Management of chronic orthostatic hypotension

Management of Chronic Otthostatic Hypotension

Chronic orthostatic hypotension is characterized by recurrent symptoms of cerebral hypoperfuslon due to low upright blood pressure levels. The initial approach should be to identify and correct reversible causes. Persistence of orthostatic hypotension suggests autonomic fallure. The goal of management is to minimize symptoms and maximize functional capacity; therefore the magnitude of blood pressure fall is not as important as the advent of symptoms. Therapy is based upon the underlying pathophysiology and the risk/benefit ratio of interventions. Patient education and nondrug measures form the cornerstone of management. Drug therapy Is often limited by unacceptable supine hypertension. Rational drug use can be governed by individualized trials of therapy. Patients with moderate or severe orthostatic hypotension are diicult to treat, but can be helped toward resumption of a normal life.

JACK ONROT, M.D. MICHAEL R. GOLDBERG, M.D., Ph.D. ALAN S. HOLLISTER, M.D., Ph.D. ITALO BIAGGIONI, M.D. ROSE MARIE ROBERTSON, M.D. DAVID ROBERTSON, M.D. Nashville,

Tennessee

Chronic orthostatic hypotension is characterized by low upright blood pressure levels and symptoms of cerebral hypoperfusion. When a reversible cause cannot be found, failure of autonomic reflexes is often responsible. Rational therapy should take into consideration the underlying pathophysiology and the risk/benefit ratio of potential interventions. The latter is especially critical, since therapy for upright hypotension frequently causes or exacerbates supine hypertension. PATHOPHYSIOLOGY

From the Autonomic Dysfunction Clinic, Departments of Pharmacology and Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee. This work was supported by Grant GM 3 1304 from the National Institutes of Health and by grants from the Hrafn Sveinbjarnarson Foundation, Nashville, Tennessee, and the American Parkinson Disease Association, New York, New York. Dr. Onrot was supported by a research fellowship from the British Columbia Health Care Research Foundation. Dr. Biaggioni is a Merck International Fellow. Dr. Hollister was a Burroughs Wellcome Fellow in Clinical Pharmacology and Dr. Robertson is the recipient of a Research Center Development Award (GM 00494). Requests for reprints should be addressed to Dr. David Robertson, Autonomic Dysfunction Clinic, Departments of Pharmacology and Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232. Manuscript accepted December 5, 1984.

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Maintenance of the upright arterial blood pressure requires appropriate reflex adjustments to the stress of gravity-induced blood pooling and decreased venous return. A fall in venous return leads to decreased ventricular filling and a decline in cardiac output and blood pressure. The dual stimuli of decreased venous return and decreased arterial blood pressure are sensed by cardiopulmonary volume receptors and arterial baroreceptors, respectively. Afferent impulses are then carried by the vagal and glossopharyngeal nerves to blood pressure control centers in the medulla. These centers integrate incoming information and initiate appropriate increases in sympathetic outflow and decreases in parasympathetic outflow. This in turn leads to a rise in norepinephrine and epinephrine levels at the effector sites. These sites include veins (constriction with augmented venous return), arterioles (constriction with elevated peripheral resistance), heart (increased heart rate and contractility), and kidneys (proximal tubular salt and water retention and activation of the renin-angiotensin-aldosterone axis [Figure I]). When these mechanisms are intact, upright systolic blood pressure will decrease slightly (5 to 10 mm Hg) and diastolic blood pressure will increase minimally (3 to 5 mm Hg). Heart rate will increase up to 20 beats per minute. Any interruption of cardiovascular reflex pathways may

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VOLUMERECEPTORS & BARORECEPTORS VIA IX, X NERVES

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Figure 1. Cardiovascular reflex responses in the maintenance of upright arterial blood pressure (see text for description).

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potentially lead to an exaggerated fall in upright blood pressure. The syndrome of chronic otthostatic hypotension is defined as recurrent symptomatology of organ hypoperfusion due to excessive blood pressure decreases on assumption of upright posture. Patients may notice anything from transient lightheadedness to syncope in association with visual disturbances, neck or head discomfort, dyspnea, or profound weakness. These symptoms are for the most part due to inadequate cerebral perfusion. DIFFERENTIAL

DIAGNOSIS

A diagnostic approach to orthostatic hypotension is given in Table I. The diagnosis of orthostatic hypotension rests on upright blood pressure measurement, but all too often this is omitted in the busy practice, Differential diagnosis is based upon careful history and physical as well as laboratory examination, which may include detailed assessment of autonomic reflexes. Our fundamental approach is to initially rule out reversible causes. Most important of these are hypovolemia and medications. Those patients with chronic, irreversible orthostatic hypotension most often have deficits in the autonomic nervous system. The evaluation of these patients is dealt with in detail elsewhere [ 1,2].

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Historical features of autonomic failure include constipation, anal sphincter incompetence with fecal incontinence, uncontrollable diarrhea, nocturia, symptoms of urinary retention or incontinence, decreased sweating, night blindness due to inability to dilate the pupil, nasal stuffiness due to loss of alpha-mediated vasoconstriction in the nasal mucosa, and impaired erections and ejaculation in males [2]. These positive historical features are rarely volunteered by the patient and must, therefore, be individually sought. It is crucial to note that most patients with autonomic failure and orthostatic hypotension also have supine hypertension. Orthostatic heart rate responses should also be assessed. Autonomic failure is suspected when the fall in blood pressure on standing is not accompanied by an appropriate increase in heart rate. Once autonomic failure is suspected, a careful search is undertaken to rule out diabetes mellitus, amyloklosis, paraneoplastic syndromes, or less common causes. When these have been ruled out, the patient is deemed to have primary autonomic failure. Detailed autonomic reflex [3] and pharmacologic [4] testing and the measurement of plasma [5] and urinary [6] catecholamines and their metabolites may be very useful in the differential diagnosis of autonomic failure. Multiple system atrophy (Shy-Drager

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Consider Drugs:

nonautonomic causes and reverse correctable factors Antihypertensives, diuretics, tricyclics, alcohol, nitrates, major and minor tranquilizers, marijuana, nasal sprays, diet pills Volume depletion: Hemorrhage, diuresis, gastrointestinal loss, etc. Tachydysrhythmias or bradydysrhythCardiac dysrhythmias: mias, heart block Secondary hypertension: Renovascular hypertension, pheochromocytoma Circulating vasodilators: Bradykinin (carcinoid), histamine or prostaglandin D2 (mastocytosis) Vasovagal syncope, carotid sinus syncoReflex vasodilatation: pe, Bezold-Jarisch reflex Adrenal hypofunction: Primary adrenal insufficiency, hypoaldosteronism Mitral valve prolapse Pregnancy Prolonged recumbency or weightlessness Fever Varicose veins If no evidence of above, then characterize autonomic failure Secondary autonomic failure Primary autonomic failure Diabetes mellitus Multiple system atrophy (ShyDrager syndrome) Amyloidosis Paraneoplastic (especially Idiopathic orthostatic hypotenlung cancer) sion (Bradbury-Eggleston syndrome) Central nervous system tumor or upper cord lesion Porphyria Selective noradrenergic failure Guillain-Barre syndrome Familial dysautonomia (RileyDay syndrome) Tabes dorsalis Baroreceptor deafferentation Vitamin deficiency (B,, BIP) Heavy metal poisoning Other somatic neuropathies

syndrome) entails autonomic failure in association with central neurologic disorders such as Parkinson’s disease, olivopontocerebellar atrophy, progressive supranuclear palsy, or other extrapyramidal syndromes [7,8]. Idiopathic orthostatic hypotension (progressive autonomic failure, Bradbury-Eggleston syndrome) is a term reserved for patients with autonomic failure in the absence of other neurologic involvement [9]. We have also recently described a young female with unique features of primary autonomic failure who seemed to have a selective failure of noradrenergic neurotransmission [lo]. Finally, orthostatic hypotension can occur in patients with interruptions of the baroreceptor afferent pathways, which may be seen after neck surgery or irradiation with damage to the vagal or glossopharyngeal nerves [ 1 I]. In this latter subgroup, both heart rate and blood pressure tend to rise and fall together in response to alterations in emotional State.

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Measures. Once the diagnosis of chronic orthostatic hypotension is made and underlying causes are dealt with, persistence of otthostatic symptoms necessitates therapy. The goal of management is to minimize symptoms. Therefore, the magnitude of blood pressure fall is not nearly as important as the advent of symptoms. For this reason, we rely heavily on “standing times”, i.e., the length of time a patient can stand motionless without heralding symptoms of orthostatic hypotension. Standing time is a more reliable and reproducible index of disease severity and functional capacity than is upright blood pressure measurement. Sphygmomanometric technique may be inadequate to assess the rapidly changing levels of arterial blood pressure often seen in these patients. When a patient is able to stand for at least five minutes, this limitation may no longer apply. In this circumstance, we do find the upright blood pressure to be helpful. Standing time and blood pressure determinations should be made with careful consideration of prior food and drug ingestion. Patient education is of prime importance in the success of most management programs. Teaching the patient how to maximize functional capacity by simple measures will improve quality of life as well as give a sense of participation in treatment. Clear oral and written explanation of the desired and adverse effects of medication will enhance compliance and minimize risk of side effects and errors in administration. A priority in treating this entity is to optimize circulating blood volume. In the absence of a functioning autonomic nervous system, the blood volume and ‘its distribution between the central and peripheral venous compartments are paramount determinants of blood pressure. Studies have shown a significant reduction in central blood volume in patients with autonomic failure [ 12,131. Most patients also have low total blood volume as well [ 121, but the reduction in central volume is more marked, suggesting a peripheral translocation of intravascular volume [ 131. Pressure measurements have shown central venous pressure, right atrial pressure, and pulmonary wedge pressure in the low-normal range even in the supine position [ 131. Patients with autonomic failure and orthostatic hypotension have inadequate conservation of sodium during low salt intake [14]. This may be due to decreased adrenergic activity in the kidney, since sympathetic nerve stimulation promotes sodium reabsorption [ 151. In addition, renin responses to low salt diet and upright posture are reduced or absent in autonomic failure [ 161. Most of these patients have supine hypertension and virtually all have elevated supine systemic vascular resistance that does not increase with upright posture [ 121. It is probable that this elevated supine pressure also contributes to the

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failure of the kidney to conserve salt and water, perhaps because of excessive circulating atrial natriuretic factor. Thus, at night when supine, these patients diurese inappropriately [17]. This leads to relative hypovolemia and orthostatic hypotension that are worse in the morning and improve during the day [ 181. One way to minimize this effect is to elevate the head of the bed on blocks to approximately 5 to 20 degrees [19,20]. This will attenuate nocturnal diuresis and the notable worsening of symptoms in the morning [17,18]. Head-up tilt at night may also minimize nocturnal shifts of interstitial fluid from the legs into the circulation. More interstitial fluid in the legs, on standing, may exert greater hydrostatic force and oppose the tendency of blood to pool. Head-up tilt also reduces supine hypertension, which is a major risk factor for cardiovascular disease. Blood pressure is highest just after a person goes to bed at night [ 181. Most treatment modalities raise supine as well as upright blood pressure. Thus, head-up tilt can minimize the effect of pressor drugs at night, a time when pressor actions are no longer necessary and may in fact be harmful. Diuretics should be discontinued and salt intake should be liberalized in all patients except those with coexisting congestive heart failure. Slight pedal edema is well tolerated and implies higher intravascular volume as well as increased interstitial hydrostatic pressure in the legs. Other modalities are available to maximize the central blood volume when it is needed most, i.e., in the upright position. Waist-high, custom-fitted elastic support garments exert graded pressure on the legs and increase interstitial hydrostatic pressure [21]. When a person assumes the upright posture, this hydrostatic pressure will tend to keep blood from pooling in the legs. Patients should be cautioned not to wear these stockings at night, since they will increase central blood volume, contribute to diuresis, and decrease interstitial fluid in the legs. It should be noted that stockings are not of much use unless they go at least to the waist. In fact, an abdominal binder in association with elastic stockings is even more useful. This will serve to augment venous return from the splanchnic bed, a major source of venous pooling. Air Force antigravity suits and shock suits have been used in the past with some success but are quite awkward and bring attention to the patient’s problems [20]. Patients should avoid activities that involve straining, such as the lifting of heavy objects. Increased abdominal and/or intrathoracic pressure at these times significantly compromises venous return and can precipitate a hypotensive episode. Coughing and straining at stool or with voiding may be particularly dangerous. Working with one’s arms above shoulder level (e.g., shaving) can lower pressure dramatically. Ambulation or shifting weight from lag to leg as opposed to standing motionless takes advan-

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tage of muscular pumping on the veins. A slightly stooped walking posture may be helpful. Squatting is also a valuable mechanism of increasing venous return, particularly when presyncopal symptoms occur. Patients may hang their lags over the side of the bed prior to standing. This minimizes hemodynamic stress, since assumption of the upright posture is broken down into two movements: (1) assumption of the seated posture and (2) standing from the seated posture. Finally, in an attempt to maintain adequate blood volume, the mineralocorticoid, 9-alpha-fludrocortisone, is used to promote salt and water retention. This drug, when titrated slowly to avoid serous hypokalemia, supine hypertension, and heart failure, is useful in optimizing blood volume [20,22] as well as enhancing the sensitivity of the blood vessels to other endogenous vasopressors such as norepinephrine [23] (see “Drug Therapy” section). The effect of meals on blood pressure in chronic orthostatic hypotension has only recently been recognized [24]. Normally there is a slight tachycardia with no blood pressure decline after eating. However, patients with autonomic insufficiency [24], the elderly [25], and those taking sympatholytic agents [24] may exhibit large postprandial falls in blood pressure. Digestion shifts blood flow to the hepatic and splanchnic beds, and as already noted, these patients are exquisitely sensitive to circulating blood volume changes. In addition, several vasoactive substances such as histamine, bradykinin, and adenosine may be elicited by meals. These substances, circulating systemically, might contribute to the hypotensive response. Patients should avoid excessive activity in the two-hour period after meals, since at these times, especially after breakfast, they are most likely to have symptomatic orthostatic hypotension. Patients should also eat smaller meals to minimize this effect. Adenosine may be partially responsible for splanchnic vasodilation after meals. Simple measures such as a cup of coffee with meals may lessen this hypotensive response [26], perhaps because of the ability of caffeine to block adenosine receptors. Pressor agents should be administered in such a way that peak effects occur in the postprandial period when they are needed most. The depressor effect of meals can also be exploited in these patients. Those who have supine hypertension benefit from a small meal or snack at bedtime in order to lower their blood pressure at night. This is especially important in those who have been receiving pressor agents during the day. Exercise needs careful consideration in these patients. Isometric exercise in normal subjects will raise the blood pressure via sympathetic activation, but can precipitate hypotension in patients with autonomic failure. A graded program of isotonic exercise such as walking may be beneficial. More vigorous exercise like jogging is rarely

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Nonpharmacologic Measures in the Management of Orthostatic Hypotension Increase total blood volume Head-up tilt (nocturnal diuresis) Liberalize salt intake Discontinue diuretics Avoid supine hypertension Head-up tilt Recliner chair during day Alcohol at bedtime Small meal at bedtime Vasodepressor at bedtime Avoid Nasal sprays Diet pills Cold preparations Eye drops Increase central blood volume Head-up tilt Support garments Antigravity/shock suits Squatting Stooped posture Standing in water Beware of Early morning exacerbation Prolonged recumbency Lifting heavy objects Isometric exercise Strenuous exercise Standing motionless Working with arms above shoulder Going up stairs Straining at stool or with voiding Large meals Hot weather Hot baths/showers Fever Coughing spells Hypotensive drugs (see Table I) Hyperventilation

our patients embark on a graded program of swimming for exercise. Exiting the water may, however, pose difficulties. Patients should be aware of other stresses that can worsen orthostatic hypotension. Symptoms tend to worsen in hot weather. This is not so much due to volume loss from sweating as to vasodilatation and increased blood flow to the skin. In addition, fever in autonomic failure may contribute markedly to otthostatic hypotension. Severe exacerbation of hypotension in association with even lowgrade fevers has developed in patients with well-controlled, stable blood pressure. Patients are also especially at risk in the shower or on arising from a hot bath. Patients are cautioned to avoid certain over-thecounter medications such as diet pills containing phenylpropanolamine [29] or nasal sprays containing phenylephrine or oxymetazoline [30]. These agents, when ingested in excess over time, can lead to significant orthostatic hypotension. All prescription medications should be carefully screened for their potential effects on blood pressure. In particular, antihypertensive medicines prescribed for supine hypertension and drugs such as tricyclic antidepressants can be quite troublesome. Alcohol tends to have a marked vasopressor influence in these patients and can worsen symptoms. Most patients learn to avoid alcohol on their own. Again, the use of alcohol can be exploited in order to treat supine hypertension at night. We often advise our patients to have a glass of wine before retiring. Patients are extremely sensitive to vasodilator agents, especially nitrates [31]. Also, beta agonist medications such as those used in asthma treatment may be dangerous to these patients [32]. These patients are hypersensitive to the effects of sympathomimetic amines and have a more exaggerated sensitivity to beta-2 agonist stimulation as opposed to beta-l [32,33]. Thus, beta-agonists may exert a marked vasodepressor effect in these patients. Some mechanical aids may allow patients to carry on activities of daily living more easily. For instance, “stadium chairs” (a cane when folded and a small seat when unfolded) can be used by severely affected patients to negotiate longer distances. Patients may use the cane for support in walking, and when symptoms ensue they unfold the chair and sit until they are ready to walk again. Recliner chairs are used so that patients can rest during the day without lying flat. This is especially important when pressor drugs are administered during the day, conferring added risk for supine hypertension. Nonpharmacologic approaches to treatment are summarized in Table II. Drug Therapy. When the aforementioned measures have been implemented and the patient remains symptomatic, drug therapy can then be instituted. Again the goal is simply to ameliorate symptoms. It is fruitless to try to pharmacologically eliminate all orthostatic blood pres-

level

tolerated because decreases in blood pressure may occur. Climbing stairs is a common hypotensive stimulus. Exercise, even while a patient is recumbent, may cause hypotension [27]. Cardiovascular reflex responses may improve with activity. Periods of inactivity and prolonged bed rest should be avoided, since they will worsen orthostatic intolerance. Prolonged bed rest, even in normal subjects, may cause mild orthostatic hypotension, and even superbly trained athletes such as astronauts experience orthostatic hypotension after the weightlessness of outer space. The ideal exercise for patients with this disorder is swimming. Submerged in water, their tolerance of upright posture is almost unlimited [28]. In this situation, hydrostatic pressure prevents blood pooling in the legs and blood pressure is well maintained. We recommend that

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Figure 2. Blood pressure response to various pressor agents in a patient with autonomic failure. Sodium balance ( 150 meq per day) was maintained in a 64year-old woman with mild autonomic failure who was taking no medications. She was studied on different days at 7 A.M. after an overnight fast. Seated blood pressures were obtained every five minutes by Dinamap recording and averaged for the corresponding 15-minute periods. Systolic (0) and diastolic (0) blood pressures are depicted for 30 minutes before and two and a half to three hours after drug administration. A, caffeine 250 mg; B, phenylpropanolamine 50 mg; C, indomethacin 50 mg; D, yohimbine 5 m7.

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sure decreases, since side effects will ensue. Aggravation of supine hypertension is the major problem encountered in the use of drugs to raise upright blood pressure. In patients with autonomic failure, systemic vascular resistance is increased even in the supine position [ 121. A further elevation in systemic vascular resistance will increase afterload and would reduce cardiac output were it not for concomitant beneficial effects at the level of the venous capacitance system. The probable major deficit in this disorder lies in an inability to increase venous return. Therefore, ideal drug therapy should augment venous return without markedly increasing systemic vascular resistance. In practice, this is very difficult, since drugs that are selectively “venoconstrictor” are not well characterized yet. The drug of choice in this syndrome remains g-alphafludrocortisone (Florinef). It may be especially useful in diabetic autonomic failure [34]. Fludrocortisone increases

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blood volume and sensitivity of blood vessels to pressor stimuli, and often greatly enhances functional capacity [ZO]. Advantages are its almost universal pressor effect, long duration of action, and predictable side affects. Congestive heart failure will limit therapy, but mild ankle edema is well tolerated. The drug dose is begun at 0.1 to 0.2 mg daily and can be titrated as high as 2.0 mg daily, taking care to avoid hypokalemia. Hypervolemia and enhanced peripheral resistance may cause excessive supine hypertension [35] and although this can be minimized, it remains the most common limiting factor in fludrocortisone use. Pressor agents are used to raise standing blood pressure. Since these agents are usually short-acting, their potential efficacy can best be assessed by a single trial dose followed by careful blood pressure and standing time monitoring (Figure 2). Patients most often have low circulating catecholamine levels [4] and “denervation”

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hypersensitivity to sympathomimetic amines [6,32]. Catecholamine receptors are often present in larger numbers [36]. Thus, pressor agents are active at lower doses. This hypersensitivity, however, may put patients at risk for lifethreatening hypertension. Indeed, pressor amines in nasal sprays, ocular preparations [37], diet pills [29], and other over-the-counter preparations may be dangerous even when recommended dosage is not exceeded. However, this hypersensitivity to sympafhomimetic amines can be exploited. Phenylpropanolamine, 25 to 75 mg three times a day, may be useful, but its pressor effect lasts only one to three hours. Nasal sprays containing phenylephrine (an alpha-l agonist) are also pressor but are even more short-lived. We instruct our patients to use these agents prior to especially stressful activities. Midodrine is an investigational alpha agonist with a longer duration of action and has been beneficial in some patients resistant to other therapeutic modalities [38]. Ephedrine’s effect is mild and short-lived and we have not found this agent useful. Since dopamine may be depressor at physiologic levels, the use of the dopamine receptor antagonist, metoclopramide, has been advocated to raise blood pressure [39]. Our success with this agent has been limited. Agents that increase catecholamine release even slightly can be used, since target organs will have exaggerated responses. Tyramine, an indirectly-acting amine, causes release of norepinephrine from storage pools. Tyramine therapy is usually combined with a monoamine oxidase inhibitor such as tranylcypromine or pargyline to prevent norepinephrine breakdown and further increase levels available to act at receptors [40]. Supine hypettension and unpredictability of effect are problems with these agents [41]. Cheddar cheese is an unreliable source of tyramine, since content varies considerably. Amphetamines [42] and methylphenidate [43] also act to increase sympathetic activity and occasionally may be useful. It is instructive to examine the relative roles of the alpha-2 agonist, clonidine, and antagonist, yohimbine, in this disorder. Studies have suggested that postjunctional vascular alpha-2 adrenoreceptors exist and may be more numerous in veins than in arterioles [44]. Since selective venoconstriction would elevate venous return without further increasing the already high systemic vascular resistance, an alpha-2 agonist theoretically would be useful. In normal subjects and mildly affected patients with autonomic failure, the central sympatholytic effect of clonidine predominates and there is a net depressor response. However, little central depressor response is seen in those severely affected patients who have minimal baseline sympathetic tone to be inhibited, and here the peripheral pressor effect predominates. Thus, clonidine is pressor in a small subset of patients with autonomic failure and severe disease [45]. This pressor effect is almost certainly due to alpha-2 stimulation peripherally, since it is not

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blocked by prazosin, an alpha-l antagonist [46]. Unfortunately, clonidine’s usefulness has been limited by its central sedative effects. It also causes a profound hypotensive response in patients with afferent baroreceptor deafferentation and is contraindicated in this entity [45]. In patients with milder disease, the depressor response to clonidine indicates some role for (albeit diminished) sympathetic outflow in maintenance of baseline vascular tone. These patients also exhibit hypersensitivity to sympathomimetic amines. Enhancing sympathetic outflow with yohimbine, a centrally acting alpha-2 antagonist [47], mildly elevates norepinephrine levels, which, in the face of hypersensitivity, may raise blood pressure dramatically [48]. So, paradoxically, both alpha-2 agonist and antagonist agents may work in autonomic failure when patients are carefully selected. Tremulousness, nervousness, and palpitations in addition to unacceptable supine hypertension may be encountered with yohimbine. Nonselective (beta-l plus beta-2) beta blockers can elevate peripheral resistance, presumably by blocking beta-2 vasodilator receptors. As noted, beta-2 hypersensitivity usually exceeds beta-l hypersensitivity and beta-2 agonism is markedly hypotensive [32]. Vasoconstrictor response to tilt may be augmented by beta blockade [49]. Studies with propranolol have shown increased peripheral resistance and attenuation of the blood pressure decline with standing [50,51]. Our experience has been less favorable. Some animal and human studies suggest that beta agonists actually increase venous return in normal subjects and beta blockers may thereby decrease venous return and limit cardiac output [52]. Propranolol may also attenuate vasoconstrictor responses to lower body negative pressure, a stress that mimics standing [53]. Negative inotropic and chronotropic effects also limit usefulness. In the elderly population, who are most susceptible to autonomic failure, side effects of beta blockers are more common and limit effectiveness. Propranolol may also enhance the depressor effect of meals [24]. The use of a beta blocker such as pindolol with partial agonist (intrinsic sympathomimetic) activity has also been advocated [33]. Pindolol may exert positive beta chronotropic, inotropic, and renin-stimulating effects in the setting of low basal sympathetic tone [54]. If beta stimulation improves venous return as suggested, pindolol may indeed be the preferred beta blocker in autonomic failure. Other investigators, however, have found this agent less useful [55]. Beta blockers have occasionally proved to be useful in mitral valve prolapse with orthostatic hypotension. Other pressor agents have been used in this disorder. Dihydroergotamine and other ergot alkaloids are quite popular in Europe and Australia. Dihydroergotamine causes selective venoconstriction and is very effective intravenously [56]. However, its use is limited by low oral bioavailability and doses in excess of 20 to 30 mg daily may be required [57]. lndomethacin may be useful

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[58,59], presumably in part by interfering with vasodilator prostaglandin synthesis. It is more effective than aspirin, ibuprofen, or naproxen. lndomethacin also increases pressor sensitivity to norepinephrine and angiotensin II [60]. Our experience, and that of others, has been less encouraging [60,61], but indomethacin, 50 mg three times a day, may be useful in preventing postprandial hypotension when given with meals [24,6 11. We reserve the use of this agent for those patients in whom a response is documented during an empirical trial of therapy. Headache and gastrointestinal upset can limit effectiveness. Antihistamines are rarely useful in autonomic failure [62], although, of course, they remain the drugs of choice for orthostatic hypotension due to systemic mastocytosis [63]. Vasopressin responses to upright posture are often deficient in autonomic failure [64]. This finding may account for the rarity of plasma hypotonicity in severely affected patients. These patients also exhibit hypersensitivity to exogenous vasopressin just as they do to norepinephrine [65]. Thus, vasopressin has occasionally been found useful. Serum sodium levels must be monitored carefully for hyponatremia during treatment. Levodopa has been given in combination with other agents but aggravates orthostatic hypotension when used alone [66]. We have not found this agent to be useful. We occasionally prescribe a vasodilator such as prazosin at bedtime in those patients receiving particularly high doses of sympathomimetic amines who are at risk for marked supine hypertension. However, prazosin can be dangerous in a patient who has to get up during the night. A novel approach using a pure arteriolar vasodilator such as hydralazine in the treatment regimen has been advocated [67]. Since systemic vascular resistance is already elevated, arteriolar vasodilation may reduce afterload and improve cardiac output in a manner analogous to vasodilator therapy for congestive heart failure. In addition, the absence of appreciable action on the capacitance bed will avoid any deleterious venodilating effects. Hydralazine could have the advantage of opposing supine hypertension caused by other drugs, thereby permitting more aggressive pressor therapy. The general utility of hydralazine in otthostatic hypotension remains to be demonstrated. The administration of 250 mg of caffeine with meals can attenuate by about 50 percent the depressor effect of food, and this is an important therapeutic measure in patients who are particularly symptomatic from postprandial hypotension [26]. Other investigational approaches such as posture-activated norepinephrine pumps [68] and atrial tachypacing [69] appear to offer little benefit to severely affected patients at present.. Atrial tachypacing may be useful in the patient with hypotension attended by subnormal heart rates. Atrial tachypacing probably does not work as well

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Drugs Used in Management of Orthostatic

111

Hypotension Mineralocorticoids: Pressor amines:

Increase

Other

9-Alpha-fludrocortisone Ephedrine Phenylephrine Phenylpropanolamine Midodrine Clonidine (in selected severe cases) Methylphenidate Amphetamines Tyramine plus monoamine oxidase inhibitor Yohimbine Caffeine indomethacin Beta blockers Vasopressin Metoclopramide Ergot alkaloids Levodopa Antihistamines

catecholamines:

pressor

agents:

as expected because it does nothing to enhance the inadequate venous return that is the major determinant of the orthostatic hypotension. Drugs used in management are summarized in Table III. SPECIAL

CONSIDERATIONS

There are some settings in which autonomic failure deserves special consideration. Hyperventilation with attendant hypocarbia slightly lowers blood pressure in normal subjects, but in autonomic failure can cause substantial decreases [3 1,701. However, breathing through a tube to extend dead space and raise carbon dioxide tension leads to increases in blood pressure [31]. Thus, the role of blood pH or carbon dioxide tension may be important. Patients with orthostatic hypotension and autonomic failure present special difficulties during anesthesia [7 11. These patients have attenuated cardiovascular reflexes and are unable to tolerate hemodynamic stress in normal fashion. Because of the possibility of blood gas changes and their effects on blood pressure, mechanical ventilation must be carefully controlled. Fluid balance is more difficult to maintain because of abnormal salt handling and, because of the enhanced sensitivity to volume changes, plays a greater role in blood pressure control. Monitoring of central volume status is recommended. Volume sensitivity can be exploited by using positional changes (Trendelenburg and reverse Trendelenburg) to control blood pressure. The preoperative pharmacologic regimen may affect cardiovascular responses during surgery. Prior to surgery, it is also useful to assess those agents that might be required intraoperatively. There will likely be heightened responsiveness to pressor agents.

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TABLE IV

Guidelines

Patient education ple measures. Head-up

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or phenylephrine or stressful

naactivi-

Chronic orthostatic hypotension can be due to a variety of causes. Many of these are reversible and can be addressed directly. Many patients will respond to simple measures or fludrocortisone alone. It is patients with moderate to severe autonomic failure who present the greatest problems in management on a long-term basis. Attention to the pathophysiologic processes underlying the orthostatic hypotension helps guide therapy (Table IV). Much of the management is “common sense” and may not always include drug use. In the more severely affected patients, rational drug use requires that therapeutic trials of individual medications be carried out with careful blood pressure and standing time monitoring. The major concern with drug therapy is exacerbation of supine hypertension. This is important, since hypertension is responsible for much of the morbidity and mortality in these patients whereas orthostatic hypotension only debilitates. Although no single treatment is very effective (as is readily evident from the profusion of available treatments), most of these patients can be helped toward resumption of a normal life.

garment

Fludrocortisone Caffeine with meals Indomethacin, sal spray ties

phenylpropanolamine, administered before

meals

Beta blockers Methylphenidate, amine oxidase Investigational gotamine,

amphetamines, inhibition

agents-yohimbine, clonidine

or tyramine midodrine,

plus

mono-

dihydroer-

* This table suggests a general guideline for the order of implementation of therapeutic measures predominantly based on risk/ benefit analysis. Of course, every management program should be individualized and the effectiveness of all measures should be established and reassessed periodically.

Another special situation concerns patients with autonomic failure and otthostatic hypotension and chest pain. In this case, the chest pain may be associated with inadequate oxygen delivery due to hypotension in the upright position. Pain can worsen with nitroglycerin (which venodilates and aggravates hypotension), but can improve on resumption of the supine position or, paradoxically, after vasopressor agents such as phenylephrine.

ACKNOWLEDGMENT

We are grateful for the secretarial assistance of Ms. Susan Britt and Ms. Dorothea Boemer in the preparation of this manuscript. Dawn Kincaid, R.N., and Cheryl Parrish, R.N., provided valuable advice. Mr. Bolton Smith, our bibliographer, is especially thanked.

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