Symptomatic Orthostatic Hypotension/Supine Hypertension

A 79‐year‐old woman was hospitalized for recurrent postural dizziness 5 years ago. Her blood pressure (BP) was 166/93 mm Hg supine and 88/53 mm Hg immediately after standing, but she could not maintain a standing position due to dizziness; her heart rate was 80 bpm and 108 bpm in the supine and standing positions, respectively. Findings from both an electrocardiogram and an echocardiogram were normal. Overnight telemetry revealed no arrhythmias. A fasting glucose was 84 mg/dL (normal, 70–110 mg/dL). Four years later, the patient was seen by a neurologist because of leg weakness when she arose from a sitting position. Her vitamin B₁₂ level was 512 pg/mL (normal, 164–1064 pg/mL). Brain magnetic resonance imaging showed minimal nonspecific white matter changes; a clinical cancer screen was negative. Intact peripheral sensation was noted. The patient's supine BP was 192/7'4 mm Hg; her BP immediately after standing was 110/54 mm Hg, with a heart rate change from 74 to 92 bpm. A diagnosis of orthostatic hypotension (OH) due to primary peripheral autonomic failure was made. A morning dose of 0.1 mg fludrocortisone was prescribed, with an increasing dose of midodrine.

The patient became incapacitated because of recurrent postural dizziness and syncope. Daytime lower extremity compression garments were prescribed but were uncomfortable and not used. Morning and postprandial symptom exacerbations were reported. Supine systolic BPs were >200 mm Hg at home and validated in the clinic.

Bedtime dosages of 10 mg hydralazine, 0.1 mg clonidine, 0.05 mg clonidine, 12.5 mg captopril, and 6.25 mg captopril were all attempted sequentially in combination with fludrocortisone 0.1 mg b.i.d., but each attempt led to worsened daytime postural symptoms. For most of the day, the patient was unable to sit up without dizziness. IV fluids were administered on several emergency room visits. Midodrine was discontinued because it made her feel “even worse” standing up.

In early February 2005, an open reduction and internal fixation were required for a right trimalleolar ankle fracture suffered following a syncopal episode. Fludrocortisone was advanced to 0.2 mg each morning and 0.1 mg each evening. The patient was hospitalized on one occasion for potassium replacement when her serum potassium was found to be 1.8 mEq/dL (normal, 3.5‐5.0 mEq/dL). There was no edema. Syncopal episodes abated somewhat, but due to significant recurrent severe postural dizziness, the fludrocortisone was increased again, to 0.2 mg b.i.d. with potassium 40 mEq t.i.d. Bipedal edema was noted. Supine BP remained at levels of 198/102 mm Hg with sitting pressures of 112/68 mm Hg. Immediately after standing, the patient's BP was 92/58 mm Hg, with lightheadedness. The patient was virtually wheelchair bound. After nonpharmacologic training with instruction from physical and occupational therapists, however, she improved and was able to perform some activities with minimal dizziness.

DISCUSSION

OH is defined as a decrease in systolic BP of 20 mm Hg, or to <90 mm Hg, or both, within 3 minutes of rising to a standing position, measured at 1 minute and again at 3 minutes. ¹ , ² , ³ , ⁴ OH is predominantly a geriatric condition, but its prevalence depends on the population studied and is related to overall functional performance. In a survey of 45 nursing homes, OH occurred in 50% of frail elderly people older than 60, ² compared with 20% of elderly medical outpatients, and less than 7% of healthy normotensive elderly community dwellers. ³ Postural symptoms of dizziness, lightheadedness, and syncope can be highly variable but are more likely to occur in the morning and postprandially. ² , ⁴ , ⁵ , ⁶ With cerebral autoregulation, long‐term adaptation may protect patients from symptoms of cerebral ischemia until the systolic pressure drops below 60 mm Hg. According to Bannister and Mathias, ⁶ “It is important not to be overconcerned about a low standing BP if the patient is without symptoms.” Prolonged bedrest with its associated deconditioning, and acute illness causing dehydration, frequently cause exacerbations; these factors should be ruled out when there is an exacerbation in a previously controlled patient. ⁴

Medications commonly cause OH and a medication check is mandatory (Table I). When volume depletion causes postural symptoms (nonneurogenic OH), the standing heart rate is usually >20 bpm higher than the supine heart rate, or >100 bpm. Elderly individuals with impaired baroreceptor function, however, may be unable to mount a physiologic tachycardia in response to significant volume depletion ³ and therefore deserve a fluid challenge for postural symptoms even in the absence of tachycardia. Neurogenic vasodepressor syncope in the elderly is usually accompanied by an increase in heart rate of <10 bpm and encompasses a spectrum of entities: 1) OH as previously defined; 2) vasodepressor carotid sinus syndrome, defined as a nonpositional decrease in systolic pressure >50 mm Hg regardless of heart rate in response to carotid sinus massage; and 3) vasodepressor neurocardiogenic syncope with diagnostic criteria determined by the heart rate response to tilt testing. ¹¹ Hypertension is an important risk factor and, as a result, commonly occurs in association with neurogenic OH in the elderly. ³

Table I.

Drugs That May Cause Orthostatic Hypotension

•α‐Adrenoceptor antagonists for prostatic hypertrophy (i.e., prazosin, terazosin) 3 , 7

• Antianginal agents (nitrates, β blockers, calcium channel blockers) 3 , 7

• Antidepressants, especially tricyclic antidepressants and monoamine oxidase inhibitors 8 ; selective serotonin reuptake inhibitors may be beneficial 1 , 9

• Antihypertensives 3 , 8

• Anti‐Parkinsonian agents, including levodopa and levodopa‐carbidopa 6 , 8

• Antipsychotics, especially phenothiazines 3 , 8

• Clonidine (may also be beneficial) 3 , 6 , 8 , 10

• Diuretics 3 , 8

Neurogenic OH is the most debilitating symptom and the most frequent indication of the dysautonomias—derangements of sympathetic or parasympathetic nervous system function. A positron emission tomographic (PET) study examining the cardiac disposition of norepinephrine has led to the latest classification of dysautonomias, designating subgroups of: 1) Parkinsonism with autonomic failure; 2) Shy‐Drager syndrome; 3) multiple system atrophy; and 4) peripheral autonomic failure. ¹² The clinical significance of making a diagnosis of Parkinsonism with autonomic failure is that OH in these patients may be responsive to levodopa‐carbidopa. Tremor, rigidity, and bradykinesia are overlapping manifestations of Parkinsonism, Shy‐Drager, and multiple system atrophy and therefore, in the absence of PET scanning, a levodopa‐carbidopa trial is worthwhile when an examination reveals these features. Pupillary dysfunction and a neurogenic bladder are characteristics of Shy‐Drager or multiple system atrophy, which usually do not overlap with Parkinsonism.

Secondary neurogenic OH due to diabetes mellitus, amyloidosis, paraneoplastic syndromes, and vitamin deficiency needs to be excluded. These exclusions were accomplished in our patient with a fasting glucose, clinical examination, and a B₁₂ level. The conclusion of the diagnostic evaluation was that this patient had primary neurogenic OH and supine hypertension due to peripheral autonomic failure. In this condition, both the OH and supine hypertension are attributed to the failure of normal baroreceptor reflexes; this occurs most commonly in elderly individuals. ⁶

Despite an improved pathophysiologic understanding of OH, however, treatment modalities remain limited and many times unsatisfactory, limited by both side effects and incomplete efficacy. Fludrocortisone is the mainstay of treatment. The use of this medication results in fluid retention and enhanced arteriolar sensitivity to catecholamines and angiotensin, along with central adrenergic effects. ⁶ , ¹³ After 6 months of treatment with fludrocortisone, plasma volumes have been observed to return to normal with a predominant effect on peripheral resistance lasting as long as 14 years. ¹³ Small trials with OH patients have reported response rates greater than 75%. ¹⁴ , ¹⁵ One syncope clinic's experience with 64 consecutive patients older than 65 years of age (mean age, 80 years), however, reported a high long‐term failure rate (38/64; 60%) with fludrocortisone, with discontinuations due to hypertension, heart failure, edema, and depression. ¹⁶ Dosage is limited by fluid accumulation, of which the initial manifestation is usually peripheral edema and hypokalemia. Headache is also a side effect. Electrolytes need to be checked 1 week following initiation of therapy and approximately each week following a dose increase. ¹

Hypokalemia may also be a late finding. Hypokalemia in patients treated with fludrocortisone occurs at a mean of 8 months, with a range of 2‐21 months. ¹⁶ Our patient illustrates how severe hypokalemia can be, with a serum potassium of 1.8 mEq/dL following an increase in dosage. Fludrocortisone is usually instituted at a starting dose of 0.1 mg q.d. to 0.1 mg b.i.d. Dosage is increased at 1‐2‐week intervals in increments of 0.1 mg according to postural symptomatology, along with edema and potassium checks following each dosage increase. Postural symptomatology is a more appropriate clinical parameter to follow, as opposed to the numeric drop in BP. Though a daily total fludrocortisone dosage range of 0.1 mg to 1.0 mg is quoted in the literature, ³ , ⁴ dosages greater than 0.2 mg b.i.d. are often poorly tolerated or endured. ² , ¹⁶

Midodrine, a peripheral adrenergic stimulator, was approved by the US Food and Drug Administration in 1996 specifically for the treatment of OH, following a series of published trials. ⁷ , ¹⁰ , ¹⁷ A gradual increase in dose at 3‐day intervals is suggested, from 2.5 mg t.i.d. to 5 mg t.i.d. to a maximal and target dose of 10 mg t.i.d. Midodrine used in conjunction with fludrocortisone can be fludrocortisone sparing; lower, bettertolerated doses of fludrocortisone become possible. ¹⁵ The most common side effects are scalp pruritus/tingling (13.5%), supine hypertension (8%), and urinary urgency (4%). ¹⁷ Drop‐out rates were 6.8% ¹⁷ and 13.5% ¹⁴ in the two larger trials.

Midodrine should not be administered within 4 hours of bedtime because the effect of the drug lasts 3‐4 hours and can increase supine hypertension. ⁴ , ¹⁸ Midodrine has also been reported to exacerbate postural symptomatology, perhaps accounting for our patient's feedback of “feeling worse” with midodrine. In a group of patients who described worsened postural symptomatology in response to midodrine, Kaufmann et al. ¹⁹ observed increased supine hypertension attributed to more severe underlying baroreceptor dysfunction and associated volume depletion. Aggravated supine hypertension in these individuals caused more significant nocturnal and morning pressure diuresis.

Several other treatments ¹⁸ such as desmopressin acetate, erythropoietin, clonidine, yohimbine, nonselective β blockers, octreotide, dihydroergotamine, indomethacin, metoclopramide, pyridostigmine, and fluoxetine ⁹ have been used successfully in small numbers of patients (Table II). These drugs are not considered standard treatment for OH, due to side effects, expense, and lessened efficacy compared with fludrocortisone and midodrine.

Table II.

Drugs Used to Treat Orthostatic Hypotension

• Fludrocortisone 1 , 3 , 4 , 6 , 13 , 14 , 15 , 18

• Midodrine 6 , 7 , 10 , 17

• Desmopressin acetate (intranasal) 6 , 18

• Erythropoietin 21

• Clonidine 6 , 18

• Yohimbine 6 , 18

• Nonselective β blockers 6 , 18

• Octreotide (subcutaneous) 18

• Dihydroxyphenylserine 18

• Dihydroergotamine 6 , 18

• Indomethacin, nonsteroidal anti‐inflammatory agents 6 , 18

• Metoclopramide, dopamine antagonists 6 , 18

• Pyridostigmine 18

• Fluoxetine 9

• Levodopa‐carbidopa for Parkinsonism with autonomic failure 8 , 20

Nonpharmacologic treatments are a cornerstone of primary management of OH/supine hypertension and always deserve emphasis with patients and their caregivers. ¹ , ¹⁶ , ²⁰ , ²² Adequate fluid intake is important. Sixteen ounces of water can allay postural symptoms for more than 60 minutes but should be avoided within 1 hour of going to bed because it can also cause supine hypertension. ²² Morning fluid intake may lessen the diurnal worsening of postural symptomatology usually attributed to the pressure diuresis of supine hypertension overnight and the resultant relative fluid‐deficient state in the morning. Additional fluid intake of 2‐2.5 L/d is recommended, along with added salt intake. ¹ , ³ , ⁴ , ¹⁸ , ²⁰ Patients with symptomatic postural hypotension are also more susceptible to postprandial postural hypotension due to splanchnic pooling. ⁶ If postprandial exacerbations are reported, such individuals should be counseled to eat more frequent, smaller meals and to plan on a 60‐minute postprandial rest period. Two cups of coffee, especially with larger meals, may enhance peripheral resistance and lessen postprandial exacerbations. ²⁰ Black licorice, via a mineralocorticoid effect, ²³ has been observed to be beneficial. Tachyphylaxis may occur, however, with caffeinated beverages. ¹⁸

Patients often discover helpful techniques on their own. ²⁴ Squatting and upper leg crossing while sitting or standing may be helpful; muscle compression that enhances venous return may lessen postural changes. Head stooping or bending over while in the standing position may permit slightly longer standing times and enhancement of function. ⁶ , ²⁴ “Staged” standing is important, where extra time is spent in the sitting position on the way to standing. ³ , ²⁵ Fitted lower extremity compression garments at least to the thigh level need to be tried for daytime usage and abdominal binders may be considered. ¹ , ⁴ , ⁶ , ¹⁸ , ²⁰ Particularly for elderly patients, however, such garments can be uncomfortable both to wear and to put on and remove. ¹ , ¹⁶ Elevating the head of the bed by 6‐9 inches or five to 10 degrees can reduce supine hypertension, as well as the pressure diuresis which leads to morning postural symptom exacerbations. ³ , ⁴ , ¹⁸ , ²⁰ , ²⁵ , ²⁶ , Table III lists the nonpharmacologic measures that should be instituted as an important component of management. An excellent patient/provider handout is available on the Internet. ²⁶ These measures greatly helped our patient to safely carry out many essential daytime functions.

Table III.

Nonpharmacologic Management of Orthostatic Hypotension/Supine Hypertension

• Patient/provider awareness of symptoms of visual change dizziness lightheadedness to take action by sitting or lying down 1 , 20 , 25 ; patient/provider take‐home information packet available on the Internet 26

• Staged standing: slow rise with intermediate sitting position 3 , 4 , 25

• Physical countermaneuvers 18 , 24 , 25 , 26 : 1) upper leg crossing while sitting or standing; 2) move feet up and down at the ankle before standing; 3) gentle “marching” on the spot rather than stationary standing; 4) resting one leg in an elevated position (on a chair) while sitting or standing; 5) squatting; and 6) stooping forward when upright

• Avoid straining or lifting i.e., coughing or straining at stool. Valsalva compromises venous return. 18 , 25 , 26 High‐fiber diet is recommended

• Exercise may cause hypotension due to vasodilatation and can be encouraged but needs to be individually tailored 6 , 25 , 26 , 27 ; hydrostatic water pressure may be beneficial in swimming and pool exercises 6 , 20 , 25

• Resting in the morning and postprandially (about 60 minutes) when postural symptomatology usually worsens 6 , 25 , 26

• Two to 2.5 L of additional fluid daily with 10 g of salt daily 3 , 18

• Elastic compression stockings to thigh level, custom fitted to achieve 30–40 mm Hg counterpressure, worn only during the day 1 , 4 , 6 , 18 , 20 ; consider an abdominal binder 6

• Elevate head of bed 5–10° or 6–9 inches to reduce supine hypertension and morning exacerbation of postural symptoms due to pressure diuresis 3 , 4 , 18 , 20 , 25 , 26

• Avoid excessive environmental temperatures (hot showers and baths) 6 , 25 , 26

• Bedtime snack or alcohol vs. supine hypertension 18 , 19 ; avoiding drinking water within 1 hour of bedtime and midodrine within 4 hours of bedtime, also vs. supine hypertension 4 , 18 , 22

• One or two cups of coffee especially with meals to reduce postprandial exacerbations 18 , 20 ; licorice 3 g daily 23

• Occupational and physical therapy for ambulatory assistance to permit rapid sitting; grab aids at home; home safety evaluation 25

One study ²² has shown an increased prevalence of left ventricular hypertrophy in patients with supine hypertension, and there is a strong correlation between the severity of OH and premature mortality. ²⁸ Such evidence and concern regarding extreme levels of supine hypertension will often lead to attempted bedtime use of short‐acting antihypertensive medications such as small doses of hydralazine, clonidine, or nitropaste. ¹⁹ , ²² Some patients will tolerate vasodilators before bedtime in combination with morning fludrocortisone; these can be titrated to balance some supine BP control with amelioration of daytime postural symptoms. Of major concern with this regimen, however, are nocturnal trips to the bathroom. Additionally, many individuals, as did our patient, describe worsened daytime postural symptoms with even small doses of short‐acting vasodilators given at bedtime.

Quality of life and function are the predominant concerns for a disease most often affecting elderly individuals, not only for themselves, but for family caregivers. Symptomatic postural hypotension can be completely debilitating, leading to increased falls and fractures, ³ , ²⁵ as with our patient. Fludrocortisone frequently becomes the mainstay of drug management to control sitting and standing dizziness, lightheadedness, and syncope, but it also may cause increased supine hypertension. For the most difficult patients, we titrate this agent to symptoms, always using the smallest dose possible to maintain some baseline level of functionality. In doing so, we recognize that these patients will often remain significantly debilitated, requiring caregiver vigilance. Such an approach may require acceptance of significantly elevated supine pressures.