In a healthy individual, close to 25% to 30% of the body’s blood volume is in the thorax while supine.² Upon standing, the effect of gravity is to displace approximately 300 to 800 mL of blood downward to the abdomen and lower extremities. This is volume drop of 25% to 30% occurs in the first few moments of standing, resulting in a decline in venous return to the heart. As a result, the heart can pump only the blood that it receives, which produces a decline in stroke volume of approximately 40% and a decline in arterial blood pressure. The area around which these changes occur is known as the venous hydrostatic indifference point (HIP), and it represents the point in the vascular system where it is independent of position. The arterial HIP is near the level of the left ventricle, and the venous HIP is around the diaphragm.

Standing also results in a substantial use of the transmural capillary pressure that is present in the dependent areas of the body, resulting in a rise in fluid filtration into the tissue spaces. This process arrives at a steady state after approximately 30 minutes of upright posture and can result in a decline in plasma volume of close to 10%.

Adequate maintenance of cerebral perfusion during upright posture is the product of the interaction of several cardiovascular regulatory systems. The exact changes that occur with standing (an active process) differ somewhat from those seen during head-up tilt (a more passive process). Wieling and van Lieshout ² have described three phases of orthostatic response: (1) the initial response (in the first 30 seconds), (2) the early steady state alteration (at 1 to 2 minutes), and (3) the prolonged orthostatic period (after at least 5 minutes upright).

In the first moments following head-up tilt, cardiac stroke volume remains constant despite the decline in venous rhythm, possibly because of the blood in the pulmonary circulation. Afterward, there is a gradual fall in both cardiac filling and arterial pressure; this results in actuation in two distinct sets of pressure receptors compressed by high-pressure receptors in the carotid sinus and aortic arch, as well as low pressure receptors in the heart and lungs. In the heart are mechanoreceptors connected by vagal afferents in each of the four cardiac chambers. These mechanoreceptors affect a tonic inhibitory effect on the cardiovascular regulatory centers of the medulla (especially the nucleus tractus solitarii). The baroreceptor neurons located here can directly activate the cardiovagal neurons of the nucleus ambiguous and dorsal vagal nucleus, while simultaneously inhibiting the sympathoexcitatory neurons of the rostral ventrolateral medulla.

The reduced venous return and fall in filling pressure that occur during upright posture reduce the stretch on these receptors. As the firing rates decrease, there is a change in the systemic resistance vessels and the splanchnic capacitance vessels. In addition, there is a focal axon reflect (the venoarteriolar axon reflex) that can constrict flow to the skin, muscle, and adipose tissue; this may contribute up to 50% of the increase in limb vascular resistance seen during upright posture.

During head-up tilt, there is also activation of the high-pressure receptors in the carotid sinus. The carotid sinus contains a group of baroreceptors and nerve endings located in the enlarged area of the internal carotid artery, just after its origin from the common carotid artery. The mechanoreceptors are located here in the adventitia of the arterial wall. The afferent impulses generated by stretch on the arterial wall are then transmitted via the sensory fibers of the carotid sinus nerve that travels with the glossopharyngeal nerve. These afferent pathways terminate in the nucleus tractus solitarii in the medulla, near the dorsal and ambiguous nuclei. The initial increase in heart rate seen during the tilt is thought to be modulated by a decline in carotid artery pressure. The slow rise in diastolic pressure seen during upright tilt is believed to be more closely related to a progressive increase in peripheral vascular resistance.

The circulatory changes seen during standing are somewhat different from those seen during tilt. Standing is a much more active process that is accompanied by contractions of muscles of both the leg and abdomen, which produces a compression of both capacitance and resistance vessels and results in an elevation in peripheral vascular resistance. This increase is sufficient to cause a transient increase in both right atrial pressure and cardiac output, which in turn causes an activation of the low-pressure receptors of the heart. This action provokes an increase in neural traffic to the brain, with a subsequent decrease in peripheral vascular resistance, which can fall as much as 40%. This change can allow a fall in mean arterial pressure of up to 20 mm Hg that can last for 6 to 8 seconds. The same mechanisms used during head-up tilt then compensate for this decline in pressure.

The early steady state adjustments to upright posture consist of an increase in heart rate of approximately 10 to 15 beats/min, an increase of approximately 10 mm Hg, and little or no change in systolic blood pressure. At this point, compared with supine posture, the blood volume of the thorax has fallen by 30%, cardiac output has increased by 30%, and heart rate is 10 to 15 beats/min higher.

At a given moment, approximately 5% of the body’s blood is in the capillaries, 8% is in the heart, 12% is in the pulmonary vasculature, 15% is in the arterial system, and 60% is in the venous system. The inability of any one of these mechanisms to operate adequately (or in a coordinated manner) can result in a failure of the body to compensate for an initial or prolonged orthostatic challenge. This, in turn, would result in systemic hypotension that, if sufficiently profound, could lead to cerebral hypoperfusion and subsequent loss of consciousness.

Historical Perspective

By the middle of the nineteenth century, physicians began to report on a group of patients who had developed a disorder characterized by exercise intolerance, severe fatigue, and palpitations.³ These symptoms would often appear suddenly without a discernible cause such as prolonged immobility, blood loss, or dehydration. At the time of the American Civil War, DeCosta described patients suffering from postural tachycardia and orthostatic intolerance, a condition he called “irritable heart syndrome”.⁴

Around the time of the World War I, a condition referred to as neurocirculatory asthenia began to be reported. The most remarkable of these was a study by Thomas Lewis, who described a condition he called the “effort syndrome.”⁵ He stated that the fatigue was “an almost universal complaint” among these patients, as well as exercise intolerance in conjunction with symptoms such as palpitations, chest pain, syncope, and near syncope. In addition, Lewis reported that these patients demonstrated a significant postural tachycardia, with heart rates changing from 85 beats/min (bpm) supine to 120 bpm while upright. In some of these patients, there was a significant decline in blood pressure while upright, whereas others demonstrated only a modest decline.⁶ Lewis concluded that in these patients “the potential reservoir in the veins takes up the blood, the supply to the heart falls away, and the arterial pressure falls rapidly,” oftentimes accompanied by a compensatory tachycardia. Lewis further wrote that the reduction in blood flow “may be sufficient to produce cerebral anemia.”

Additional reports appeared,7,8 and this condition was later elucidated by Schondorf and Low, who performed extensive evaluations of 16 patients who suffered from extreme fatigue, exercise intolerance, bowel hypomotility, and lightheadness.⁹ During head-upright tilt table testing, these individuals displayed distinctly abnormal cardiovascular responses to upright posture, with heart rate elevations to as high as 120 to 170 bpm within the first 2 to 5 minutes of upright tilt. Some of these patients became hypotensive, but the majority remained normotensive, and a small percentage became hypertensive. In describing the condition, they used the term “postural orthostatic tachycardia syndrome” (POTS).¹⁰ Later investigations have found that POTS is not a single entity; rather, it is a heterogeneous group of disorders with similar clinical characteristics.^6,11,12

Definitions

The hallmark of these disorders is orthostatic intolerance, the definition of which is the occurrence of symptoms upon standing that are generally relieved by becoming supine. As noted earlier, these patients will complain of symptoms such as palpitations, fatigue, exercise intolerance, lightheadedness, nausea, headache, near syncope, and syncope. Because the amount of autonomic failure that these patients exhibit is not severe and the physical findings are often subtle, they can be misdiagnosed as having chronic anxiety or a panic disorder.

Some patients can be so severely affected that the regular activities of daily life such as housework, bathing, and eating can greatly exacerbate symptoms. Studies have shown that some patients with POTS can suffer from the same degree of functional impairment as patients with congestive heart failure or chronic obstructive pulmonary disease. Interestingly, the severity of the symptoms can be greater in patients with POTS than in those with more severe autonomic failure syndromes, such as pure autonomic failure. A grading system to classify the severity of orthostatic intolerance has been developed (similar to that used in congestive heart failure) as noted in Box 104-1.

The effect of the disorder is substantial. It is presently estimated that 500,000 to 1 million people suffer from POTS in the United States. Of these, at least 25% are disabled and unable to work or attend school. Especially tragic is the fact that the majority of these patients are young and are most symptomatic during what is usually the most productive part of a person’s life.

POTS is currently defined as the presence of symptoms of orthostatic intolerance associated with a postural change in heart rate of 30 bpm (or a rate that exceeds 120 bpm that occurs within the first 10 minutes of standing or upright tilt). This change should occur in the absence of other chronic debilitating conditions, such as prolonged bed rest or medications that impair vascular tone. It has been suggested that in children, a more appropriate cut off would be an increase at 40 bpm. It should be kept in mind that many patients with orthostatic intolerance might not display orthostatic hypotension (a drop of >20/10 mm Hg upon standing). Indeed, they could have only a small decline in blood pressure, have no change at all, or have an increase in blood pressure upon standing. Some investigations have noted that the focus on heart rate can cause many of the other autonomic symptoms to be overlooked, such as alterations in thermoregulatory, sudomotor, bowel, and bladder function. For many patients, these complaints are often more troubling than the orthostatic ones.

Classification

In some ways, POTS is best considered as an abnormal physiological state (somewhat akin to the term heart failure) that can be caused by a wide range of different disorders. Although differing ways of classifying POTS have been proposed, the system that follows is clinically useful and conforms with current scientific knowledge.⁶

POTS can be classified as being primary or secondary. The primary forms are not associated with other illnesses, and the secondary forms occur in association with another known disease or disorder. Proper recognition of subtypes is often important in management. The primary forms are divided into two major subtypes; the first and largest of these is referred to as the partial dysautonomia (also called neurogenic) form. These patients are afflicted with a mild form of peripheral autonomic neuropathy, the principal manipulations of which appear to be an inability of the peripheral vasculature to initiate or maintain an adequate degree of peripheral vasoconstriction in the face of orthostatic stress. The inability results in a much greater than normal degree of blood pooling in the depending areas of the body while upright, which in turn provokes a compensatory increase in both heart rate and myocardial contractibility in an attempt to maintain adequate degree of cerebral perfusion. While these responses can be initially compensatory, the degree of peripheral vascular pooling can increase over time and exceed the compensatory effect. Many of these patients will become increasingly dependent on this peripheral skeletal muscle pump to maintain adequate blood pressure until further degrees of peripheral venous pooling occurs in the mesenteric vasculature. One of the more striking features that these patients might display is the development of a deep, mottled (almost blue colored) discoloration in the lower extremities upon standing (a finding referred to as acral cyanosis). This excessive degree of peripheral vascular pooling can result in a state of functional hypovolemia. Some studies have suggested that the vascular dysregulation extends to the cerebral vasculature’s autoregulatory functions as well, which might help to explain the frequent complaint of cognitive impairment that many patients report.

There is a female predominance in this form of POTS (a 5 : 1 female-to-male ratio), suggesting a possible causative role for a woman’s reproductive hormones. The majority of patients report that their symptoms appeared abruptly after a febrile illness (presumed to be viral). Surgery and pregnancy are also frequently related to the onset of symptoms. Trauma (most often from motor vehicle crashes) and electrical injuries have also been known to precipitate symptoms. Patients will complain of extreme fatigue, syncope, near syncope, palpitations, exercise intolerance, blurred vision, and a generalized sense of weakness. As mentioned previously, many patients will complain of cognitive impairment. A significant number of patients will also report nausea, bloating, altered bowel habits, abnormal sweating, pain in the extremities, and a sensation of always feeling cold. The severity of the symptoms often wax and wane. Many women will relate that their symptoms increase in the 4 to 5 days preceding their menstrual cycles.

Most researchers believe that this form of POTS is often immune mediated in nature. Several studies have demonstrated that patients with postviral POTS have serum autoantibodies to α3 acetylcholine receptors in the peripheral autonomic ganglia.¹³ Other autoantibodies await identification. Recent studies have suggested a link with mitochondrial disorders, which might also be immune mediated. Other etiologies most likely exist as well.

One subtype of the partial dysautonomic form of POTS appears to affect adolescents, a group labeled as developmental. The usual age of onset is approximately 14 years and often follows a period of rapid growth.¹⁴ Symptoms reach their peak at approximately 16 years of age. Symptoms of orthostatic intolerance, and often migraines, may be of such intensity that the patient is disabled. Symptoms will often fade over the ensuing years, so that by young adulthood (19 to 20 years of age) approximately 80% will have experienced a significant recovery. The etiology here remains unclear, but is believed to reflect a transient period of autonomic imbalance that can occur in rapidly growing adolescents.

A second and much less common type of primary POTS is referred to as the hyperadrenergic form,¹⁵ in which patients tend to report a more gradual and progressive onset of symptoms. They will often complain persistent tachycardia, tremor, hyperhidrosis, and anxiety. Patients frequently complain of always feeling “too hot.” The distinguishing characteristic of this group is an orthostatic hypertension that occurs in addition to a postural tachycardia. A large number of these patients complain of migraines, and some will report a significant increase in urinary output after only brief periods of upright posture. Most will display exaggerated response to isoproterenol infusion. Many patients with hyperadrenergic POTS will have significantly elevated serum norepinephrine levels (>600 ng/mL) during upright posture.

There is sometimes a family history of the disorder, of which there are possibly two forms. The best understood subtype is a genetic disorder in which a single-point mutation causes a dysfunction in the norepinephrine reuptake transport protein that cleans and recycles norepinephrine spillover in response to a wide range of sympathetic stimuli resulting in a hyperadrenergic state that can mimic the state caused by a pheochromocytoma.¹⁶ A second type of hyperadrenergic POTS appears to be autoimmune in nature and is characterized by an abrupt onset following an acute febrile illness (presumed to be viral). This form can overlap with inappropriate sinus tachycardia syndrome. Investigators have isolated autoantibodies to β1 cardiac receptors that stimulate the sites without producing a tachyphylaxis.

The term secondary POTS is used to describe the wide variety of conditions that result in varying degrees of peripheral autonomic denervation with relative sparing of cardiac innervation.¹⁷ The most frequent cause of secondary POTS is diabetes mellitus. It can also be seen as a result of multiple sclerosis, amyloidosis, sarcoidosis, systemic lupus erythematosus, Sjögren syndrome, alcoholism, Lyme disease, chemotherapy (with the vinca alkaloids in particular).¹⁸

A particularly noteworthy form of secondary POTS occurs in conjunction with the connective tissue disorder known as the joint hypermobility syndrome (JHS), or type III Ehlers-Danlos syndrome.¹⁹ An inherited condition, JHS is characterized by joint hypermobility, soft velvety skin with variable hyperextensibility, and connective tissue fragility. Patients will also demonstrate easy bruising, premature varicose veins, diffuse joint and muscle pain, and orthostatic acrocyanosis. Patients with JHS can develop orthostatic intolerance because of the presence of abnormally elastic tissue in the vasculature, resulting in an increased vessel disposability in response to the increase in hydrostatic pressure that occurs during orthostatic stress. This change can allow for an excessive degree of peripheral venous pooling with a resultant compensatory tachycardia. Gazit et al. reported that up to 70% of patients with hypermobility syndrome suffer from some degree of orthostatic intolerance.^19a Many adolescents with the developmental form of POTS will have features of JHS.

At times, POTS is the presenting sign of a more severe form of autonomic disorder, such as pure autonomic failure or multiple system atrophy. In addition, POTS can be the presenting sign of a paraneoplastic syndrome that occurs in association with adenocarcinomas of the lung, breasts, pancreas, and ovary. It has been found that some of these tumors produce autoantibodies against postganglionic acetylcholine receptors in the autonomic ganglia, not dissimilar to those that have been found in the postviral autonomic neuropathies.²⁰

Evaluation and Management

The first and most critical step is to obtain a detailed history followed by a thorough physical examination and a complete neurologic examination. It is important to identify conditions that can cause orthostatic intolerance (e.g., anemia, dehydration, other chronic debilitating illnesses). In addition, any medications that could cause or worsen the condition should be identified (e.g., vasodilators, tricyclic antidepressants, monoamine oxidase inhibitors, alcohol).

A careful physical examination is paramount. Blood pressure and heart rate should be obtained in the supine, sitting, and standing positions and after 2 and 5 minutes of standing. It is helpful to be able to watch the lower extremities for the appearance of mottled bluish discoloration (referred to as acral cyanosis) that reflects venous pooling. The results obtained during standing are quite variable; therefore, it is best to perform tilt table testing on most patients, because this setting is more controlled with fewer variables and with more reproducible results (i.e., better than that seen with neurocardiogenic syncope). Other tests of autonomic nervous system function could be useful in select patients with POTS as a way of measuring the degree of systemic autonomic involvement. Sudomotor function can be determined by thermoregulatory sweat testing or by assessment of skin conductance, skin resistance, or sympathetic skin potentials. Serum catecholamine levels, both in the supine and upright positions, should be obtained in patients suspected of having the hyperadrenergic form of POTS. Bowel motility studies are useful in ascertaining the degree of gastrointestinal involvement. More detailed descriptions of autonomic testing can be found elsewhere.6,21

An important differential diagnosis is with inappropriate sinus tachycardia. There are several similarities between inappropriate sinus tachycardia and POTS, in particular with the hyperadrenergic form. Clinical presentations are much the same, and inappropriate sinus tachycardia is seen more frequently in women. Increased heart rate responsiveness to isoproterenol is seen in both conditions, suggesting that they represent different points on the spectrum of the same disease process. The major differences are that patients with POTS seem to display a greater degree of postural change in heart rate, and the resting (supine) heart rates infrequently exceed 100 bpm, compared with inappropriate sinus tachycardia (resting heart rates greater than 100 bpm are more common).

It should also be remembered that POTS can occur because of another disorder. These patients can exhibit symptoms of POTS, but they often also have signs and symptoms of the primary disorder. Although some degree of weight loss may be seen in patients with POTS, extreme cachexia is uncommon and should prompt the search for other disorders (e.g., malignancy, diabetes). In some patients with secondary POTS, the underlying disorder might not be evident at first and will only become apparent over time.

Treatments must be individualized to meet the particular needs of each patient. Any medication that the patient is taking that could contribute to the problem should be discontinued when possible (see Box 14-1). In addition, underlying conditions that could cause POTS-like state should be identified and treated (e.g., sarcoidosis, malignancy). Patient and family education as to the nature of the problem is critical, in particular relation to avoidance of aggravating factors such as extreme heat, dehydration, and drinking alcohol. Patients with the partial dysautonomic (PD) form of POTS are encouraged to increase their fluid and sodium intake (at least 2 L of fluid and 3–5 g of salt per day). Compression hose are sometimes helpful but must provide 30 mm Hg counterpressure and be waist high to be effective.

One of the most important aspects of treatment is reconditioning,²² because it augments venous return through enhancement of the skeletal muscle pump. Many patients are often deconditioned and find that aquatic activities are better tolerated as a starting point. Recumbent bikes are also useful, as are rowing machines. The initial goal is to have the patient perform 20 to 30 minutes of continuous aerobic activity at least three times per week, as well as interspersed periods of resistance training.

Regarding pharmacotherapy, treatment must be individualized, and is initiated with the goal of getting patients well enough to pursue reconditioning. No drug is currently approved by the U.S. Food and Drug Administration for the treatment of POTS; therefore, any use of pharmacotherapy is done “off label.” Knowledge of the subtype is important in choosing appropriate pharmacotherapy (Table 104-1).

Table 104-1

Therapeutic Options in Postural Orthostatic Tachycardia Syndrome *

PD, Partial dysautonomic; H, hyperadrenergic; SC, subcutaneous.

^*The U.S. Food and Drug Administration has not approved any drug for treating postural orthostatic tachycardia syndrome.

For the patients with partial dysautonomic POTS, therapies are oriented toward increasing fluid volume and augmenting peripheral vesicular resistance. It is common to begin with the mineralocorticoid agent fludrocortisone, which promotes sodium and fluid and sensitizes peripheral α-receptors to the patients’ own catecholamine. Oral desmopressin is also used as a volume-expanding agent. The next step is to use a vasoconstrictor such as midodrine, starting at a dose of 5 mg orally three times per day (usually with meals). Dosages can be titrated up to 15 to 20 mg orally four times per day, if necessary.²⁰ Because patients are most symptomatic early in the morning, they are advised to take their midodrine dose approximately 15 minutes before getting out of bed. Patients are also advised that they can take an extra 5-mg dose as needed if severe breakthrough symptoms occur. The most common problems encountered with midodrine are nausea, goose bumps, and scalp itching. If midodrine is not tolerated, methylphenidate can be an effective alternative, especially because it comes in several long-acting preparations. Some investigators have also advocated the use of yohimbine.

A useful agent in managing this form of POTS is pyridostigmine, which is an acetyl cholinesterase inhibitor that facilitates neural transmission at the ganglionic level in both the sympathetic and parasympathetic nerves.²³ Several studies have suggested a greater than 50% response rate with the agent. Doses range from 60 to 120 mg orally three times daily. Principal side effects include nausea and diarrhea.

In some patients, small doses of a β-blocker such as propranolol can be effective in controlling excessive heart rate responses to upright posture.²⁴

If patients continue to be symptomatic, add either a serotonin reuptake inhibitor or a norepinephrine reuptake inhibitor. Although the serotonin reuptake inhibitors are useful in the prevention of neurocardiogenic syncope, the norepinephrine reuptake inhibitors are somewhat more helpful in patients with POTS. Bupropion is used in the XL form starting at 150 mg orally each day and titrating to 300 mg daily, if necessary.

In patients who have proved refractory to the aforementioned agents, therapy with injected octreotide is often attempted.²⁵ As a potent vasoconstrictor of the mesenteric vasculature, it is administered by subcutaneous injection. Doses range from 50 to 200 µg twice daily. A long-acting form lasting 28 days is also available. Another agent used in refractory patients is erythropoietin; it augments vascular volume by causing an increase in red cell mass and seems to have direct vasoconstrictive effects. Because erythropoietin (EPO) must be administered by subcutaneous injection and because of its expense, its use is usually reserved to refractory patients.²⁶

Before starting EPO, a complete serum blood count (CBC) as well as serum iron, total iron binding capacity, and ferritin level should be obtained. EPO can be used as long as the hematocrit (HCT) is less than 50. The usual starting dose is 10,000 units injected subcutaneously once weekly. It usually takes 4 to 6 weeks to see the full effect of a particular dose amount. Although the red cell augmentation effect and the hemodynamic effect are independent, they tend to rise in parallel. Patients appear to achieve the best hemodynamic effect when the HCT does not exceed 50. If the HCT on EPO therapy goes over this amount, the patient can usually skip doses until it drops below 50, and then restart EPO at a lower dose (in a manner not dissimilar to the way warfarin is managed with respect to the international normalized ratio).

The most common complaint of patients receiving EPO therapy is pain at the injection site. This pain can be minimized by allowing the EPO (which is kept refrigerated) to warm before injection. One way to do this is to roll the vial between the hands until it becomes warm. An additional way to minimize injection discomfort is to place an ice cube on the injection site 3 to 5 minutes before use; alternatively, a lidocaine patch or cream can be applied 15 to 30 minutes before use.

Many patients will require supplemental oral iron for EPO to have its best effect. If no clinical improvement is seen from the starting EPO dose after 4 to 6 weeks, the weekly dose can be increased to 20,000 units. This dose is exceeded rarely in patients with POTS. A rare complication of EPO therapy is that the patient can develop a serum sickness–like reaction to EPO, characterized by fever, chills, nausea, and a general sense of malaise. This has occurred in only a handful of patients over the last 12 years; it resolves promptly after the agent is discontinued.

In patients who are refractory to all other forms of therapy, intermittent intravenous saline therapy can be used. The usual dose is 1 L of normal saline solution one to three times per week. Although this is effective, problems with obtaining intravenous access often require permanent subcutaneous port placement. Long-term port use exposes the patient to potentially life-threatening infections.

For patients with the hyperadrenergic form of POTS, therapies are directed at release or receptor effects of norepinephrine. β-Adrenergic blocking agents are useful, but tend to work best when combined with an α-blocking effect. Labetalol and carvedilol are useful, as is the agent nebivolol. Clonidine is an α2 receptor agonist that produces a central sympatholytic effect, and it is useful for treating patients. Some investigators have reported that methyldopa can be useful, whereas other groups have suggested that phenobarbital can help in refractory patients.¹⁵

It should be remembered that patients with POTS can experience an inability to pursue normal employment or educational opportunities and often suffer significant psychological disruption. Patients frequently require the services of psychologists, social workers, and lawyers to address these aspects of their illness. The attitude of the treating physician is crucial. Hope is a powerful medicine that should be encouraged by all.