitated that studies were carried out only at rest.
720 Observations began 15 minutes after insertion of the intravascular catheters. Electrocardiogram and intravascular pressures were recorded continuously throughout the study. Cardiac output was measured by the direct oxygen Fick method over 4-minute periods at mean times of 15 and 5 minutes before and 5, 30, 60, 90, 120, 150, and 180 minutes after the start of an intravenous infusion of phentolamine. Phentolamine in a concentration of 20 mg. per ml. was given by a motor-driven pump in an initial dose of 5 mg. per minute for 1 minute followed by a dose of 1-2 mg. per minute, the dose being adjusted in each patient to reduce the supine mean systemic arterial pressure by approximately 25 mm. Hg. The infusion was stopped after 3 hours; the systemic arterial pressure returned gradually to preinfusion levels during the subsequent 12-24 hours.
Group B.-The six patients in perform light supine leg exercise.
this group were able to 15 minutes after insertion of the intravascular catheters, tests began with a 6-minute period of light supine leg exercise at a work-load just sufficient to double the resting oxygen uptake. Cardiac output was measured during the last 2 minutes of exercise. The patient then rested quietly for 20 minutes; the resting cardiac output was measured during the final 4 minutes of this period. An intravenous infusion of phentolamine was then started in a concentration and dose similar to that in the patients in group A so as to reduce the mean systemic arterial pressure by 25 mm. Hg. The infusion was continued for 1 hour, after which the resting cardiac output was again measured over 4 minutes followed by a second 6-minute period of exercise with a further cardiac output
during the final 2 minutes of exercise, electrocardiogram and intravascular pressures were again recorded continuously throughout. measurement
made
The
Laboratory Techniques The aortic and left ventricular pressures were measured means of nylon catheters (75 cm. x0-l cm.) introduced percutaneously from the brachial arteries. Pressures and mixed-venous blood-samples were obtained from the pulmonary artery through a double-lumen 9F catheter introduced under radiological screening control from an antebrachial vein. The common zero reference level for all pressures was set at 10 cm. below the sternal angle with the patient supine. Pressures were transduced by Statham P23D6 strain-gauges. Using this method of measurement of the cardiac output by the direct oxygen Fick method, its reproducibility both at rest and during supine leg exercise is 7%.7 Blood-gas tensions were measured by a direct polargraphic method (E.I. Laboratories) calibrated by gases analysed on a Lloyd-Haldane apparatus. The electrocardiogram and intravascular pressures were recorded on an ultraviolet light recorder (S.E. Laboratories model 3012).
by
Measurements, Calculations, and Statistical Methods Mean pressures were measured from electronically intePhasic pressure measurements were grated records. averaged over two whole respiratory cycles. The mean systolic and mean diastolic pressures were measured by planimetric integration of the left ventricular and aortic pressure
pulse components
over
one
respiratory cycle.8
Left ventricular work was calculated as the product of cardiac output and mean systolic pressure.9° The systemic and pulmonary vascular resistances were calculated with respect to surface area.1o Statistical analyses were based on orthodox methods 11; the significance of differences between groups relates to the comparison of means.
Results
Clinical Effects All patients spontaneously reported conspicuous reduction in breathlessness at rest immediately after the phentolamine infusion, and those who a
exercised also noted much reduced breathlessness during exertion after Fig. 1-Chest radiographs of infusion of phentolamine (1
a
patient: (a) before, and (b) 12 hours after minute).
a
3-hour
mg. per
phentolamine. The electrocardiogram was continuously monitored and did not reveal any dysrhythmias or any other change during or after the phentolamine infusion. Chest radiographs before and after the infusion revealed conspicuous clearing in pulmonary oedema (fig. 1) and reduction in heart size (fig. 2). No side-effects of the drug were observed apart from mild nausea in three patients and diarrhoea in two patients; these side-effects were mild, undistressing, and of short duration in all instances; they did not require
symptomatic patient: (a) before, and (b) 12 hours after phentolamine (1 mg. per minute).
Fig. 2-Chest radiographs of intravenous infusion of
a
a
3-hour
treatment.
Haemodynamic Effects Group A (table i, fig. 3).-The indi-
721 I.4BU I—CIRCULATORY STUDIES IN PATIENTS WITH SEVERE HEART-FAILURE BEFORE AND AFTER INTRAVENOUS INFUSION OF PHENTOLAMINE: A GROUP
expressed as meanj:s.E.M. A-V = Systemic-pulmonary arterial blood-oxygen content difference. s.A.= Systemic arterial pressure. P.v.R.= Pulmonary vascular resistance. S.v.R.=Systemic vascular resistance. a-APo. = Alveolar-air/systemic-artena!-blood-oxygen tension gradient. * p < 0-05. t P < 0-02. 1p< 0-01. § P < 0-001. Probabilities relate to comparison of group means.
Data
vidual haemodynamic characteristics in this group of patients were similar. Before phentolamine, the resting cardiac output was severely reduced, the heart-rate raised, and the left ventricular end-diastolic and pulmonary-artery mean pressures significantly increased above the normal range. The response to intravenous phentolamine was similar in all patients. The reduction in the systemic arterial mean pressure was immediately followed by a significant increase in stroke volume and cardiac output, and a consistent fall in left ventricular end-diastolic pressure, with a concomitant reduction in the pulmonary-artery mean pressure. The averaged reduction in pulmonary vascular resistance was not
statistically significant. These changes were maintained throughout the 3-hour period of the phentolamine infusion. TABLE II-CIRCULATORY STUDIES IN PATIENTS WITH SEVERE HEARTAND FAILURE BEFORE AFTER INTRAVENOUS INFUSION OF PHENTOLAMINE : GROUP B
Data
expressed as mean::!:s.E.M. Systemic-pulmonary arterial blood-oxygen s.A. = Systemic arterial pressure. S.V.R. Systemic vascular resistance. P. V.R. =Pulmonary vascular resistance.
A-V
Fig. 3-Changes
=
content
difference.
=
at rest
during infusion of phentolamine in six
patients with severe heart-failure. Results as means.B.M. LV,E.D,P. =Left ventricular end-diastolic pressure.
a—Apo = Alveolar-air/systemic-arterial-blood-oxygen-tension gradient. *P<0-05. P < 0-001. fp<0’02. tP<0’01. Probabilities relate to comparison of group means.
722 out the infusion. A similar significant shift to the left in the left ventricular function curve after phentol. amine was observed in the six patients in group B, again without statistically significant changes in heart. rate.
Fig. 4-Changes during exercise during infusion of phentolamine in six patients with severe heart-failure. Results as mean-S.E.M. with probability of significance of
grouped
differences.
Group B (table n, fig. 4).-The hxmodynamic findings in these patients and their response to exercise before and after phentolamine were again remarkably consistent. In the control study the resting cardiac output and stroke volume were reduced and their response to exercise severely impaired. The left ventricular enddiastolic pressure was considerably raised at rest and further increased significantly during exercise; the
pulmonary-artery
mean
pressure
was
concomitantly
increased. After 1 hour of phentolamine infusion, during which time the resting systemic arterial mean pressure was reduced by 20 mm. Hg, the resting cardiac output response to exercise was raised to within nearly The resting left ventricular endnormal limits. diastolic pressure was significantly reduced after phentolamine, and the increase during exercise significantly less than that in the control study. The pulmonary-artery mean pressure was concomitantly reduced both at rest and during exercise after phentolamine.
Left Ventricular Function (fig. 5) The relationship between left ventricular stroke work and end-diastolic pressure before and after phentolamine infusion is illustrated in fig. 5. In the six patients in group A studied at rest, the infusion of phentolamine was immediately followed by a large
Effects
on
reduction in end-diastolic pressure and an increase in stroke work output by the ventricle without change in heart-rate. These changes were maintained through-
Fig. 5-Mean changes in left ventricular function induced by phentolamine at rest and during exercise in patients with severe
heart-failure.
=Left ventricular stroke work index. Numbers next to graph points represent time in minutes before or after start of phentolamine infusion. L.V.S.W.I.
Respiratory Effects (tables I and II) Group A.-In the six patients studied at rest in this group there was no significant change in respira. tory-rate or minute-ventilation throughout the phen. tolamine infusion. A small but statistically significant increase in oxygen uptake began 1 hour after the start of the infusion. There was no significant change in the alveolar-air/systemic-arterial oxygen-tension gradient (a-A gradient) and no significant change in the systemic arterial blood-gas tensions or pH throughout the infusion. Group B.-In the six patients studied at rest and during exercise in this group there were no statistically significant changes in respiratory-rate, minute-ventilation, oxygen uptake, a-A gradient, or systemic arterial blood-gas tensions or pH at rest or during exercise. Discussion
These studies clearly demonstrate the therapeutic value of reducing the systemic vascular resistance with the vasodilator drug phentolamine in patients with severe left ventricular failure. The rationale for the use of this drug in this situation was based on the following physiological considerations. The onset of pumping failure of the left ventricle is accompanied by reflex vasoconstriction in most of the regional vascular territories, the raised systemic resistance serving to maintain the aortic blood pressure and flow to the cerebral and coronary circulations. However, if maintained, this increase in resistance has two important aggravating effects on left ventricular function in the failing heart: widespread peripheral vasoconstriction redistributes the blood volume towards the heart and lungs, further dilating the failing ventricle, and since myocardial oxygen consumption is directly related both to ventricular volume and the pressure component of left ventricular work, the reflex increase in systemic resistance can be expected to increase progressively oxygen usage by the dilated ventricle. This chain of events may be interrupted by reduction of systemic resistance. The reflex constriction of arterioles and veins accompanying heart-failure is accomplished nearly entirely through the activity of sympathetic adrenergic alpha-receptors in the peripheral vascular territories, especially those of the skin, renal, and splanchnic circulations. Phentolamine, a specific alpha-receptor antagonist, blocks this vasoconstriction.1,12,13Thus, phentolamine could be expected to prove efficacious in heart-failure for two reasons: by increasing the capacity of the peripheral vessels, particularly the veins, the drug will act in a similar manner to a venous tourniquet or bleeding, acutely reducing the volume of blood in the dilated heart; by reducing the pressure component of the work of the left ventricle, myocardial oxygen consumption will be directly reduced.14 Although these studies afford no clueas to the proportionate importance of these two mechanisms in the relief of left ventricular failure in these
723
patients, they confirm the immediate symptomatic and hsemodynamic benefits of phentolamine in severe heart-failure if given in sufficient dose to reduce the systemic vascular resistance to a level of blood-pressure that affords no hazard to the cerebral and coronary circulations. Some of the beneficial effects of the drug on cardiac performance may have been due to a reflex increase in sympathetic activity secondary to the fall in systemic blood-pressure. An increase in sympathetic drive to the ventricle (inotropic effect) cannot be entirely discounted from our findings, but the fact that there was no increase in heart-rate (chronotropic effect) probably indicates that any reflex increase in inotropic
activity was relatively small. It has also been suggested that the drug may directly stimulate the myocardium.15 Gould et a1.,3on the basis of evidence derived from strain-gauges on the right ventricle of the anxsthetised dog and from measurements of left ventricular dp/dt (max) in intact normal subjects and patients recovered from heart-failure, concluded that the drug had a significant positive inotropic effect. Although the validity of this conclusion is questionable, since the increases in myocardial force and speed of contraction were accompanied by conspicuous changes
,
in heart-rate and arterial pressure in many of the animals and patients, experiments in our laboratory have confirmed that the drug has a positive inotropic effect in the denervated dog heart in which arterial e pressure and heart-rate were closely controlled. 16 Dairman et al." found that intravenous phentolamine (5 mg. per kg.) resulted in a threefold increase in conversion of tyrosine- 14C to noradrenaline in the heart, brain, and adrenal glands of the rat. This evidence suggests that phentolamine may increase
myocardial contractility by two mechanisms-indirectly, by reflex sympathetic stimulation secondary to the reduction in systemic blood-pressure, and directly, probably by stimulation of the cardiac beta-receptors in the myocardium on the left ventricle. 16 e We should also mention the possible role of phentolamine in the relief of the insulin suppression observed in patients with severe heart-failure. Insulin and glucose are vital for the maintenance of pumping function of the failing heart. 18- 22 Severe pumping failure of the heart is associated with suppression of insulin secretion whatever the aetiology of the heartfailure. 23-27 Phentolamine produces an immediate and significant reversal of this insulin suppression. 28 It may be that, although the vasodilator actions of phentolamine in unloading the failing left ventricle may play the predominant role in the relief of heartfailure, the effects of the drug in supporting myocardial metabolism by release of insulin suppression may also play an important if subordinate role in these circumstances.
Despite the apparent simplicity of this therapeutic application of phentolamine, it seems to have received little previous clinical or experimental attention. After investigating the haemodynamic effects of the drug on the systemic and pulmonary circulations, Taylor et al." suggested that phentolamine might benefit patients in severe left heart-failure. Weil and Bradley 12a
observed that the drug increased the cardiac output and skin and renal blood-flows in patients in circulatory shock, but concluded that the associated fall in blood-pressure limited its use in this situation. Gould et al. found that the drug significantly increased both cardiac output and systemic arterial pressure in hsemorrhagic shock in dogs; the same group also reported the conspicuous clinical effects of the drug in patients with pulmonary oedema, but haemodynamic data were given for only one patient. 29 Our results seem to be the first to describe the haemodynamic benefits that accrue from the use of the drug in patients with severe left ventricular-failure. The mechanisms involved in the relief of symptoms of breathlessness afforded by phentolamine in these patients are obscure. Although the relief of dyspnoea was closely correlated in time and extent with the fall in left ventricular end-diastolic and pulmonary arterial pressures, and presumably a reduction in the pulmonary blood volume,13,3o the amelioration in symptoms was unaccompanied by any change in the respiratory-rate or ventilatory volumes in any patient. However, some of the relief in breathlessness following phentolamine may have been due to its bronchodilator effects. The drug is completely effective in preventing experimental histaminic and allergic bronchoconstriction both in the guineapig 31 and in man. 32 This action of the drug may have played a subordinate
mean
role in the relief of the bronchoconstrictor symptoms associated with pulmonary oedema. Although digitalis and diuretics remain the mainstay of treatment of severe heart-failure they are often of limited usefulness, especially in severe left ventricular failure after myocardial infarction or ischsemic heartdisease. Indeed, in these circumstances, the administration of agents that directly enhance the inotropic state of the myocardium, such as digitalis, may exert paradoxical effects in that they may increase oxygen demand and, since oxygen supply is critically limited, further ischsemic damage and functional impairment may ensue. In these situations intravenous phentolamine may afford a means of rapidly reversing left ventricular failure, especially if it is used in conjunction with digitalis and diuretics. This approach may also offer advantages in the long-term treatment of heart-failure. Although present treatments are with the support of the concerned nearly entirely the digitalis glycosides heart either with failing directly or by reduction of the plasma volume with diuretics, these results suggest that treatment also directed towards relief of the increased work-load of the heart in failure may afford significant clinical benefit when other methods have been unsuccessful. Oral preparations of the adrenergic alpha-receptor-blocking drugs deserve further investigation in this respect. We thank Sister F. Ellis, Sister R. Cox, and the nursing staff of the medical professorial unit, Mr. R. Stafford and the technicians and nursing staff of the Cardiovascular Unit for their help and cooperation throughout these studies. P. A. M. is a senior Wellcome Foundation research fellow, B. S. is a senior Ciba research fellow. The work was supported by grants from the Wellcome Foundation and the Leeds and West Riding Medical Research Trust.
Requests
for
reprints should be addressed
to
S. H. T.
724
INDICATIONS FOR ORAL GLUCOSE-TOLERANCE TESTS DURING PREGNANCY
J. M. MALINS Diabetic Clinic, General Hospital, Birmingham B4 6NH N. G. SOLER
Diabetes was uncommon amongst women referred by obstetricians for 50 g. oral glucose tolerance test (G.T.T.) during the third trimester of pregnancy; it was found in only 8 out of 200 women investigated. Of these 8 diabetics 1 had a history of a stillbirth, 2 had glucosuria in pregnancy, and 5 had first-degree diabetic relatives. The indications for oral G.T.T.S during pregnancy have been reviewed. In urines collected after meals a single finding of glucosuria can be ignored in the absence of a family history of diabetes or of a history of previous abnormal G.T.T.S, stillbirths, or large babies, but two or more tests showing glucosuria in excess of " light " ’Clinistix’ or "trace" ’ Clinitest’ call for investigation even when there are no other pointers to the diagnosis of diabetes.
Summary
Introduction
" FLORID " diabetes with symptoms may be first discovered during pregnancy. It is managed in the same way and carries a similar prognosis to pregnancy in known diabetics.1 The main purpose of oral glucose-tolerance tests (G.T.T.) during pregnancy is to detect women with a milder degree of diabetic abnormality. In most cases this mild abnormality disappears when the pregnancy is over,and it is for these cases that the term " gestational diabetes"" should be reserved.3 Gestational diabetics have increased fetal wastage compared with women with normal carbohydrate tolerance,4 and their infants are at risk of neonatal complications such as large birthweight, hypoglycaemia, and respiratory distress.5 We have recorded the frequency of diabetes and other minor G.T.T. abnormalities amongst glucosuric pregnant women and women referred for investigation because of various " other " indications. A comparison is also made with the G.T.T. results in unselected healthy pregnant women attending a general practice. Patients and Methods
1.
2.
Taylor, S. H., Sutherland, G. R., MacKenzie, G. J., Staunton, H. P., Donald, K. W. Circulation, 1965, 31, 741. Evans, G. L., Smulyan, H., Eich, R. H. Am. J. Cardiol. 1967, 20, 216.
Gould, L., Zahir, M., Ettinger, S. Br. Heart J. 1969, 31, 154. Gould, L., Ettinger, S., Carmichael, A., Lord, P., Hofstra, P. Angiology, 1970, 21, 330. 5. Medical Research Council statement on Responsibility in Investigations on Human Subjects. Br. med. J. 1964, ii, 178. 6. Ormrod, R. ibid. 1968, ii, 7. 7. Taylor, S. H., Pakrashi, B. C., Galvin, M., Sharma, B., Majid, P. A. Unpublished. 8. Taylor, S. H., MacDonald, H. R., Robinson, M. C., Sapru, R. P. Br. Heart J. 1967, 29, 352. 9. Dexter, L., Whittenberger, J. L., Haynes, F. W., Goodale, W. T., Gorlin, R., Sawyer, C. G. J. appl. Physiol. 1951, 3, 439. 10. Taylor, S. H., Sutherland, G. R., Hutchison, D. C. S., Kidd, B. S. L., Robertson, P. C., Kennelly, B. M., Donald, K. W. Am. Heart J. 1962, 63, 239. 11. Fisher, R. A. Statistical Methods for Research Workers. Edinburgh, 1946. 12. Weil, M. H., Bradley, E. C. J. clin. Invest. 1965, 44, 1030. 13. Taylor, S. H., MacKenzie, G. J., George, M., McDonald, A. Br. Heart J. 1965, 27, 627. 14. Sarnoff, S. J., Braunwald, E., Welch, G. H., Case, R. B., Stainsby, W. N., Macruz, R. Am. J. Physiol. 1958, 192, 148. 15. Goodman, L. S., Gilman, A. The Pharmacological Basis of Therapeutics; p. 557. New York, 1965. 16. Taylor, S. H., Snow, M., Linden, R. J. Unpublished. 17. Dairman, W., Gordon, R., Spector, S., Sjoerdsma, A., Udenfriend, S. Fedn Proc. 1968, 27, 240. 18. Scheuer, J. Am. J. Cardiol. 1967, 19, 385. 19. Cascarano, J., Chick, W. L., Seidman, L. Proc. Soc. exp. Biol. Med. 1968, 127, 25. 20. Weissler, A., Kruger, F. A., Baba, N., Scarpelli, D. C., Leighton, R. F., Gallimore, J. K. J. clin. Invest. 1968, 47, 403. 21. Owen, P., Thomas, M., Opie, L. Lancet, 1969, i, 1187. 22. Taylor, S. H. Br. Heart J. 1971, 33, 329. 23. Taylor, S. H., Saxton, C., Majid, P. A., Dykes, J. R. W., Ghosh, P., Stoker, J. B. Lancet, 1969, ii, 396. 24. Allison, S. P., Chamberlain, M. J., Hinton, P. Br. med. J. 1969, iv, 3. 4.
776.
Sharma, B., Majid, P. A., Pakrashi, B. C., Dykes, J. R. W., Taylor, S. H. Br. med. J. 1970, ii, 396. 26. Majid, P. A., Ghosh, P., Pakrashi, B. C., Ionescu, M., Dykes, J. R. W., Taylor, S. H. Br. Heart J. 1971, 33, 329. 27. Taylor, S. H., Majid, P. A. J. mol. cell. Cardiol. 1971, 2, 293. 28. Majid, P. A., Saxton, C., Dykes, J. R. W., Galvin, M. C., Taylor, S. H. Br. med. J. 1970, iv, 328. 29. Gould, L., Zahir, M., Shariff, M., Guiliani, M. Jap. Heart J. 1970, 11, 141. 30. Murphy, G. W., Schreiner, B. F., Yu, P. N. Circulation, 1971, 43, 145. 31. Gould, L. Am. Heart J. 1969, 78, 276. 32. Kerr, J. W., Govindaraj, M., Patel, K. R. Br. med. J. 1970, ii, 139. 25.
The the
referred for oral G.T.T.s by obstetricians Birmingham Maternity Hospital between January, 1968, and December, 1969. At the antenatal clinics of this hospital urines are tested for glucose withQinistix’ and ’Clinitest’ (Ames) at every attendance, and 100 women had G.T.T.s because of the single indication of glucosuria in pregnancy. Another 100 pregnant women had G.T.T.S for other indications such as family history of diabetes, a history of having borne 10 Ib. (4500 g.) babies or stillbirths, abnormal G.T.T.s during past pregnancies, hydramnios, and obesity. Only 38 of these women with other indications were known to have glucosuria. No mothers of congenitally deformed babies were studied, whilst abortions and infertility were not considered as at
women were
individual indications. 50 consecutive unselected women attending a general practice during the same period were used as controls and also had G.T.T.S in the third trimester. Details of age and parity of all the women studied are shown in table I. TABLE I-AGE AND PARITY OF WOMEN STUDIED
done on an outpatient basis between the and twenty-eighth thirty-second weeks of pregnancy, The women were advised to continue their normal diet and physical activities in the days preceding the test. They fasted for twelve hours before attending hospital at 9 A.M. on the morning of the investigation and the test started half an hour later. A 50 g. glucose load dissolved in 250 ml. of orange or lemon flavoured water was used throughout the series. Nausea was not commonly encountered at this late stage of pregnancy, but when it occurred the test was repeated. The Hoffman method6 on a Technicon‘ AutoAnalyzer ’was used for the determination of capillary blood-sugars fasting and half-hourly after the 50 g. glucose loads. G.T.T. diabetes was defined according G.T.T.s were