Clinical manifestations

Presentation and course

Patients with POTS are mainly young (aged between 15 years and 40 years) and are predominantly female (80; 153; 156). A typical patient is a female of childbearing age, who often first displays symptoms in adolescence (156). Disease onset may be precipitated by immunological stressors (eg, viral infection) (156). Exacerbating factors can include exertion, food ingestion, and elevated ambient temperatures (80). POTS has been associated with a wide variety of conditions, including diabetes, some autoimmune disorders, infections, trauma, surgery, stress, headache (including migraine), mastocytosis, Marfan syndrome, and the hypermobility type of Ehlers-Danlos syndrome (Table 1) (05; 134; 109; 80; 09; 160; 41; 58; 01; 20; 85; 84; 90; 117; 159; 21; 79; 89). Although there are anecdotal reports of POTS developing after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) (20; 85; 84), some lay media reports have erroneously indicated—based on a single anecdotal report (84) and some follow-up commentary (20; 84)—that a significant proportion of patients with post-COVID-19 symptoms might be improved with treatment for POTS; so far, evidence that COVID-19 causes POTS at some significant level is lacking, although the nonspecific symptoms in prolonged COVID-19 patients include some with various dysautonomias that may include POTS. In adults, the prevalence of POTS is low in chronic fatigue syndrome, is not different from the rate in fatigued patients without chronic fatigue syndrome, and is not related to disease severity or treatment outcome (123).

Table 1. Conditions Associated with Postural Orthostatic Tachycardia

A single-institution survey study evaluated the most common occurring symptoms in patients with POTS, symptoms with greatest impact on quality of life in patients with POTS, and symptoms that lead to emergency department visits in patients with POTS (18).

Palpitations, dizziness, and other symptoms of POTS occur mainly when standing upright and are typically relieved by sitting or lying flat. The symptoms of postural orthostatic tachycardia syndrome suggest a hyperadrenergic state and impaired cerebral perfusion. Presyncope is common with POTS, but less than a third of the patients experience syncope (109). Chest discomfort may be a feature, but it is not associated with coronary artery stenosis (109). Orthostatic headache, when present in POTS, tends to be bifrontal, bitemporal, or holocephalic but occasionally may have a nuchal or occipital distribution, clearly distinct from the “coat-hanger” distribution sometimes seen with orthostatic hypotension and then attributed to trapezius ischemia (86). Orthostatic headache affects approximately two thirds of patients with POTS, especially among those younger than 30 years of age (67). Fatigue and palpitations on assuming an upright posture are very common (61; 96; 99).

Symptoms not attributable to orthostatic intolerance include functional gastrointestinal or bladder disorders, chronic headache, fibromyalgia, and sleep disturbances (09; 168). Bowel irregularities are common, and many patients are co-diagnosed with irritable bowel syndrome. Investigations of the gastrointestinal symptoms in POTS are conflicting with some studies reporting delayed gastric emptying and delayed colonic transit in most patients (51; 168), whereas others report that rapid gastric emptying is more common than delayed gastric emptying (102; 75). However, gastric emptying disturbances were not significantly associated with gastrointestinal symptoms, autonomic symptoms, or measured autonomic dysfunction (102). A quarter of POTS patients have delayed small bowel transit with hypocontractility patterns within the small bowel, including decreased contractions/minute and a decreased motility index (168). Persistent, gastrointestinal symptoms and disease severity are significantly associated with the serum level of antimuscarinic acetylcholine receptor (mAChRs) antibodies (150).

Almost all patients with POTS and orthostatic headache also have nonorthostatic headaches fitting criteria for migraine (67). Patients with POTS also have higher subjective daytime sleepiness and worse sleep and health-related quality of life (07).

Table 2. Symptoms of Postural Orthostatic Tachycardia Syndrome (Particularly When Upright)

Table 3. Diagnostic Criteria for Postural Orthostatic Tachycardia Syndrome

Clinical diagnostic criteria have been proposed (109; 83; 154; 57; 61). These criteria may not be applicable to children and adolescents (137; 19; 52), and, in particular, the heart rate criteria (≥30 bpm) for POTS are not appropriate in younger individuals (19). Higher postural heart rates in children do not predispose individuals to the development of POTS (19). In addition to the orthostatic tachycardia, physical findings in postural orthostatic tachycardia syndrome can include a murmur or click of mitral valve prolapse (although significant mitral regurgitation is unusual) and prominent dependent acrocyanosis (109). Dependent acrocyanosis, present in about half of patients with POTS, is characterized by a dark reddish-blue discoloration of the legs, which are cold to the touch (109). This acrocyanosis is apparently due to decreased cutaneous blood flow rather than increased blood pooling in venous capacitance vessels (32; 141; 109).

Syncope (both with tilt table testing and clinically) occurs much more commonly in patients with postural tachycardia syndrome than in patients with orthostatic hypotension (97).

Symptoms may be exacerbated by fatigue, exercise, heat, dehydration, the postprandial state, menses, various medications, fibromyalgia, and migraine (154; 106; 140).

Although patients with postural orthostatic tachycardia syndrome may appear anxious, they do not have an increased lifetime prevalence of psychiatric disorders in general (116). Nevertheless, cognitive and behavioral factors, including somatic hypervigilance associated with anxiety and depression, may contribute to symptom chronicity and disability (09; 04). Indeed, orthostatic intolerance is significantly correlated with depression and diminished quality of life but not with the maximal heart rate increment (87). Patients with POTS report mild anxiety and moderate depressive symptoms and demonstrate severe somatization and elevated anxiety sensitivity (30). Patients with POTS have deficits in selective attention and cognitive processing, even in the seated position when orthostatic stress is minimized (04). Diminished cognitive performance in POTS is associated with slow oscillations in cerebral blood flow (143).

Prognosis and complications

Although outcomes are variable, most patients with POTS have a "relatively favorable" prognosis (68; 139). At 1 year of follow-up, orthostatic symptoms improve in most patients, and more than one third no longer fulfill tilt criteria, although changes in the magnitude of the posture-induced increment in heart rate are modest (68). About half of patients spontaneously recover within 1 to 3 years (27).

Six out of seven adolescents with POTS report resolved or improved symptoms--some only intermittent--when assessed an average of 5 years after initial treatment; adolescent patients with persistent symptoms at this point tend to have more physical than mental concerns (10).

Most patients are eventually able to resume their daily activities without marked limitations (139).

The course of POTS is variable during pregnancy and the postpartum period but did not appear to affect the rate of adverse pregnancy outcomes (88).

Biological basis

Anatomic localization

Neuropathic postural orthostatic tachycardia syndrome is thought to result from a restricted dysautonomia due to patchy or preferential sympathetic denervation of the blood vessels in the legs and kidney, whereas central hyperadrenergic POTS is thought to result from a primary excessive sympathetic nervous system discharge that secondarily affects the blood vessels, heart, and kidneys (147; 50; 131; 138; 109; 125). Neuropathic POTS is characterized by decreased adrenergic vasoconstriction, whereas hyperadrenergic POTS is characterized by increased adrenergic vasoconstriction (125).

Patients with postural orthostatic tachycardia syndrome develop symptoms of orthostatic intolerance before any change in cerebral perfusion is detected (118). In addition, cerebral autoregulation is preserved in POTS (130). However, cerebral hypoperfusion may occur with prolonged standing as a result of hypocapnia from hyperventilation (94).

The mechanism of orthostatic headaches in postural orthostatic tachycardia syndrome is unknown but may be caused by a relative CSF hypovolemia or reduced orthostatic CSF pressure (86); this may explain the empirically observed therapeutic response to volume expansion or application of abdominal binders.

Dependent edema when upright has been attributed to venous pooling in the lower extremities (148) and more recently to blunted arterial vasoconstriction causing passive redistribution of blood within venous capacitance beds (141) and increased microvascular filtration with increased arterial flow (142).

Some patients with postural orthostatic tachycardia syndrome have elevated levels of autoantibodies against the adrenergic alpha 1 receptor and the muscarinic acetylcholine M4 receptor (43).

Pathophysiology

Postural orthostatic tachycardia syndrome is a syndrome caused by a heterogeneous group of disorders with differing pathophysiologies (146; 86; 109; 57; 91; 09; 58; 105). Proposed pathophysiological mechanisms (not necessarily mutually exclusive) have included hypovolemia (in some with a hypokinetic circulation maintained by a vasoconstricted state), decreased cerebral and peripheral blood flow, an abnormality of brainstem regulation, lower limb dysautonomia as part of a limited length-dependent small-fiber autonomic neuropathy (with intact cardiac autonomic innervation), disturbed sympathetic-parasympathetic balance, impaired sympathetically mediated vasoconstriction, a deficient or dysfunctional norepinephrine transporter, (possibly in some cases as a result of epigenetic modification of the norepinephrine transporter gene), a hyperadrenergic state with increased sympathetic drive, impairments in the renin-angiotensin-aldosterone system, impaired endothelial nitrous oxide-mediated functions, beta-adrenergic receptor supersensitivity, deconditioning, volume dysregulation, an autonomic cardiac neuropathy, and a small heart size (so-called "Grinch syndrome") with reduced blood volume (31; 55; 54; 53; 73; 133; 157; 86; 110; 38; 115; 34; 44; 08; 09; 166). Deconditioning is present in almost all patients with POTS and may play a central role in the pathophysiology (103) and also in the persistence of symptoms over time.

Several distinct pathophysiological subtypes of postural orthostatic tachycardia syndrome have been recognized, including neuropathic and central hyperadrenergic forms (109; 58).

Neuropathic postural orthostatic tachycardia syndrome is thought to result from a restricted dysautonomia due to patchy or preferential sympathetic denervation, particularly of the blood vessels in the legs and kidney, with resultant hypovolemia and increased orthostatic venous pooling, and a secondary compensatory increase of sympathetic nervous system outflow (147; 50; 131; 138; 109). A subset of neuropathic patients with POTS may have a mild small-fiber neuropathy with abnormalities of unmyelinated nerve fibers in the skin as well as reduced myocardial postganglionic sympathetic innervation (45). Patients with neuropathic POTS have normal sympathetic neuronal release of norepinephrine in the arms but less norepinephrine release and corresponding sympathetic activation in the legs (54). Patients with POTS and hypovolemia also have inappropriately low levels of standing plasma rennin activity and aldosterone compared with normovolemic patients, indicating disruption of the renin-angiotensin-aldosterone axis contributing to hypovolemia and impaired sodium retention, possibly from impaired sympathetic modulation of renin release due to partial sympathetic denervation involving the kidney (109). Some patients with neuropathic POTS report symptom onset after a febrile illness (presumed to be an immune-mediated postviral autonomic neuropathy) or after pregnancy, immunizations, surgery, sepsis, or trauma (131; 109; 154). Ganglionic acetylcholine receptor antibodies are detectable in 10% to 15% of patients with neuropathic POTS (157; 154). POTS with acetylcholine receptor antibodies is a heterogeneous condition associated with preceding infection and high frequencies of syncope and fatigue (74). Persistent, gastrointestinal symptoms and disease severity are significantly associated with the serum level of antimuscarinic acetylcholine receptor (mAChRs) antibodies (150). Other cases of neuropathic POTS have recognized causes of autonomic neuropathy, including diabetes mellitus, amyloidosis, sarcoidosis, alcoholism, systemic lupus erythematosus, Sjögren syndrome, heavy metal intoxication, paraneoplastic neuropathies, and following some forms of chemotherapy (eg, with vinca alkaloids).

Central hyperadrenergic postural orthostatic tachycardia syndrome is an uncommon form of postural orthostatic tachycardia syndrome (representing approximately 10% of patients with POTS) thought to result from a primary excessive sympathetic nervous system discharge that secondarily affects the blood vessels, heart, and kidneys (59). Such patients often have extremely high upright norepinephrine levels, often higher than 1000 pg/ml and occasionally higher than 2000 pg/ml (109). Central hyperadrenergic POTS is often associated with orthostatic hypertension (109). At least some of these cases are due to dysfunction or blockage of the norepinephrine transporter that clears norepinephrine from the synaptic cleft. A norepinephrine transporter point mutation has been identified in a kindred with central hyperadrenergic POTS (OMIM #604715) (133; 122), and various drugs that inhibit the norepinephrine transporter (eg, most antidepressants and cocaine) are associated with marked orthostatic tachycardia and increased upright plasma norepinephrine concentrations; these drugs also profoundly reduce baroreflex control of sympathetic tone, increase responsiveness to vasoactive medications, and attenuate the response to sympathetic stimuli (132; 151).

Mast cell activation disorders may overlap with postural orthostatic tachycardia syndrome (134; 109; 58). Symptoms can include episodic flushing, dyspnea, headache, lightheadedness, dizziness, palpitations, excessive diuresis, nausea, vomiting, and diarrhea. Flushing can be triggered by prolonged standing, exercise, the premenstrual portion of the ovulatory cycle, meals, and sexual intercourse (109). Patients with mast cell activation disorders may also have a hyperadrenergic response to standing with both orthostatic tachycardia and hypertension. It is not clear whether mast cell activation produces a hyperadrenergic response via vasoactive mediators or whether sympathetic stimulation causes mast cell activation via release of norepinephrine and neuropeptide Y (05; 109).

The role of inflammatory mediators in POTS is unclear, but sympathetic activation in POTS is associated with increased circulating interleukin-6 in both lean and obese patients (98).

Although POTS is typically thought to be sporadic, familial cases have been identified (108). In affected families, autonomic dysfunction appears to be transmitted as an autosomal dominant trait with incomplete penetrance and a skewing of the sex ratio (108). Affected individuals are predominantly female (72% or approximately five of seven cases are female).

Epidemiology

Postural orthostatic tachycardia syndrome has a distinct female predominance, with about 80% of cases occurring in females (27; 156). The prevalence ranges between 0.2% and 1.0% in developed countries (27).

Postural orthostatic tachycardia syndrome primarily affects women of childbearing age, with 80% to 90% of cases being women and most cases occurring between the ages of 15 and 50 years (53; 121; 86; 109; 38; 154; 91; 12). Onset frequently occurs following pregnancy, major surgery or trauma, or presumed viral illness (109; 12). Symptoms in women are frequently exacerbated during the premenstrual phase of the ovulatory cycle (109). A smaller proportion (10% to 15%) has a family history of orthostatic intolerance (154).

There is a strong association between POTS and joint hypermobility or Ehlers-Danlos syndrome (124; 06; 13). In adolescents, over half have joint hypermobility (either Ehlers-Danlos syndrome or hypermobility spectrum disorder), and more than one third have a putative autoimmune or inflammatory trigger including infection, surgery, or trauma (12). However, “the purported association of these entities stems from an overlapping pool of vague, subjective symptoms, which is inadequate evidence to conclude that any such relationship exists” (70).

Anecdotal reports of POTS onset following COVID-19 infection (60; 11; 56; 101; 02; 46; 69; 23; 26; 28; 77; 126) or less commonly following vaccination for COVID-19 infection (119; 48; 127; 76) or improvement in POTS following COVID-19 infection (95) do not by themselves establish a causal association. The very fact that all these disparate anecdotes have been reported should cast sufficient doubt that they could all be causally related to COVID-19 or to vaccination for COVID-19. Formal epidemiologic studies (eg, case-control studies) are necessary to begin to establish such a causal relationship. Although a large cohort study did find a possible association between POTS and COVID-19 vaccination, there was a far stronger link with SARS-CoV-2 infection (71; 77; 126).

POTS has significant negative effects on employment, economic status, and quality of life for affected individuals, although existing studies are quite limited and appear biased by strong relationships with patient advocacy groups, even to the point of study design and execution (14).

Differential diagnosis

Confusing conditions

Numerous patients who do not meet criteria for postural orthostatic tachycardia syndrome are nevertheless given that diagnosis by providers for patients with postural symptoms without tachycardia, orthostatic tachycardia without symptoms, and those with orthostatic tachycardia but another overt cause for excessive tachycardia (114).

The differential diagnosis of POTS includes presyncopal dizziness (eg, orthostatic hypotension), disequilibrium, prolonged bed rest or deconditioning, medication-induced autonomic dysregulation, symptomatic secondary orthostatic tachycardia (eg, due to active bleeding, anemia, dehydration), hyperthyroidism, anxiety with hyperventilation syndrome or panic attacks, pheochromocytoma, multiple endocrine neoplasia type 2B, neurally mediated presyncope or syncope, chronic fatigue syndrome, and mitral valve prolapse syndrome (66; 109; 65).

Postural orthostatic tachycardia syndrome is often misdiagnosed as anxiety with hyperventilation syndrome or panic disorder, but much of the anxiety attributed to patients with POTS appears to be due to a misinterpretation of the physical (somatic) symptoms of a hyperadrenergic state (eg, palpitations) (109).

Paroxysmal hyperadrenergic symptoms can also occur in patients with pheochromocytoma, but (in comparison with postural orthostatic tachycardia syndrome patients) those with pheochromocytoma do not have clearly orthostatic symptoms, more commonly have symptoms while recumbent, generally have even higher plasma norepinephrine levels, and have elevated plasma free-metanephrines and urinary metanephrines (72; 24; 78; 42; 109; 155).

Associated or underlying disorders

Exacerbating factors can include exertion, food ingestion, and elevated ambient temperatures (80). POTS has been associated with a wide variety of conditions including diabetes, some autoimmune disorders, infections, trauma, surgery, stress, mastocytosis, and the hypermobility type of Ehlers-Danlos syndrome (Table 1) (05; 134; 109; 80; 09; 160; 41; 58; 01; 20; 85; 84).

Diagnostic workup

Although diagnostic criteria have been developed for POTS, no single set of criteria is universally accepted (100).

Plasma norepinephrine levels should be measured in both supine and standing positions (after at least 15 to 30 minutes in each position). Supine norepinephrine levels are often at the high end of the normal range in patients with postural orthostatic tachycardia syndrome, whereas standing norepinephrine levels are usually elevated (often more than 600 pg/ml), reflecting an increased sympathetic neural tone while upright (109; 154). Although some authorities have incorporated a standing norepinephrine level of higher than 600 pg/ml into diagnostic criteria (109), such levels occur in a minority of patients with POTS (eg, 29% in the Mayo Clinic experience) (154). Plasma norepinephrine levels are not a perfect biomarker for sympathetic nervous system activity in general or in POTS because levels are affected by the release of norepinephrine from sympathetic neural activity and from adrenomedullary stimulation, leakage from storage vesicles, and by clearance (as a function, for example, of norepinephrine transporter activity) (38).

Blood volume is often low in postural orthostatic tachycardia syndrome patients (31; 55; 149; 110; 109; 115; 154). Low blood volume can be demonstrated with nuclear medicine tests that measure plasma volume or red cell volume. A low 24-hour urinary sodium excretion (less than 100 mEq of sodium per 24 hours) can also be used to indicate a low blood volume (25; 154).

Tilt-table testing is controversial for evaluation of patients with postural orthostatic tachycardia syndrome (109). Because the tilt-table test utilizes passive standing, the patients do not support their own weight or maintain balance and so do not utilize their “skeletal muscle pump.” Although the tilt-table test is fairly sensitive with a 30 bpm threshold for orthostatic tachycardia, it has a low specificity (less than 25%), with many control subjects developing orthostatic tachycardia with tilt-table testing (113; 109; 107).

EKG should be done to exclude an accessory bypass tract or cardiac conduction abnormalities and a Holter monitor helps exclude a reentrant dysrhythmia (especially in patients with paroxysmal tachycardia with sudden onset and offset) (109). MIBG myocardial scintigraphy may help distinguish patients with neuropathic POTS from patients with other forms of orthostatic intolerance (44).

The American Academy of Neurology’s Therapeutics and Technology Assessment Subcommittee has advocated clinical autonomic testing for patients with postural orthostatic tachycardia syndrome (03), although the supporting evidence for this recommendation as applied to clinical practice is limited. Patients with POTS often have an intense pressor response to Valsalva (109). Vagal function is usually preserved (134; 109). An associated mast cell activation disorder in patients with POTS and co-existent complaints of episodic flushing can be diagnosed by measuring urinary methylhistamines in individual 2-hour voids following a severe flushing spell (134; 109).

Management

There is no universally effective therapy for postural orthostatic tachycardia syndrome. Management of POTS includes avoidance of precipitating factors, volume expansion, physical counter-measures, exercise training, pharmacotherapy, and behavioral-cognitive therapy. Existing medications should be reviewed, and any potentially contributory medications should be withdrawn, especially vasodilators, diuretics, yohimbine, and medications that inhibit the norepinephrine transporter (eg, many antidepressant and attention deficit disorder medications) (132; 158; 109). Potentially underlying causes of secondary POTS (eg, diabetes, amyloidosis) should be sought and treated.

Nonpharmacological treatments. Nonpharmacological treatment can include increasing fluid/salt intake, increasing aerobic exercise, lower-extremity strength training, and compression stockings, as well as counseling and training for management of pain or anxiety and family education (34; 35; 36; 57; 153). Aggravating factors (eg, dehydration, extreme heat) should be avoided. Increasing fluid intake to 8 to 10 cups (2.0 to 2.5 liters) per day and increasing dietary salt to 200 to 300 mEq of sodium per day will help expand blood volume, but note that a liberal salt diet is usually insufficient to achieve this level of salt intake, so salt tablets (NaCl 1 gm taken orally, three times daily) may be required. Salt supplementation may improve symptoms, plasma volume, and orthostatic responses in patients with POTS (161). A 24-hour sodium excretion of less than 124 mmol per 24 hours is helpful as an indicator of the effectiveness of salt supplementation in children and adolescents (165). Regular light aerobic and resistance exercise is beneficial (162; 154; 34) and should be encouraged as it will also help decrease deconditioning and increase blood volume. However, vigorous exercise may aggravate symptoms because of intramuscular and cutaneous vasodilation that accompanies exercise and because there may be straining that increases intraabdominal and intrathoracic pressures and decreases venous return to the heart; prolonged fatigue is also a concern in these patients. A cautious escalation of exercise, maintaining the heart rate within the target range, will help avoid a counterproductive exacerbation of symptoms that could discourage further efforts. Moderate compression (30 to 40 mmHg) thigh-high stockings (or preferably either waist-high compression stockings or thigh-high compression stockings plus an abdominal binder with an application pressure of 20 mmHg to help compress the splanchnic circulation) will help minimize peripheral venous pooling and enhance venous return, cardiac filling, and cardiac output (109; 154). As in patients with orthostatic hypotension, such stockings are difficult to put on and are uncomfortable to wear, so compliance is often a problem. Similarly, abdominal binders are often poorly tolerated.

Compared with a sham device, an impedance threshold device to increase inspiratory resistance and increase negative intrathoracic pressure improves heart rate control in patients with POTS during head-up tilt for a brief period (10 minutes) (37). It remains to be seen whether this approach will have clinical utility.

A neck compression collar has also been reported to alleviate orthostatic symptoms in patients with POTS (93).

Pharmacological treatments. There are little high-quality data about the effectiveness of individual medications in the treatment of POTS (47). No medications for POTS have been studied with well-designed, long-term, randomized clinical trials; therefore, no medications are presently approved by the U.S. Food and Drug Administration for treatment of POTS.

Fluid loading with an oral rehydration solution improved short-term orthostatic tolerance in a small, controlled study, suggesting that is a convenient, safe, and effective therapy for short-term relief of orthostatic intolerance (82).

Pharmacological treatment can include beta-blocking agents to blunt orthostatic increases in heart rate, alpha-adrenergic agents to increase peripheral vascular resistance, mineralocorticoid agents to increase blood volume, and serotonin reuptake inhibitors (57).

Limited randomized crossover trials, open-label trials, pharmacological properties, and clinical experience suggest that fludrocortisone, clonidine, midodrine, beta-blockers, pyridostigmine, and selective serotonin reuptake inhibitors provide partial relief in selected patients (33; 112; 49; 109; 154; 16; 35; 62; 153; 167; 152).

Other agents suggested to be helpful in improving orthostatic tolerance and some of the hemodynamic abnormalities of POTS include the following: erythropoietin, a hematopoietic growth factor and glycosylated protein hormone; desmopressin (DDAVP), a synthetic analogue of the naturally occurring hormone vasopressin that acts as an antidiuretic hormone to conserve water in the kidneys; octreotide, a somatomedin analogue; ivabradine, a selective sinus node blocker with no effect on blood pressure; and phenylephrine, an alpha-1-adrenergic agonist (141; 49; 63; 64; 81; 92; 17). Acute decompensation can be treated with intravenous saline (40; 109; 154).

When hypovolemia is known or strongly suspected, the mineralocorticoid fludrocortisone acetate (a synthetic aldosterone analogue) at a dose of 0.05 to 0.10 mg orally at bedtime can help expand plasma volume through sodium retention, in addition to other effects that act to increase peripheral resistance by increasing alpha-adrenergic receptor sensitivity. Fludrocortisone is generally used at night when the body experiences the greatest natriuresis and diuresis. At these doses, fludrocortisone is generally well tolerated, but side effects can include hypokalemia, hypomagnesemia, acne, supine hypertension, peripheral edema, congestive heart failure, exacerbation of peptic ulcer disease, hyperglycemia, and steroid myopathy. High-dose therapy is associated with an increased risk of sudden death. Acute volume loading with saline does not improve cardiovascular responses to exercise in POTS, despite improvements in resting hemodynamic function (29).

Other agents that can be considered to help expand blood volume include desmopressin and erythropoietin.

Midodrine, an alpha-sympathomimetic drug, functions as a vasopressor in patients with neurogenic orthostatic hypotension or in postural orthostatic tachycardia syndrome. Midodrine is probably an effective treatment for the neuropathic form of POTS, but not for hyperadrenergic POTS (125). In adults, midodrine is administered orally at a dose of 2.5 to 10 mg, three times daily. The last dose should be taken 3 to 4 hours before bedtime to minimize supine hypertension. Side effects of midodrine include marked increases in supine hypertension, piloerection (goosebumps), paresthesias, pruritus (especially scalp), nausea, and urinary retention and hesitancy in males. Midodrine should be avoided or used with caution in patients with coexisting ischemic heart disease, cardiac dysrhythmias, or peripheral vascular disease. Midodrine is also used to treat children with POTS, but it is not universally effective (167); elevated levels of plasma copeptin (above 10.482 pmol/L) is a predictive biomarker for the likelihood of successful treatment of children with POTS using midodrine hydrochloride (167).

Central sympatholytic medications can be helpful in suppressing sympathetic nervous system tone in patients with the central hyperadrenergic form of postural orthostatic tachycardia syndrome. For example, clonidine, a presynaptic alpha2 receptor agonist that acts centrally to decrease sympathetic tone, can be tried at a dose of 0.05 to 0.2 mg orally two times a day, or alternatively methyldopa, a false neurotransmitter, can be tried at a dose of 125 to 250 mg orally three times a day (53; 109). Side effects of clonidine include erythema, xerostomia, dizziness, fatigue, and somnolence.

Low-dose beta-blockers, such as propranolol 10 to 20mg orally two to four times a day, can help with heart rate control but need to be used cautiously, especially at higher doses that may produce orthostatic hypotension and fatigue (109; 111; 35). Patients with elevated standing norepinephrine levels generally respond better to treatment with beta-blockers than those with lower standing norepinephrine levels (154; 164). Low-dose oral propranolol (20 mg orally) significantly decreases tachycardia and improves symptoms, whereas higher-dose propranolol (80 mg orally) may worsen symptoms (111).

In a study of the short-term efficacy of combined treatment with a reduced-osmolarity oral rehydration salt formulation and propranolol in children with POTS, the frequency of syncopal attacks was significantly reduced and the symptom scores for orthostatic intolerance were improved with this regimen (163).

Pyridostigmine has been found to be helpful in the treatment of neurogenic orthostatic hypotension (129; 135; 136; 128), has theoretical potential in postural orthostatic tachycardia syndrome because of its actions at the autonomic ganglia and peripheral muscarinic parasympathetic receptors, and has been reported in a randomized crossover trial to be helpful in patients with POTS (112; 109). By its peripheral actions, it helps to restrain the heart rate; and by its ganglionic effects, it may augment the cholinergic efferent limb of the baroreceptor reflex while standing (and yet have little if any effect on augmenting blood pressure while recumbent). Pyridostigmine dosages of 30 to 60 mg orally two times a day alone or in combination with propranolol have been recommended for patients with POTS (109; 62). Because of its cholinergic effects, pyridostigmine may exacerbate diarrhea-predominant irritable bowel symptoms and so be poorly tolerated in some patients with POTS, and only approximately half of patients can tolerate pyridostigmine for this reason (109; 62).

The safety and efficacy of ivabradine have been evaluated for POTS in a single, small, short-term, randomized cross-over trial in which it was safe and effective in significantly improving heart rate and quality of life in patients with hyperadrenergic POTS (152). Other available information on ivabradine in POTS comes from prospective open-label trials, retrospective cohort studies, and various case reports (22; 39). Ivabradine is a selective and specific inhibitor of the I(f) current in the sinoatrial and atrioventricular nodes that acts to decrease heart rate and myocardial oxygen consumption at rest and during exercise (22; 39). Ivabradine provided symptomatic relief of POTS without blood pressure lowering (22; 39). The most common side effects were dizziness, nausea, headache, and fatigue, but often did not result in discontinuation of treatment (39). A randomized controlled trial is needed, but for now ivabradine is an option for patients with POTS who have failed or are unable to tolerate other treatment options, especially for those with hyperadrenergic POTS (39; 152).

Surgical therapies. In intractable cases, atrioventricular node ablation and dual chamber pacemaker implantation has been anecdotally reported as helpful (92).

An anecdotal case has been reported in which resolution of POTS occurred after percutaneous alcohol sympatholysis at T2 for comorbid craniofacial hyperhidrosis, both conditions are considered disorders of sympathetic regulation (15).

Another anecdotal case has been reported in which resolution of POTS occurred after implantation of a vagal nerve stimulator for intractable childhood-onset epilepsy (104). An ongoing clinical trial is evaluating the effects of transdermal vagal nerve stimulation and POTS (104).