PATHOPHYSIOLOGY

When a normal individual stands, about 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 pressure-sensitive cardiopulmonary volume receptors and arterial baroreceptors. This leads to baroreflex-mediated sympathetic activation with increases in stroke volume and peripheral vasoconstriction and parasympathetic withdrawal with increase in heart rate (Fig. 28-1). These rapid hemodynamic changes prevent blood pressure from falling; their failure causes orthostatic hypotension.

Figure 28-1 Effect of gravity on arterial and venous pressure in an upright posture. Below heart level, both arterial and venous pressures increase. Above heart level, pressures decrease. Within the cranium, the perfusion pressure (arterial-venous) remains relatively constant because of the subatmospheric pressure in cerebral sinuses.

Rights were not granted to include this figure in electronic media. Please refer to the printed book.

(From Hainsworth R: Pathophysiology of syncope. Clin Auton Res 2004; 14[Suppl 1]:18-24.)

When arterial blood pressure falls below a critical level, cerebral blood flow also decreases. When systolic blood pressure is around 50 mm Hg at brain level (which corresponds to a systolic blood pressure of approximately 70 mm Hg at cardiac level when a person is standing) (Fig. 28-2), the autoregulatory capacity of cerebral blood flow reaches maximum vasodilation and is unable to compensate for a further fall in blood pressure.

Figure 28-2 Simplified outline of autonomic blood pressure regulation by the baroreflex. The baroreflex is a classic example of regulatory feedback control as exerted by the autonomic nervous system. Information is collected by pressure-sensitive receptors located in the walls of cardiopulmonary veins, the right atrium, and within almost every large artery of the neck and thorax, particularly within the carotid and aortic arteries. Venous and the aortic arch baroreceptors relay their information via fibers that course within the vagus nerve (cranial nerve X). Carotid sinus baroreceptor nerve activity is relayed centrally by the carotid sinus (Hering’s) nerve, then through the glossopharyngeal nerve (cranial nerve IX). Afferent fibers from baroreceptors have their first synapse in the nucleus tractus solitarii (NTS) of the medulla oblongata, a structure that also receives input from many other cardiovascular brain centers, such as the area postrema. The NTS provides excitatory input to the caudal ventrolateral (CVL) medulla, which in turn provides inhibitory influence on the rostral ventrolateral (RVL) medulla, where the pacemaker neurons that originate sympathetic tone are located. Axons from RVL neurons synapse with cell bodies of preganglionic sympathetic neurons in the intermediolateral column of the spinal cord, which send axons outside the central nervous system. These “preganglionic” axons synapse in peripheral ganglia with postganglionic efferent sympathetic neurons, which release norepinephrine at target organs; this results 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. Parasympathetic activity is also modulated by the NTS, through projections to the nucleus ambiguus (NA), where preganglionic cardiac parasympathetic neurons are located. An increase in blood pressure stretches baroreceptors and increases firing of afferent fibers, which results in activation of the NTS and the caudal ventrolateral (CVL) medulla, which in turn inhibit the RVL to produce sympathetic withdrawal. Activation of the NTS also results in activation of the nucleus ambiguus, leading to parasympathetic activation. The end result is a decrease in vascular tone, myocardial contractility, and heart rate, which brings blood pressure back to “baseline” levels. In general, sympathetic activation is accompanied by parasympathetic withdrawal, and vice versa. This is probably explained by the central integration of both pathways, as exemplified by the role of the NTS in baroreflex responses. Sympathetic activation to the different organs is not homogeneously distributed and depends on the stimuli and afferent pathways involved. For example, mental stress induces sympathetic activation and increases blood pressure but causes vasodilation of the forearm vasculature. AVP, arginine vasopressin; IML, intermediolateral column; PVN, paraventricular nucleus; SON, supraoptic nucleus.

In addition to these almost instantaneous changes in vascular tone and heart rate directly mediated by autonomic innervation, other longer term mechanisms that contribute to the maintenance of upright blood pressure are also influenced by the baroreflex. These mechanisms are impaired in patients with autonomic failure and contribute to their orthostatic hypotension. Increased sympathetic renal nerve activity induces tubular sodium reabsorption directly¹ and by stimulating the secretion of renin from the juxtaglomerular apparatus.² Renin and converting enzyme convert circulating angiotensinogen into angiotensin II, which is a vasoconstrictor and secretagogue of aldosterone from the adrenal medulla. Aldosterone retains sodium in the kidney, increasing extracellular fluid volume. Patients with autonomic failure have low renin and low aldosterone levels. In addition, unloading of thoracic baroreceptors releases the antidiuretic hormone from the neurohypophysis into the systemic circulation.^3,4 Acting on specific receptors in vascular smooth muscle cells,⁵ vasopressin produces vasoconstriction, and in the kidney it causes water retention and expands extracellular fluid volume.⁶ Baroreflex-mediated vasopressin release is blunted in some patients with autonomic failure.

Two other circulating vasoactive peptides, atrial natriuretic factor (ANF) and endothelin, are involved in the regulation of blood pressure and extracellular fluid volume, and their secretion may also be controlled, at least in part, by autonomic reflexes. ANF is secreted from atrial myocites⁷ when atrial pressure increases. ANF produces natriuresis, relaxation of vascular smooth muscle, and inhibition of renin and aldosterone secretions.^8–10 When right atrial pressure decreases, as during the upright posture, circulating levels of ANF quickly fall, contributing to vasoconstriction and expansion of extracellular fluid volume. Whether ANF is released by the direct effect of pressure on the cardiocytes or by a centrally mediated autonomic reflex is still unclear. Kaufmann and colleagues found that the response of circulating ANF to changes in atrial pressure is preserved in patients with baroreflex impairment, which suggests that a local intracardiac reflex regulates the secretion of the peptide.¹¹ Endothelin, a powerful vasoconstrictor synthesized by endothelial cells,¹² has an important role in the local control of the circulation.¹³ In addition, however, endothelin is synthesized by neurons in the paraventricular and supraoptic nuclei of the hypothalamus¹⁴ and is co-released with vasopressin from the neurohypophysis into the bloodstream when thoracic baroreceptors are unloaded.¹⁵ The physiological function of the endothelin released into plasma during baroreflex activation remains to be defined, but it is likely that circulating endothelin contributes to the vasoconstriction that maintains blood pressure in the upright posture.¹⁵

DIAGNOSIS AND EVALUATION OF ORTHOSTATIC HYPOTENSION

Orthostatic hypotension produces a characteristic clinical history. Symptoms of lightheadedness and tunnel vision occur on standing, never while the person is lying down, and are always relieved immediately on sitting or lying down, because cerebral blood flow is passively restored. Failure to meet these criteria suggests other causes of impaired consciousness (e.g., hypoglycemia, seizures, cardiac arrhythmias).¹⁶ In patients with diabetes or other peripheral neuropathies, proprioceptive abnormalities lead to feeling of unsteadiness that patients refer as dizziness, which may wrongly suggest orthostatic hypotension. In addition to the classic lightheadedness with blurred vision and syncope, symptoms of chronic orthostatic hypotension may include vague generalized weakness, fatigue, cognitive impairment, and pain in the shoulders and back of the neck (coat hanger pain).

Many patients with chronic autonomic failure can tolerate very low orthostatic blood pressures with few symptoms of cerebral hypoperfusion, perhaps because their cerebral autoregulatory capacity is well preserved.¹⁷ However, physical exercise, prolonged standing, the postprandial state, or mild volume depletion exacerbates orthostatic hypotension and invariably triggers symptoms of cerebral hypoperfusion, including presyncope or syncope.

The diagnosis of orthostatic hypotension relies on simple measurements of blood pressure and heart rate after the patient has lain down for 5 to 10 minutes and after 1 to 3 minutes of standing. Orthostatic hypotension is arbitrarily defined as a decrease in systolic blood pressure of at least 20 mm Hg and in diastolic blood pressure of at least 10 mm Hg within 3 minutes of standing, in association with symptoms of cerebral hypoperfusion.¹⁸ On occasion, the diagnosis of orthostatic hypotension may require repeated measurements of blood pressure throughout the day. In patients with autonomic impairment, the severity of orthostatic hypotension is worse early in the morning or about 30 minutes after a meal compared to the rest of the day.

Concomitant measurements of heart rate are crucial for adequate interpretation of results. Side effects of medications are arguably the most common causes of orthostatic hypotension. The most common culprits are tricyclic antidepressants, diuretics, nitrates, and α blockers used to treat benign prostatic hypertrophy. In these cases, there is usually a compensatory increase in heart rate in association with orthostatic hypotension. In contrast, the presence of symptomatic orthostatic hypotension without an adequate compensatory increase in heart rate is sufficient clinical indication of autonomic failure (Fig. 28-3). The diagnosis can be easily confirmed with simple measurements of heart rate and blood pressure (Table 28-1). No single test completely differentiates patients with autonomic failure from age-matched control subjects, but together these tests provide a reliable indicator of the presence and severity of cardiovascular autonomic impairment.

Figure 28-3 A, Patients with autonomic failure have reversal of the normal diurnal variation in natriuresis, with about twice as much urine volume (Uvolume) (dark bars) and sodium excretion (lighter bars) during the night as during the day. Crea, creatinine. B and C, Patients with autonomic failure have reversed circadian rhythm of blood pressure (BP) and heart rate (HR). B, subject with autonomic failure; C, normal subject. bpm, beats per minute.

TABLE 28-1 Assessment of Autonomic Function: Bedside Physiological Tests

R-R, R wave to R wave; R-R_exp, R-R interval during expiration; R-R_insp, R-R interval during inspiration.

CAUSES OF AUTONOMIC FAILURE

The most common cause of autonomic failure is autonomic neuropathy secondary to diabetes mellitus. Any systemic illness that causes peripheral neuropathies that affect somatic nerves may also affect autonomic fibers. Citetreeman (2005) lancet from suggested reading list in general, the primary condition is clinically apparent.

Primary forms of autonomic failure are rarely the result of congenital deficiency of the enzyme dopamine β-hydroxylase. Affected patients cannot synthesize norepinephrine in sympathetic nerves.¹⁹ Most cases of primary autonomic failure are caused by degeneration of autonomic neurons.²⁰ Autonomic failure is a prominent feature of two of the most prevalent neurodegenerative diseases: the Lewy body syndromes and multiple-system atrophy (MSA). The Lewy body syndromes, so named because of characteristic cytoplasmic eosinophilic neuronal inclusions (Lewy body, Lewy neuritis) found in the brain and peripheral autonomic nerves of affected patients, manifest with three different but overlapping phenotypes: pure autonomic failure, with neuronal degeneration restricted mostly to peripheral autonomic neurons and autonomic failure as the sole clinical finding; Parkinson’s disease, with prominent degeneration of the substantia nigra and other brainstem nuclei, in addition to peripheral autonomic neurons, and clinical findings dominated by motor abnormalities with varying degrees of autonomic failure; and dementia with Lewy bodies, a disorder with extensive cortical involvement, in addition to degeneration of brainstem nuclei and peripheral autonomic neurons and, clinically, severe cognitive impairment associated with parkinsonism and autonomic dysfunction.

The second type of neurodegeneration with prominent autonomic failure, MSA, affects neurons in basal ganglia, cortex, and spinal cord, sparing peripheral autonomic neurons, with characteristic glial cytoplasmic inclusions but no Lewy bodies. MSA has two phenotypes: parkinsonian and cerebellar, named MSAp and MSAc according to the predominant motor abnormality. Severe autonomic failure is prominent in both phenotypes.²¹

The differential diagnosis between primary neurodegenerative autonomic disorders can be difficult. There are three common diagnostic challenges. First, it is often very difficult to distinguish, early on in the disease process, between pure autonomic failure and MSA because patients with MSA can present initially with isolated autonomic failure. It may be impossible to rule out MSA and make a definitive diagnosis of pure autonomic failure during the first 1 to 2 years of disease onset. Follow-up may be required before a definitive diagnosis can be made. MSA has a more rapid progression, with disability resulting from worsening of the movement disorder, which commonly occurs 6 to 8 years after onset of symptoms. Another differential diagnosis challenge is that between MSA and Parkinson’s disease. Patients with otherwise classical Parkinson’s disease can have severe orthostatic hypotension. Patients with MSA rarely have the onset of unilateral resting tremor typical of Parkinson’s disease and, in general, respond poorly to levodopa. Third, studies suggest that autoimmune autonomic neuropathy can resemble pure autonomic failure clinically but with more prominent gastrointestinal abnormalities.

Autonomic failure with an acute or subacute (less than 3 months) clinical onset is suggestive of an autoimmune autonomic neuropathy. In most cases, the precise cause is not known, but in some patients, ganglionic nicotinic acetylcholine receptor (nAChR) autoantibodies are found. Clinical autonomic impairment is more pronounced in patients with high antibody titers, which indicates a pathogenic role for the nAChR antibodies.²² In addition to orthostatic hypotension, patients have dry eyes and dry mouth, severe upper gastrointestinal motility impairment, large pupils that react poorly to light and accommodation, and neurogenic bladder.²³

Autoimmune autonomic neuropathy with a subacute onset may also occur as a paraneoplastic syndrome.²⁴ This is commonly associated with anti-Hu antibodies (also known as type 1 antineuronal nuclear antibody), most often in patients with small cell lung cancer but also in those with other malignancies.²⁵ Other antibodies associated with paraneoplastic autonomic neuropathy include Purkinje cell cytoplasmic antibodies type 2 and antibodies to the neuron cytoplasmic protein collapsin response-mediator protein-5. The clinical onset is generally subacute; acute or chronic manifestations are unusual. As in autoimmune autonomic neuropathy, prominent clinical findings are orthostatic hypotension, bowel hypomotility, bladder dysfunction, pupillomotor and sudomotor dysfunction, and xerophthalmia.

MANAGEMENT

In general, a stepwise approach to treatment according to the severity of the symptoms is preferable.²⁶ Table 28-2 shows general management guidelines, but treatment should be individualized. Some recommendations may actually be contraindicated in a given patient. The initial approach is always to remove any of the conditions enumerated in Table 28-2 that may induce or aggravate orthostatic hypotension. The suggestions for management described as follows are relevant to patients with orthostatic hypotension caused by autonomic impairment.

TABLE 28-2 Stepwise Approach to Management of Orthostatic Hypotension

* See Table 28-3.

Nonpharmacological Therapy

In patients with persistent symptoms, conservative nonpharmacological therapy is indicated. Patients with autonomic failure are unable to conserve sodium, and liberalization of sodium intake is generally recommended. These patients have exaggerated nocturnal diuresis with relative hypovolemia and worsening of orthostatic hypotension early in the morning. Elevating the head of the bed with 6- to 9-inch blocks can reduce nocturnal diuresis by reducing nocturnal hypertension. This simple maneuver may ameliorate orthostatic hypotension the following morning. During the day, wearing waist-high custom-fitted elastic support stockings exerts pressure on the legs and reduces venous pooling. It is important to avoid wearing support stockings in the supine position because they may contribute to diuresis and supine hypertension. Support stockings, however, are difficult to wear, and compliance is low. Most of the pooling of blood, however, occurs in the abdomen.²⁷ Therefore, patients can try using an abdominal binder as an alternative to support stockings (Table 28-3).²⁸

TABLE 28-3 Pharmacological Agents for the Treatment of Orthostatic Hypotension

Agent	Dosage	Side Effects
Sodium chloride	1g/meal	Nausea, diarrhea
Fludrocortisone (Florinef)	0.1-0.3 mg/day	Hypokalemia, congestive heart failure, supine hypertension
Midodrine (ProAmatine)	5-10 mg*	Scalp itching, goose bumps
Yohimbine (Yocon)	5.4 mg*	Nervousness, tremor
Indomethacin (Indocin)	25 mg	Gastrointestinal discomfort, peptic ulcer
L-Dihydroxyphenyl serine (DOPS)†		Supine hypertension

Please refer to more detailed sources for complete list of side effects and contraindications.

* A dose of these short-acting pressor agents, given before exertion, improves orthostatic symptoms for 2-3 hours. In general, administration of >3 doses/day is discouraged, to avoid side effects and development of tolerance.

† Available only in Japan.

It has been discovered that rapid intake of 500 mL of water results in an acute (within 30 minutes) and transient (lasting about 60 minutes) increase in blood pressure in patients with autonomic failure.²⁹ This pressor effect can be substantial (Fig. 28-4) and can be used to alleviate orthostatic hypotension. It is commonly recommended that patients drink 500 mL of water about 15 minutes before getting out of bed in the morning, when symptoms are at their worst.

Figure 28-4 Example of the pressor response produced by 500 mL of tap water in a patient with multiple-system atrophy. DBP, diastolic blood pressure; SBP, systolic blood pressure.