Disorders of the Autonomic Nervous System

Autonomic Pathways

Autonomic regulation depends on three main components. Afferent fibers continuously sense changes in blood pressure (baroreceptors), blood oxygenation, and other chemical signals (chemoreceptors), pain (sensory afferents), and cortical stimulation. These signals are integrated in brainstem centers that ultimately modulate sympathetic and parasympathetic outflows, which are transmitted to target organs via efferent fibers. The baroreflex provides an example of these pathways ( Figure 63-1 ). This is a redundant system, with input from multiple independent afferent pathways that ensure maintenance of cardiovascular regulation even after partial damage. The afferent limb of this reflex includes pressure-sensitive receptors located in the walls of cardiopulmonary veins, the right atrium, and within almost every large artery of the neck and thorax, but particularly within the carotid sinus and aortic arch. Stimulated by stretch, these low- and high-pressure baroreceptors monitor venous and arterial pressures, respectively, and relay that information to brainstem centers. Information from the venous and aortic arch baroreceptors is carried centrally via fibers that course within the vagus nerve (X cranial nerve). Carotid sinus baroreceptor nerve activity is relayed centrally first via the carotid sinus (Hering) nerve, then through the glossopharyngeal nerve (IX cranial nerve) before arriving at the same brainstem centers.

Afferent fibers from these multiple baroreceptors have their first synapse in the nucleus tractus solitarius of the medulla oblongata. This nucleus inhibits sympathetic tone and is crucial to baroreflex function. Destroying it (e.g., by experimental lesion or neurologic damage) leads to loss of baroreflex function, resulting in episodes of hypertension and tachycardia. In addition to the afferent input arising from the baroreceptors, the nucleus tractus solitarius also receives modulating input from many other cardiovascular brain centers, such as the area postrema. The nucleus provides excitatory inputs to the caudal ventrolateral medulla, which in turn inhibits the rostral ventrolateral medulla, where the pacemaker neurons that produce sympathetic tone are believed to be located. Rostral ventrolateral medulla neurons project to the preganglionic sympathetic neurons in the intermediolateral column of the spinal cord that send fibers outside the central nervous system. Parasympathetic activity is also modulated by the nucleus tractus solitarius, through projections to preganglionic parasympathetic neurons in the nucleus ambiguus and the motor nucleus of the vagus (see Figure 63-1 ).

The importance of autonomic mechanisms in the regulation of blood pressure is most evident when they fail. Damage of baroreflex afferents (e.g., as a consequence of radiation or surgery), leads to labile blood pressure that is very difficult to control. At the other extreme, degeneration of central or efferent structures, as seen in patients with primary autonomic failure, leads to disabling orthostatic hypotension. In the most severe cases, patients are only able to stand for a few seconds before profound orthostatic hypotension causes loss of consciousness (i.e., orthostatic syncope). These disorders are described later in this chapter.

Posture (Orthostatic) Test

Perhaps the most informative and simplest autonomic evaluation is the posture test. The patient's blood pressure and heart rate are measured after 5 to 10 minutes in the supine position and repeated after the subject stands motionless for 3 to 5 minutes. There is value in repeating measurements at each of these time points, as one single measurement may or may not be informative. Ideally, beat-to-beat plethysmography is the most informative, but if this is not available, then repetitive manual measurements of both heart rate and blood pressure will enable a clearer assessment and lead to a more accurate diagnosis, especially in cases where the autonomic failure is mild to moderate rather than severe.

Virtually all patients with severe autonomic failure will have an immediate fall in blood pressure on standing. Other autonomic conditions associated with delayed orthostatic hypotension may require a 30-minute stand test to make the diagnosis, but they are usually not associated with widespread autonomic neuropathy. Older patients may find it extremely tiring to stand for 30 minutes unassisted and a passive tilt test, during which data is recorded continuously and the patient is supported physically, will increase the tolerance of completing the test.

Heart rate is crucial in interpreting blood pressure changes. Patients with severe autonomic failure characteristically have no or little (about 10 to 15 beats/min) increase in heart rate despite profound orthostatic hypotension. A greater increase in heart rate usually indicates that other conditions (e.g., volume depletion or medications) are contributing to orthostatic hypotension.

Orthostatic Hemodynamic Assessment With Sphygmomanometer

Routinely, clinicians use the auscultatory or oscillometric method with a sphygmomanometer. In 1996, a consensus committee of the American Autonomic Society and the American Academy of Neurology defined orthostatic hypotension as a drop of at least 20 mm Hg in systolic blood pressure and/or 10 mm Hg in diastolic blood pressure within the first 3 minutes of orthostasis. This definition was intended primarily for clinical situations where orthostatic blood pressure changes are measured with a sphygmomanometer or automatic oscillometric blood pressure monitors.

Orthostatic Hemodynamic Assessment With Beat-to-Beat Monitoring

The introduction of new noninvasive beat-to-beat finger arterial blood pressure monitors led to concerns that the consensus definition of orthostatic hypotension, originally intended for the sphygmomanometer, may lack clinical relevance when applied to beat-to-beat data. Some orthostatic hypotension definitions based on continuous hemodynamic assessment include initial orthostatic hypotension and can only be measured with continuous noninvasive monitoring. Initial orthostatic hypotension is defined as a transient blood pressure decrease, within 15 seconds after standing, of more than 40 mm Hg in systolic blood pressure and/or more than 20 mm Hg in diastolic blood pressure, with symptoms of cerebral hypoperfusion.

The advantage of using continuous noninvasive measurement of finger arterial blood pressure over the conventional sphygmomanometer or the oscillometric measurement method is that the former provides continuous patterns of response that can be visualized and analyzed, not only for blood pressure but also for derived hemodynamic parameters. As a result, three different orthostatic response patterns have been recognized and studied in adults and older people, based on the morphology of the blood pressure recovery after standing ; these three patterns are the quick recovery pattern, which is the normal physiologic response; the slow recovery pattern, which is known to occur in pathologic conditions such as carotid sinus denervation or carotid sinus hypersensitivity ; and the failure to recover pattern, which is classically observed in patients with autonomic failure. These three “morphologic” patterns of orthostatic blood pressure response have been characterized in research studies using a cluster analysis technique.

Noninvasive Autonomic Tests

Heart rate responses to deep breathing (i.e., respiratory sinus arrhythmia) and to the Valsalva maneuver are simple yet informative autonomic tests. They require real-time monitoring of the heart rate. Respiratory sinus arrhythmia is assessed during controlled breathing at a rate of six deep breaths per minute ( Figure 63-2 ). The expiratory/inspiratory (E/I) ratio is calculated by dividing the longest R-R interval by the shorted R-R in inspiration. This E/I ratio decreases progressively with age. Subjects younger than 40 years usually have a ratio less than 1.2 ( Figure 63-3 ). Having the subject blow against a 40 mm Hg pressure for 12 seconds induces a Valsalva maneuver. A 5- to 10-mL syringe can be used as a mouthpiece, which is connected to a sphygmomanometer to monitor pressure. A small leak should be introduced into the system to ensure the subject uses thoracic effort. The increase in intrathoracic pressure produces a transient fall in blood pressure with narrowing of the pulse pressure during phase II (strain), whereas the blood pressure overshoots above baseline values during phase IV (after release) ( Figure 63-4 ). In autonomic failure, the blood pressure continues to fall during phase II and the normal overshoot is absent during phase IV. Thus, appropriate evaluation of the Valsalva response requires continuous recording of blood pressure, which can be accomplished noninvasively with finger plethysmography (Finapres, Portapres, or Task Force Monitor) or tonometry of the radial artery (Colin). Even if the blood pressure cannot be monitored, heart rate responses are useful. The blood pressure changes described previously produce reciprocal baroreflex-mediated changes in the heart rate. The heart rate increases during the hypotensive phase II of the Valsalva maneuver and decreases during the blood pressure overshoot of phase IV. Valsalva ratio is defined as the maximum heart rate during the maneuver divided by the lowest heart rate obtained within 30 seconds of the peak heart rate. As with the E/I ratio, the Valsalva ratio decreases with age and results should be interpreted accordingly (see Figure 63-3 ). Normal reference ranges have been suggested.

Spectral Analysis of Heart Rate and Blood Pressure

Blood pressure and heart rate are kept within a relatively narrow range because of autonomic baroreflex mechanisms. Within this narrow range, however, blood pressure shows substantial variability. Most of this variability is not random but, rather, follows natural rhythmic patterns, which can be studied using spectral analysis techniques. Importantly, these patterns are modulated by the respiratory frequency. In particular, respiration frequency influences heart rate variability, and this interaction is under baroreflex control via the vagus nerves. The “respiratory peak” of heart rate variability, evident in the high-frequency spectrum, can be used to assess cardiac parasympathetic function.

Respiration also modulates blood pressure, but this is mediated through mechanical events and does not reflect autonomic mechanisms and is not affected by autonomic blockade. In contrast, blood pressure exhibits a lower frequency rhythm (Mayer waves). This is mediated in part by sympathetic modulation of vascular tone. There is substantial interindividual variability in the spectral analysis of heart rate and blood pressure, making these methods less suitable for the diagnosis of individual patients with less than severe autonomic impairment. Nonetheless, population studies have shown that impaired heart rate variability as shown by spectral analysis of heart rate is an independent predictor of mortality in patients after myocardial infarction and in patients with diabetes mellitus. Independent of disease status, heart rate variability has been found to be impaired in people with physical frailty.

Assessment of Baroreflex Function

Several methods can be used to quantify the changes in heart rate (or R-R interval) produced by unit change of blood pressure. These methods require the simultaneous monitoring of blood pressure and heart rate. Baroreflex function can be assessed by measuring the reciprocal changes in blood pressure and heart rate that occur spontaneously, or during the phase IV of the Valsalva maneuver. Blood pressure can be increased with phenylephrine or decreased with nitroprusside and the gain of the baroreflex expressed as the change in R-R interval per unit of blood pressure (expressed in msec/mm Hg) during the linear portion of this relationship. Each of these methods provides slightly different normative values of baroreflex gain. It is important to note that changes in blood pressure affect all baroreflex afferents, including carotid sinus and aortic high-pressure receptors and low-pressure receptors located in the venous circulation. The carotid sinus reflex can be selectively investigated by producing positive and negative pressure to the neck, to simulate decreases and increases in intracarotid pressure, respectively. All of these methods rely on instantaneous changes in heart rate, which depend exclusively on the parasympathetic limb of the baroreflex. The sympathetic limb of the baroreflex can be assessed by relating changes in blood pressure to reciprocal changes in muscle sympathetic nerve activity (MSNA).

Baroreflex Function

There is a progressive decline in baroreflex sensitivity with aging as a result of both vascular and neural deficits. Cardiovagal baroreflex gain (i.e., the reciprocal heart rate changes produced by changes in arterial pressure) declines with age, but the ability of the cardiopulmonary baroreflex to inhibit sympathetic nerve traffic has been reported to be well preserved with age in healthy adults. Hence vagal, but not sympathetic, baroreflex gains vary inversely with individuals' age and their baseline arterial pressures. There is no correlation between sympathetic and vagal baroreflex gains.

Cardiac Parasympathetic Function

Cardiac vagal innervation decreases with age, as clearly shown by a progressive reduction in respiratory sinus arrhythmia (see Figure 63-3 ). Experimental evidence suggests that long-term physical activity attenuates the decline in cardiovagal baroreflex gain by maintaining neural vagal control, but among older adults, the level of fitness does not prevent the decrease in cardiac vagal function, suggesting that age-related decline in cardiac vagal function cannot be completely prevented by physical activity.

Systemic Sympathetic Function

MSNA increases progressively with age, likely because of increased central nervous system drive ( Figure 63-5 ). Sympathetic nerve traffic increases in a region-specific manner; outflow to skeletal muscle and the gut increases but decreases to the kidney. The increase in central sympathetic outflow results in higher levels of plasma norepinephrine with age, but reduced norepinephrine clearance appears to play a role as well. It is suggested that age-related elevations in whole-body and abdominal adiposity can explain why basal MSNA increases with age in healthy humans. The relation between body fat and MSNA is observed in both young and older populations. Tanaka, Davy, and Seals showed that although body mass index (BMI) was similar in groups of younger and older subjects, both total body fatness and abdominal adiposity were greater in the older subjects and were directly related to baseline levels of MSNA. Data indicate that circulating concentrations of leptin are related to both adiposity and MSNA. Thus, age-associated elevations in total and abdominal adiposity may be linked to increases in MSNA, at least in part, via elevations in leptin levels. In contrast to sympathetic neuronal activity, adrenaline secretion from the adrenal medulla is greatly reduced with age, and adrenaline release in response to acute stress is attenuated in older men. Plasma adrenaline concentration remains normal, however, because of reduced plasma clearance.

End-Organ Responsiveness

The number of β-adrenergic receptors in lymphocytes remains steady in older age, and there are higher neurotransmitter levels. However, β-adrenergic responses to norepinephrine are blunted with progressive aging, probably because of β-adrenergic receptor downregulation in response to higher circulating levels of norepinephrine, a defect in G protein receptor complexes and reduced adenyl cyclase activity. Depressed β ₁ responses lead to impaired cardioacceleration and reduced cardiac contractility. Reduced β ₂ responses produce increased vascular tone because α ₁ vasoconstriction ability remains unchanged. The combination of age-related vascular stiffening and depressed β-adrenergic function results in reduced arterial baroreflex sensitivity in older subjects. Blood pressure in older subjects is sustained by increased peripheral vascular tone, despite depressed cardioacceleration. Because of a higher reliance on vascular resistance, dehydration and vasodilator medications pose a high risk for hypotension and syncope in older subjects. Vasovagal syncope is commonly seen in older adults whose symptoms include presyncope, falls, or syncope. Postjunctional α-mediated vasoconstriction is also impaired in older adults.

Vascular Changes

Aging stiffens blood vessels and alters vasomotor function. In older patients, coronary vasodilation capacity is reduced because of reduced nitric oxide release by the senescent endothelium. Conversely, endothelin release by the endothelium is increased in older people, promoting vasoconstriction. These alterations increase susceptibility to myocardial ischemia, particularly during increased demand stresses such as tachyarrhythmias, and can also impair cerebral autoregulation, increasing susceptibility to syncope. Other age-dependent cardiovascular alterations that can increase predisposition to syncope are increased left ventricular afterload and myocyte hypertrophy. These alterations lead to impaired diastolic filling and chronic ischemia that may predispose patients to cardiac arrhythmias and decrease ventricular volume that may manifest as syncope. Decreased preload volume, precipitated by vasodilators, dehydration, or blood pooling can dramatically reduce cardiac output and precipitate syncope. Susceptibility to atrial fibrillation increases with age because of reductions in pacemaker cells, progressive fibrosis of the cardiac conduction system, and concomitant cardiovascular diseases that alter atrial morphology. In older patients, impaired diastolic filling and a reduction of up to 50% in cardiac output can develop during atrial fibrillation and lead to syncope and unexplained falls.

Neuroendocrine Changes

Plasma renin and aldosterone levels fall with age, and atrial natriuretic peptide increases fivefold to ninefold. The vasopressin response to hypotension may also be reduced. These changes make sodium and water conservation less effective and intra­vascular volume depletion more frequent, thus increasing the tendency for syncope. In addition, many older people have an impaired thirst response to increases in osmolality and do not consume sufficient fluids to prevent hypovolemia.