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Treatment of orthostatic and postprandial hypotension

Treatment of orthostatic and postprandial hypotension
Jose-Alberto Palma, MD, PhD
Horacio Kaufmann, MD
Section Editors:
Michael J Aminoff, MD, DSc
Peter Kowey, MD, FACC, FAHA, FHRS
Deputy Editor:
Richard P Goddeau, Jr, DO, FAHA
Literature review current through: Dec 2022. | This topic last updated: Sep 19, 2022.

INTRODUCTION — Orthostatic hypotension (OH) describes a reduction in systolic blood pressure of at least 20 mmHg or a reduction in diastolic blood pressure of at least 10 mmHg, usually within the first three minutes of standing or head-up tilt on a tilt table. Postprandial hypotension (PH) is a related condition encountered when this reduction in blood pressure occurs within 15 to 120 minutes after eating.

OH that occurs when the baroreflex is impaired is called neurogenic OH. OH may also occur when intravascular volume is markedly depleted. The patient with acute OH due to volume depletion should be treated with volume replacement.

This topic will review the treatment of symptoms related to chronic OH and PH due to neurogenic causes. The causes and evaluation of OH are discussed separately. Postural tachycardia syndrome (POTS), a related syndrome, is also discussed separately.

(See "Mechanisms, causes, and evaluation of orthostatic hypotension".)

(See "Postural tachycardia syndrome".)

TREATMENT GOALS — The goal of treatment for patients with neurogenic OH is to attenuate symptom burden and the risk of falls and reduce target organ damage and mortality. (See "Mechanisms, causes, and evaluation of orthostatic hypotension", section on 'Complications'.)

Treatment is geared to prevent or alleviate symptoms and their impact on daily function rather than a target blood pressure (algorithm 1).

We start with nonpharmacologic measures for asymptomatic patients and those with mild OH symptoms. Patients who are asymptomatic may require education and nonpharmacologic measures only. It should be noted that patients with cognitive impairment and some patients with mild symptoms might not recognize or report symptoms of OH. (See 'Nonpharmacologic measures' below.)

Medications are added for those who do not respond to nonpharmacologic measures or have more severe symptoms. (See 'Pharmacotherapy' below.)

We titrate the use of medications to provide symptom relief while minimizing the associated risk of their adverse effects. Supine hypertension is among the most frequent adverse effect occurring in approximately 50 percent of patients with OH. (See 'Supine hypertension' below.)

NONPHARMACOLOGIC MEASURES — Nonpharmacologic measures are first-line therapy for neurogenic OH (algorithm 1) [1,2]. Nonpharmacologic therapy may provide effective symptom relief and avoids adverse effects associated with medications [1]. These measures include the removal of potential offending medications, an increase in salt and water intake, lifestyle modification, dietary interventions, and the use of compression stockings and abdominal binders [1].

These approaches are based largely on clinical experience as studies to evaluate efficacy, particularly long-term, are limited. The following measures should be implemented, when possible (table 1).

Discontinue exacerbating medications — Recognition and discontinuation of medications that cause OH are the first steps. When the potentially offending medication cannot be discontinued or for patients with mild symptoms, reducing the dose may be sufficient. Several classes of medications may be implicated, including beta-adrenergic antagonists, alpha-adrenergic agonists, and tricyclic antidepressants (table 2).

Increase salt and water intake — Patients with OH should increase dietary salt and water intake to increase intravascular volume [2]. Rapid intake of water induces an osmopressor reflex in the hour after ingestion due to the reduction of osmolarity in the portal vein.

In addition to drinking water during meals and before exercise, we advise keeping a pitcher of water at the bedside and drinking rapidly before getting out of bed in the morning [3]. Ingesting 500 mL of water upon awakening and reaching 1.5 to 3 L per day is a reasonable target [4-6].

High sodium-containing foods or salt tablets also may be beneficial. While the optimal dose will vary among patients, we typically use a target dose of 6 to 10 g/day of sodium or a target urinary sodium level of 150 to 200 mEq [4-7].

Urinary sodium and water excretion may be increased in patients with OH due to reduced sympathetic outflow to the kidney as well as pressure natriuresis caused by supine hypertension. The resulting reduction in central blood volume can be attenuated by increasing sodium and water intake [8-10]. In one study, water drinking prior to supine exercise improved orthostatic tolerance post-exercise [10].

Modify daily activities and lifestyle — We advise lifestyle changes in patients with OH to help alleviate symptoms. Throughout the day, patients are subject to various orthostatic demands that may be managed by simple countermeasures. As a result, emphasizing practical management principles is paramount. These measures include the following [3]:

Patients should arise slowly, in stages, from supine to seated to standing. This maneuver is most important in the morning, when orthostatic tolerance is lowest.

We caution patients to avoid Valsalva-like maneuvers (that may acutely increase intrathoracic pressure) such as frequent, violent coughing or straining with a closed glottis to defecate. Constipation may need to be treated with stool softeners and diet changes, and cough suppressants may be indicated.

Patients should limit walking in very hot or humid weather, avoid overheating, and minimize entering hot showers and saunas, as exposure to warm temperatures causes skin vasodilation to reduce venous return and worsen OH.

We teach patients to tense the legs and contract abdominal and buttock muscles while actively standing to alleviate symptoms. Crossing the legs while standing is also useful but may be difficult for older adult patients and those with movement disorders. In one series of seven patients with autonomic neuropathy, this procedure raised cardiac output by 16 percent and systemic blood pressure by 13 percent [11,12]. Without leg crossing, five of the patients reported dizziness within 10 minutes of standing up; leg crossing allowed all to stand for 10 minutes or more [11]. Another study also found that tensing lower body muscles in the legs, buttocks, and abdomen before arising from a squatting position blunted the hypotensive response and clinical symptoms in a series of 13 patients with OH [12,13].

For patients who sleep supine, we advise raising the head of the bed 30 to 45 degrees. Patients may prefer a wedge pillow or an electric adjustable bed or mattress. This lowers blood pressure and decreases renal perfusion, thereby decreasing nocturnal diuresis, which can be pronounced in these patients. These changes relieve OH by expanding extracellular fluid volume and may reduce end-organ damage by reducing supine hypertension. (See 'Supine hypertension' below.)

Only small case series and clinical experience support the efficacy of this intervention, but its effect in patients with autonomic failure can be dramatic [14]. In one series of nine older inpatients with OH, 6 inches of head-of-bed elevation during sleep was associated with higher blood pressure and improved mobility after one week of treatment [15]. A follow-up study by the same investigators found that this same intervention in 100 community-dwelling patients had no effect on symptoms or hemodynamic parameters after six weeks [16].

We encourage patients to engage in an exercise program as cardiovascular deconditioning worsens OH. As an example, a small study of five older adult patients with symptoms at baseline during tilt-table testing showed that an exercise regimen consisting of walking or climbing stairs for 30 to 45 minutes per day three times per week for six months resulted in symptom resolution during a repeat tilt-table test [17].

Exercise in a recumbent or seated position (eg, using a stationary bicycle or a rowing machine) is better tolerated than in the standing position. Exercise in a swimming pool is encouraged, as the hydrostatic pressure of water counteracts the gravity-induced fall in blood pressure and improves orthostatic tolerance. Of note, patients must be very careful when getting out of the swimming pool, as the sudden decrease of hydrostatic pressure when exiting the pool can trigger venous pooling and worsen symptoms of OH.

Modifying meals can alleviate symptoms for patients with OH susceptible to falls in blood pressure after meals [18,19]. (See 'Postprandial hypotension' below.)

Use compression stockings and abdominal binders

The use of custom-fitted elastic compression stockings permits the application of graded pressure to the lower extremities and lower abdomen, thereby minimizing peripheral blood pooling. It is essential that such stockings extend to the waist since most peripheral pooling occurs in the splanchnic circulation.

These stockings are often poorly tolerated by many patients, particularly those with painful peripheral neuropathies or motor dysfunction and those living in hot climates. They may be difficult to put on and take off. Compression stockings may be contraindicated for patients with evidence of leg ischemia due to peripheral vascular disease or with extensive skin lesions on their lower extremities. (See "Compression therapy for the treatment of chronic venous insufficiency", section on 'Contraindications'.)

One report of 10 patients found that compression stockings for patients with OH and a history of falls reduced the average degree of orthostasis in the group as a whole and abolished orthostatic dizziness in seven [20]. In a crossover study of 21 patients, use of compression bandages was associated with reduced orthostatic blood pressure decrease and symptoms compared with control [21].

Abdominal binders ameliorate the orthostatic blood pressure fall for some patients with OH and may be better tolerated than compression stockings of the legs and abdomen [1,22,23]. In a crossover study of 15 patients with Parkinson disease and OH, the use of an elastic abdominal binder reduced blood pressure fall on head-up tilt and, in a four-week open-label follow-up, improved symptoms of OH as assessed by questionnaire [24]. While generally better tolerated than elastic compression stockings, compliance with abdominal binders may be a problem for some patients owing to discomfort.

PHARMACOTHERAPY — Nonpharmacologic measures are often insufficient to prevent symptoms and complications of OH, particularly in patients with moderate to severe symptoms. Such patients often need pharmacologic intervention.

Two drugs are approved by the US Food and Drug Administration (FDA) for the treatment of symptomatic neurogenic OH (nOH): the alpha-adrenergic agonist midodrine and the norepinephrine precursor droxidopa [25]. Fludrocortisone, a synthetic mineralocorticoid, which is not specifically approved by the FDA for the treatment of nOH, is widely used but can lead to sustained hypertension in the supine position and other adverse effects. Numerous other agents from diverse pharmacologic groups have been tested in small trials, but there is limited evidence to support their use [2,26,27].

Stepwise approach and monitoring — Nonpharmacologic measures should be maximized before starting and must be continued after initiating pharmacotherapy.

Pharmacologic approaches are based on two complementary strategies: expanding intravascular volume (typically with fludrocortisone) and increasing peripheral vascular resistance with other medications (table 3).

The selection of one strategy, the other, or both depends on the specific features and needs of each patient as well as the degree of peripheral sympathetic denervation, as determined by plasma norepinephrine levels (algorithm 1) [28].

For patients with persistent OH symptoms in whom nonpharmacologic measures such as volume augmentation with salt and water intake are insufficient to replenish intravascular volume, we suggest a regimen that starts with fludrocortisone to augment volume and provide symptom relief. This approach may not be sufficient for some patients and is not ideal for those whose symptoms did not improve temporarily with volume augmentation.

For patients with symptoms of OH unresponsive to nonpharmacologic measures such as volume augmentation, we suggest short-acting vasoconstrictor agent (such as a sympathomimetic or atomoxetine) as initial pharmacotherapy after nonpharmacologic measures have been implemented. Measuring plasma norepinephrine levels can aid in the selection of the vasoconstrictor agents. We typically use a sympathomimetic agent (eg, midodrine or droxidopa) for patients with a supine norepinephrine level <220 pg/mL [28], and atomoxetine, a norepinephrine transporter (NET) inhibitor, for other patients [29]. (See "Mechanisms, causes, and evaluation of orthostatic hypotension", section on 'Additional testing'.)

The therapeutic goal is to ameliorate symptoms while avoiding adverse effects. It is important to titrate therapy according to symptoms rather than blood pressure values.

Patients taking medications for OH should be taught how to measure their blood pressure and should provide to the clinician, for monitoring, a series of blood pressure recordings taken over several days, including when supine, sitting, and standing upon awakening; before and one hour after lunch; and before retiring to bed [30]. These home readings are useful for safety (supine hypertension) and efficacy monitoring. The use of ambulatory blood pressure monitoring can assist to personalize pharmacologic treatment [31].

For the rare patient with OH and severe anemia who has low serum erythropoietin concentrations, a trial of erythropoietin should be offered as a first line of treatment. (See 'Erythropoietin' below and "Anemia of chronic disease/anemia of inflammation", section on 'ESAs'.)

Initial therapy

Fludrocortisone — For patients with OH symptoms that improve modestly or temporarily with nonpharmacologic measures to replete intravascular volume such as increased salt and water intake, fludrocortisone may provide symptom relief. Such patients are likely to have persistent volume depletion.

Fludrocortisone is started at a dose of 0.05 mg per day, administered in the morning. If needed, it can eventually be increased up to 0.2 mg per day; little benefit is obtained by further dose increases, but the risk of adverse effects increases significantly. Fludrocortisone requires at least five to seven days of treatment to exert significant clinical effect. Increments should not occur more rapidly than weekly.

Short-term adverse effects with fludrocortisone are frequent and include hypokalemia, ankle edema, and supine hypertension [32]. While fludrocortisone is well tolerated by most patients with chronic autonomic failure, many patients with OH discontinue the drug due to adverse effects. In one study of 64 patients with OH, one-third stopped taking fludrocortisone within six months due primarily to worsening supine hypertension, edema, and heart failure [33].

The symptomatic benefits of fludrocortisone must be individually weighted with its long-term adverse effects. Generally, we advise against long-term treatment with fludrocortisone for most patients. A possible exception could be patients with OH and short life expectancy (eg, multiple system atrophy) in whom the symptomatic benefit outweighs the risk of long-term adverse effects.

Patients receiving fludrocortisone are advised to eat potassium-rich foods or take potassium supplements (potassium chloride 20 mEq/day) to reduce the risk of hypokalemia.

Dependent edema may be managed with compression stockings when mild but may be worsened in many older patients with autonomic dysfunction who have concurrent conditions that promote edema.

Supine hypertension is discussed in greater detail separately. (See 'Supine hypertension' below.)

Long-term use of fludrocortisone exacerbates hypertension and organ damage, including left ventricular hypertrophy, congestive heart failure, and renal failure and is associated with a higher risk of all-cause hospitalization in patients with OH [34].

Fludrocortisone (9-alpha-fluorohydrocortisone) is a synthetic mineralocorticoid that increases renal sodium and water reabsorption, therefore expanding intravascular volume and increasing blood pressure in all positions. After a few weeks of treatment with fludrocortisone, however, there is an "escape phenomenon" [35], whereby blood volume returns to pretreatment levels but a pressor effect persists, presumably due to increased peripheral vascular resistance [32], which may drive long-term adverse effects. Fludrocortisone also enhances the pressor effect of sympathomimetic agents. A systematic review of 13 studies including 513 patients with OH found only very low certainty evidence that fludrocortisone improves orthostatic symptoms [36]. The strength of these conclusions is limited by the small size of studies, short-term follow up, risk of bias, and heterogeneity among study populations.

Sympathomimetic agents — For patients with OH symptoms that do not improve with nonpharmacologic measures to replete intravascular volume such as increased salt and water intake and who have a serum norepinephrine level <220 pg/mL, we use a sympathomimetic agent as initial pharmacotherapy. Two sympathomimetic pressor agents are approved by the FDA for the treatment of nOH: the alpha-1-adrenergic agonist midodrine and the norepinephrine precursor droxidopa.

No direct comparisons have been performed between midodrine and droxidopa. The choice of either agent is based on the clinician experience, patient preference, and the adverse effect profile.

Other direct and indirect sympathomimetic agents, including ephedrine and pseudoephedrine as well as methylphenidate and dextroamphetamine sulphate [37-39], are no longer used in the treatment of nOH because of lack of efficacy or intolerable central nervous system adverse effects.

Midodrine — Midodrine should be titrated from 2.5 to 10 mg two to three times a day, owing to variable patient sensitivity to this agent. The maximum dose should not exceed 40 mg/day. Midodrine exerts an initial symptomatic benefit in most patients with OH, although tachyphylaxis may occur. Patients should not take midodrine within three to four hours of bedtime to limit supine hypertension. (See 'Supine hypertension' below.)

Midodrine should not be used for patients with severe heart disease, uncontrolled supine hypertension, or urinary retention. Supine hypertension occurs because of baroreceptor denervation (even in untreated patients with autonomic failure) and as an adverse effect of antihypotensive treatment. Other potential adverse effects include pilomotor reactions (goose flesh), pruritus, gastrointestinal complaints, and urinary retention [40]. Midodrine has no direct effect on heart rate as it does not stimulate cardiac beta-adrenergic receptors.

Midodrine, an oral prodrug, is activated to desglymidodrine, the active alpha agonist. It is rapidly absorbed from the gastrointestinal tract and reaches a peak plasma concentration in 20 to 40 minutes; its plasma half-life is 30 minutes. It does not cross the blood-brain barrier and causes both arterial and venous constriction. Systematic reviews concluded that the available data warranted only low confidence that midodrine is effective for OH [40,41]. However, the reviews were flawed by the inclusion of trials in patients with different disorders and endpoints. In addition, several well-designed double-blind placebo-controlled studies, some performed subsequent to this review, confirmed the efficacy of midodrine to increase standing blood pressure and improve orthostatic tolerance in patients with nOH [40,42-45].

Droxidopa — Droxidopa is started at 100 mg three times daily. The target dose is from 100 to 600 mg up to three times a day, depending on individual circumstances. For example, for a patient with a movement disorder and OH who is active for only a few hours in the morning (eg, showering, preparing breakfast), it is reasonable to use a single morning droxidopa dose and skip the afternoon and evening doses. Other patients with different needs may receive droxidopa only twice daily or take a higher dose in the morning with lower doses in the afternoon and evening. Supervised titration guided by symptom relief and blood pressure response is used to identify the optimal dose for each patient.

Droxidopa may be less effective in patients with nOH and Parkinsonism receiving high doses of carbidopa (higher than 200 mg/day) as carbidopa blocks the conversion of droxidopa to norepinephrine.

The most common adverse effects of droxidopa are supine hypertension, headache, and nausea. Patients should not take droxidopa within three to four hours of bedtime to limit supine hypertension. The risk of supine hypertension may be lower with droxidopa than midodrine [46]. (See 'Supine hypertension' below.)

L-dihydroxyphenylserine (DOPS; droxidopa) is an oral synthetic amino acid, identical to levodopa but with an added hydroxyl group. After oral administration, droxidopa is decarboxylated to norepinephrine, the naturally occurring sympathetic neurotransmitter. Patients with nOH retain the ability to convert droxidopa into norepinephrine and thereby increase their blood pressure.

The short-term efficacy of droxidopa was evaluated in three clinical trials, involving 460 patients with nOH [25,47-51]. Patients receiving droxidopa reported reduced burden of symptoms, improved performance with activities of daily living, and increased upright systolic blood pressure compared with patients who received placebo [52,53]. Fewer falls, improved standing blood pressure, and reduced symptoms were sustained for patients taking droxidopa at 6 to 12 months in open-label cohort studies [54,55]. Since the conversion of droxidopa to norepinephrine bypasses the dopamine beta-hydroxylation step of catecholamine synthesis, droxidopa is the ideal therapeutic agent for patients with dopamine beta-hydroxylase deficiency, a rare hereditary disorder; such individuals are unable to synthesize norepinephrine and epinephrine in the central and peripheral nervous system. Droxidopa also showed benefit in patients with familial amyloid polyneuropathy [47,56].

NET inhibitors — For patients with OH symptoms that do not improve with nonpharmacologic measures to replete intravascular volume such as increased salt and water intake and who have a serum norepinephrine level >220 pg/mL, we start with atomoxetine, a norepinephrine transporter (NET) inhibitor, as initial pharmacotherapy. In our experience, atomoxetine is safe, well tolerated, and effective for patients with OH and normal or elevated norepinephrine levels.

Atomoxetine is a short-acting NET inhibitor that increases standing blood pressure and reduces the burden of symptoms for patients with nOH [57-59]. The initial dose is typically 10 mg two times a day, which can be increased to 18 mg two times a day, depending on symptom relief and blood pressure response.

NET inhibition enhances vasoconstriction at the sympathetic neurovascular junction and vasodilation at alpha-2-receptors in the central nervous system. For patients with OH and central autonomic dysfunction (eg, multiple system atrophy), however, only peripheral vasoconstriction is apparent, making NET inhibitors particularly appealing for these patients. The higher the plasma norepinephrine level, the greater the pressor effect and expected symptomatic improvement [29].

Second-line combination therapy — For patients with a suboptimal response to initial monotherapy, we typically add a medication that may exert a synergistic benefit. As an example, a sympathomimetic agent may be used in combination with fludrocortisone or alone as first pharmacotherapy for those unable or unwilling to tolerate fludrocortisone adverse effects. Combining fludrocortisone with an alpha agonist can have synergistic effects and allow for a lower dose of both agents [42,43]. Although no controlled studies have been performed, concomitant use of droxidopa with norepinephrine reuptake inhibitors (eg, atomoxetine, venlafaxine) or with midodrine enhances the pressor effect. Caution is advised with drug combinations as supine blood pressure may increase markedly.

Adjunctive or alternative therapeutic options — For patients with persisting symptoms despite trials with initial mono- or combination therapy, substitution or replacement with other less well-studied medications may be helpful. These include pyridostigmine, erythropoietin, and nonsteroidal antiinflammatory drugs (NSAIDs). Evidence of their efficacy is limited, and use is determined by the clinician experience, patient preference, and adverse effect profile.

Pyridostigmine — Pyridostigmine, a cholinesterase inhibitor, enhances cholinergic neurotransmission in sympathetic and parasympathetic ganglia. A randomized crossover study showed that pyridostigmine was associated with an increase in systolic blood pressure, on average, by only 4 mmHg [60]. The combination of 5 mg midodrine with 60 mg pyridostigmine was slightly more effective than pyridostigmine alone. Similarly, combining pyridostigmine with atomoxetine appears to have a synergistic effect to increase blood pressure and improve orthostatic tolerance [61].

Erythropoietin — Recombinant human erythropoietin increases standing blood pressure and improves orthostatic tolerance for patients with the anemia that often occurs with autonomic failure [62,63]. A trial of erythropoietin should be used as a first line of treatment for all patients with OH and anemia who have low serum erythropoietin concentrations.

Recombinant human erythropoietin, epoetin alpha, is administered subcutaneously or intravenously at doses between 25 and 75 units/kg three times a week until a hematocrit that approaches normal is attained. Lower maintenance doses (approximately 25 units/kg three times a week) may subsequently be used. Iron supplementation is usually required, particularly during the period when the hematocrit is increasing. (See "Anemia of chronic disease/anemia of inflammation", section on 'ESAs'.)

In one series of eight patients, erythropoietin increased the mean hematocrit from 34 to 45 percent and the standing blood pressure from 81/46 to 100/63 [62]. Orthostatic dizziness improved in six patients; three developed supine hypertension. The elevation in blood pressure may be mediated by increases in red cell mass and central blood volume and by direct or indirect neurohumoral effects on the vascular wall. (See "Hypertension associated with erythropoiesis-stimulating agents (ESAs) in patients with chronic kidney disease".)

Nonsteroidal antiinflammatory drugs — NSAIDs are rarely effective as monotherapy, but very limited evidence suggests that they may be useful adjunctive agents for some patients treated with fludrocortisone or a sympathomimetic agent [64].

EXPERIMENTAL OPTIONS — In a minority of patients, nonpharmacologic measures and conventional pharmacotherapies may be ineffective, and experimental therapies might be considered.

Medications of limited or uncertain benefit — Several agents have been reported to improve symptoms of OH, including vasopressin analogues, yohimbine, caffeine, and others. Data on the safety and efficacy of agents are limited, based on case reports and small series. Patients should be carefully monitored for adverse effects.

Beta-blockers and clonidine are not recommended due to their hypotensive effects.

Vasopressin analogues – Vasopressin analogues have a limited role in OH. Both V1 and V2 receptor agonists have been used. Their mechanism of action may be enhanced by supersensitivity to vasopressin among patients with autonomic failure because of reduced postural release of this hormone. V1 and V2 receptor agonists have different modes of action.

The synthetic vasopressin analogue desmopressin acts on the V2 receptors in the collecting tubules but has no V1 receptor vasoconstricting potential. Desmopressin can be taken via the nasal or oral route. In a three-day trial, desmopressin prevented nocturia and overnight weight loss and reduced the morning postural fall in blood pressure in five patients with autonomic failure [65]. Careful and continued monitoring of serum sodium concentration is required before and after initiating therapy. If hyponatremia develops, treatment with desmopressin should be stopped.

The V1 receptor agonists, such as lysine-vasopressin nasal spray and intramuscular triglycyl-lysine vasopressin, may increase blood pressure and peripheral vascular resistance due to a direct vasopressor effect, thereby improving symptoms of OH [66]. No controlled clinical trial has been conducted, and therefore the use of V1 receptor agonists cannot be recommended.

Yohimbine – Yohimbine is a centrally active, selective alpha-2-adrenergic antagonist that increases sympathetic nervous system efferent output by blocking central and/or presynaptic alpha-2-adrenergic receptors (which are inhibitory). In subjects with residual sympathetic nervous system outflow, yohimbine (8 mg three times daily) produced a modest pressor effect [67]. Adverse effects included anxiety, tremor, palpitations, diarrhea, and supine hypertension. Yohimbine has limited availability in the United States.

In a single-blind randomized crossover treatment trial in 31 patients with severe autonomic failure, a single dose of yohimbine (5.4 mg) was associated with an average 11 mmHg improvement in standing diastolic blood pressure compared with placebo-treated patients [68]. Patients also reported an improvement in presyncopal symptoms.

Caffeine – Caffeine has a well-established pressor effect that is in part due to blockade of vasodilating adenosine receptors. Caffeine improves OH and may attenuate postprandial hypotension in patients with autonomic failure. Typical doses are 100 to 250 mg three times a day with meals, either as tablets or caffeinated beverages (one cup of coffee and tea contains approximately 85 and 50 mg of caffeine, respectively) [69]. Caffeine may exacerbate an existing tremor, however. Because of the diuretic effect of caffeine, care should be taken to replenish fluids and avoid dehydration.

DihydroergotamineDihydroergotamine, an ergot alkaloid that interacts with alpha-adrenergic receptors, has a selective venoconstrictor effect. As a result, it may increase venous return in patients with OH without producing a significant increase in peripheral vascular resistance. Although dihydroergotamine is an effective pressor intravenously and intramuscularly, low oral bioavailability results in an inconsistent effect when it is taken orally [70].

Ergotamine-caffeine (1 mg/100 mg) combination is available in tablet form for the treatment of migraine and may be tried as occasional symptomatic treatment or up to twice-daily dosing for patients with OH [4]. No controlled trials support their efficacy.

Dopamine antagonists – The dopamine antagonists, metoclopramide and domperidone (which is not approved by the FDA), may be effective in chronic OH [71]. These agents appear to inhibit the vasodilating and natriuretic effect of dopamine or increase noradrenaline release by blocking prejunctional inhibitory dopamine receptors. They should not be used in patients with Parkinsonism. The risk of tardive dyskinesia and other extrapyramidal effects limits their long-term use.

Monoamine oxidase inhibitors – Combination therapy consisting of tyramine and a monoamine oxidase inhibitor was designed to promote release of norepinephrine from neuronal storage and prevent synaptic breakdown. Initial reports were optimistic; however, this regimen can cause severe supine hypertension, an unpredictable response, and, in some cases, may fail to abolish orthostatic symptoms [72].

Ambulatory norepinephrine infusion – For selected patients with refractory OH due to primary autonomic failure, ambulatory, patient-controlled infusion of norepinephrine may be an effective therapy [73]. In one series of six patients, four had a continued benefit from this therapy, without adverse effects, for up to 19 months [74].

Experimental surgical therapies — Novel interventions for refractory symptoms are under investigation. In an unblinded case report, a thoracic spinal cord stimulation device combined with accelerometers to detect changes in body position was used successfully to increase blood pressure when standing in a patient with severe neurogenic OH due to multisystem atrophy [75]. Blood pressure improvement has also been reported in some patients with OH due to spinal cord injury using epidural spinal stimulation [76-78]. Additional data are warranted to assess the safety, tolerability, and efficacy of these invasive experimental procedures and to determine which patients might benefit most.

SUPINE HYPERTENSION — Supine hypertension is described by a systolic blood pressure of at least 140 mmHg or a diastolic blood pressure of at least 90 mmHg after at least five minutes in the supine resting position. Supine hypertension is a common treatment-limiting complication of OH and may require specific interventions [79].

The prevalence of neurogenic supine hypertension is 30 to 50 percent in Parkinson disease, 40 percent in multiple system atrophy, and 50 to 70 percent in pure autonomic failure. Supine hypertension in patients with chronic autonomic failure can result in end-organ damage [80,81], higher incidence of cardiovascular events, and shorter survival [82]. The blood pressure threshold that requires treatment and the target to prevent organ damage in this setting is uncertain.

Treatment of supine hypertension focuses on reducing blood pressure to lower the risk of target organ damage without worsening hypotension. Achieving this goal is challenging, and no long-term treatment approach to supine hypertension has been systematically evaluated. Several options may be useful to address supine hypertension in patients with neurogenic OH [83]:

Initial therapy includes nonpharmacologic measures:

Patients should avoid lying down during the day, especially after taking pressor agents, and, if tired, should rest in a seated position.

A carbohydrate-rich snack or an alcoholic drink before bedtime lowers blood pressure. The application of an abdominal heating pad to lower blood pressure by inducing splanchnic vasodilation may be helpful [84].

Lowering the dose of medications for OH and avoiding administration within a few hours of bedtime is advised [3].

Patients should sleep in a semi-sitting position with the head of the bed raised to at least 30 to 45 degrees.

For persistent supine hypertension, medications may be necessary:

A transdermal nitroglycerin patch (0.025 to 0.1 mg/hour) may be used at night and removed in the morning prior to the assumption of an upright position [85,86].

Other short-acting antihypertensive agents (eg, captopril, hydralazine) may also be tried [4].

However, significant hypotension may occur in some patients; thus, the dose must be individually titrated and tailored. To avoid syncope and dangerous falls, patients should be cautioned to be extremely careful if they must arise at night, since orthostatic symptoms will be exacerbated.

POSTPRANDIAL HYPOTENSION — Postprandial hypotension (PH) is defined as a fall of at least 20 mmHg in systolic blood pressure within two hours of eating. Both OH and PH are due to impaired baroreflex-mediated vasoconstriction. Hypotension after meals regularly occurs in patients with OH and, for some, may be the initial manifestation. In cases of isolated PH, there is defective splanchnic vasoconstriction, although additional mechanisms such as insulin- and gastrointestinal peptides-mediated vasodilation might also be involved.

As with OH, PH is common in older patients and in patients with neurologic disorders [87]. (See "Mechanisms, causes, and evaluation of orthostatic hypotension", section on 'Postprandial hypotension'.)

The optimal regimen to manage symptomatic PH has not been defined. The same principles noted for OH (such as avoidance of volume depletion and certain drugs) should also be applied to patients with postprandial symptoms. As examples, among 20 patients with PH and heart failure but preserved left ventricular systolic function, the successful withdrawal of furosemide in 13 significantly lessened the maximum fall in both the systolic (-25 to -11 mmHg; p <0.001) and diastolic blood pressures (-18 to -9 mmHg; p = 0.01) [88]. Among 11 patients with severe OH who drank 480 mL of water in less than five minutes, baseline blood pressure increased from 83±6/53±3.4 mmHg to 114±30/66±18 mmHg 35 minutes later [8]. After a meal, blood pressure declined less in patients who drank water during the meal than in patients who did not.

Modification of meals may be helpful in selected patients [1,18]:

Avoiding large meals

Ingesting meals low in carbohydrates

Avoiding alcohol intake

Drinking water with meals

Avoiding activities or sudden standing immediately after eating

Lying semirecumbent for 90 minutes after meals may be necessary for some patients. Patients should try to walk in between meals.

Several medications have been shown to improve blood pressure for patients with PH, but the effect on symptoms has not been adequately evaluated [89]. Options include:

Acarbose, an alpha-glucosidase inhibitor and oral hypoglycemic agent, was found to attenuate PH in a small trial of patients with autonomic failure [90].

Somatostatin and somatostatin analogues such as octreotide attenuate the pancreatic and gastrointestinal hormone response to food ingestion by inhibiting the release of vasoactive gastrointestinal peptides. They also enhance cardiac output and increase forearm and splanchnic vascular resistance thereby preventing pooling of blood in the gut [18,91]. The net effect is attenuation of the fall in the postprandial blood pressure in patients with autonomic failure [92]. Subcutaneous doses of octreotide range from 25 to 200 mcg 30 minutes before each meal. Adverse effects of nausea and abdominal cramps limit the use of these agents.

Caffeine has also been thought to be effective in this disorder and has been shown to reduce the magnitude of postprandial blood pressure falls in healthy volunteers [69,93-95]. However, a controlled trial in patients with postprandial syncope showed no reduction of blood pressure decline [96].

Guar gum has been associated with an attenuated blood pressure response in healthy adults as well as in patients with diabetes [97-99].

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Orthostatic hypotension (The Basics)")


Treatment goals – The goal of treatment in patients with neurogenic orthostatic hypotension (OH) is to attenuate symptom burden and the risk of falls and to prevent target organ damage and mortality. Treatment is geared to prevent or alleviate symptoms and their impact on daily function rather than a target blood pressure. (See 'Treatment goals' above.)

Initial nonpharmacologic treatment – Nonpharmacologic measures are first-line therapy for neurogenic OH (algorithm 1). These include removal of potentially offending agents (table 2), increase in salt and water intake, lifestyle modification, dietary interventions, and the use of compression stockings or abdominal binders (table 1). (See 'Nonpharmacologic measures' above.)

Pharmacologic treatment options – Pharmacologic approaches are based on two complementary strategies: expanding intravascular volume and increasing peripheral vascular resistance with other medications (table 3). The selection of one strategy, the other, or both depends on the specific features and needs of each patient as well as the degree of peripheral sympathetic denervation, as determined by plasma norepinephrine levels (algorithm 1). (See 'Pharmacotherapy' above.)

For patients with persistent OH symptoms in whom nonpharmacologic measures such as volume augmentation with salt and water intake are insufficient to replenish intravascular volume, we suggest fludrocortisone to augment volume to provide symptom relief (Grade 2C). Fludrocortisone acetate is started at a dose of 0.05 mg per day, administered in the morning. If needed, it can be titrated up to 0.2 mg per day. (See 'Fludrocortisone' above.)

For patients with symptoms of OH unresponsive to nonpharmacologic measures such as volume augmentation, we suggest a short-acting vasoconstrictor agent such as a sympathomimetic or atomoxetine (Grade 2C). A sympathomimetic agent (eg, midodrine or droxidopa) may be preferred in patients with a supine norepinephrine level <220 pg/mL and atomoxetine preferred for other patients (algorithm 1). (See 'Sympathomimetic agents' above and 'NET inhibitors' above.)

-Midodrine is used at 2.5 to 10 mg two to three times a day. Droxidopa is used at a target dose from 100 to 600 mg up to three times a day. (See 'Midodrine' above and 'Droxidopa' above.)

-Atomoxetine is a short-acting norepinephrine transporter inhibitor that increases standing blood pressure and reduces the burden of symptoms for patients with neurogenic OH. The dose is typically 10 to 18 mg two times a day. (See 'NET inhibitors' above.)

Supine hypertension – Supine hypertension is a common treatment-limiting complication of OH and may require specific interventions. These may include using nonpharmacologic treatments for OH, reducing the dose or adjusting the timing of medications for OH, avoiding supine positioning, or using short-acting medications to lower blood pressure. (See 'Supine hypertension' above.)

Postprandial hypotension – Postprandial hypotension (PH) occurs in patients with OH and can be the only manifestation of OH. PH is defined as a fall of at least 20 mmHg in systolic blood pressure within two hours of eating. PH may respond to similar nonpharmacologic measures used for OH. Smaller meals, with low carbohydrate and adequate salt content, may also ameliorate symptoms. (See 'Postprandial hypotension' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Roy Freeman, MD and Norman M Kaplan, MD, who contributed to earlier versions of this topic review.

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