EFFECTS OF ATROPINE ON HEART-RATE IN HEALTHY MAN

EFFECTS OF ATROPINE ON HEART-RATE IN HEALTHY MAN

12 Survival of Group-C Patients The results of treatment were unsatisfactory in group C. Since these results may be of importance for the indications...

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12

Survival of Group-C Patients The results of treatment were unsatisfactory in group C. Since these results may be of importance for the indications and principles of future treatment the course of the disease in these patients has been tabulated in detail (fig. 2) on the basis of a complete follow-up until death. Most patients died within six months of the day of tracheostomy, and the periods of discharge were short. 5 patients died during respirator treatment. In 10 patients who died during continued admission or at later admissions this treatment was not reinstituted. Discussion Acute severe respiratory failure in patients seen for the first time practically always indicates artificial ventilation, since it is seldom possible in the acute situation to evaluate the underlying condition or to predict the outcome of the episode. Extreme disturbances of blood-gas values and

neurological symptoms including profound coma not restrain the therapeutic efforts. Usually, the apparently desolate condition can be reversed without residual damage; only 2 of our patients had severe anoxic brain lesions. In those special cases where use of respiratory depressants or uncontrolled administration of oxygen are suspected, treatment is imperative. In our series tracheostomy and a course of respirator severe

should

in a group of with life-threatening respiratory failure superpatients on chronic diffuse lung disease. imposed The rationale for such temporary substitution of the ventilatory function is the assumption that the failure may partly be due to reversible factors, such as lung infections,

treatment were the

standard

heart-failure, drugs,

oxygen,

treatment

fever, asthma, anaemia,

or

exhaustion. The aim is to restore the state preceding the acute deterioration. This aim was attained in about half of our patients in so far as they left hospital with their usual physical ability. This habitual physical ability is the decisive prognostic factor. Due regard is too seldom paid to this seemingly simple fact, and therefore a comparison of results reported from different medical centres is impeded. Our patients of group A (previously able to live a fairly active life) usually regained complete independence of the respirator within less than four weeks. Their prospects of several years’ survival were fair, and about half of them could resume some work. Patients with a more restricted physical ability (group B) had a higher mortality during and after admission; but more than half of those discharged were still able to

mere

manage

personal requirements.

It seems that patients in these two groups are likely to benefit from a limited period of artificial ventilation; and with very few exceptions, such as rapidly progressing malignancies or severe cerebral affections not due to hypoventilation, we consider this treatment indicated. The same treatment was used for the severely incapacitated patients of group C, and it was intended to be temporary. Certainly most of the patients could be weaned from the respirator; but the later results were poor. 9 of the 21 patients died during admission; 1 survived for nearly three years, 1 (in a respirator) survived for twenty months, and the remaining patients died within ten months of tracheostomy. The prognosis of the group-C patients in this period is grave. If respirator treatment is instituted, one must realise that in most cases it must be continued permanently or as intermittent ventilation for part of the day or with

somewhat longer intervals. A few patients of the initially less incapacitated groups, and some patients undergoing tracheostomy before anamnestic information is available, may prove to have similar requirements. This small number of patients dependent on continuous care require supervision and surroundings that are not

provided by ordinary hospital departments (Bertoye et al. 1965, Engberg 1961). For some of them organised home care may be feasible; others will need institutions analogous with those existing for persons disabled by respiratory insufficiency of another aetiology—e.g., poliomyelitis. Requests for reprints should be addressed to K. R., Centrallaboratoriet, Blegdamshospitalet, Copenhagen N, Denmark. REFERENCES

Barnett, T. B., Burrows, B., Dunner, E., Durrance, J. R., Renzetti, A. D., Jr, Schmidt, H., Stead, W. W., Paulsson, D. L. (1960) Am. Rev. resp. Dis. 82, 746. Bates, D. V., Klassen, G. A., Broadhurst, C. A., Peretz, D. I., Anthonisen, N. R., Smith, H. J. (1965) Ann. N.Y. Acad. Sci. 121, 781. Bertoye, A., Garin, J.-P., Vincent, P., Giroud, M., Monier, P., Humbert, G. (1965) Lyon méd. J. 214, 389. Bradley, R. D., Spencer, G. T., Semple, S. J. G. (1964) Lancet, i, 854. Engberg, E. (1961) ibid. i, 1106. Gotsman, M. S., Whitby, J. L. (1964) Thorax, 19, 89. Grendahl, H., Refsum, H. E. (1965) Acta med. scand. 177, 539. Munck, O., Sund Kristensen, H., Lassen, H. C. A. (1961) Lancet, i, 66. Sadoul, P., Aug, M.-C., Gay, R. (1965) Bull. Physio-path. Resp. 1, 489. Siggaard-Andersen, O. (1963) Acid-Base Status of the Blood. Copenhagen. Jørgensen, K., Næraa, N. (1962) Scand. J. clin. Lab. Invest. 14, 298. Statistisk Arbog (1965) Statistisk Departement, Copenhagen. Sund Kristensep, H., Jessen, O., Rasmussen, K. (1967) Postgrad. Med. J. 43, 244. —

EFFECTS OF ATROPINE ON

HEART-RATE IN HEALTHY MAN D. A. CHAMBERLAIN M.A., M.D. Cantab., M.R.C.P. SENIOR MEDICAL REGISTRAR

PAUL TURNER M.D., B.Sc. Lond., M.R.C.P. READER IN CLINICAL PHARMACOLOGY, AND WELLCOME SENIOR RESEARCH FELLOW IN CLINICAL SCIENCE

J. M. SNEDDON B.Sc. Lond. RESEARCH ASSISTANT

From the Departments of Cardiology and the Clinical Pharmacology Division of the Medical Professorial Unit, St. Bartholomew’s Hospital, London E.C.1

Increasing doses of intravenous atropine given to ten healthy volunteers in whom the sympathetic innervation of the heart had been blocked by propranolol, and the effect on heart-rate was measured both at rest and during exercise. The dose required to produce maximum inhibition of vagal control of the sinoatrial node ranged from 0.025 to 0.04 mg. per kg. body-weight. The degree of vagal tone was an important determinant of dose requirement. Summary

were

Introduction

ATROPINE is used to block parasympathetic activity on the heart, both for research and therapeutically in the treatment and prevention of bradycardia and arrhythmias. An intravenous dose of 2 mg. has been considered adequate to produce complete blockade of vagal action on the sinoatrial node in man (Jones et al. 1961, Kahler et al. 1962), but Jose and Collison (1965) have used 0-04 mg. per kg. body-weight for this purpose, implying that 3 mg.

13 may be required in some individuals. There is, however, little published evidence to confirm the dose range necessary to achieve maximal effect on heart-rate. or more

Crawford (1923), Marzulli and Cope (1952), and Cullumbine et al. (1955) used intramuscular or subcutaneous smaller peak response than the intravenous route. Lewis et al. (1921) based their assertion that up to gr. 1/10 (6 mg.) atropine intravenously was sometimes necessary to produce full vagal blockade of the heart on observations made in patients with atrial fibrillation, but the effects on the atrioventricular and sinoatrial nodes may not be identical. Furthermore, the dual control of heart-rate by the parasympathetic and sympathetic systems has, until recently, prevented the ready interpretation of data, for the cardioregulatory centres were believed to be reciprocally linked so that stimulation of one was associated with inhibition of the other (Rushmer 1960). Although this inverse relation is no longer accepted (Glick and Braunwald 1965), one cannot assume that changes in heart-rate after atropine are due to vagal inhibition alone. The introduction of &bgr;-sympathetic antagonists has obviated the difficulty by permitting the isolation of the heart from sympathetic influences: under these conditions, changes in heart-rate with atropine can more validly be assumed to reflect accurately alterations in vagal tone. We have investigated the effects of increasing doses of atropine on heart-rate during rest and exercise in healthy volunteers pretreated with propranolol, and have determined the amounts required to provide ’maximum blockade of parasympathetic control of the sinoatrial node.

administration, giving

a

Volunteers and Methods Ten healthy volunteers were investigated. They comprised eight male students and two female students aged 22-23. Heart-rate was measured on a Sanborne direct-writing electrocardiograph at a paper speed of 25 mm. per second and by determining the time taken for five complete cardiac cycles indicated by the R waves; when sinus arrhythmia was detected in resting tracings, ten cycles were used, to increase the accuracy of the calculation of average heart-rate. At the start of each experiment the volunteers rested for at least 10 minutes before records were taken. Measurements of heart-rate were made first at rest supine, secondly after the volunteers had been standing for 30 seconds, and subsequently during the last 10 seconds of each of six 2-minute periods of exercise taken consecutively on a motor-driven treadmill at the following grades: 1 m.p.h. on the flat, 2 m.p.h. on the flat, 3 m.p.h. on the flat, 3 m.p.h. on a 3° incline, 3 m.p.h. on a 6° incline, and 3 m.p.h. on a 9° incline. This routine was followed on several occasions for each volunteer: without drugs, after oral propranolol alone, and after both oral propranolol and increasing doses of intravenous atropine sulphate using increments of 0-6 mg. until no further increase in heart-rate was observed in comparable measurements either at rest or during exercise. The injections of atropine were all timed to take 60 seconds, and the sequence of measurements detailed above was started only when the resting heart-rate had reached a peak, indicated by electrocardiographic recordings taken every 30 seconds after the completion of the injection. The dose of oral propranolol used to achieve &bgr;-sympathetic blockade was 80 mg., given 90 minutes before the experiments were performed. This dose of propranolol was shown to be effective by comparing the response of the heart-rate to inhaled isoprenaline before and after the drug in each of the volunteers (Chamberlain 1967): the amount of isoprenaline required to increase heart-rate by approximately 30 beats per minute was individually determined, and the challenge was repeated, but with twice the amount of isoprenaline, 90 minutes after the oral propranolol; the average rise in rate before propranolol was 33 beats per minute, and after propranolol only 1 beat per minute.

The investigation included a comparison of the slowing in heart-rate achieved by propranolol with the subsequent increase in rate in the same individuals after peak doses of atropine. Suitable data were available from five young patients with normal hearts who were investigated before undergoing upper thoracic sympathectomy, and these observations are included with the results from the volunteer students. Doses of Atropine Heart-rate

Results to Cause Maximum Increases in

Required

The supine resting heart-rate increased progressively as greater doses of atropine were given, up to a peak response with 1-8 mg. in three volunteers, 2-4 mg. in four, and 3-0 mg. in the remaining three. These doses corresponded to a range of 0-025-0-041 mg. per kg. body-weight. Further increments in dose produced no greater augmentation of rate. A significant negative correlation was found between the dose of atropine (in mg. per kg.) necessary to produce the maximum effect on heart-rate and the supine resting heart-rate in the control experiments before any drugs had been given (r= -0-73; P <

002).

The smaller doses of atropine had a relatively greater effect during exercise than at rest. For example, the rise in heart-rate at rest after 1-2 mg. averaged only 46% of that produced by the full atropinising doses; the corresponding figure at 3 m.p.h. on the flat was 62%, and on a 3° incline it was 71 %. Initial

Effects of Atropine

on

Resting

Heart-rate

In all the volunteers the effect of 0-6 mg. atropine was slow the heart-rate for about 1 minute (fig. 1); no increase in rate above the control value was observed in most of the volunteers at this dose level. Doses of 1-2 mg., 1-8 mg., and 2-4 mg. produced transient slowing followed by tachycardia. No slowing was observed with doses of 3-0 mg. or more, but it may have happened during or immediately after the injection when the rate was not being measured. The maximal effect of 1-2 mg. atropine on heart-rate usually developed about 90 seconds after the completion of the injection, but larger doses produced a peak response after about 60 seconds. to

Effect of Parasympathetic and Sympathetic

Blockade

on

Heart-rate

In observations made on ten volunteers and five at rest, a significant negative correlation was found between the fall in heart-rate after oral propranolol and the subsequent rise in rate after maximal doses of intravenous atropine (r= -0-52; p=0-05).

patients

Fig. 1-Mean changes in heart-rate after intravenous administration of atropine sulphate in increasing doses to ten volunteers who had been pretreated with propranolol.

14 After sympathetic and parasympathetic effects on the heart had both been blocked, an increase in heart-rate still occurred consistently during strenuous exercise (fig. 2). The mean increase was 18 beats per minute (S.E.M., 3-0).

increments in a larger number of experiments, but we felt limited by the amount of inconvenience to which we could reasonably subject our volunteers. The information obtained is, however, sufficient to confirm that a dose of 0-04 mg. per kg. of atropine is adequate to block as Discussion as possible parasympathetic control of the During each experiment, heart-rate was measured both effectively sinoatrial node in fit young people, and that smaller doses at rest and during increasing grades of exercise, but are required in individuals with less vagal tone. The atropine always had most influence on the resting heartupper limit of the required dose range is exactly that used rate. This was to be expected, because one of the principal and Collison (1965) in their work on intrinsic mechanisms of exercise tachycardia is a withdrawal of by Jose heart-rate. vagal inhibition on the sinoatrial node; vagal tone is We are not aware of any serious contraindications to the absent at maximal heart-rates which are consequently use of this dose of atropine in fit people. The drug is unaffected by atropine (Robinson et al. 1953). The remarkable for its wide therapeutic ratio, and doses of up decreasing influence of atropine, and consequently of to 200 mg. have been used therapeutically in psychiatry vagal tone, as the volunteers exercised at greater work et al. 1958). Nevertheless, well-known unpleasant (Miller loads is shown in fig. 2. side-effects occur. Besides the inevitable dryness of the Considerable variation was noted in the doses of mouth and difficulty in accommodation, experienced by atropine required to produce a maximum effect on resting our volunteers at the higher dose ranges, some also heart-rate, even when allowance was made for differences of nausea, lightheadedness, and of difficulty complained in body-weight. The choice of an intravenous route with micturition. ensured that this was not due to factors of absorption, and Transient slowing of the heart-rate was noted in most in each case care was taken to make observations only tests immediately after the atropine had been given. This when atropine was exerting its peak effect. The variation has been widely observed in the past and develops effect therefore represented either differences in sensitivity to because atropine has an initial vagotonic action (Goodman atropine between individuals, or differences in require- and Gilman 1965). The duration of slowing was found to depend upon dose (fig. 1). After 0-6 mg. it lasted for about 1 minute, and in most volunteers the heart-rate never rose above the control value. Doses of 1-2-2-4 mg. produced slowing in the first 15 seconds, but tachycardia developed within 30 seconds of the completion of the injection. No slowing was observed with doses of 3-0 mg. or more, but it is possible that it occurred during the injection when rate was not being measured. The slowing of heart-rate was often associated with abnormalities of the P waves of the electrocardiogram and disturbances in atrioventricular conduction. This effect has also been described by others (Wilson 1915, Enescu and Vacareanu 1938, Jones et al. 1961). Atropine is most frequently given in a dose of 0-6 mg., especially in anxsthesia. The effect of this dose on the heart-rate and rhythm is therefore of considerable practical importance; it is unlikely to be effective in countering the effects of increased vagal tone, and may indeed enhance it. When speed of action is of prime importance in situations where tachycardia itself will not be harmful, a dose of 3 mg. may be most suitable. The pharmacological blockade of sympathetic and Fig. 2-Mean heart-rates in ten volunteers supine, standing, and after exercise. parasympathetic control of the heart-rate proved of interest in two other respects. First, at rest the fall in ment resulting from inequality of vagal tone. Two heart-rates achieved by propranolol were negatively observations suggest that vagal tone is likely to be the correlated with subsequent rises after maximal doses of more important determinant of dose: first, a significant atropine. Analysis of data from fifteen individuals showed negative correlation was found between resting control the relation to be statistically significant. This implies that heart-rate and the dose requirement for complete parapeople with slow resting heart-rates have not only high sympathetic blockade, and secondly, small doses of vagal tone but also little sympathetic tone; conversely, atropine had a relatively greater effect on residual vagal those with high resting rates have less vagal tone but also tone during moderate exercise than on vagal tone at rest greater sympathetic tone. Second, during exercise a significant rise in heart-rate was obtained despite blockade of in the same individual. These findings accord with the observation by Kauf (1926) that a dose of atropine sympathetic and parasympathetic pathways. This rise was sufficient to cause striking cardiac acceleration in an unlikely to have been due to residual sympathetic drive because the doses of propranolol used were shown to be untrained individual may be relatively ineffective in an athlete. highly effective in blocking the effect on rate of circulating The dose increments of atropine used by us were catecholamines, and because the same effect has been relatively large. More accurate dose ranges may have been noted consistently in similar experiments performed after defined, and better correlations obtained, by using smaller both propranolol and cardiac sympathetic denervation

15

(Chamberlain and Shinebourne 1967). A substantial rise in heart-rate during exercise can also be obtained in dogs with total cardiac denervation and extirpation of the adrenal glands (Donald and Shepherd 1963). The mechanism of this residual rate response remains to be determined. We thank the students who volunteered to take part in the and Dr. Peter Rudge for his assistance in the early part of the work. J. M. S. is in receipt of a grant from the Board of Governors of St. Bartholomew’s Hospital. Requests for reprints should be addressed to D. A. C., St. Bartholomew’s Hospital, London E.C.!.

experiments,

REFERENCES

Chamberlain, D. A. (1967) M.D. thesis, University of Cambridge. Shinebourne, E. A. (1967) Unpublished. Crawford, J. H. (1923) J. Pharmac. exp. Ther. 22, 1. Cullumbine, H., McKee, W. H. E., Creasy, N. H. (1955) Q. Jl exp. Physiol. 40, 309. Donald, D. E., Shepherd, J. T. (1963) Am. J. Physiol. 205, 393. Enescu, J., Vacareanu, N. (1938) Archs Mal. Cœur, 31, 1223. Glick, G., Braunwald, E. (1965) Circulation Res. 16, 363. Goodman, L. S., Gilman, A. (1965) The Pharmacological Basis of Therapeutics; p. 254. New York. Jones, R. E., Deutsch, S., Turndorf, H. (1961) Anesthesiology, 22, 67. Jose, A. D., Collison, D. R. (1965) Med. Res. 1, 135. Kahler, R. L., Gaffney, T. E., Braunwald, E. (1962) J. clin. Invest. 41, 1981. Kauf, E. (1926) Wien. klin. Wschr. 39, 212. Lewis, T., Drury, A. N., Wedd, A. M., Iliescu, C. C. (1921) Heart, 9, 207. Marzulli, F. N., Cope, O. B. Cited by Craig, F. N. (1952) J. appl. Physiol. 4, 826. Miller, J. J., Schwarz, H. H., Forrer, G. R. (1958) J. clin. exp. Psychopath. 19, 312. Robinson, S., Pearcy, M., Brueckman, F. R., Nicholas, J. R., Miller, D. I. (1953) J. appl. Physiol. 5, 508. Rushmer, R. F. (1960) in Medical Physiology and Biophysics (edited by T. C. Ruch and J. F. Fulton); p. 715. Philadelphia. Wilson, F. N. (1915) Archs intern. Med. 16, 989. —

THYROTOXICOSIS AND HASHIMOTO GOITRE IN A PAIR OF MONOZYGOTIC TWINS WITH SERUM LONG-ACTING THYROID STIMULATOR M. I. V.

JAYSON*

M.B. Lond., M.R.C.P. REGISTRAR, DEPARTMENT OF RHEUMATOLOGY, ROYAL FREE HOSPITAL, LONDON W.C.1

D. DONIACH, Lond., M.R.C.P.

N. BENHAMOU-GLYNN

M.D.

D.Sc. Paris

SENIOR LECTURER

RESEARCH FELLOW

I. M. ROITT Oxon, M.C.Path.

D.Phil.

READER, RHEUMATOLOGY RESEARCH DEPARTMENT MIDDLESEX HOSPITAL MEDICAL

SCHOOL,

LONDON

W.1

D. J. EL KABIR M.A., M.B. Cantab. OF THE MEDICAL RESEARCH COUNCIL NEUROENDOCRINOLOGY RESEARCH

UNIT, DEPARTMENT

OF HUMAN

ANATOMY, UNIVERSITY

OF OXFORD

Of a of female monozygotic twins, one Summary had pair thyrotoxicosis, progressive exophthal-

Introduction

INVESTIGATIONS of autoimmunity in Hashimoto’s thyroiditis and in primary thyrotoxicosis suggest that the two diseases are closely connected. The long-acting thyroid stimulator (L.A.T.S.) detectable in up to 80% of thyrotoxic sera (Munro 1967) is probably responsible for the continuous stimulation of the thyroid gland in Graves’ disease, although it is chemically distinct from the pituitary thyroid-stimulating hormone (McKenzie 1965, Adams 1965). L.A.T.S. has all the biochemical and immunological characteristics of a gamma-globulin (IgG) (Kriss et al. 1964, Beall and Solomon 1966a, Miyai and Werner 1966) and can be absorbed out specifically with thyroid tissue (Kriss et al. 1964, Beall and Solomon 1966b, Carneiro et al. 1966, El Kabir et al. 1966). It is therefore thought that this abnormal thyroid stimulator is an autoantibody and that thyrotoxicosis may be considered, with Hashimoto’s disease and primary myxcedema, as a variant of thyroid autoimmune disease. The monozygotic twins described here illustrate the relation between Hashimoto’s disease and thyrotoxicosis and further emphasise the autoimmune features associated with these two clinical conditions. Methods L.A.T.S.

Assay assayed by McKenzie’s method (McKenzie and Williamson 1966) as described by El Kabir et al. (1966); this depends upon the protracted release of 1311 from the prelabelled thyroid of mice injected with thyrotoxic serum. IgG was separated from the serum of the Hashimoto twin by ammoniumsulphate precipitation and diethylaminoethyl-cellulose chromatography, and concentrated to give a final solution containing L.A.T.S. was

50 mg. per ml. Genetic Markers The monozygosity of the twins was established on the basis of finger-ridge counts, maximal AtD angles, cephalic index, and serum-isoenzyme tests (carried out at the Galton Laboratory of Human Genetics, University College, London), and by phenotyping the twins’ blood-groups, performed by the Medical Research Council Blood Group Reference Laboratory.

Autoantibody Tests Thyroid-antibody titres were performed at intervals over a 8-year follow-up. Thyroglobulin-precipitin tests were carried out in Ouchterlony gel plates and the tanned-red-cell (T.R.C.) method was used to establish the thyroglobulin-antibody titres. Complement fixation (C.F.T.) was used to titrate the thyroid and gastric microsomal antibodies, which were detected by the double-layer immunofluorescent test. Intrinsic-factor antibodies were looked for by a charcoal assay. All methods are described in a manual on autoimmune serology available from the Immunology Section, World Health Organisation, Geneva. Tests for rheumatoid factors included the FII latex fixation and sheep-cell-agglutination test (S.C.A.T.).

Case-reports The twins (A and B) were born on April 12, 1928. A was the first born and B was the heavier twin but their exact birthweights

mos, and asthma while the other had

a Hashimoto goitre, asthma, and rheumatoid arthritis. The long-acting thyroid stimulator (L.A.T.S.) was demonstrable in the sera of both sisters although in the Hashimoto twin, concentration of the IgG was necessary to obtain an unequivocal result. The presence of L.A.T.S. in a patient with autoimmune thyroiditis in the absence of any signs of Graves’ disease and the finding of these two disorders in identical twins points to a common immunological defect and a possible genetic factor in their ætiology.

* Present address: Department of Medicine, Royal Infirmary, Bristol.

y

Fig. 1-Twins A and B in 1962.