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7645 Saturday 7 March I970 HYPOTENSIVE THERAPY IN STROKE SURVIVORS A. BARHAM CARTER Neurological Unit, Ashford Hospital, Ashford, Middlesex; Queen Alexandra Hospital, Millbank, London S.W.1; and Department of Neurosurgery, St. George’s Hospital, London S.W.1 Summary A prospective randomised controlled trial of hypotensive therapy in 97 hypertensive patients surviving an ischæmic-type stroke was started in 1964 and terminated 4 years later. The patients were under 80 years of age, consecutively admitted to one hospital and the control and treated groups compared well for age, sex, and severity of hypertension. The drugs used were methyldopa, bethanidine or debrisoquine combined with restriction of salt intake, weight reduction, and thiazide diuretics, and the results were analysed with regard to survival and recurrence rates. Hypertension was defined as diastolic if this pressure was 110 mm. Hg or above, and as systolic if this pressure was over 160 mm. Hg with the diastolic below 110 mm. Hg. The mortality-rate at the end of a 2 to 5 year follow- up was 26% in the treated group and 46% in the untreated, and the non-fatal recurrence-rate 14% in the treated and 23% in the controls. Good smooth control was essential to success, untreated patients doing better than those whose control was unsatis- factory. In patients aged over 65 treatment of systolic hypertension was of no benefit, although the diastolic hypertensives improved marginally with treatment. As age increased this effect was progressively less apparent but the figures are probably too small to mean anything. In this series significant improve- ment occurred in treated hypertensive patients who had survived a stroke if they were aged 65 or below, but not if they were older. Introduction IT is generally agreed that hypertensive patients with accelerated hypertension and those with cardiac, ophthalmic, or renal involvement benefit from hypo- tensive therapy. There is less agreement about those with uncomplicated hypertension, and even less about those whose hypertension has been complicated by a stroke. Adams 1 has questioned whether the prognosis of stroke survivors is affected by hyper- tension, especially in elderly patients, and Leishman’s work 2 confirms that strokes occur even in well- controlled patients. Many other workers have thought that patients with a diastolic pressure of 110 mm. Hg or over benefit from treatment.3-7 I describe here a controlled trial designed to see if the natural history of a group of hypertensive patients surviving an ischasmic type of major completed stroke has been improved by effective hypotensive therapy. Patients and Definitions A prospective study was started in January, 1964, and planned to end in December, 1968, of all hypertensive survivors below the age of 80 of ischaemic type major strokes admitted to Ashford Hospital, Middlesex, in these 5 years. However, after 4 years it was thought unethical to continue the controlled trial in view of the results, and so the end-point was taken as December, 1967. Ischaemic Stroke An ischaemic stroke was defined as a cerebrovascular episode in which the neurological defect persisted without improvement for more than 48 hours, in which the cere- brospinal fluid was clear and colourless, and in which the diagnosis of systemic cerebral embolism could reasonably be excluded. In my experience 6 moss of these patients would have had a true ischaemic cerebral infarction due to occlusion of large or medium cerebral arteries. However, the finding of microaneurysms in the brains of nearly all hypertensive patients over the age of 50 dying from cere- brovascular disease,8-10 suggests that these may contribute to the production of ischaemic-type strokes and casts some doubt on the validity of the proposition that large-vessel occlusion is always the cause: Small thromboses and hxmatomas were found by these workers as common complications of the aneurysms, and they reported the extension of thrombi to the parent vessel with the pro- duction of local ischaemic infarcts, as noted by Rosenberg 11 giving rise to the " status lacunatus " of Miller Fisher 12 and others. Since, in deep lesions, one cannot differentiate between haematomas and infarcts, the phrase " ischaemic-type stroke " is used here to include all these manifestations and to exclude only obvious cerebral haemorrhage or embolism. Hypertension Hypertension is difficult to define-casual sphygmo- manometer readings on the same patient at different times fluctuate and any dividing line between normal and abnormal pressure has to be set arbitrarily. However, Dunne 13 has shown that after the third visit to an out- patient department the pressure settles down so that further variation is very small, and there is general agree- ment that anyone with a persisting diastolic pressure of 110 mm. Hg or over is hypertensive 10,14-16; there is less agreement when systolic pressure is raised dispropor- tionate to diastolic pressure, but many physicians accept that a persisting systolic pressure above 160 mm. Hg represents systolic hypertension. I have taken a diastolic pressure of 110 mm. Hg or above as representing diastolic hypertension and a systolic pressure above 160 mm. Hg with a diastolic below 110

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Page 1: HYPOTENSIVE THERAPY IN STROKE SURVIVORS

7645

Saturday 7 March I970

HYPOTENSIVE THERAPY IN

STROKE SURVIVORS

A. BARHAM CARTER

Neurological Unit, Ashford Hospital, Ashford, Middlesex;Queen Alexandra Hospital, Millbank, London S.W.1; and

Department of Neurosurgery, St. George’s Hospital,London S.W.1

Summary A prospective randomised controlledtrial of hypotensive therapy in 97

hypertensive patients surviving an ischæmic-typestroke was started in 1964 and terminated 4 yearslater. The patients were under 80 years of age,consecutively admitted to one hospital and the controland treated groups compared well for age, sex, andseverity of hypertension. The drugs used were

methyldopa, bethanidine or debrisoquine combinedwith restriction of salt intake, weight reduction, andthiazide diuretics, and the results were analysed withregard to survival and recurrence rates. Hypertensionwas defined as diastolic if this pressure was 110 mm.

Hg or above, and as systolic if this pressure was over160 mm. Hg with the diastolic below 110 mm. Hg.The mortality-rate at the end of a 2 to 5 year follow-up was 26% in the treated group and 46% in theuntreated, and the non-fatal recurrence-rate 14%in the treated and 23% in the controls. Good smoothcontrol was essential to success, untreated patientsdoing better than those whose control was unsatis-factory. In patients aged over 65 treatment of systolichypertension was of no benefit, although the diastolichypertensives improved marginally with treatment.As age increased this effect was progressively less

apparent but the figures are probably too small tomean anything. In this series significant improve-ment occurred in treated hypertensive patients whohad survived a stroke if they were aged 65 or below,but not if they were older.

Introduction

IT is generally agreed that hypertensive patientswith accelerated hypertension and those with cardiac,ophthalmic, or renal involvement benefit from hypo-tensive therapy. There is less agreement about thosewith uncomplicated hypertension, and even lessabout those whose hypertension has been complicatedby a stroke. Adams 1 has questioned whether theprognosis of stroke survivors is affected by hyper-tension, especially in elderly patients, and Leishman’swork 2 confirms that strokes occur even in well-controlled patients. Many other workers have thoughtthat patients with a diastolic pressure of 110 mm. Hg

or over benefit from treatment.3-7 I describe here acontrolled trial designed to see if the natural historyof a group of hypertensive patients surviving anischasmic type of major completed stroke has beenimproved by effective hypotensive therapy.

Patients and Definitions

A prospective study was started in January, 1964, andplanned to end in December, 1968, of all hypertensivesurvivors below the age of 80 of ischaemic type majorstrokes admitted to Ashford Hospital, Middlesex, in these5 years. However, after 4 years it was thought unethicalto continue the controlled trial in view of the results,and so the end-point was taken as December, 1967.

Ischaemic Stroke

An ischaemic stroke was defined as a cerebrovascular

episode in which the neurological defect persisted withoutimprovement for more than 48 hours, in which the cere-brospinal fluid was clear and colourless, and in which thediagnosis of systemic cerebral embolism could reasonablybe excluded. In my experience 6 moss of these patientswould have had a true ischaemic cerebral infarction due toocclusion of large or medium cerebral arteries. However,the finding of microaneurysms in the brains of nearly allhypertensive patients over the age of 50 dying from cere-brovascular disease,8-10 suggests that these may contributeto the production of ischaemic-type strokes and casts somedoubt on the validity of the proposition that large-vesselocclusion is always the cause: Small thromboses andhxmatomas were found by these workers as common

complications of the aneurysms, and they reported theextension of thrombi to the parent vessel with the pro-duction of local ischaemic infarcts, as noted by Rosenberg 11

giving rise to the " status lacunatus " of Miller Fisher 12and others.

Since, in deep lesions, one cannot differentiate betweenhaematomas and infarcts, the phrase " ischaemic-typestroke " is used here to include all these manifestationsand to exclude only obvious cerebral haemorrhage or

embolism.

HypertensionHypertension is difficult to define-casual sphygmo-

manometer readings on the same patient at different timesfluctuate and any dividing line between normal andabnormal pressure has to be set arbitrarily. However,Dunne 13 has shown that after the third visit to an out-

patient department the pressure settles down so thatfurther variation is very small, and there is general agree-ment that anyone with a persisting diastolic pressure of110 mm. Hg or over is hypertensive 10,14-16; there is less

agreement when systolic pressure is raised dispropor-tionate to diastolic pressure, but many physicians acceptthat a persisting systolic pressure above 160 mm. Hgrepresents systolic hypertension.

I have taken a diastolic pressure of 110 mm. Hg orabove as representing diastolic hypertension and a systolicpressure above 160 mm. Hg with a diastolic below 110

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486

mm. Hg as systolic hypertension. Diastolic hypertensionis commonly associated with small-vessel disease, involve-ment of the renal circulation, hypertensive cardiomyo-pathy, and intracerebral microaneurysms. The systolichypertensive patient with a high pulse pressure is more

likely to show rigidity and hardening of large and mediumarteries such as is commonly found in the ageing process,and the smaller and prearteriolar vessels are not usuallyaffected. These findings give a pathological basis for theclinical separation of these two types and this is useful in

practice because diastolic hypertension carries the worseprognosis.

Patients were judged to be hypertensive if they con-tinued to fulfil the above pressure criteria 2 weeks afteradmission. This allowed any effects of the stroke itself orof bed rest and hospital life to stabilise and left a reasonabletime for adjustment of dosage of hypertensive drugs beforedischarge from hospital.Patients

Besides patients with cerebral haemorrhage, embolism,tumour, or accelerated hypertension, it was thoughtethically correct not to include in the series those with anobvious need for hypotensive therapy; and patients withattacks of left ventricular failure, congestive cardiacfailure, gross radiological cardiac enlargement, variouscardiac arrhythmias, or evidence of renal failure wereexcluded.

In the 4-year period 244 patients under the age of 80survived a major ischaemic-type stroke, and 104 (43%)of these were hypertensive. 4 men and 1 woman wereexcluded because hypotensive therapy was considered

obligatory in their case. 99 patients (56 men, 43 women)

TABLE I-COMPARISON BETWEEN THE TWO GROUPS OF TREATED AND

UNTREATED PATIENTS WITH REGARD TO AGE, SEX, AND TYPE OFHYPERTENSION *

’* Including the two lost patients.

formed the final series. These were placed at random intotreated (50) or control (49) groups. The two groupsmatched reasonably closely with regard to numbers, age,sex, and severity of hypertension (table I).

Hypotensive Therapy and ComplicationsThe treated patients attended the follow-up clinic

monthly for the first year and thereafter 3-monthlyabout the same time of day and usually seeing thesame physician. The blood-pressure was taken withthe patient lying, sitting, and after standing for oneminute, and the average of these figures was recorded.After the first visit stability seemed to be achieved inthose who were well controlled, although there wereoccasional " escapes " from the effects of treatment.Some patients tended not to attend regularly andbecause of this were more difficult to observe and tocontrol.

Hypotensive DrugsPatients with systolic hypertension were first

advised to restrict salt intake and were given thiazide

diuretics. If these were ineffective small doses of

methyldopa were substituted; up to 1 g. daily individed doses proved adequate for this group, mostpatients being controlled by 750 mg. with, or if

possible without, a diuretic. This combination wasalso the treatment of choice initially for patients withdiastolic hypertension because postural and exertionalhypotension is less striking and the control corre-

spondingly smoother than it is with more powerfuldrugs.17 Larger doses up to 2 g. daily were oftenneeded for this type of patient but if good controlwas not obtained at this level it was thought betterto change the drug than to push it to the limits oftolerance. The next choice lay between guanethidine,bethanidine, and debrisoquine. Previous experiencehad shown that diarrhoea and hypotensive episodeswere troublesome side-effects of guanethidine andlikely to put patients against hypotensive drugs, andits long action made control slower than was expedient.Therefore bethanidine or debrisoquine was preferred,their action being shorter and side-effects fewer, andduring the trial it seemed a little easier to use debris-oquine although occasionally bethanidine workedbetter. The initial dose of either drug was 10 mg.three or four times a day with a maximum of 200 mg.daily, and thiazide diuretics were added if necessary.Control of HypertensionGood control implied a lowering of diastolic

pressure to between 90 and 100 mm. Hg in patientswith diastolic hypertension, and of systolic pressureto below 160 mm. Hg in those with systolic hyper-tension. Occasionally higher readings would befound even in patients considered well controlled butthe dosage was not increased unless such readingsoccurred on successive visits. Patients were con-

sidered poorly controlled if they abandoned treat-

ment, were unreliable in the regular taking of theirtablets, or were found to have escaped control in aquarter or more of their visits. 9 patients out of 49were considered failures, giving an 82% success-rate,which is slightly less than that obtained by Prichardet al .,17 but greater than that reported in otherseries.18-20 Probably this moderately successful ratedepended on frequent attendance in the first year oftreatment when variation seemed greater than later

on, continued adjustment of dosage, and the use ofthree reasonably effective and acceptable hypotensivedrugs.Complications

Just over a third of the patients (17) complained ofside-effects of hypotensive therapy, but this numbermay be smaller than is strictly accurate because it wasconsidered unwise to ask direct questions. However,all the men were warned that they might feel dizzyat night when they got out of bed to urinate, and theywere advised to sit down for this purpose.

8 patients were changed from methyldopa to

bethanidine or debrisoquine because side-effectsprevented them taking their tablets-lethargy, drowsi-ness, nightmares, headaches, and " feeling off colour

"

were the commonest. Postural or exertional dizzineswere not considered side-effects but due to over-

dosage ; however, 5 patients had to be changed todebrisoquine because good control with methyldopa

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487

was impossible without this symptom which was

usually most troublesome in the morning. 12 patientscould not be satisfactorily controlled on methyldopa2 g. daily and a thiazide diuretic. 8 of these volun-teered that they had not realised the drug was makingthem lethargic and off colour until they discontinuedit. Most of these were much happier with bethanidineor debrisoquine, although 1 man was disappointedthat ejaculation had not recommenced when the

drug was changed.One patient had haemolytic anxmia as a result of

methyldopa after 14 months’ treatment. No case ofjaundice, severe depression, or diarrhoea was

encountered.The 7 poorly controlled patients comprised 5

who said they would rather keep their hypertensionthan continue to take the tablets. Of these 1 thoughthe was being poisoned, 1 had become impotent, 2" felt quite well without them ", and 1 " was upsetby any medicine ". The 2 other patients defaultedalthough answering their follow-up letters. In no

patient who attended regularly was it impossible tocontrol the hypertension and it seems that althoughno drug is ideal we now have effective hypotensiveagents. Propranalol may prove to be better thanthe agents used here but was not tried until 1969.

Results

Of the 99 patients in the trial, 2 have been lost tofollow-up-a treated man aged 65 and an untreatedwoman of 70-so results are available for 49 treatedand 48 untreated patients. This 98% success is

probably due to the series comprising only personalpatients from the immediate environs of a district

hospital and to the cooperation of their family doctors.13 out of 49 treated patients (26-5%) and 22 out

of 48 untreated patients (46%) have died. Controlseems to be very important in prognosis (table II)since the mortality-rate was 17-5% among well-controlled treated patients but 66% in the poorlycontrolled group, even higher than the death-ratefor untreated patients. This high mortality in thefailed-treatment group may be due to the harmfuleffects of wide fluctuations of pressure, and in 2 outof the 6 deaths the immediate cause was aneurysmaldissection of the aorta confirmed at necropsy. Thedifference in mortality (treated v. untreated) is statis-tically significant (with X2 3-6; p=0-05); and if thewell-controlled group is compared with the untreatedgroup the significance is even greater (P=0-015). Afurther breakdown (table 11) shows that the prognosisof untreated systolic hypertension is better than thatof untreated diastolic hypertension, that treated

TABLE II-MORTALITY-RATES (FOLLOW-UP FOR 2-6 YR.) IN RELATIONTO TYPE OF HYPERTENSION AND CONTROL

TABLE III-RELATION BETWEEN DEATHS AND LENGTH OF FOLLOW-UP

systolic hypertension has the best prognosis of all,but that all 4 of the poorly controlled systolic hyper-tensive patients died, 2 from dissecting aneurysm ofthe aorta and 2 from cardiac failure. Thus in thissmall series poorly controlled patients have faredworse than those who had no treatment. As expected,mortality increases with the passing of time (tableIII), at about 8% per annum.Causes of Death

13 (37%) died from extracranial cardiovasculareffects, 13 (37%) from recurrent strokes, 6 fromrespiratory disease, 1 from street accident, and 2 ofunknown causes (table iv). A high proportion ofnecropsy confirmation was obtained because from alocal population patients are usually readmitted to

TABLE IV-ANALYSIS OF DEATHS *

* Confirmation was obtained at necropsy in 25 patients and from thefamily doctor in 6.

the hospital that cared for them originally. The

finding that cardiovascular disease is as common a

cause of death as stroke recurrence, which accountedfor only just over a third of the total deaths accordswith the experience of other workers. In 430 strokesurvivors Baker et al.21 reported that 42% of deathswere cardiovascular, but only 23% were due to recur-rent infarction and, surprisingly, no patient in theirseries died from cerebral haemorrhage, although intheir hypertensive patients the fatal recurrence roseto 28 %. Marshall and Shaw 22 reported that 43 % ofthe deaths in their patients were due to a recurrenceof the stroke, which is more in agreement with the

figure for my series. Only 3 out of 13 deaths in thetreated group were due to recurrent stroke comparedwith 10 out of 22 deaths in the untreated series.

Recurrence

There were 31 recurrences of major strokes in theseries of which 13 were fatal, 10 in the untreated and3 in the treated group. Of the 18 non-fatal recurrences11 were in the untreated and 7 in the treated, so thatthere were 21 (44%) total major recurrences in theuntreated compared with 10 (20%) in the treated

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TABLE V-PERCENTAGE RATE OF RECURRENCES IN THE TWO GROUPS

patients. These numbers are very much too smallfor any valid comparisons but if anything are infavour of treatment. Baker et al.21 found that cerebralinfarctions recurred in 28% of their hypertensivepatients and 21% of their normotensive; just underhalf of these recurrences were fatal.

Figures for minor strokes or transient cerebralischaemic attacks are not available.Of the 11 non-fatal recurrences in the untreated

group 7 were in the 30 patients with diastolic hyper-tension and 4 in the remaining 18 with systolic hyper-tension. Similarly of the 7 recurrences in the treated,4 were in the 3! patients with diastolic and 3 in the17 with systolic hypertension, so that treatment hasonly slightly diminished the risk of non-fatal recur-rences in this series. For the fatal recurrences the

figures in the untreated group were 6 out of 30 withdiastolic and 3 out of 19 with systolic hypertensionand in the treated group 2 out of 32 with diastolicand 1 out of 18 with systolic, so that treatment seemsto have reduced the fatal-recurrence rate (table v).

Discussion

Is there any evidence that untreated hypertensionworsens the prognosis of stroke survivors ? Adams 1

suggests that there is not. He and Merrett,23 in aseries of 710 hemiplegic patients, found no evidenceof an adverse effect of hypertension on mortality aftercerebral infarction. However, their work can becriticised on three counts: (1) 207 patients were

omitted because they came under care more thanfour weeks after their stroke; (2) the highest restingsingle blood-pressure reading at the beginning ofconvalescence was taken as indicating the presence orabsence of hypertension; and (3) the patients wereelderly and no other factors influencing prognosiswere discussed. The Framingham study 24 has con-firmed the widely held clinical belief that hypertensionincreases the risk of stroke, both haemorrhagic andischaemic; five times as many cerebral infarctions

developed in hypertensive patients as in those whosepressure was normal. One might predict that hyper-tension would increase the risk of recurrence or deathin stroke survivors, but Adams 1 claimed that respira-tory complications and atheroma are more likely tocause death in this group than are the effects of hyper-tension and argued that, after an ischasmic stroke,the cerebral circulation is less vulnerable to the directhazards of hypertension. However, hypertensionoften increases with age and it is not unknown for

hypertensive patients who have had a cerebral infarc-tion to die from the effects of cerebral haemorrhage,although Adams’ view that this is much less commonthan further infarction is undoubtedly true. Leishman’sviews accord with those of Adams on this point, andhe reported that mortality in hypertensive strokesurvivors could be reduced only by preventing cerebral

haemorrhage and renal failure but not by reducingthe number of ischxmic reinfarctions.2

Other workers’ experience is more favourable tothe view that it is worth reducing hypertension aftera stroke. Marshall and Kaeser 3 prospectively investi-gated 177 patients who had recovered from a cerebralinfarction and found that 96% of normotensive

patients had survived more than two years comparedwith 75% of the hypertensive group. Carter 6 reportedthat hypertension was an important long-term factorin the prognosis of stroke survivors, and more so inmen than women; his 5-year-survival rates were 25%for hypertensive men and 60 % for hypertensive womencompared with 92% for normotensive men and 88%for normotensive women. Rankin 25 had earlier

reported increasing mortality in hypertensive strokesurvivors, and Lindgren 26 reported 5-year-survivalrates of 37% for hypertensive cerebral-infarctsurvivors and 55% for normotensive patients.Marquardsen,27 in a retrospective study of 769 Danishpatients, reported 6-year-survival rates of 28% in

hypertensive patients compared with 54% in normo-tensives. And many other workers accept that hyper-tension is a bad prognostic factor in cerebral infarc-tion...29 9

From this evidence it seems certain that hyper-tension predisposes to stroke incidence and probablethat it worsens the prognosis of stroke survivors.Whether treatment of the hypertension can alterthis prognosis does not yet seem to be established,although the report by Baker et al. 21 is of interest.In their 430 survivors of cerebral infarction the

prognosis was a little, but not significantly, betterin the normotensive group. But there was no greatdifference between the outcome of moderate andsevere hypertension; they suggested that this mightbe due to "the fact that patients were followed

closely with careful management of hypertension".Their study certainly does not invalidate the pro-position that hypotensive treatment may improve theprognosis of this group of patients, and even impliesthat if the hypertensive patients had not been treatedtheir prognosis would have been worse.The trial reported here supports this contention.

After four years the preliminary results suggestedthat to deny hypertensive patients the benefit of

hypotensive therapy after a stroke would be wrong,and since the beginning of 1968 treatment has beenthe rule for non-geriatric patients. Mortality has beensignificantly reduced in both categories of hypertension(table 11) but at first sight little value seemed to accruefrom dividing hypertension into the two types, since

TABLE VI-OUTCOME IN RELATION TO AGE AND TYPE OF

HYPERTENSION

D =DiastoIie hypertension.S = Systolic hypertension.

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489

there was no significant difference between their

prognoses. However, when the age factor was con-sidered the untreated patients over sixty-five years of agewith systolic hypertension did better than the treated,and although the treated diastolic hypertensivepatients fared a little better the numbers are too

small to be of any value (table vi). This supportsAdam’s 1 contention that the elderly hemiplegicwith hypertension has as good a prognosis as the

normotensive, and unless the diastolic pressure is

high it is probably unnecessary to treat this age-group.

Control of hypertension is an exacting task not tobe left to others, since patients’ morale depends agreat deal on their seeing a familiar figure in a familiarenvironment, and only by personal exhortation canthey be persuaded to stick to the rules. The firstfew months are the most difficult since hypotensivereactions occur while the dose is being adjusted, andthese reactions can be very disconcerting, although nopatient in this series experienced any permanentneurological deficit as a result of a known hypotensiveattack. The worst attacks were associated withexertion-a much more important but less well

recognised cause of hypotension than simple changeof posture. Whether cardiac infarction may be

precipitated by hypotension is uncertain and obvi-

ously some of the hazards of therapy have fortunatelyescaped this small series. As with anticoagulanttherapy, hypotensive treatment is bothersome andshould not be lightly undertaken, and the easy viewis to suggest, as some do, that both are useless; butit seems from this study that hypotensive therapy hasbenefited comparatively young hypertensive patientswho have survived a stroke.

Part of the expenses of this research project were covered bya grant from the clinical research subcommittee of the NorthWest Metropolitan Regional Hospital Board.

REFERENCES

1. Adams, G. F. Br. med. J. 1965, ii, 253.2. Leishman, A. W. D. Lancet, 1963, i, 1284.3. Marshall, J., Kaeser, A. C. Br. med. J. 1961, ii, 73.4. Hodge, J. V., McQueen, E. G., Smirk, H. ibid. 1961, i, 1.5. Carter, A. B. Proc. R. Soc. Med. 1963, 56, 483.6. Carter, A. B. Cerebral Infarction. Oxford, 1964.7. Hamilton, M., Thompson, E. N., Wisniewski, T. K. M. Lancet,

1964, i, 235.8. Charcot, J. M., Bouchard, C. Arch. physiol. norm. path. 1868,

110, 643.9. Ross Russell, R. W. Brain, 1963, 86, 425.

10. Cole, F. M., Yates, P. O. J. Path. Bact. 1967, 93, 393.11. Rosenberg, E. F. Archs intern. Med. 1940, 65, 545.12. Fisher, C. M. Cerebrovascular Disease. Springfield, Illinois, 1960.13. Dunne, J. F. Lancet, 1969, i, 391.14. Hill, A. B., Marshall, J., Shaw, D. A. Q. Jl Med. 1960, 29, 597.15. Hill, A. B., Marshall, J., Shaw, D. A. Br. med. J. 1962, ii, 1003.16. Prineas, J., Marshall, J. Br. med. J. 1966, i, 14.17. Prichard, B. N. C., Johnston, A. W., Hill, I. D., Rosenheim,

M. L. ibid. 1968, i, 135.18. Bath, J., Pickering, D., Turner, R. ibid. 1967, ii, 519.19. Johnson, P., Kitchin, A. H., Lowther, C. P., Turner, R. W. D.

ibid. 1966, i, 133.20. Hamilton, M., Kopelman, H. ibid. 1963, i, 15121. Baker, R. N., Schwarz, W. S., Ramseyer, J. C. Neurology, 1968

18, 933.22. Marshall, J., Shaw, D. A. Br. med. J. 1959, i, 1614.23. Merrett, J. D., Adams, G. F. ibid. 1966, ii, 802.24. Kannel, W. B. Cerebral Vascular Diseases; p. 53. London, 1967.25. Rankin, J. Scott. med. J. 1957, 2, 200.26. Lindgren, S. O. Acta psychiat. scand. 1958, 33, 343.27. Marquardsen, J. Natural History of Acute Cerebrovascular Disease;

p. 118. Cophenhagen, 1969.28. Ford, A. B., Katz, S. Medicine, Baltimore, 1966, 45, 223.29. David, N. J., Heyman, A. J. chron. Dis. 1960, 11, 394.30. Pincock, J. G. Ann. intern. Med. 1957, 46, 925.

GOITRE PROPHYLAXIS BY ADDITION

OF POTASSIUM IODATE TO BREAD

Experience in Tasmania

F. W. CLEMENTS

School of Public Health and Tropical Medicine, Universityof Sydney, and Commonwealth Department of Health,

AustraliaH. B. GIBSON J. F. HOWELER-COY

Department of Health Services, Tasmania

Summary In March/April, 1966, potassium iodatewas substituted for some potassium

bromate in the bread improver used throughoutTasmania, as a universal prophylactic against endemicgoitre. The rate of addition of iodate was 2 parts permillion of bread by weight. After a preliminarysurvey in 1949, tablets containing 10 mg. potassiumiodide had been made available to infants, preschoolchildren, and schoolchildren through schools andchild-health centres for weekly consumption for

approximately sixteen years. State-wide surveys at

five-year intervals showed a slow steady reduction inthe prevalence of goitre, but in some regions the ratesremained high. It was presumed that this was due toineffective distribution of the tablets. Since 1966there has been a further striking reduction in theprevalence of goitre, and the 1969 rates for the wholeState are similar to these in a non-goitrous region.Some unexplained regional variations were noted inthe latest survey. It is concluded that the incorpora-tion of 2 parts per million potassium iodate in breadis an effective prophylactic against endemic goitre.

Introduction

Tasmania has long been recognised as an endemicgoitrous region. The intensity of the thyroid enlarge-ment varies from one region to another, probablydue to the nature of terrain and the extent of earlier

glaciation.Although there may be other factors in the setiology

of the endemic goitre, the Tasmanian health authori-ties have accepted that the main factor is iodine

deficiency, for in 1950 a programme of iodine pro-phylaxis was introduced for schoolchildren, infants,and preschool children. Because the mandatory useof iodised salt was unacceptable, the method chosenwas the distribution to the selected groups of tablets

containing 10 mg. potassium iodide, one tablet to betaken weekly. The distribution was through schools,and child-health centres. Over sixteen years some

thirty-six million tablets were distributed.Surveys were made of a significant percentage of the

school population at five-yearly intervals up to 1965when a report of the results of five State-wide surveyswas completed. 1 The prevalence of endemic goitrefell progressively over the sixteen years of the pro-phylactic programme, but the condition was not

eliminated, and there were comparatively large groupsof the population, where, because of the lack of co-operation between schoolteachers and health authori-ties, the distribution of the tablets was so spasmodic asto be apparently non-effective. Furthermore, thedistribution through child-health centres to infants