EDITORIALS

Therapeutic Strategies for Orthostatic Intolerance:Mechanisms, Observations, and Making Patients

Feel Better

Tomas Kara, MD, Virend K. Somers, MD, PhD

Abnormalities in orthostatic tolerance result from anumber of disease processes and are often dis-abling and difficult to treat. Conditions resulting

in orthostatic intolerance include primary autonomicfailure, multiple system atrophy, autonomic neuropathydue to systemic conditions such as diabetes and amyloid-osis, and idiopathic orthostatic intolerance (also knownas chronic orthostatic intolerance or postural orthostatictachycardia syndrome, among other names). Whereasthe former conditions are due to well-defined, identifi-able, autonomic neuropathic states, the pathophysiologyof idiopathic orthostatic intolerance is less clear. Thereare also other disorders of orthostatic tolerance that areassociated with drug therapy, whether because of hypo-volemia due to diuretics or due to impaired vasoconstric-tion resulting from drugs such as prazosin. Aging andprolonged bed rest may also induce varying degrees oforthostatic intolerance in healthy persons.

In patients with orthostatic intolerance due to hypo-tension, the inability to maintain blood pressure whilestanding can be consequent upon decreased blood vol-ume, impaired arterial and venous constriction, or inap-propriate cardiac chronotropic responses to standing. Bycontrast, in patients with idiopathic orthostatic intoler-ance, blood pressure does not fall, heart rate is fast, andsymptoms of palpitations, lightheadedness, fainting, diz-ziness, and even syncope develop (1,2). Although it isimportant to differentiate between hypotensive ortho-static intolerance and idiopathic orthostatic intolerance,both conditions may benefit from treatment with thesame agents.

Therapeutic strategies based on pathophysiologicmechanisms are typically directed at increasing bloodvolume, enhancing venous return (by crossing legs [3] orwith compression stockings), inducing systemic arterialvasoconstriction or venoconstriction, and improving theheart rate response to standing. The paradoxes that char-acterize hypoadrenergic orthostatic hypotension may

modify treatment approaches. First, the supine hyperten-sion that is typical of these conditions is often exacerbatedby some of the therapeutic options, thus enhancing thelikelihood of developing hypertensive end organ disease(4). Second, adrenergic receptor sensitivity may increasebecause of low levels of norepinephrine (5,6). Alpha-2(�2) adrenergic agonists such as clonidine, which nor-mally lower blood pressure (7), instead induce arterialconstriction, increase forearm vascular resistance, andincrease supine blood pressure (8). Third, these patientsdemonstrate excellent autoregulation of the cerebral cir-culation and are often able to tolerate systemic bloodpressures �70 mm Hg while standing, with only minimalsymptoms (9).

This issue of the Journal includes two papers related tothe treatment of patients with orthostatic syndromes.The paper by Victor and Talman (8) concerns a mecha-nism in search of a therapeutic effect, whereas Shannon etal. (10) describe a therapeutic effect in search of a mech-anism. These different investigative strategies offer prom-ising approaches with the potential to affect patient man-agement.

Victor and Talman note that postjunctional �-adren-ergic receptors are located mainly on venous capacitancerather than arterial resistance vessels. They hypothesizethat the �-adrenergic agonist clonidine, which raisesblood pressure in patients with hypoadrenergic ortho-static hypotension, may maintain standing blood pres-sure in these patients through venoconstriction. Theirdata show that both clonidine and dihydroergotamineincreased supine blood pressure and forearm vascular re-sistance. Dihydroergotamine, a known venoconstrictoragent, increased venous tone, whereas clonidine had nosignificant effect. This differential physiologic effect mayhave important implications for predicting the therapeu-tic response since dihydroergotamine improved ortho-static tolerance far more than did clonidine. Clonidinewas also associated with stupor and central apnea thatrequired intensive care monitoring (11).

Several important insights emerge from the study byVictor and Talman. First, the arterial vasoconstrictor ef-fect of a pharmacologic or other agent may not relate toany therapeutic effect. Second, venoconstriction may beimportant in treating these patients. Third, in vitro phe-

Am J Med. 2002;112:419 – 421.From the Department of Medicine, Divisions of Hypertension and Car-diovascular Diseases, Mayo Clinic, Rochester, Minnesota.

Manuscript submitted January 29, 2002, and accepted in revisedform February 3, 2002.

�2002 by Excerpta Medica, Inc. 0002-9343/02/$–see front matter 419All rights reserved. PII S0002-9343(02)01071-9

nomena do not always hold true when evaluated in com-plex, real-life disease conditions. Victor and Talman alsoallude to the limited efficacy of midodrine as a generaltherapeutic strategy in patients with autonomic failure.This limitation of a widely used therapy calls for a clearcharacterization of the mechanisms and benefits of othertherapeutic approaches such as dihydroergotamine, andthe evaluation of more unorthodox approaches such aswater drinking.

Shannon and colleagues (10) suggest well-timed rapidconsumption of appropriate volumes of water as a short-term treatment for orthostatic hypotension, whether sec-ondary to standing or postprandial, in patients with au-tonomic failure. They also show that excessive and inap-propriate tachycardia when standing can be mitigated bywater drinking in patients with idiopathic orthostatic in-tolerance. These findings are best understood when con-sidered together with an earlier study of theirs, in whichthey demonstrated that drinking about half a liter of tapwater in a few minutes resulted in an increase in bloodpressure in patients with multiple system atrophy or pureautonomic failure (12). This pressor response was lessevident in healthy elderly subjects and not apparent inhealthy young controls. While the mechanism for thepressor response is unknown, the authors suggested thatslight increases in plasma norepinephrine levels afterdrinking water may have induced significant pressor re-sponses because of heightened adrenergic receptor sensi-tivity (12). This effect would be less evident in healthyyoung subjects because of intact baroreflex and other ho-meostatic mechanisms that buffer the change in pressure.

Shannon et al. (10) propose that the therapeutic effectof water is enhanced because the reflex mechanisms thatbuffer blood pressure changes are impaired in patientswith autonomic failure. Such patients may experiencemarked hypotension while standing or after meals. In-deed, in the present paper they describe that these pa-tients had significant attenuation of orthostatic and post-prandial hypotension after drinking water. Standing timemore than doubled after water drinking. Water alsoblunted the orthostatic tachycardia in patients with idio-pathic orthostatic intolerance. In these patients, standingis often accompanied by marked tachycardia and no hy-potension, but patients nevertheless developed light-headedness. It is not clear, however, whether the patientsin their study experienced any clear symptomatic benefitfrom the attenuated tachycardia response induced by wa-ter drinking. This observation would have implicationsfor the pathophysiology of idiopathic orthostatic intoler-ance and would help us understand the interaction be-tween the tachycardia per se and the symptoms.

Shannon et al. provide a strong rationale for waterdrinking as an economic adjunctive therapeutic strategyin patients with hypoadrenergic orthostatic hypotension,and perhaps idiopathic orthostatic intolerance as well.

Their data suggest that the effects of water are not specificto a particular disease state or condition and can be man-ifest in patients with autonomic failure while standingand after meals, and also in patients with idiopathic or-thostatic intolerance. The mechanism invoked to explainthe pressor effect of water in hypoadrenergic orthostatichypotension—norepinephrine release in the setting ofincreased receptor sensitivity— cannot be easily recon-ciled with the blunted tachycardia when water drinking isused in managing idiopathic orthostatic intolerance. Incontrast to hypoadrenergic orthostatic hypotension,which is characterized by a marked diminution in nor-epinephrine release, patients with idiopathic orthostaticintolerance have increased muscle sympathetic nerve ac-tivity while supine (13) and increased plasma norepi-nephrine concentrations when both supine and standing(14 –16). In patients with a familial type of idiopathicorthostatic intolerance, faster heart rates and increasedplasma norepinephrine concentrations segregated with afunctional mutation of the norepinephrine transportergene (17). In a recent study of the effects of pharmacolog-ically blocking norepinephrine transport selectivelyand thus inducing impaired norepinephrine reuptake,Schroeder and colleagues found that selective norepi-nephrine reuptake inhibition created a phenotype resem-bling idiopathic orthostatic intolerance (18). It is notclear why norepinephrine release in response to waterdrinking would attenuate tachycardia on standing.Whether liquids other than water elicit similar effects willneed to be addressed. Alcoholic beverages, for example,may exacerbate orthostatic hypotension (19). Also im-portant is whether water demonstrates comparable effi-cacy in attenuating orthostatic hypotension resultingfrom secondary autonomic dysfunction, a problem fre-quently encountered in patients with diabetes.

Both these studies in this issue of the Journal neverthe-less have clear and important implications for treatingpatients with orthostatic problems. Perhaps a primarygoal of achieving venoconstriction may be more effectivein treating hypoadrenergic orthostatic hypotension, aswould be a definitive identification of the mechanism ofthe pressor effect of water, which may guide us towards amore targeted and sustained therapeutic strategy.

Potential developments in device technology that maycomplement these and other strategies include the bionicbaroreflex (20) and intelligent cardiac pacemakers. Tak-ing their cue from triggers such as a fall in blood pressure,decreases in venous return, or changes in impedance ofthe right ventricle, these devices could increase heart rateas needed, minimizing chronotropic insufficiency andthus attenuating the severity of orthostatic hypotension.Chronotropic support may also lead to the further use ofbeta-blockers and other medications in supine hyperten-sion.

Disorders of orthostatic tolerance are complex, diffi-

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cult to treat, and often not well understood by health carepersonnel. This problem is confounded further by incon-sistencies in nosology, with one syndrome complex oftenhaving three or four names. The studies by Victor andTalman and by Shannon and colleagues increase our un-derstanding and extend the scope of therapies availablefor patients who have difficulty compensating forchanges in posture.

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19. Narkiewicz K, Cooley RL, Somers VK. Alcohol potentiates ortho-static hypotension: implications for alcohol-related syncope. Circu-lation. 2000;101:398 –402.

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