Orthostatic hypotension (OH) is a significant medical problem; it occurs in about 6% of healthy elderly in the community, 18% to 54% of nursing home residents, and up to 60% in hospitalized elderly. The incidence of OH increases exponentially after age 65, and its importance is likely to increase as our population ages. OH is not only a cause of disability and impaired quality of life, but it is also associated with a 2.6-fold increase in the risk of falls, and is an independent risk factor for increased mortality. The prototypical patient with orthostatic hypotension is a frail elderly, with multiple comorbidities and on multiple medications. Hypertension is the most common comorbidity among patients with OH; it is present in approximately 70% of patients. Conversely, orthostatic hypotension is present in about 10% of patients referred to hypertension specialists, and in community studies hypertension is strongly associated with OH. Coexistence of hypertension with orthostatic hypotension represents a management challenge as the treatment of one condition can worsen the other. It is important, therefore, that physicians treating hypertensive patients be knowledgeable of the pathophysiology of orthostatic hypotension, which will ultimately guide its treatment.
Pathophysiology
When a normal individual stands, up to 700 mL of blood pools in the legs and lower abdominal veins. Venous return decreases, resulting in a transient decline in cardiac output. The reduction in central blood volume and arterial pressure is sensed by cardiopulmonary volume receptors and arterial baroreceptors. Afferent signals from these receptors reach vasomotor centers in the brainstem. Efferent fibers from these centers reduce parasympathetic output and increase sympathetic outflow. Norepinephrine is released from postganglionic sympathetic nerve terminals at target organs, resulting in an increase in heart rate and cardiac contractility, partial restoration of venous return and diastolic ventricular filling by venoconstriction, and an increase in peripheral resistance by arteriolar vasoconstriction. As a net effect of these adaptive mechanisms, upright cardiac output remains reduced by 10% to 20% compared with supine, systolic blood pressure (SBP) is reduced by 5 to 10 mm Hg, diastolic blood pressure increases by 2 to 5 mm Hg, mean blood pressure remains almost unchanged, and heart rate increases by 5 to 20 beats per minute.
Impairment in these compensatory autonomic neural mechanisms results in OH. Primary neurodegenerative disorders of the autonomic nervous system are the cause of the most severe cases of OH. The common pathology of these disorders are deposits of alpha-synuclein forming Lewy bodies in peripheral noradrenergic nerves (pure autonomic failure, Parkinson disease) or glial cytoplasmic inclusions in central autonomic pathways (multiple system atrophy). In the vast majority of patients, however, OH is the result of milder forms of autonomic impairment (often related to aging or diabetes) superimposed with other aggravating factors (often medications).
Clinical Consequences of OrthostATic Hypotension
OH impairs the functional status and quality of life of patients affected by it. Furthermore, it is associated with a 2.6-fold increase in the risk of falls in the elderly, and this association remains after correcting for other risk factors. Patients with OH commonly experience syncope and falls, an association that has been documented in 24% to 31% of patients presenting to emergency department visits. Multiple epidemiological studies have reported that OH is associated with coronary artery disease, stroke, and heart failure. The presence of OH doubles the risk of developing chronic kidney disease, and as an independent risk factor it is comparable with having coronary artery disease, smoking, hypertriglyceridemia, and other risk factors that receive more attention. Importantly, during the past 2 decades, evidence from cross-sectional and longitudinal epidemiological studies has identified OH as an independent risk factor for cardiovascular morbidity and all-cause mortality.
Orthostatic hypotension, therefore, represents a burden to the United States health care system. A recent report showed that the overall annual rate for OH-related hospitalization is 36 per 100,000 U.S. adults, and this rate increases steadily with age and can be as high as 233 per 100,000 in those age 75 or older. Considering that the U.S. demographic is rapidly changing, with the elderly population representing nearly 20% of the total U.S. population in the next 20 years, the impact of OH-related hospitalizations will be a greater challenge to our health services and the medical community.
Evaluation of the Patient with Orthostatic Hypotension
OH is defined as a sustained reduction of SBP of at least 20 mm Hg or diastolic blood pressure (DBP) of 10 mm Hg within 3 min of standing, or head-up tilt to at least 60 degrees. In hypertensive patients, a reduction in SBP of 30 mm Hg is considered a more appropriate criterion for orthostatic hypotension because the magnitude of the orthostatic blood pressure fall is dependent on the baseline blood pressure. Typical symptoms of OH are lightheadedness, dizziness, fatigue, dimming of vision, and shoulder (“coat hanger”) pain. Patients may be asymptomatic or may have difficulty identifying their symptoms. It is useful to consider that, as a general rule, symptoms should never start while the patient is supine, should occur mostly while standing, and should be quickly relived by seating or lying down. Symptoms tend to be worse in hot environments and if patients stand still. The severity of OH is also greater in the morning, so much so that the diagnosis of OH is more likely to be made if orthostatic vitals are taken in the morning than in the afternoon.
The evaluation and diagnosis of OH can be done at the bedside. Autonomic testing, often restricted to specialized units, is helpful to assess the presence and severity of autonomic impairment (neurogenic OH). It is, however, not essential. Measuring orthostatic blood pressure and heart rate is often all that is needed. A significant decrease in orthostatic blood pressure that is not associated with an appropriate increase in heart rate is indicative of neurogenic OH. Another practical alternative to specialized testing is to clinically try to improve OH by removing factors that can trigger or aggravate OH (see below under management); any significant OH that remains is likely to have an important neurogenic component.
The list of etiologies that cause neurogenic OH is long but most become apparent after a comprehensive evaluation. In principle, any disease that causes peripheral neuropathy can cause autonomic neuropathy and neurogenic OH. In practice, diabetes mellitus (DM) is the most common culprit. Tight glucose control can delay the progression of autonomic neuropathy in type 1 diabetes, but the evidence for type 2 diabetes is less clear. B12 deficiency should be ruled out because its treatment can lead to improvement of OH. Special attention should be given to patients that develop severe OH with a subacute onset and rapid progression, for they often have an autoimmune or paraneoplastic syndrome; in some cases neurogenic OH can be the presenting problem which leads to the diagnosis of the underlying disease.
Management of Hypertension in the Patient with Orthostatic Hypotension
When encountering a hypertensive patient with concomitant orthostatic hypotension, it is tempting to ease the antihypertensive treatment, in an attempt to prevent syncope and falls. Current evidence, however, suggest that such an approach is misguided. In studies of elderly living in the community, the incidence of OH increased from 2% to 5% when hypertension was present, but was greatest (19%) in those with uncontrolled hypertension. Importantly, the presence of OH per se did not increase the risk of falls, whereas elderly with uncontrolled hypertension and OH had more than a two-fold increase risk of falls. This observation argues in favor of treating both OH and hypertension in these patients.
The obvious question is what antihypertensives should be used in patients with OH, and which should be avoided? There is limited evidence from randomized controlled trials on which to base recommendations. It stands to reason that antihypertensives that interfere with autonomic orthostatic compensatory mechanisms will worsen OH, and observational studies have indeed found that the use of alpha blockers, beta-blockers, and central sympatholytics are associated with OH. A similar association is also found with the use of thiazide diuretics. No significant associations were found between the presence of OH and the use of calcium channel blockers. The presence of OH was reduced in patients receiving angiotensin receptor blockers in one study, increased in patients taking angiotensin-converting enzyme (ACE) inhibitors in another, and no association was observed in patients using antihypertensives targeting the renin-angiotensin system in a third study.
Some patients may have isolated supine hypertension. This is most commonly observed in patients with severe primary forms of autonomic failure, in whom seated blood pressure may be completely normal or only slightly elevated. There is no agreement as to whether or not isolated supine hypertension should be treated. Supine hypertension, however, is associated with left ventricular hypertrophy and decreased renal function. Furthermore, severely affected patients can lose up to 2 kilograms of weight during the night. This is caused by pressure diuresis and explains why patients are worse early in the morning. Treatment of supine hypertension, therefore, could theoretically improve OH. During the day, simply avoiding the supine position is the best way to treat these patients. During the night, several antihypertensives given at bedtime have been shown to reduced supine hypertension, including nitroglycerine patch (to be removed first thing in the morning), nebivolol, losartan, and sildenafil. Unfortunately none have been shown to improve next morning OH either because they do not reduce nighttime diuresis or they have residual hypotensive effects in the morning.
Management of Orthostatic Hypotension in the Hypertensive Patient
Goal of Treatment and Overall Strategy
The main goal of treatment of OH is to reduce symptoms and improve the patients’ functional status and quality of life. This requires an increase in standing blood pressure. A recent study in patients with Parkinson disease and OH found that symptoms were absent if mean standing blood pressure (BP) was above 75 mm Hg. This likely reflects the threshold BP below which cerebral autoregulation is overcome. Conversely, increasing BP above that level provides no additional therapeutic benefit. Thus, the goal should not be to “normalize” upright blood pressure, but to raise it only enough to alleviate symptoms.
The ideal therapy will selectively improve upright BP while having no effect on supine BP. Most pressor agents, however, have an opposite effect, and produce a greater increase in supine or seated BP than in standing BP. In the absence of orthostatic pressor selectivity, therapies should have a quick onset and short duration of action to avoid worsening supine hypertension. Particularly in patients with hypertension, therefore, it is preferable to use short-acting pressor agents only to prepare patients to stand up, and should be avoided when patients lie down.
We assume that reducing orthostatic hypotension will result in prevention of syncope and falls, but this has not been shown for any of the therapies currently available. Even less certain is that the treatment will prevent the increase in mortality associated with OH. It could be argued that pharmacological treatment (e.g., with fludrocortisone or pressor agents) may even have a negative impact on cardiovascular outcomes.
Current treatment recommendations are based mostly on studies in small numbers of patients with primary forms of autonomic failure and severe OH, with limited evidence of long-term efficacy in randomized controlled clinical trials. No studies have been designed to include the most common forms of OH, patients with diabetes, or elderly hypertensive patients with multiple comorbidities.
Remove Offending Factors
The first step in the management of OH is to remove any potential factor that could precipitate or contribute to OH. Medications are among the common offenders. Amitriptyline, often used to treat pain in sensory neuropathies (which is often seen in patients with autonomic neuropathies), is a common culprit. In patients with hypertension and OH, certain medications should be avoided, such as diuretics and alpha-blockers but without abandoning antihypertensive treatment altogether (see previously). Physicians also need to be aware of “hidden” antiadrenergic agents. Tamsulosin, commonly used to treat benign prostatic hyperplasia, is an alpha-blocker with preferential selectivity for the α 1A receptor in the prostate versus the α 1B receptor in blood vessels. This selectivity, however, is not absolute, and tamsulosin increases the risk of orthostatic hypotension in susceptible individuals. Trazodone is used as an antidepressant, but it is often overlooked that it is also a potent alpha 1 -blocker that can worsen or trigger OH. Tizanidine is marketed as a “central muscle relaxant,” but pharmacologically it is an α 2 agonist very similar in chemical structure and antihypertensive properties to clonidine and can also cause orthostatic hypotension. Congestive heart failure is a common comorbidity in patients with OH, and is often treated with “vasodilating” beta-blockers than have alpha-blocking properties (carvedilol, labetalol) or that promote nitric oxide (nebivolol). These agents do lower BP in autonomic failure patients, and if cardioprotection is desired it would seem preferable to use nonvasodilating beta-blockers. Finally, erectile dysfunction is often an early (albeit nonspecific) sign of autonomic impairment, and phosphodiesterase inhibitors used in its treatment can produce profound decreases in BP in patients with autonomic failure.
Food digestion induces pooling of blood in the splanchnic circulation with hemodynamic consequences that are similar to those that occur on standing. It is not surprising then that patients with autonomic failure can have substantial drops in BP after meals. The nadir in BP is usually seen 30 minutes after a meal, is worse with high carbohydrate foods, and can be prevented by delaying glucose absorption with 50 to 100 mg acarbose. The presence of postprandial hypotension should be investigated in all patients with significant OH because its treatment can provide significant symptomatic relief without the use of pressor agents.
Nonpharmacological Countermeasures
Patients should use physical countermeasures that reduce venous pooling, thereby improving venous return and cardiac output. These include standing slowly and in stages, avoid standing motionless, and tensing the leg muscles. Compression stockings can be used to decrease venous pooling on standing, but because most of the pooling occurs in the abdomen waist-high stockings that produce at least 15 to 20 mm Hg pressure are required, but they are difficult to put on, limiting compliance. Many patients and physicians rely on knee-high or thigh-high stockings, but experimental data indicate that leg compression does not improve orthostatic tolerance. On the other hand selective abdominal compression is effective. This provides a rationale to use abdominal binders, worn as tight as possible, as an alternative to waist-high compression stockings. We have recently found that an automated abdominal binder, servo-controlled to maintain an abdominal pressure of 40 mm Hg, is as effective as midodrine in improving orthostatic tolerance acutely. Theoretically, an abdominal binder has all the properties of an ideal treatment for OH, particularly in patients with hypertension; because it is applied only on standing, it selectively increases upright blood pressure, and its onset and offset of action are immediate ( Table 42.1 ). However, the long-term effectiveness and tolerability of this approach has not been tested.
