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CEREBRAL BLOOD FLOW AND ANTIHYPERTENSIVE DRUGS IN THE ELDERLY

S.Strandgaard

Department of Medicine and Nephrology B,Herlev Hospital, Copenhagen,Denmark

Introduction: There is no study of the effect of antihypertensive

drugs on cerebral bloood flow (CBF) in old age,i.e. no investigator has systematically measured CBF in elderly patients before and during antihypertensive treatment. Despite this,some light can be thrown on the subject from studies on the effect of ageing on the brain and the vascular system,as well as from studies of CBF and its autoregulation in young and middle-aged patients.

Autoregulation of cerebral blood flow: The term autoregulation denotes the intrinsic ability

of an organ to maintain its perfusion in the face of a changing perfusion pressure.Autoregulation can be demon- strated in many organs,but is particularly obvious in the brain,where neurogenic influences on blood flow are paradoxically minor.The perfusion pressure of the brain may change as arterial pressure falls or rises,or intra- cranial pressure rises.The smaller arteries and arterioles respond to decreases in perfusion pressure by dilatation, and to increases in perfusion pressure by constriction. At "the lower blood pressure limit of autoregulation", autoregulatory vasodilatation becomes inadequate,and CBF decreases.Conversely,at the "upper blood pressure limit o f autoregulation",autorequlatory vasoconstriction is overridden by high transmural pressure,and CBF increases.

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The mechanism of CBF autoregulation is unknown;myogenic, metabolic and neurogenic factors have been invoked,but no generally agreed conclusion has been reached as to the nature of the phenomenon.Even though the autoregulatory response probably basically is myogenic,i.e.intrinsic to vessel wall muscle,it is strongly influenced by metabolic, chemical and to a lesser degree neurogenic mechanisms.Thus, in the brain,blood flow is closely coupled to metabolic demandsithis is sometimes erroneously termed "autoregulation" but more properly is referred to as metabolic regulation. Acidosis of the brain tissue,e.g.caused by ischaemia,may altogether abolish autoregulation.Perivascular autonomic nerves in the brain apparently have no resting tone.During bleeding,however,alpha-adrenergic stimulation causes some constriction of the larger cerebral resistance vessels, thus counteracting autoregulation.

Factors influencing cerebral blood flow in old age: CBF is decreasing in old age,in proportion to a loss

of neuronal tissue and decreased metabolic demands ( l 1 2 ) . Apart from this "physiological" change,a number of disease processes common in the elderly may influence CBF and its regulation.

Dementia,of the "senile" as well as the "multiinfarct" variety will further decrease the cerebral metabolic demands of old age and cause a low CBF ( 3 ) .

Atherosclerosis of larger cerebral resistance vessels may compromise autoregulation distal to a stenosis of e.g. the medial cerebral artery.Autoregulatory dilatation of the smaller resistance vessels behind such a stenosis may be exhausted in the resting stateland hence minor falls in blood pressure. may-lead to focal cerebral ischaemia. Global loss of autoregulation,presumably due to athero- sclerosis,has been described in elderly people with ortho- static hypotension and disabling dizziness (4).

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Diabetes mellitus may cause chronic impairment of CBF autoregulation (5).It is uncertain whether this is due to atherosclerosis of larger resistance vessels or to diabetic angiopathy of small resistance vessels in the brain.

Stroke,ischaemic or haemorrhagic,in the acute phase is associated with a complicated haemodynamic pattern of mixed ischaemia and hyperaemia.If permanent brain damage follows an acute stroke,CBF will be chronically decreased corresponding to the decreased metabolism.Autoregu1ation may be chronically lost in an infarcted brain area.

Hypertension profoundly influences CBF autoregulation, as it will be discussed below.

Hypertensive adaptation of autoregulation of cerebral blood flow.The effect of antihypertensive treatment:

In chronic hypertension,the lower end of the CBF auto- regulation curve is shifted towards high blood pressure, i.e.to the right on the blood pressure axis (fig.l).This has been demonstrated in young and middle-aged hypertensive patients ( 6 ) as well as in experimental animals with hypertension of a few months duration (7,8).This functional haemodynamic adaptation in hypertension is probably caused by structural hypertensive vascular changes (9).Hyper- tensive vascular disease causes thickening of vessel walls and narrowing of vessel lumina,thereby reducing the capacity for maximal dilatation.

Structural hypertensive vascular changes have two components:a reversible component of smooth muscle hyper- trophy and logging of sodium and water in the vessel wall; and a non-reversible component of connective tissue pro- liferation and degenerative changes.Reversibility of functional haemodynamic adaptation in hypertension will expectedly depend on the extent of reversible as opposed to non-reversible structural changes in the vessels.In young animals,e.g.in young rats with renal hypertension (10)

106. CEREBRAL BLOOD FLOW Percent of rest

100 '

50s

100 '

501

Normotensive pa t ien ts

4

Hypertensive pat ients /c- J

50 100 150 200

Treated hypertensive (, patients

Fig.1: The lower blood pressure limit of autoregulation of cerebral blood flow as determined during acute,controlled hypotension in normotensive and hypertensive man.In untreated or poorly controlled hypertension,the autoregulation curve is shifted towards high pressure (top).In effectively treated hypertensive patients, the curve is intermediate between the curves of normotensives and severely hypertensives,suggesting some readaptation during antihypertensive treatment (bottom). From Strandgaard:Autoregulation of cerebral blood flow in hypertension,Circulation 1976;53:720-727,reproduced by permission of the American Heart Association,Inc.

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hypertensive adaptation of CBF autoregulation is fully reversible in the course of a few months of antihyper- tensive treatment.In young and middle-aged effectively treated hypertensive patients,CBF autoregulation may or may not be readapted towards normal (6,fig.l) .In elderly hypertensive patients,CBF autoregulation has not been studied,but non-reverible hypertensive vascular structural changes would be expected to prevail in this age group, and hence functional vascular readaptation is not likely to take place when the blood pressure is lowered.Further, in the elderly,atherosclerotic narrowing of the larger cerebral arteries may contribute to impairment of auto- regulation by exhausting autoregulatory arteriolar dila- tation in the resting state,as discussed above.Thus,two haemodynamic factors contribute to an increased risk of cerebral ischaemia during antihypertensive treatment in elderly patients.

Aiming at a proper balance between risks and benefits of antihypertensive treatment in elderly patients:

In elderly patients,hypertension is a risk factor €or stroke as it is in the young and middle-aged (11). So far,the beneficial effect of antihypertensive treat- ment with respect to stroke prevention has not been proven in the elderly.Further,there is little doubt that elderly people with high blood pressure are not infrequently overtreated,even though there are only occasional reports of this in the literature (12).In this controversial field,the results of the European Working Party on Hyper- tension in the Elderly are eagerly awaited.

At present,the author would recommend a conservative approach to the elderly hypertensive individual.Treatment should not be withheld,but it should aim at some reduction rather than a complete normalization of blood pressure. Diastolic pressure should not be brought below 90-100 mmHg.

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When the blood pressure is lowered,the clinician should be carefully monitoring the elderly hypertensive patient for signs and symptoms of clinical cerebral ischaemia,of which an increasing dizziness is often prominent.Elderly patients who become increasingly dizzy when given anti- hypertensive drugs should be allowed to keep their blood pressure at a level at least somewhat above normal.

It has not been studied whether some antihypertensive drugs when given chronically have particular beneficial effects on the brain and its circulation,in analogy with the cardiac effects of beta-blockers.Hence,elderly patients,from the point of view of the cerebral circulation, can be treated with the same drugs as young and middle- aged hypertensive patients.Drugs that tend to cause postural hypotension,however,should be avoided in the elderly.

Conclusion: Antihypertensive treatment may or may not protect

elderly hypertensive patients against stroke.Antihyper- tensive treatment is more likely to cause cerebral ischaemia in elderly hypertensive patients than in young and middle-aged patients.A reasonable,conservative approach when antihypertensive treatment is given to elderly patients is to aim for some reduction but not a complete normalization of the blood pressure.

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2.Meyer,C.H.A.,Lowe,D.,Meyer,M.,Richardson,P.L.& Neil-Dwyer,G:Subarachnoid haemorrhage:Older patients have low cerebral blood flow.Brit.Med.J.1982:2:1149- 1153

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3.Simard,D.,Olesen,J.,Paulsonl0.B.,LassenlN.A.& SkinhBj,E.: Regional cerebral blood flow and its regulation in dementia. Brain 1971;94:273-288

4 . W o l l n e r , L . , M c C a r t h y , S . T . , S o p e r , N . D . W & Macy,D.J.:Failure of cerebral autoregulation as a cause of brain dysfunction in the elderly.Brit.Med.J.1979;1:1117-118

5.Bentsen,N.,LarsenIB.& Strandgaard,S.:Chronic impairment of CBF autoregulation in man.Observations in hypertensive and diabetic patients.Pp 5.22-5.23 in Blood Flow and Metabolism of the Brain,ed.by Harper,A.M.,Jennett,B.,Miller,D.& Rowan,J.Churchill Livingstone 1975

6.Strandgaard,S.:Autoregulation of cerebral blood flow in hypertensive patients.The modifying influence of prolonged antihypertensive treatment on the tolerance to acute,drug- induced hypotension.Circulation 1976;53:720-727

7.Jones,J.V.,Fitch,W.,MacKenzielE.T.,Strandgaard,S.& Harper, A.M.:Lower limit of cerebral blood flow autoregulation in experimental renovascular hypertension in the baboon. Circulation Res.1976;39:555-557

8.Barry,D.I.,Strandgaard,S.,Graham,D.I.,Br~ndstruplO., Svendsen,U.G.,Vorstrup,S.,Hemmingsen,R.& Bolwig,T.G.: Cerebral blood flow in rats with spontaneous and renal hypertensi0n:resetting of the lower limit of autoregulation. J.Cereb.Blood Flow Metab.1982;2:347-353

g.Folkow,B.:The haemodynamic consequences of adaptive structural changes in the resistance vessels in hyper- tension.Clin.Sci.l971;41:1-12

lo.Barry,D.I.,Vorstrup,S.,Jarden,J.O.,Svendsen,U.G.,Br~ndstrup, O.,Graham,D.I.& Strandgaard,S.:Chronic antihypertensive treatment restores normal autoregulation to the cerebral circulation in the rat.Acta Neurol.Scand.l982;suppl 90, 65: 164-165

ll.Shekelle,R.B.,Ostfeld,A.M.& Klawans,H.L.:Hypertension and risk of stroke in an elderly population.Stroke 1974;5: 71-76

12.Jackson,G.,Pierscianowski,T.A.,Mahon,W.& Condon,J.: Inappropriate antihypertensive therapy in the elderly. Lancet 1976;2:1317-1318