drug treatment of - postgraduate medical journal · 86 postgraduatemedicaljournal february 1956...

85

DRUG TREATMENT OF HYPERTENSIONBy E. G. MCQUEEN, M.B., M.R.C.P. and F. H. SMIRK, M.D., F.R.C.P.Department of MedicinP, University of Otago Medical School, Dunedin, New Zealand

Hypertension is the commonest cause of heartfailure and apoplexy. Untreated, the most severeform, malignant hypertension, kills within 6 to 12months in go per cent. of the cases (Keith, Wagenerand Barker, i939; Schottstaedt and Sokolow,I953). There are few diseases in which treatmentrequires more of the medical attendant in terms ofknowledge and attention to detail, but there arefew diseases, even with the most modern thera-peutic advances, in which such a dramatic improve-ment in prognosis and in the relief of distress canbe achieved. The principle of treatment, recog-nition of which changed the whole outlook, is theeffective reduction of blood pressure, in mostcases to near normal levels.

In nephritis, pyelonephritis, Cushing's synd-rome and coarctation of the aorta the nature of thedisorder causing the hypertension is known,though the mechanisms whereby the bloodpressure is actually raised are still obscure. Inessential hypertension the basic causes are amatter for conjecture, but they appear to becomparatively harmless, so that the symptoms andsigns of essential hypertension are restricted tothose which are apparently the consequences ofhigh blood pressure as such, or vasoconstriction.The survival rate for untreated hypertensive

patients grouped according to the appearances ofthe fundi as classified by Keith, Wagener andBarker (I939) is shown in Fig. ia. Fig. ib

KEITH, WAGENER & BARKER DUNEDIN SERIESSERIES (1939)

10oo =|IO0O800

0 20 30 40 50

EXAMINATION EXAMIONATION

GE roup Z

A B

Group 2 Group 4

FIG. i.-Survival under treatment of patients grouped according to severity of fundal changes. Dunedinseries includes all cases continuing treatment to death or present time.

60 : 60

0 0w 40 40

.--z

30' w 30

20' n 20

Group 4

IO 20 30 40 50TIME IN MONTHS AFTER FIRST TIME IN MONTHS AFTER FIRST

EXAMINATIONA ]

FIG. x.--Survival under treatment of patients grouped according to severity of fundal changes. Dunedinseries includes all cases continuing treatment to death or present time.

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86 POSTGRADUATE MEDICAL JOURNAL February 1956shows the survival rate for our treated series andincludes all cases continuing treatment to deathor to the present time. A number of these hadmarked impairment of renal function at the timeof initiation of therapy and cases of knownnephritis are included. Group 2 in the treatedseries included a number of unusually severecases, particularly of heart disease. The improve-ment in prognosis dates from the introduction ofeffective methods of blood pressure control, inthis clinic initially with hexamethonium bromideby injection (Restall and Smirk, 1950), and laterwith pentolinium orally (Smirk, I952a, b) and bypentolinium in combination with reserpine (Doyle,McQueen and Smirk, 1954; Smirk, Doyle andMcQueen, 1954). Elsewhere, improvements inprognosis have been demonstrated with varyingdegrees of blood pressure control by sympa-thectomy (Morrissey, Brookes and Cooke, I953;Smithwick, I955). Claims have also been ad-vanced for other hypotensive agents such asveratrum alkaloids (Freis and Stanton, 1948;Hoobler, 1954), and l-hydrazinophthalazine(Schroeder, 1952; Taylor et al., I954).The very great improvement in the outlook for

severely hypertensive patients, as shown in Fig. i,and in their comfort, has been brought about byeffective reduction of the blood pressure-to fullynormal levels in the trough of the blood pressurefall, and to very much reduced levels at othertimes. It is insufficiently realized that thebenefits to which reference will be made can beobtained only by attention to the strictest detailof management. The standard of care requiredis more exacting than that of a well run diabeticclinic. It is probable that the necessary experi-ence can best be gained by special clinics to whichlarge numbers of cases can be referred. Suchclinics, furthermore, can justify the appointmentof technical assistants and the development ofother facilities.

MethodsMany substances capable of reducing the blood

pressure therapeutically are now available. Ofthese the methonium compounds are the mosteffective and their use will be considered in detail.Rauwolfia alkaloids have also demonstrated theirvalue, in particular as adjuvants to the methoniumcompounds. Other substances which have beenwidely employed, but whose use is considered tobe of limited value, will be considered briefly.Amongst this group are:

I. Hydrazinophthalazine (Apresoline). Thissubstance is an effective hypotensive agent and hasbeen used chiefly in association with the methon-ium compounds. It may cause headache andother immediate side effects. Additionally, there

is a significant risk of delayed toxicity, as shownby the development of a syndrome resemblingrheumatoid arthritis and lupus erythematosus.This, in our opinion, renders it unsuitable forroutine use. It may have a special place in themanagement of a few exceptional patients whodevelop a state of resistance to the methoniumcompounds.

2. Veratrum compounds. The veratrum alka-loids are powerful hypotensive agents. Parenteraldoses of as little as o.I mg. of the pure alkaloidsmay reduce the blood pressure to normotensive,or even to hypotensive, levels, even in severehypertensives. Unfortunately, doses effective inreducing the blood pressure to satisfactory levelsfrequently induce vomiting and other toxic effects.The most careful control of dosage is necessary,and then only about one in four patients obtain auseful fall of blood pressure without excessivelytroublesome side effects (Smirk and Chapman1952; Doyle and Smirk, I953). The patientswhose blood pressure can be satisfactorily control-led are usually mild cases and even in these thegap between the hypotensive and toxic dosesseems to narrow with continued administration.Although in our clinic some 80 patients underwenta trial of treatment with these substances, theyhave not proved sufficiently satisfactory for theiruse to be continued in any of them.

3. Thiocyanates. The effect of thiocyanatesalone in controlling blood pressure is limited andthe attainment of effective blood pressure levelscarries a risk of toxic side effects. When thio-cyanate is administered in association withmethonium compounds equal degrees of bloodpressure reduction can be obtained with smallerdoses of methonium and at blood levels of thethicyanate well below those likely to be effectivealone (McQueen, unpublished). In clinicalpractice Rauwolfia alkaloids are preferred for thispurpose.

The Methonium CompoundsPentolinium has replaced hexamethonium as

the ganglion blocking agent for routine use. It isthe corner stone of treatment in severe hyper-tension. It is effective in smaller doses thanhexamethonium (approximately I/5th), its dura-tion of action is considerably longer, and it ismuch more satisfactory for oral administration.A new ganglion blocking agent, SU 3088, resemblespentolinium in its therapeutic action (Grimsonet al., 1955; Smirk and Hamilton, I955). Thesecompounds block autonomic ganglia and, accordingto some recent work, they also inhibit sympatheticcentres in the central nervous system (Dontas andNickerson, 1955). Hence they reduce bloodpressure by diminution in the peripheral resistance.



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Febnary I956 McQUEEN AND SMIRK: Drug Treatment of Hypertension 87

INITIAI DOSES AND DOSAGE INCREMENTS OF METHONIUM COMPOUNDSDose may be Average

Initial dose raised by Highest final duration](mg.) increments of daily dose used significant

(mg.) (mg.) action (mg.)Pentolinium bitartrate, oral .. .. .. 20 20 1400 8-I2+

Pentolinium bitartrate, simple aqueous,' retard,'subcutaneous ..... .. .. .. 3 0.5-1.5 140 8-2+

Hexamethonium bromide, simple aqueous,subcutaneous .. .. .. .. 15 5 1200 2-3

Hexamethonium bromide' retard,' subcutaneous 20 5-10 1200 3-5SU 3088 (' Ecolid'), Ciba, oral .... o* 1i0 1000 8-I2+

SU 3088 ('Ecolid'), Ciba, simple aqueous,subcutaneous .. .. ..... I 0.5 o00 8-I2+*This drug is at present available for oral administration only in the form of 50 mg. tablets. We consider these too

large for safety in initial dosage and recommend they be dissolved in a measuring cylinder and the appropriate fractionmeasured in this way.

With large falls in blood pressure there may be adecrease in cardiac output, probably due todiminution in venous return. A fall in venouspressure may, at times, be observed to precedethe fall in arterial pressure. In congestivecardiac failure the marked falls in venous pressuremay be associated with an increase in the cardiacoutput. Cerebral blood flow is usually main-tained adequately, except at very low bloodpressures.The effects on renal haemodynamics are

ordinarily transient, brief falls in renal plasmaflow and glomerular filtration rate being succeededby rapid restoration to levels approximating theinitial ones. In cases with severe renal damage,however, excessive reduction in blood pressuremay produce considerable and prolonged reduc-tion in function with nitrogen retention. Addi-tionally, where there is an important impairmentin the renal function, the falls of blood pressurefrom therapeutic doses may be prolonged becauseof delayed excretion. Administration of Ansolysenover a long period has not, in our experience,caused interference with renal function when thisin satisfactory initially.Many of the changes in blood pressure after

methonium administration depend upon theincapacity of the sympathetic nervous system tomaintain the normal circulatory reflex functions.Thus, in the erect posture, the blood pressure fallsbecause of the absence of reflex sympatheticvasoconstriction. This additional fall of bloodpressure in the sitting and standing postures isused therapeutically; by controlling the posture ofpatients much lower falls of blood pressure areobtained, even with smaller doses. The proper

employment of posture during treatment isessential to successful management.

In patients under the action of methonium saltsan additional fall of blood pressure usually followsmeals, presumably due to uncompensated splan-chnic dilatation. Postural hypotension is markedly-exaggerated by a salt-free diet or by loss of blood,even in quite small amounts, such as 250 ml.

Parasympathetic effects include paralysis ofaccommodation, pupillary dilatation, diminishedsecretion of saliva, diminished secretion of acid inthe stomach, diminished gastric and intestinalmotility, diminution of potency in the male andoccasionally urinary retention. These all consti-tute side effects of greater or lesser severity whichwill be discussed later.

Rauwolfia and its DerivativesSince direction of the attention of Western

countries, particularly by Vakil (I949), to extractsof Rauwolfia serpentina, use of these compoundshas increased with impressive rapidity. Numerouspreparations of the total alkaloids are availablecontaining varying proportions of the activeprinciples. Amongst the score or so of alkaloidswhich have now been isolated in pure form fromRauwolfia serpentina, reserpine (Miiller, Schlittlerand Bein, 1952) possesses sedative and othercentral nervous system effects apparently closelyapproximating those of the crude extracts, whilstit and also rescinnamine (Klohs et al., 1954) havebeen shown to have specific antihypertensiveproperties. Another alkaloid, canescine (deser-pidine) (Schlittler et al., 1955) from the relatedspecies Rauwolfia canescens, also has a hypotensiveaction. These three pure substances have been



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88 POSTGRADUATE MEDICAL JOURNAL February 1956

employed in this clinic rather than the cruderpreparations of which the constitution isuncertain.

ReserpineReserpine exerts its hypotensive action, at least

in part, through the central portions of thesympathetic nervous system, in particular bydiminishing reflex pressor vasomotor activity(Bein, 1953; Trapold et al., 1954). Its sympa-thetic vasomotor depressor function can be seenin the rabbit with one sympathectomized ear.In this animal vasodilatation can be seen to occurafter administration of reserpine in the ear withintact nerve supply, whereas it fails to appear inthe denervated ear (McQueen, Doyle and Smirk,1955). Additionally, at least in rats and rabbitsand possibly in man, there is a peripheral effectcausing dilatation in vessels, the tone of which isbeing maintained either by nervous or by humoralmeans (McQueen, Doyle and Smirk, I955;McQueen and Blackman, I955). These actions,including the capacity to decrease reflex pressorresponses, are also possessed by rescinnamine andcanescine. In experiments with isolated organs,rescinnamine and canescine have a shorterperiod of action than reserpine. The differencesmay be due to their relatively greater solubility.

In man a hypotensive effect of reserpine can be'observed with large doses orally within a fewhours (Doyle and Smirk, I954), but even whengiven intravenously there is a time lag of, on theaverage, about one to two hours (Hughes et al.,1955) before the minimum pressure is reached,and in therapeutic doses given by mouth, a monthmay elapse before the full extent of the fallbecomes apparent. In general, when reserpineis given alone, blood pressure falls are of relativelysmall order, but in a few patients they may be veryconsiderable, well beyond the range resulting fromfull sedation. Of still more practical importanceis the enhancement by reserpine of the hypo-tensive effect of other agents, particularly themethonium compounds. As a result of thisenhancement, much smaller doses of pentolinium(Ansolysen) suffice to maintain a good control overthe blood pressure, and thereby side effects arelessened. The daily fluctuations of blood pressureare much less on the combination of reserpine andpentolinium than on pentolinium alone (Doyle,McQueen and Smirk, I955).

Side effects from reserpine consist in flushingof the face, nasal obstruction, feelings of coldness,shivering, diurnal lassitude, disturbed sleep withnightmares, and, in about o1 to I5 per cent. of thecases treated on reserpine in this clinic, a signi-ficant degree of mental depression such as to makeits abandonment seem advisable. In a few

psychiatric treatment has been necessary. In thevery severe cases depression has lasted somemonths after all Rauwolfia drugs were dis-continued. In several of the patients developingthe more severe manifestations there had beenprevious episodes of endogenous depression.Now, we avoid the use of reserpine in suchpatients.There is a tendency towards retention of salt in

patients on reserpine and congestive cardiacfailure may be aggravated by it. Patients gainweight, both probably from this cause and fromincreased appetite.Rescinnamine

Rescinnamine appears to have a hypotensiveeffect which in man is a little less than that ofreserpine, but in some patients a higher dose canbe tolerated without important side effects, so thatthe blood pressure lowering effect which can beachieved may be even greater than with reserpine.Rescinnamine appears to have a lesser tendencyto induce depression, and lassitude and diurnalsomnolence are considerably less marked. Anappreciable number ofpatients in whom depres-sion has occurred on reserpine have relief onchanging to rescinnamine, with maintenance of anequal degree of blood pressure control (Smirk andMcQueen, I955). We have, however, encounteredpatients who have developed depression onrescinnamine. Some patients complain ofanorexia, abdominal discomfort and insomnia,and may lose weight. As with reserpine, rescin-namine is of most value when used in conjunctionwith pentolinium.Canescine

Preliminary trial of canescine (recanescine) hasindicated that it too has a hypotensive action,.though of a less powerful order than that ofreserpine or rescinnamine. Side effects appearto'be somewhat similar to those of rescinnamine.Some patients who had had moderate mentaldepression on reserpine lost this symptom whentransferred to canescine.

Detail ofManagementPreliminary Investigations

In addition to a routine clinical investigation,attention is directed to some investigations whichare of particular'value in prognosis and in deter-mining a therapeutic regime. The Keith, Wagenerand Barker grading of the optic fundi should bedetermined. The basal blood pressure, that isthe lowest pressure recorded under conditions ofphysical, emotional and metabolic rest, should beestimated. The method involves sedation, pre-paration as for basal metabolic rate and certain



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February 1956 McQUEEN AND SMIRK: Drug Treatment of Hypertension 89

other procedures, including repeated measurementof the blood pressure at half-minute intervals for15 minutes or more, in order to desensitize thepatient to the emotional stimulus provided by theobserver and his sphygmomanometer.A chest X-ray, electrocardiogram, a blood urea

or non-protein nitrogen and a urea concentrationtest should also be performed. Indications forother tests may be provided by the clinical findings,as for instance pyelography, tests for phaeo-chromocytoma, Cushing's syndrome, etc.

Selection of PatientsThe existence of complications arising directly

from the height of the blood pressure constitutesan indication for treatment. Grade IV or gradeIII retinal changes, congestive cardiac failure ofhypertensive origin, or hypertensive encephalo-pathy, call for an immediate and effective controlof the blood pressure, which almost alwaysinvolves the use of methonium compounds. Thediscovery of a high blood pressure on a singleoccasion does not necessarily indicate that treat-ment should be instituted, although the occurrenceof very high readings of the casual blood pressure(systolic greater than 230, diastolic greater than130) usually means that treatment is necessary.The association with high casual readings of a highbasal blood pressure, I6o to io or more,strengthens the indication, and evidence ofcardiac enlargement or a left ventricular strainpattern in the electrocardiogram would beconfirmatory. Age and sex are also important;high casual, and especially basal, levels in theyounger age groups, particularly in males, havea poor outlook in the untreated case.

Renal disease with impaired excretion does notcontraindicate treatment but calls for particularcare in supervision, as delayed excretion ofmethonium compounds may lead to excessiveaction unless the dosage is suitably adjusted.Ischaemic heart disease with angina in hyper-tensive patients is frequently benefited sympto-matically by reduction of blood pressure,presumably by decreasing the cardiac overload(Doyle and Kilpatrick, 1954). Excessive falls ofblood pressure, however, are likely to induceanginal pain and should be avoided. One mayaim at a pressure of say I40 over 90 in the trough ofthe blood pressure fall with the patient in thestanding posture. In hypertensive patients witha history of recent cerebral vascular accidentundue lowering of the blood pressure shouldlikewise be avoided. With increasing experiencewe find some patients of over 70 with definitehypertensive manifestations derive benefit fromtreatment. The initial doses of hypotensive drugsshould be half of the usual amount and this should

be increased by small increments to an effectivelevel.

Detail of TreatmentPatients with malignant hypertension or hyper-

tensive heart failure should be admitted to hospitalso that an effective blood pressure reduction maybe secured without delay. Methonium compoundsare pre-eminently valuable, and where there isurgency, parenteral administration may be used toinstitute treatment. In most cases the.' retard'preparation is satisfactory from the outset. Themajor doses should be given in the early morningand at night with a supplementary dose in theearly afternoon. In almost all severe cases achange may be made later to oral therapy withpentolinium (but not with hexamethonium).In the less severe cases oral pentolinium can beused from the outset. Initial doses and incre-ments are shown in the table in which also theduration of effect is shown.

In all cases it should be the aim to adjust dosageso that the blood pressure at the trough of theblood pressure fall reaches levels in the region ofI20 over 85 (standing). It is only by achieving fallsto fully normal levels that adequate duration ofeffect is likely to be achieved. In ambulantpatients the effects of individual doses must bemeasured in the erect posture, as well as sittingand lying, and the regulation of the dosage levelis based on the standing blood pressure, otherwisefaintness may be experienced at the time ofmaximum action of the drug.

Accurate recording of the time-course of drugaction requires frequent blood pressure estimationsThis is best performed by technicians speciallytrained for the task, who also carry on the observa-tions at a special clinic as often as it may beindicated after the discharge of the patient.The importance of posture in the satisfactory

control of the blood pressure requires particularemphasis in the patient confined to bed. Suchpatients are best nursed on a 'cardiac' bed inwhich the trunk can be propped up at an angle of45° from the horizontal. It is only when patientsare nursed in this posture that full use is made ofthe hypotensive properties of the methoniumcompounds. After discharge from hospital itis still necessary for patients to continue sleepingin a similar posture, propped up with pillows at anangle of 45°, or with blocks I ft. 4 in. high beneaththe head of the bed.

Tolerance develops rapidly to the methoniumcompounds. It may be demonstrated on the dayafter the first effective doses of methoniumcompounds have been administered. To main-tain adequate blood pressure falls, doses must beraised daily at first and later every few days.



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90 POSTGRADUATE MEDICAL JOURNAL February 1956

After two or three months the dose is compara-tively stable, although minor fluctuations mayoccur. Toleration is lost if the methoniumcompound is suspended for more than a few days,and when dosage is resumed, it must be at alower level.The dose of pentolinium required to achieve

adequate blood pressure reduction varies con-siderably. The final dosage of parenteralpentolinium (' retard') may be anything from5 to 50 mg., and of oral pentolinium anythingfrom 60 to 600 mg. two or three times daily.Equivalence of oral and parenteral doses is shownin the table.

Relief of Acute Clinical ManifestationsWith fully adequate control over the blood

pressure level papilloedema should invariablydiminish within three weeks and have disappearedwithin three to six months. Soft exudates clearrapidly and haemorrhages also soon disappear.Hard exudates with star-shaped macular figuresseldom disappear with less than six months'effective treatment, and may take I2 months todisperse. The manifestations of hypertensiveheart disease are rapidly brought under control.After even the first day of effective blood pressurecontrol, paroxysmal nocturnal dyspnoea no longeroccurs, and exertional dyspnoea rapidly diminishesin severity. Pulmonary oedema is seen by X-raysto diminish rapidly in degree and disappearwithin a few days. These results are achieved inmost cases having a fully adequate regime of bloodpressure control without recourse to digitalis,mersalyl or salt-free diet. Manifestations ofright-sided failure usually disappear more slowly,and in a number of these maintenance treatmentwith digitalis is necessary (Hamilton et al., 1955).The relief of cardiac asthma may be immediate,

and the other manifestations of congestive cardiacfailure usually disappear rapidly with a fullyadequate regime without recourse to digitalis,mersalyl or salt-free diet.

Failure to achieve such results has been, in ourexperience, the result in almost all cases of in-experience or insufficient attention to detail on thepart of the physician. It is seldom that one cannotobtain a degree of control over the blood pressurelevels sufficient to achieve the kind of resultreferred to above.

Side Effects of Methonium CompoundsThe parasympathetic side effects of pentolinium

are seldom altogether absent with effective doses,but may be relieved by various parasympathomi-metic drugs. Dryness of the mouth may bebenefited by pilocarpine, I/32 or 1/64 gr.given by mouth before meals. Blurring of vision

may be helped by eserine or physostigmine drops,1/32 per cent., but is often best managed by theprescription of extra lenses for use during theperiod of impaired accommodation. Constipationis the most inconvenient side effect, and isparticularly troublesome with oral treatment whenit may cause marked irregularity in absorption ofthe pentolinium. Prolonged constipation may besucceeded by bouts of diarrhoea with an increaseof the hypotensive action. In the most severecases paralytic ileus may occur and the risk of thisdangerous complication makes oral administrationrisky when the single oral dose necessary toproduce adequate hypotensive effect rises to morethan 600 mg. Constipation can, in most cases,be avoided by a paraffin emulsion-phenol-phthalein mixture and the laxatives to whichthe patient is accustomed. Prostigmine, 15 mg.tablets, at times give relief when the usual purga-tives have failed. In males impotence is frequent,particularly amongst the older men, althoughyounger men may not be severely affected.Dysuria is not a frequent complaint except whensome organic obstruction exists, most frequentlyprostatomegaly. Patients in whom methoniumcompounds have regularly induced retentionbefore prostatectomy may be able to tolerate themwithout difficulty later.

Pentolinium in Combination with Reserpine orRescinnamineManagement of methonium side effects has

been rendered much more satisfactory by the useof Rauwolfia alkaloids in combination withpentolinium. On the addition of reserpine indoses of o.25 to 0.5 mg. per day the dose ofpentolinium needed to produce the same bloodpressure lowering effect begins to diminish aftertwo or three days and continues to diminish overseveral weeks. Eventually as little as half of theoriginal dose of pentolinium may be necessary,and methonium side effects are thereby reduced.There is also an important lessening of the dailyfluctuations of blood pressure, with abolition of thehigh and potentially dangerous peaks which occureven with the best regimes employing methoniumcompounds alone. There is, however, a dangerwhich will be referred to in the next section.

Reserpine AloneReserpine has been widely used for the treatment

of milder cases. It is probable that many of theseare cases of labile hypertension in which the bloodpressure is raised above normal levels onlyintermittently. In such patients, particularly,the blood pressure may be maintained at fullynormal levels. Even severe hypertensives oc-casionally exhibit considerable falls of blood



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February 1956 McQUEEN AND SMIRK: Drug Treatment of Hypertension g9

pressure and these are regularly greater than thoseproduced by simple sedation or placebos.

Unfortunately in addition to the relativelyminor side effects occurring early on, such as nasalobstruction, looseness of the bowels, diurnallassitude or disturbed sleep at night with night-mares, mental depression may occur. This maycome on after anything from a few weeks to morethan 12 months of successful therapy. Among200 patients treated with Rauwolfia alkaloids,mostly reserpine, we have encountered minor ormajor degrees of depression in about 40 patients.Our impression has been that reserpine is rathermore liable to cause depression than rescinnamine.While many of these patients have improvedrapidly following cessation of this form of treat-ment, the severity and prolonged duration, ofothers has been a source of considerable anxiety.Five patients required psychiatric treatmentincluding in some patients shock therapy. One ofour cases committed suicide and we know of othersuicides and attempted suicides in New Zealand.Most of the depressions occurred in patients takingI to 1.5 mg. of reserpine daily. We now useo.25 to 0.5 mg. daily in the hope that there will bea lower incidence of depression.

While the degree of improvement in the condi-tion of severe hypertensives seems to us to warrantthe continued use of this substance, usually as anadjunct to methonium compounds, we haveformed the impression that its routine use inmild hypertensives is unjustified.Control of Blood Pressure in Outpatients

Except in the most severe cases, treatment isbest instituted as an outpatient in a special clinicat which patients attend throughout the day,returning home at night. Patients attend daily atfirst and later at less frequent intervals. To thisclinic are also referred the most severe patientsafter their discharge from hospital. Blood pres-sures are recorded half-hourly during the day byspecially trained technicians. The blood pressureis measured in the sitting and standing positionsand, if necessary, lying. Casual blood pressurereadings at visits to ordinary outpatient clinics orto private practitioners, are likely to be misleading,although less so on the combination of reserpineand pentolinium than in those on pentolinium alone.A number of private practitioners in this countryarrange for groups of their hypertensive patients toattend on certain days when a series of readingscan be taken by their secretary or nurse.

In the absence of such methods of controlconsiderable information can be gained by carefulenquiry into the subjective manifestations experi-enced by the patients. Frequent faintness at thetime of maximum drug action indicates excessive

effect and the oral dose of pentolinium required is20 mg. below the level inducing faintness.Patients can tell when the regime is producingadequate falls by standing upright for one minuteat the time of maximum methonium effect. If nosensation of faintness is experienced, the doseshould be increased by the increments shown inthe table until it just does produce faintness onstanding still for this length of time.There is no doubt, however, that a special clinic

at which day tests can be arranged at short notice,and as often as necessary, provides the idealfacilities for the fully adequate blood pressurecontrol by which only can the best results beachieved.

SummaryAppreciation of the fundamental importance of

effective control of the blood pressure has been themajor factor in the great improvement in prognosisof hypertension. However, meticulous attentionto the detail of management is necessary to achievethe best possible results.The most effective agent for control of blood

pressure is pentolinium (pentapyrrolidinium,Ansolysen) which should be used for managementof the most severe cases from the outset. Thedose of pentolinium required is decreased by theaddition of reserpine to the regime; hence sideeffects are reduced. The occurrence of significantdepression on reserpine may be alleviated some-times by a change to rescinnamine, but depressionmay occur also on rescinnamine. The incidenceof mental depression is such that it is doubtfulwhether reserpine should be used in mild cases.It is our impression that its main use is in thecombination with pentolinium for severe cases.Methods of control of treatment are outlined.

It is emphasized that only by the strictestattention to the detail of management can theexcellent results of fully adequate blood pressurecontrol be achieved.

It should now be accepted that failures to arrangean effective regime and to relieve reversiblemanifestations of hypertension are in almost allcases due to iatrotechnical deficiencies.

BIBLIOGRAPHYBEIN, H. J. (x953), Experientia, 9, 107.DONTAS, A. S. and NICKERSON, M. (I955), J. Pharmacol.,

113, i6.DOYLE, A. E. and KILPATRICK, J. A. (I954), Lancet, i, 9o5.DOYLE, A. E., McQUEEN, E. G. and SMIRK, F. H. (I954),Proc. Univ. Otago med. Sch., 32, 4.DOYLE, A. E., McQUEEN, E. G. and SMIRK, F. H. (1955),Circulation, I , 170.DOYLE, A. E. and SMIRK, F. H. (i953), Brit. Heart J., 15, 439DOYLE, A. E. and SMIRK, F. H. (I954), Lancet, i, xo96.FREIS, E. D. and STANTON, J. R. (1948), Amer. Heart J.,36,723.Bibliography continued on page 107.



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February 1956 HAYWARD: The Cardiac Risk in Anaesthesia and Surgery 107

low sodium diet, digitalis and injections ofmersalyl will improve cardiac efficiency and makethe operative and post-operative course smoother.If emergency surgery is essential and there is notime for adequate pre-operative treatment of heartfailure the operative risk is increased although eventhen it is often surprising how well these patientsdo. Under these circumstances the patientglould be digitalized rapidly, using digoxin1.5 to 2 mg. in a single oral dose which will producean effect in three to four hours. If greater speedof action is needed, i mg. of digoxin should begiven slowly intravenously, but the intravenousroute must be avoided if the patient has beenreceiving digitalis by mouth previously. Thesepatients should be anaesthetized propped up, butmay be placed flat when the laboured breathing ofheart failure has been relieved by anaesthesia.

In the post-operative period they should benursed propped up, digitalis should be continuedand mercurial diuretics should be started early.Particular care should be taken to prevent chestinfection and leg exercises should be started earlyto minimise the risk of thromboembolism.The aetiology of the heart disease is in general

less important than the pre-operative functionalstatus of the patients in assessing the risk ofanaesthesia and surgery. However, in certaintypes of heart disease, particularly aortic valvulardisease or heart block, the risk of difficulties underanaesthesia is increased even though the patienthas no symptoms. Patients with known coronarydisease, with a history of angina pectoris orprevious cardiac infarction are especially suscepti-ble to hypotension or hypoxia but if these twofactors can be avoided operation is usually well

tolerated. A history of recent cardiac infarctionwithin the previous three months, or of increasingseverity of anginal attacks, should cause all exceptemergency operations to be postponed. Theparticular risk in these patients is the occurrence ofserious ventricular arrhythmias but if operationis essential the risk can be decreased by givingquinidine sulphate 5 gr. three times a day pre-operatively and continuing the drug during theearly post-operative period.

Prostatectomy in the elderly patient withhypertension and arteriosclerotic heart diseasecarries a mortality nearly three times as high as inthe patient with a normal heart7 and the increasedrisk should be taken into consideration whendeciding the nature of the surgical treatmentPartial thyroidectomy for hyperthyroidism can besafely carried out in patients with heart disease aswith adequate pre-operative treatment withthiouracil drugs the operation can be done whenthe patient is in the euthyroid state. If however,the heart disease is serious, treatment with radio-active iodine is preferable.The use of local instead of general anaesthesia

for cardiac patients has little to recommend itexcept for minor procedures such as dentalextraction and a properly administered generalanaesthetic is both safer and pleasanter for thepatient.

REFERENCES:I. BLUMGART, H. L., SCHLESINGER, M. J. and DAVIS, D.

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I34.3. McMILLAN, M. K. R. (x955), Brit. med. Bull., II, 229.4. HAYWARD, G. W. (I955), Brit. med. J., i, 136Ir.5. ECKENHOFF, J. E., HAFKENSCHIEL, J. H. and LAND-

MESSEN, C. M. (I947), Amer. J. Physiol., 148, 582.6. DELORME, E. J. (I955), Brit. med. Bull., II, 22I.7. MORRISON, D. R. (1948), Surgery, 23, 561.

Bibuography continuedfrom page 9I-E. G. McOueen. M.B.. M.R.C.P.. and F. H. Smirk. M.D.. F.R.C.P.GRIMSON, K. S., TARAZI, A. K. and FRAZER, J. W. (1955),Circulation, Ix, 733.HAMILTON, M. DOYLE, A. E., McQUEEN, E. G. and SMIRK,F. H. To be published.HOOBLER, S. W. (r954), Amer. Y. Med., 17, 259.HUGHES, W. M. MOYER, J. H. and DAESCHNER, W. C., Jr.(I055), Arch. inter. Med., 95, 563.KEITH, N. M., WAGENER, H. P. and BARKER, N. W. (1939),Amer. J. Med. Sci., I97, 332.KLOHS, M. W., DRAPER. M. D. and KELLER, F. (I954),7. Amer. chem. Soc., 76, 2843.McQUEEN, E. G. and BLACKMAN, J. G. (1955), Proc. Unit.

Otago med. Sch., 33, 5.McQUEEN, E. G., DOYLE, A. E. and SMIRK, F. H. (I955),Circulation, xI, I6x.MORRISSEY, D. M., BROOKES. V. S. and COOKE, W. T.

(I953), Lancet, i, 403.MULLER, J. M., SCHLITTLER, E. and BEIN, H. J. (1952),Experientia, 8, 338.RESTALL, P. A. and SMIRK, F. H. (I95o), N.Z. med. J., 49, 2o6

SCHLITTLER, E., ULSHAFER, P. R., PANDOW, M. L.,HUNT, R. M. and DORFMAN, L. (x955), Experientia, I, 64.SCHOTTSTAEDT, M. F. and SOKOLOW, M. (1953), Amer.

Heart J., 45, 331.SCHROEDER, H. A. (1952), Circulation, 5, 28.SMIRK, F. H. (i952a), Proc. Univ. Otago med. Sch., 30, 13.SMIRK, F. H. (i952b), Lancet, ii, 1002.SMIRK, F. H. and CHAPMAN, O. W. (1952), Amer. Heart J.,43, 586.SMIRK, F. H., DOYLE, A. E. and McQUEEN, E. G. (1954),Lancet, ii, I59.SMIRK, F. H. and HAMILTON, M. (1955), Proc. Univ. Otagometd. Sch., 33, x.SMIRK, F. H. and McQUEEN, E. G. (I955), Lancet, ii, xx5.SMITHWICK, R. H. (x955), J. Chronic Dis., i, 477.TAYLOR, R. D., CORCORAN, A. C., DUSTAN, H. P. andPAGE, I. H. (I954), Arch. intern. Med., 93, 705.TRAPOLD, J. H., PLUMMER, A. J. and YONKMAN, F. F.(1954), g. Pharmacol., 110, 205.VAKIL, R. J. (I949), Brit. Heart J., II, 350.



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