114

stimulus and interest it creates in the management of

patients with myocarcial infarction. Successful resusci-tation from cardiac arrest becomes more common in the

general wards and indeed during the first year of thisunit, 11 patients were admitted to the unit after successfulresuscitation in the wards, and of these 5 eventually lefthospital. On the other hand, if one thinks only ofsurvivors from cardiac arrest, one ignores the effect of theunit in other directions-e.g., the prompt recognition andtreatment of serious arrhythmias.

All who have experience with coronary-care units agreethat their value largely depends on the medical and nursingstaff. The staffing requirements of an efficient unit areconsiderable and must limit the number of hospitals whereunits can be set up. It follows that the best possible useof existing units must be made and we feel it is importantthat an element of research is incorporated in the policiesof most units. Obviously not all patients sustaining amyocardial infarction can be admitted to a unit but furtherresearch may result in new treatment which can be appliedto patients in general wards and even at home as well asthose in intensive-care areas.

We thank the consultant physicians of the Royal Infirmary for theirinterest and cooperation in the establishment of the coronary-careunit and, in particular, Dr. A. Doig, Dr. R. M. Marquis, Dr. J. D.Matthews, and Dr. J. Richmond for their participation in the workof the unit; the nurses, senior registrars, registrars, senior house-officers, and lecturers who staffed the unit; Prof. L. G. Whitby forproviding assistance and Dr. A. Smith for the results of serum-creatine-kinase estimations. The Board of Management of the RoyalInfirmary and the South-Eastern Regional Hospital Board (Scotland)have been generous in their support of the unit. The British HeartFoundation has supported a research fellow and provided funds forresearch equipment. Miss Edith 0. McKeating has given valuablesecretarial help.

Requests for reprints should be addressed to D. M. L., Depart-ment of Medicine, Royal Infirmary, Edinburgh 3.

REFERENCES

Brown, K. W., MacMillan, R. L., Forbath, N., Mel’grano, F., Scott, J. W.(1963) Lancet, ii, 349.

Conference Report (1966) Am. J. Cardiol. 17, 736.Day, H. W. (1965) ibid.

— (1966) Cited by Meltzer and Kitchell (1966).Fluck, D. C., Olsen, E., Pentecost, B. L., Thomas, M., Fillmore, S. J.,

Shillingford, J. P., Mounsey, J. P. D. (1967) Br. Heart J. 29, 179.Freis, E. D., Schnaper, H. W., Johnson, R. L., Schreiner, G. E. (1952)

J. clin. Invest. 31, 131.Goble, A. J., Sloman, G., Robinson, J. S. (1966) Br. med. J. i, 1005.Honey, G. E., Truelove, S. C. (1957) Lancet, i, 1155, 1209.Julian, D. G., Valentine, P. A., Miller, G. G. (1964a) Med. J. Aust. i, 433.

— — — (1964b) Am. J. Med. 37, 915.Kirby, B. J., McNicol, M. W. (1966) Lancet, ii, 1054.Kouwenhoven, W. B., Jude, J. R., Knickerbocker, G. G. (1960) J. Am. med.

Ass. 173, 1064.Lown, B., Amarasingham, R., Neuman, J. (1962) ibid. 182, 548.

— Fakhro, A. M., Hood, W. B., Thorn, G. W. (1967) ibid. 199, 188.Macdonald, H. R., Rees, H. A., Muir, A. L., Lawrie, D. M., Burton, J. L.,

Donald, K. W. (1967) Lancet, i, 1070.Mackenzie, G. J., Taylor, S. H., Flenley, D. C., McDonald, A. H.,

Staunton, H. P., Donald, K. W. (1964) ibid. ii, 825.McNicol, M. W., Kirby, B. J., Bhoola, K. D., Everest, M., Freedman, S.,

Price, H. V. (1965) Br. med. J. ii, 1270.Meltzer, L. E. (1966) in The Current Status of Intensive Coronary Care.

American College of Cardiology Symposium, New York.— Kitchell, J. R. (1966) Progr. cardiovasc. Dis. 9, 50.

Oliver, M. F., Julian, D. G., Donald, K. W. (1967) Am. J. Cardiol. (in thepress).

Paulk, E. A., Hurst, J. W. (1966) ibid. 17, 695.Peel, A. A. F., Semple, T., Wang, I., Lancaster, W. M., Dall, J. L. G.

(1962) Br. Heart J. 24, 745.Robinson, J. S., Sloman, G., McRae, C. (1964) Med. J. Aust. i, 427.Schnur, S. (1953) Ann. intern. Med. 39, 1014.Smirk, F. H. (1949) Br. Heart J. 11, 23.Yu, P. N., Imboden, C. A., Fox, S. M., Killip, T. (1965) Mod. Concepts

cardiovasc. Dis. 34, 23, 27.Wahlberg, F. (1963) Am. Heart J. 65, 749.World Health Organisation (1959) Tech. Rep. Ser. W.H.O. no. 168, p. 18.

EFFECT OF WALKING ON BLOOD-

PRESSURE IN SYSTEMIC HYPERTENSION

JOHN HAMERM.D., Ph.D. Lond., M.R.C.P.

CARDIOLOGIST

JAMES FLEMINGM.B. Edin., M.R.C.P.

SENIOR REGISTRAR

ELLIOT SHINEBOURNEM.B. Lond., M.R.C.P.RESEARCH ASSISTANT

From the Cardiac Department, St. Bartholomew’s Hospital,London E.C.1

Summary The effect of walking on the arterial blood-pressure (B.P.) and cardiac output has been

investigated in seventeen patients with systemic hyper-tension.The systolic pressure becomes higher on exercise, but

the rise is not progressive as the work-load is increased.In many patients the cardiac output is lower than normalat rest and during exercise, suggesting left-ventriculardisease. The systemic resistance is abnormally high atrest, and although the resistance falls on exercise the valuesremain greater than normal in most patients. A highresistance on exercise distinguishes severe hypertensives.The casual B.P. gives a better estimate of the B.P. on

exercise than the basal reading obtained after several daysin hospital. Labile hypertensives, with normal B.P. at restafter a few days in hospital, show a brisk rise in systolicB.P. on exertion to levels similar to those found in patientswith fixed hypertension. The cardiac effects of hyper-tension seem to be more closely related to the casual andthe exercising B.P.S than to the basal pressure, and patientswith labile hypertension should not necessarily beregarded as having a benign form of the disease.

Introduction

THE adverse effects of systemic hypertension on theperipheral vessels and the left ventricle are, in general,related to the level of the arterial blood-pressure (B.P.).The severity of hypertension is usually determined fromB.P. measurements at rest. However, in patients leadingnormal lives, the pressure during exercise must also betaken into consideration. Casual B.P. readings may bemisleading because of the effects of anxiety or other

stimuli, but during strenuous exercise these effects are

largely eliminated and the severity of the persistentchanges in the peripheral vessels can be estimated. B.P.

measurements during exercise would therefore be

expected to provide a useful indication of the severity ofsystemic hypertension. We have measured the B.P. in anunselected series of hypertensive patients while they werewalking on a treadmill. Since the sphygmomanometercannot be used accurately under these circumstances theintra-arterial pressure was recorded directly. Thisapproach allowed us to measure the cardiac output bythe indicator-dilution technique.

Patients and Methods

Seventeen patients, aged 22-64 years, have been studied(table I). All had significant degrees of hypertension, wittdiastolic B.P.s of 100 mm. Hg or more, and some patients alsohad evidence of ischxmic heart-disease. The optic fundishowed papillcedema in one patient, and exudates 06h2emorrhages in four patients. Severe left-ventricular hyptrtrophy was evident in the electrocardiogram (E.C.G.) in sevenpatients, and four patients showed evidence of previous cardiacinfarction.

All patients were admitted to hospital for several days before

115

TABLE I-CLINICAL FEATURES

’Graded 0-4. t Second studies were done on these patients. C.T.R. =cardiothoracic ratio. L.V.H. =left-ventricular hypertrophy.

the exercise test. Intravenous pyelography was done in mostpatients and was followed by renal arteriography if there werechanges suggesting vascular abnormality. In one patient anaortic coarctation had been repaired many years before, anotherpatient had a double renal artery, and a third patient hadunilateral hydronephrosis. There was no evidence of a renalcause for the hypertension in the remaining subjects. Plasmasodium and potassium levels were not abnormal, and theblood-urea level was less than 55 mg. per 100 ml. in all cases.Urinary vanillyl-mandelic-acid was estimated in many

patients and showed no abnormality.The patients were classified initially by their casual B.P.

readings as outpatients. Six patients with casual diastolic B.P.Sof 140 mm. Hg or more were regarded as having severe hyper-tension (group A). The remaining patients, with casual diastolicB.P.s between 130 and 100 mm. Hg, were classed as moderatehypertensives, and were further subdivided by the level of theirdiastolic B.P.s after a few days in hospital. Five patients hada fall in diastolic B.P. of less than 25 mm. Hg by the beginningof the study, indicating relatively fixed hypertension (group B).Six patients had more labile hypertension (group C), with a fallin diastolic B.P. of at least 25 mm. Hg, leading to a restingdiastolic B.P. of 100 mm. Hg or less at the beginning of thestudy.The more severe degree of hypertension in group A was

evident from the higher incidence of serious retinal changes.The E.C.G. evidence of left-ventricular hypertrophy was moreimpressive in group A than in group B, but serious E.c.G.

changes were found in all the groups including group C.The exercise test was carried out in the fasting subject

without premedication. After a preliminary walk on the tread-mill, small polyethylene catheters (PE 160) were insertedpercutaneously in the left basilic vein to the axilla, and in theright brachial artery for 5-10 cm. Arterial B.P. was measuredwith reference to the sternal angle, using a ’ Statham P23G ’strain gauge and a Devices Sales Ltd. direct-writing recorder.Cardiac output was measured from indicator-dilution curvesobtained with a Gilford model 103 IR ’ densitometer ora Cambridge Mark II’densitometer, using indocyanine greenand calibrating the curves by the dynamic method (Shine-bourne, Fleming, and Hamer 1967). All blood withdrawn forthe indicator-dilution curves was immediately returned to thepatient through the arterial catheter. The B.C.G. was recordedthroughout with a modified CR5 lead, and was used to measureheart-rate. Measurements were obtained after 20 minutes’ rest

in the supine position, after 2 minutes in the erect position, andbetween the 4th and 6th minutes of exercise on the treadmill.Measurements were made at 2 m.p.h. on the level, at 3 m.p.h.on the level, and at 3 m.p.h. on 3° and 6° slopes, unless exercisewas limited by dyspnoea or fatigue. Work-loads which pro-duced angina in the few susceptible patients were excludedfrom the study.A second study was carried out in five patients (table i).

Results were not obtained at every work-load in each subject.All the tests included supine and erect resting measurements,and measurements at 3 m.p.h. on the flat. Data at 2 m.p.h. onthe flat and at 3 m.p.h. on 3° and 6° slopes were obtained inroughly half the tests. No attempt has been made to correctfor variations in body size. The systemic resistance wascalculated as the mean arterial B.P. (mm. Hg) divided by thecardiac output (litres per minute). Pressure-time per minute

(the tension-time index of Welch et al. 1957) was selected as anindex of left-ventricular work, and was calculated as the productof mean arterial ejection pressure, ejection-time, and heart-rate.

Results (table 11)The arterial B.P. was little affected by standing (fig. 1).

There was a sharp rise in systolic B.P. on walking in eachgroup. High systolic B.P.S were reached at the first work-load, a natural walking pace (2 m.p.h.), and did notincrease further at greater work-loads. In the labile

hypertensives (group C), who had a relatively low restingB.P., the rise in systolic pressure was much greater than inthe fixed hypertensives (group B), so that the systolicpressures on exercise were similar in the two groups,despite the wide difference in resting pressures. The

highest systolic pressures reached on exercise in all groupswere similar to the casual pressures obtained as out-

patients. The diastolic pressures were little affected byexercise and remained well below the casual value. In

group B there was a tendency for the diastolic pressuresto fall at the greater work-loads. The diastolic pressuresin group C rose at first, but tended to fall again as thework-loads increased.The resting cardiac output in the supine position was

between 4 and 7 litres per minute in most patients.Two patients (one in group A and one in group B) hadresting outputs greater than 7 litres per minute, and two

116

TABLE II-EFFECTS OF EXERCISE IN 3 GROUPS OF HYPERTENSIVE PATIENTS (MEANS STANDARD DEVIATIONS)

patients in group A had resting outputs below 4 litresper minute. There was a progressive increase in outputin all groups as the work-load increased, but in the severehypertensives (group A) the values were below those in theother groups at high work-loads (fig. 2). Limiting heart-rates (170-180 per minute) were reached in only threesubjects, one in each group.The systemic resistance was high in the supine position,

and rose sharply on standing as the output fell. Theresistance in the erect position at rest was always above20 units. As the output increased on exercise theresistance fell, but the severe hypertensives (group A) hadhigher resistances than the moderate hypertensives (groupsB and C) at the higher work-loads. The resting resistanceswere lower in the labile (group C) than in the fixed(group B) hypertensives, but this difference was lost on

exercise. Some

patients in these

groups showedmore profoundfalls in resistanceon exercise thanothers (fig. 2).Pressure-time

per minute tendedto follow the

changes in arterialsystolic B.P. Therewere no differ-ences between the

groups in the time

occupied by left-ventricular ejec-tion. The severe

hypertensives(group A) showeda high pressure-time per minuteat rest and on

slight exercise. In

Fig. I-Mean systolic and diastolic B.P. atrest and while walking at increasingwork-loads in three groups of patientswith hypertension (w———w s severe,0-0 fixed, X-X labile).The patients with labile hypertension had

lower resting B.P.S than those with fixedhypertension, but the difference betweenthese groups was lost on exercise.

the labile hypertensives (group C) the relatively low valuesat rest rose to levels similar to those in group B on exercise

(fig. 2).Discussion

The use of a treadmill to assess the response to exercise

provides a familiar type of work, but has the disadvantagethat the work-load cannot be measured precisely. Sincea heavier person must do more work for a given setting ofthe treadmill, no correction for body size is required(Erickson et al. 1946). Measurements were made betweenthe 4th and 6th minutes of exercise when circulatoryconditions were relatively stable.The possibility that the circulatory status of our patients

was modified by the procedure must be considered.

Anxiety produces vasoconstriction in some vascular bedswhich may persist despite the vasodilator effects of mildexercise. The higher resting B.P.S in group B than ingroup C at the beginning of the study may indicatea greater susceptibility to changes of this type, and thesharp rise in B.P. found at the first work-load (2 m.p.h. onthe flat) in each group may have a similar cause. Theeffect of these reflexes is likely to be abolished by morestrenuous exercise. The normal cardiac output in the

supine position at rest in our less severely affected patients,and the absence of any undue fall in B.P. or output on

standing, indicate that there was little tendency to syncope.In general the response of our hypertensive patients to

exercise was similar to that reported by Varnauskas (1955)and Sannerstedt (1966). The overall pattern was of anormal or reduced cardiac output and an abnormally highperipheral resistance at rest and on exercise, but there wasconsiderable individual variation in the findings. Innormal subjects the systolic B.P. rises on exercise, butthere is little change in diastolic pressure (Hanson et al.1966, Strandell 1964). The changes on exercise in ourhypertensive patients were similar, but groups A and Cshowed an exaggeration of the normal rise in systolicpressure. The absence of a progressive rise in systolic ordiastolic pressure as the work-load was increased indicatesthat the peripheral resistance fell as the cardiac output rose.

117

Fig. 2-Mean cardiac output (left-hand side, in litres per min.), peripheral resistance (centre, in units), and pressure-time perminute (right-hand side, in mm, Hg/sec. per min.) at rest and while walking at increasing work-loads in three groups of

patients with hypertension (8-8 severe, 0-0 fixed, X-X labile).

The cardiac output did not increase as much on exercise in the patients with severe hypertension as in the other groups. The

systemic resistance fell on exercise, but remained higher in the patients with severe hypertension than in the other groups. Pressure-time per minute, an index of left-ventricular work, was lower at rest in the labile group, but rose on exercise to levels similar to thosefound in patients with fixed hypertension.

The cardiac output at rest and on exercise in our patientswas generally below the average value expected in normalsubjects (Sannerstedt 1966, Hanson et al. 1966, Strandell1964). No patients had an abnormally high cardiac out-put. The output on exercise was particularly low in thesevere hypertensives (group A). Similar findings havebeen reported in severe hypertensives by Taylor et al.

(1957) and Sannerstedt (1966), and may indicate somedegree of left-ventricular failure. This suggestion is

supported by the serious E.c.G. and radiological changesin our patients (table i).The systemic resistance in the erect position at rest was

always above the upper normal limit of 20 units (Sanner-stedt and Varnauskas 1964). Sannerstedt (1966) found theupper normal limit of the resistance on bicycle exercise tobe 12 units at an output of 10 litres per minute and 9 unitsat 15 litres per minute. All the severe hypertensives(group A) and most of the moderate hypertensives (groupsB and C) had resistances higher than this at correspondingoutputs, but in some moderate hypertensives with rela-tively low resting values the resistance fell to normal levelsat the high work-loads (fig. 2). The resistances on exercisewere similar in the fixed and the labile hypertensives(groups B and C), suggesting that the essential change inthe circulation is of the same degree in the two groups.The higher resistances under these circumstances in thesevere hypertensives (group A) confirms that the processis more extensive in these patients.The estimation of " systemic resistance " is, of course,

merely an expression of the relation between pressure andflow in the systemic circulation. In view of the difficultiesof interpretation that have arisen on the pulmonaryresistance, the application of this concept to the morecomplex systemic circulation might be regarded as ofdubious value. Brod (1963) has clearly shown thatdifferent peripheral vascular beds may react in differentways in systemic hypertension, vasodilatation in muscleand skin being associated with vasoconstriction elsewhere.

Nevertheless, the changes in resistance are a usefulmeasurement of the way the body is accommodating theincrease of cardiac output on exercise, and the maladjust-ment that allows a raised B.P. at rest persists on exercisedespite the widespread vasodilatation that must occur inskeletal muscle, heart muscle, and skin.

The high systolic B.P. at low exercise-loads leads toa high value for the pressure-time per minute, and thereis little further increase at greater work-loads. Since the

resting value is high in groups A and B the increase inpressure-time per minute on strenuous exercise is

relatively slight, suggesting that left-ventricular work isnot very greatly increased by exercise in these patients,although in some cases the increase may be critical. Therapid rise in systolic pressure on exercise in group C isreflected in the pressure-time per minute, which indicatesa substantial increase in left-ventricular work under thesecircumstances. It seems clear that labile hypertensiveswith pressures falling to normal after resting for a fewdays cannot necessarily be regarded as having a benignform of the disease.

Although the value of the basal B.P. as an index ofprognosis in hypert nsion is well established (Smirk 1957),the present study suggests that the B.P. during exercise isalso important. In patients leading normal lives it seemslikely that the effective load on the circulation duringwaking hours is more nearly represented by the casual orexercising B.P. than by the basal pressure. The moderatelabile hypertension of our group-C patients might bethought, from the basal B.P., too mild to require treatment,but the fall in resting B.P. during the few days in hospitalin these patients is promptly reversed by exercise. Theconsiderable left-ventricular disease in this group (table i)is further evidence of the importance of the B.P. on

exercise as an estimate of the severity of systemic hyper-tension.

Requests for reprints should be addressed to J. H.References overleaf

118

DR. HAMER AND OTHERS: REFERENCES

Brod, J. (1963) Br. Heart J. 25, 227.Erickson, L., Simonson, E., Haylor, H. L., Alexander, H., Keys, A. (1946)

Am. J. Physiol. 145, 391.Hanson; J. S., Tabakin, B. S., Levy, A. M. (1966) Br. Heart J. 28, 557.Sannerstedt, R. (1966) Acta med. scand. 180, suppl. 458.

— Varnauskas, E. (1964) Abstracts of 4th European Congress ofCardiology p. 289. Prague, 1964.

Shinebourne, E. A., Fleming, J., Hamer, J. (1967) Br. Heart. J. (in the press).Strandell, T. (1964) Acta med. scand. 175, suppl. 414.Smirk, F. H. (1957) High Arterial Pressure. Oxford.Taylor, S. H., Donald, K. W., Bishop, J. M. (1957) Clin. Sci. 16, 351.Varnauskas, E. (1955) Scand. J. clin. Lab. Invest. 7, suppl. 17.Welch, G. H., Sarnoff, S. J., Braunwald, E., Stainsby, W. N., Case, R. B.,

Macruz, R. (1957) Surg. Forum, 7, 294.

EFFECTS OF NATURAL AND ARTIFICIAL

MENOPAUSE ON PLASMA AND URINARY

CALCIUM AND PHOSPHORUS

M. M. YOUNGM.B. Durh.

OF THE SCIENTIFIC STAFF

B. E. C. NORDIN

M.D., Ph.D. Lond., F.R.C.P.DIRECTOR

MEDICAL RESEARCH COUNCIL MINERAL METABOLISM UNIT,GENERAL INFIRMARY, LEEDS 1

Summary Plasma and urinary levels of calcium andphosphorus have been determined in 39

healthy premenopausal women, 28 post-menopausalwomen in whom the menopause had been natural, and 51women who had undergone bilateral salpingo-oophorec-tomy. The levels were increased after the menopause,particularly where this had been artificial. It is suggestedthat loss of œstrogenic activity at the menopause results inincreased bone resorption. It is not clear, however,whether the resultant negative calcium balance is thecause of or the result of osteoporosis in post-menopausalwomen.

Introduction

THE relation between osteoporosis and the menopausewas first noted by Albright et al. (1941) when they des-cribed 42 cases of spinal osteoporosis, all but 2 of them inpost-menopausal women, 9 of whom had undergone anartificial menopause. Donaldson and Nassim (1954) foundno relation between osteoporosis and an artificial meno-pause, but radiological observations by workers usingwidely differing techniques have all suggested that loss ofbone density in women starts at or around the menopause(Meema et al. 1965, Nordin et al. 1965, Saville 1965).We describe here certain differences in plasma and

urinary calcium and phosphorus between premenopausaland postmenopausal women which may be related to theresorption of vertebral bone which seems to happen aboutthe time of the menopause.

Volunteers, Controls, and MethodsThe sample comprises 39 healthy premenopausal women

aged 33-53, 28 healthy postmenopausal women between theages of 46 and 66, and 51 women between the ages of 30 and 66who had undergone bilateral salpingo-oophorectomy within thepast fifteen years, generally for menorrhagia or uterine fibroids.The healthy women included members of unit staff andambulant outpatients without organic disease. The artificial

menopause cases were selected at random from the records ofthe Women’s Hospital, Leeds. The menopause was defined asthe time of the last menstrual period.

All the women attended a special clinic at 9 A.M. after anovernight fast, when 20 ml. of clotted blood was obtained for

the estimation of calcium and phosphorus and creatinine.Urine covering the two-hour period 8 to 10 A.M. was

collected at the same time. Each patient also collected a

twenty-four-hour urine sample on a gelatine-free diet.Calcium, phosphorus, and creatinine were estimated in serum

and urine, and hydroxyproline was measured in urine bystandard ’ AutoAnalyser ’ (Technicon) methods described inAutoAnalyser N.3 1964. In our hands the measurement of

plasma-calcium with the AutoAnalyser using the’ Complexon’reagent has a standard deviation of ± 0-08 mg. per 100 ml.(Knowles 1967).

Plasma-levels of calcium and phosphorus are expressed inmg. per 100 ml. The urinary calcium is expressed as thecalcium/creatinine ratio (Nordin 1959) and the hydroxyprolineas the ratio to creatinine (Allison et al. 1966). The phosphate/creatinine clearance ratio was calculated from the simplifiedformula of Nordin and Fraser (1954) and the phosphate-excretion index (P.E.I.) from the formula of Nordin and Fraser(1960).

ResultsPlasma-calcium

Plasma-calcium levels in the three groups are shown in

fig. 1 and the mean value in table i. The mean plasma-

Fig. 1-Individual and mean (± 2 S.E.M.) plasma-levels of calciumand phosphorus.(A) Premenopausal.(B) Postmenopausal (natural).(C) Postmenopausal (artificial).

calcium in the premenopausal women was 9-32 mg. per100 ml.; in the postmenopausal (natural) group it was9-62 and in the postmenopausal (artificial) group it was9.81 mg. per 100 ml. The differences between the meansin the premenopausal and in the postmenopausal groupsis highly significant (table i).Plasma-phosphorusThe plasma-phosphorus levels are shown in fig. 1 and

TABLE I-RELATION BETWEEN MENOPAUSAL STATE AND PLASMA/CALCIUMAND PHOSPHORUS