Orthostatic Intolerance

Orthostatic intolerance is a confusing topic. Some of the confusion originates from recent appreciation of the condition's clinical variants, some originates from the emerging understanding of its diverse underlying pathophysiologies, and some originates from its nomenclature, which seems to change at least every year.

The term orthostasis literally means standing upright. Orthostatic intolerance (OI) may be defined as "the development of symptoms while upright, during standing that are relieved by recumbency." Although the use of a term such as orthostatic intolerance logically implies the presence of signs and symptoms when upright, variations in blood flow and blood pressure (BP) regulation are also found when supine or sitting, but these may require special equipment to detect and therefore may not be easily discernable until orthostatic stress becomes evident.

Standing successfully requires the interplay of blood volume, physical, neurologic, humoral, and vascular factors that compensate for the effects of gravitational venous pooling. Under ordinary conditions, acute humoral alterations have little to do with the initial response to standing upright but may play an important role during chronic orthostatic intolerance or relatively late during upright standing. Also, changes in such factors may affect resting or tonic responses and thus may influence overall vascular regulation through background effects.

If symptoms initiate while supine, then there is no OI. Transient OI is commonly experienced during dehydration or infectious disease. Typical signs and symptoms include: loss of consciousness or lesser cognitive deficits (memory loss, decreased reasoning and concentration); visual difficulties; lightheadedness; headache; fatigue; either increases of BP (hypertension), decreases of BP (hypotension); weakness; nausea and abdominal pain; sweating; tremulousness; and exercise intolerance.[1] Unless in harm's way (e.g., standing on a cliff), OI is not lethal. Some OI findings, such as nausea and sweating pertain directly to autonomic activation. However, loss of consciousness, severe lightheadedness, and neurocognitive loss relate to central nervous system (CNS) dysfunction and oblige recumbence.

CNS symptoms are produced by altered brain blood flow perhaps involving the brainstem. Cerebral Blood Flow (CBF) velocity is shown in the image below for two common forms of OI, vasovagal syncope (VVS) and postural tachycardia syndrome (POTS). Cerebral autoregulation may be compromised[2] as in POTS[3] and VVS[4] and may be reduced by hyperventilation and hypocapneic cerebral vasoconstriction.[5] Involuntary postural hyperventilation, mostly hyperpnea, is observed in all VVS patients[6] and 50% of POTS patients in our laboratory.[7] Trigeminal, sympathetic, or parasympathetic nerve activity may also affect orthostatic CBF.[8]

Orthostatic intolerance is not always due to autonomic or other compensatory dysfunction and can be due to inadequate responses of compensatory mechanisms to environmental stressors. For example, someone who is dehydrated may be unable to stand up without resulting orthostatic hypotension but no autonomic dysfunction is present and therefore neurogenic orthostatic hypotension is not present; instead, the autonomic and other regulatory systems cannot adequately compensate for the loss of circulating blood volume.

On the other hand, neurogenic OI, in which adrenergic vasoconstriction is defective, is associated with primary autonomic failure; patients with related diseases cannot remain standing and have detectable autonomic abnormalities in all postural positions. Therefore, OI encompasses any condition with blood flow, heart rate, and cardiorespiratory regulation inadequacy that are demonstrable in the upright position but may also have abnormal findings in all positions. Under such circumstances, OI is often the most obvious manifestation of a more widespread impairment in integrative neurovascular physiology.

The various types of OI are discussed in the sections that follow.

Initial orthostatic hypotension

Orthostatic hypotension (OH) is defined as a sustained reduction of systolic BP >20 mmHg or diastolic BP >10 mmHg within 3 minutes of standing or following head-up tilt to ≥60o.[9] The requirement of a sustained reduction rules out initial orthostatic hypotension (IOH). This definition is relatively recent and was assembled by a consensus panel in 2011.[9] Before that, there was no consistent definition of OH. Non-neurogenic OH can be caused by drugs, dehydration, blood loss, age, and illnesses that secondarily cause acute or chronic hypovolemia. Neurogenic OH is identified with autonomic failure due to inadequate release of norepinephrine from sympathetic vasomotor neurons leading to vasoconstrictor failure.[9] Neurogenic OH is rare in the young since most causes of autonomic failure are acquired with age either as a primary (e.g., pure autonomic failure, PAF) or secondary (diabetes) disease. Autonomic failure can be primary with pre-ganglionic, post-ganglionic, or both(e.g., Parkinson’s disease) forms of sympathetic dysfunction.[10] However, there exist congenital genetic variants such as Familial Dysautonomia (Riley-Day syndrome)[11] and the exquisitely rare dopamine beta-hydroxylase deficiency (DBH deficiency).[12] Autonomic failure can be autoimmune[13] and may present with the post-infectious Guillain-Barre syndrome although autonomic dysfunction seems to have little effect on ultimate outcome.[14] Autonomic failure is most commonly acquired as a secondary aspect of systemic disease such as diabetes.[15] Sympathetic cardiac denervation is a central aspect of Parkinson’s disease,[16] and may be found in other forms of autonomic failure. Cardiac parasympathetic innervation is also often defective resulting in a steady fall in BP with little reflex tachycardia during orthostatic challenge as shown in the image below.

Non-neurogenic OH is relatively common in the young. It can be caused by drugs or hypovolemia (e.g., dehydration, hemorrhage). It is by far the most common form of OH in the young. There is no failure of autonomic function but rather incomplete ANS compensation for excessive non-autonomic stressors.

Neurogenic OH (NOH) signifies serious autonomic illness. It is identified with true autonomic vasoconstrictor failure due to the inadequate release of norepinephrine from sympathetic nerves[9] and HR may not increase appropriately with standing.

Postural tachycardia syndrome

Postural tachycardia syndrome (POTS) is defined by day-to-day symptoms of orthostatic intolerance (OI) associated with excessive upright tachycardia but not with hypotension (see image below).[17, 18]

Excessive tachycardia in adults is defined by an upright increase in HR exceeding 30 bpm or to a heart rate exceeding 120 bpm. Recall that the normal HR response to orthostasis is an increase in HR while autonomic failure patients often have no significant increase in HR when upright. Larger heart rate increments are observed in the young with POTS,[19] which is important to know in avoiding over-diagnosis. Symptoms of OI must be concurrent with the excessive tachycardia. No symptoms, no POTS. Tachycardia and concurrent symptoms are very often observed during extremely prolonged orthostatic testing which are therefore to be avoided if the specific diagnosis of POTS is to be made. POTS has often been divided into subgroups designated "neuropathic POTS", in which it is assumed that partial sympathetic denervation or adrenergic hypoactivity is present, and "hyperadrenergic POTS", in which upright adrenergic overactivity dominates the picture.[20]

Neuropathic POTS

As originally described, neuropathic POTS is caused by decreased sympathetic adrenergic vasoconstriction in the lower limbs, associated with reduced leg norepinephrine spillover[21] and reduced vasoconstriction of the lower extremities.[22] There is often increased blood flow ("high flow") in the lower extremities even while supine. Another neuropathic variant has normal lower extremity hemodynamics ("normal flow") but decreased regional sympathetic adrenergic vasoconstriction in the splanchnic circulation.[23] Neuropathic POTS can represent an autoimmune autonomic neuropathy.[13] Thus, when upright, neuropathic POTS patients have greater than normal redistribution of blood to the dependent vasculature causing baroreflex mediated tachycardia and vasoconstriction. The cardiac baroreflex response is also blunted in POTS.[24] Central hypovolemia can also result in hyperpnea and hypocapnia in nearly 50% of patients[7] through a baroreflex mediated mechanism.[25]

Hyperadrenergic POTS

The tachycardia of hyperadrenergic POTS is caused by increased pre-synaptic or post-synaptic adrenergic potentiation. This might include central sympathetic activity and increased sympathetic nerve activity. Increased supine sympathetic activity has been reported,[17] but not universally.[26] To date, our laboratory has only observed increased upright muscle sympathetic activity in one POTS patient. One cause of hyperadrenergic POTS is increased synaptic norepinephrine. The norepinephrine transporter deficiency heterozygote[27] is the prime example of this mechanism but has been found as an autosomal mutation in only one pedigree. Less severe, possibly epigenetic norepinephrine transporter (NET) deficiency has also been demonstrated recently and may have a wider prevalence.[28]

Alternative considerations of mechanism include modulation of the adrenergic synapse through enhanced norepinephrine synthesis and release, and enhanced post-synaptic affinity, which may be modulated by local and humoral transmitters. Thus, for example, the reciprocal actions of nitric oxide (NO) and angiotensin-II respectively reduce and enhance adrenergic activity. The role for NO as an inhibitory neurotransmitter is now well known.[29] Nitrergic NO released from nerves having parasympathetic activity act at pre-synaptic and post-synaptic sites to decrease adrenergic transduction,[30] the process by which a sympathetic nerve impulse causes vascular smooth muscle contraction. This includes reduction of the release and binding of norepinephrine from the neurovascular synapse,[31] interference with post-synaptic neurotransmission,[32] chemical denaturing of norepinephrine,[33] and down-regulation of adrenergic receptors.[34]

Conversely, studies of sympathoexcitation show that angiotensin-II acts through AT1 receptors to increase production of reactive oxygen (ROS) and nitrogen species within the brain at pre-synaptic sympathetic neurons[35] and act in the periphery where they produce pre- and post-synaptic augmentation of sympathetic transduction, and upregulation of adrenergic receptors.[34] In addition, the release and binding of norepinephrine is facilitated,[31] as are the effects of norepinephrine, in the presence of angiotensin-II. This depends critically on the formation of ROS,[36] which also decreases NO,[37] often uncoupling nitric oxide synthase.[38] This mechanism occurs in a variant of "hyperadrenergic POTS" associated with tachycardia, pallor, vasoconstriction ("low flow"), and absolute hypovolemia even while supine.[39] NO, plasma renin, and serum aldosterone are decreased,[40] while plasma angiotensin-II[23] is increased by a defect in ACE-2.[41]

Postural syncope (vasovagal syncope, acute OI, simple faint)

Syncope (fainting) is defined as "complete loss of consciousness due to transient global cerebral hypoperfusion characterized by rapid onset, short duration, and spontaneous complete recovery.”[42, 43] Most syncope is caused by systemic hypotension and reduced cerebral blood flow. It is possible that a cerebrovascular accident could present in similar fashion[44] although it has never been reported in pediatrics. Syncope can be caused by orthostatic hypotension (OH), which has already been discussed. OH is easily ruled out by a 3-minute standing test (see the figure below).

Syncope is divided among cardiovascular syncope, frequently arrhythmic or structural cardiopulmonary disease, and reflex or neurally mediated syncope. Cardiogenic syncope can be life-threatening and has a poor prognosis unless the cardiac pathophysiology is treated. Cardiogenic syncope is not OI because recumbency does not specifically produce improvement. Reflex syncope has a good prognosis.[45] Reflex syncope includes vasovagal syncope and situational syncope including carotid sinus syncope,[46] which is essentially unknown to pediatrics. Deglutition,[47] defecation,[48] micturition,[49] and cough[50] syncope are rarely observed in the young; and hair grooming[51] and adolescent stretch[52] syncope variants are particular to adolescence. Fainting during exercise raises a "red flag" for cardiogenic syncope and further sport activity should be curtailed until cardiac evaluation is complete. Nevertheless, the most common cause of exercise-related syncope in the young isVVS.[53] Cardiogenic syncope, although not usually posturally related, cannot be automatically dismissed following a first faint. Therefore, the first and consequent episodes prior to cardiovascular evaluation should be treated as urgent. If fainting is subsequently found to be non-cardiogenic then urgency is reduced and simple maneuvers often suffice to acutely deal with the circumstances. Cardiologists are often involved in early evaluation of syncope because initial assessments should determine whether the condition is of cardiac or non-cardiac etiology. Cardiac diseases, when found, are treated specifically. Cardiac syncope may first manifest during exercise, which puts the most physiologic stress on coronary, systemic, and pulmonary circulations and on overall cardiac function. Exercise-related syncope or syncope with cardiac symptoms (e.g., tachycardia, chest pain) indicates a search for underlying heart disease. However, exercise-related syncope in the young is most often noncardiogenic and thephysiology may resemble simple faint.

However, even when neurocardiogenic hypotension is involved, the pathophysiology and clinical history may be more complex, involving changes in respiration with dyspnea and chemoreflex and baroreflex dysfunction that might suggest exercise-provoked heart disease. Still, despite the relative degree of concern attendant to fainting in the young athlete, most such episodes are noncardiogenic in origin. Nevertheless, this should not obviate the need to evaluate such patients for potentially lethal cardiac disease. Cardiogenic syncope is well described elsewhere and is not discussed herein.

Postural syncope and emotional or phobic syncope comprise VVS, the largest subgroup within the reflex syncope category.[54] Regional or system-wide loss of vasodilation is an element in all VVS, at least as a terminal event; it may not always be due to loss of sympathetic nerve activity. Postural syncope is acute OI and approximately two-thirds of patients are female, while teenage boys with this tend to be tall, thin, and rapidly growing.[54] Loss of consciousness is often preceded by a prodrome of OI symptoms, particularly lightheadedness, nausea, sweating, weakness, and blurred vision. Traditionally, postural syncope was believed to be due to reflexes from a hypercontractile, underfilled heart analogous to the Bezold-Jarisch reflex.[55] Evidence to the contrary has accrued; such stimulus would be short-lived. Because of baroreceptor unloading[56] very few afferent nerves were excited in the original experiments by Oberg and Thoren in the moribund hemorrhaged cat.[57] VVS can occur ina ventricular denervated transplant recipient[58] and the heart is neither empty nor hypercontractile prior to syncope.[59] As yet we do not completely understand the pathophysiology of simple faint.[60]

In the most common variant of postural faint occurring in young patients, postural faint comprises three stages (see the image below), which strongly resemble the circulatory changes found during hemorrhage.[61]

After initial orthostatic hypotension and restoration of circulatory homeostasis, BP stabilizes while HR increases in Stage 1. BP stability distinguishes postural faint from true OH. BP often exhibits rhythmic fluctuations during this stage referred to as “Mayer waves”[62] with an approximate 10-second period (0.1Hz). Similar periodicity is shared by fluctuations in heart rate, sympathetic nerve activity, and peripheral resistance. The fluctuations are the closed loop time for sympathetic baroreflex response (i.e., the time it takes for detection and compensation for BP changes).[63] Oscillations are accentuated during central blood volume reductions such as occur during orthostasis. During this stage total peripheral resistance increases to sustain BP in the face of a reduced cardiac output (see the image below).

During Stage 2, BP slowly declines as the baroreflex increases HR further. The decrease in BP is most often related to decreased cardiac output,[46] even though sympathetic activity[64] and peripheral arterial resistance[65] are sustained. Thereafter, resistance and pressure oscillations decrease despite sustained sympathoexcitation. Hyperpnea and hypocapnia occurs at this stage in most patients.[6] In some patients Stage 2 is abbreviated. This is especially true for patients with convulsive syncope in whom episodes occur abruptly in association with asystole.

Convulsive or asystolic syncope (see the image below) is distinguished from epilepsy by decreased EEG activity in the former and by nearly immediate resolution of opisthotonic posturing by recumbence. Despite appearances, asystolic faints are not cardiogenic but reflex mediated and are a relatively uncommon form of simple vasovagal fainting that may also be found in phobic fainting.

Several mechanisms have been proposed for VVS in some patients. VVS patients with decreased resting BP had reduced tyrosine hydroxylase and NE synthesis, and a group of normotensive had excess NET.[44] A selective deficit of splanchnic vasoconstriction and venoconstriction has also been demonstrated.[22] Prodromal OI symptoms begin during the Stage 2 and clinicians might therefore entertain a diagnosis of POTS in the laboratory setting. Clinical history offers the best way to distinguish patients with acute episodic faints with long periods free of symptoms (postural syncope) from POTS, in which symptoms are chronically present; Indeed, the prodrome of simple faint and the signs and symptoms of POTS are similar because they may have similar initial pathophysiology – excessive reduction in central blood volume resulting in reflex tachycardia.[22, 66, 23] Postural fainters, corresponding to pale and vasoconstricted, hyperadrenergic POTS patients are not generally observed. Forthe most part, in our experience, POTS patients have day-to-day symptoms but do not faint, while syncope patients have episodic faints but not daily symptoms. This distinction has become less clear with time. Thus, some chronic OI (POTS) patients faint, and some episodic fainters also have underlying daily symptoms of OI. However, fainting of POTS patients in laboratory must be viewed cautiously and cannot, by itself, be regarded as proof of real-world fainting. A “real-world” clinical history compatible with fainting is compulsory.

In the last stage, Stage 3, CBF, BP, and HR rapidly fall in that order, seemingly defying BP–CBF causality.[67] Similar effects are often seen in nonlinear systems of all kinds whenever a sufficiently strong external signal entrains linked signals. Thus, recent work shows that both cardiovagal and sympathetic baroreflex efferent arms are impaired prior to fainting, and Mayer waves disappear. Similarly cerebral autoregulation becomes impaired with entrainment of CBF, BP, and HR by an extrinsic signal, which may be hyperpneic respiration.[4, 68] Why baroreflex integrity is lost is not yet known, but this results in abnormal BP-HR and BP-MSNA functional relationships such that HR, BP, and sympathetic nerve activity all decrease resulting in bradycardia, hypotension, and sympathetic silence.[69] The faint is associated with marked systemic vasodilation while CBF falls with declining BP. Recent work challenges the necessity of sympathetic silence as the precipitant of the finalhypotension.[44] While vasodilation always occurs, the sympathetic baroreflex can fail with or without sympathetic silence because of a loss of the functional relationship between blood pressure and sympathetic activation. Loss of functional connections between BP and sympathetic nerve activity, but not heart rate, occurs in patients with vasodepressor syncope where vasodilation without bradycardia occurs. While there is a loss of the sympathetic efferent baroreflex causing progressive loss of compensatory vasoconstriction, the cardiovagal baroreflex remains intact.

POTS and postural syncope are both associated with hyperpneic hyperventilation.[6, 70, 7] Hyperpnea and resultant hypocapnia precede unconsciousness in virtually every vasovagal syncope patient.[6] Hypotension and bradycardia might be explained by the pulmonary stretch reflex unfettered by compensatory baroreflex effects.[71, 68] The cause of hyperpnea is unclear but may relate to the ventilatory efferent arm of the arterial baroreflex.[25] Similar findings of hyperpnea are found in approximately 50% of POTS patients with central hypovolemia who do not faint.

Very frequent or extremely prolonged syncope can point to psychogenic syncope or conversion responses. These are easily distinguished from true syncope in the laboratory because there is no hypotension or reduced CBF, but attacks may be real to the patient. Some patients may have had bonafide VVS interspersed with more frequent psychogenic episodes as learned or conditioned responses. One school of thought suggests that such patients actually experience the symptoms of true VVS without the signs.

Orthostatic intolerance is common but often misunderstood. Investigation of the condition is an evolving field of integrative physiologic study. Postural VVS is identified with acute orthostatic intolerance. Despite its ubiquity, scientists do not yet understand why some people faint. POTS is identified with chronic orthostatic intolerance. POTS, however, remains a heterogeneous entity, likely of varied etiologies. Until better understanding is achieved, treatment remains more guesswork than science.

Normal orthostatic regulation

Orthostasis stresses regulatory capabilities of the circulatory system[72] including an intact heart, intact vascular structure and function, adequate blood volume, and intact physical pumps comprising the skeletal muscle pump - leg muscles that compress leg veins - and the respiratory-abdominal muscle pump, which enhances systemic venous return during respiration.[73, 74] Upright stance causes dependent venous pooling. Muscle pumps propel blood back to the heart when upright and during exercise.[73] Enabling the skeletal muscle pump forms an important class of physical “countermeasures” against orthostatic intolerance.[75, 76]

Apart from muscle pumps, rapid orthostatic circulatory adjustments depend on the autonomic nervous system (ANS) comprising sympathetic and parasympathetic arms forming a framework for heart rate (HR) and blood pressure (BP) stability. The myogenic response[77] and flow dependent mechanisms[78] primarily act to ensure tissue level perfusion and autoregulation. The sympathetic arm acts through its primary vascular neurotransmitter norepinephrine[79] , and co-transmitters neuropeptide Y and ATP[80] to produce arterial vasoconstriction and venoconstriction, increase cardiac contractility and HR, stimulate adrenal epinephrine release, and control the neuroendocrine and vascular function of the kidney and long term BP control. The parasympathetic arm via vagal nerve efferents contributes most to heart rate changes at rates less than the intrinsic rate.[81] Recent work indicates strong vagal influences on sympathoexcitation[82] and important effects on nitrergic (nitric oxidecontainingnerves) vasodilation of the large cerebral arteries.[83] Endocrine and local systems (e.g., nitric oxide, local angiotensin) impact the vascular milieu but are slower to develop, often acting to modulate or set tonic activity of the ANS.[80] Autonomic control of HR and BP during orthostasis is provided by subsystems designated “baroreflexes” (pressure reflexes), loosely grouped as arterial and cardiopulmonary baroreflexes, which maintain BP under changing conditions such as orthostasis.[84]

When supine, blood volume within the central thoracic vasculature is relatively large, although a disproportionate amount (25-30%) of blood is stored within the splanchnic venous reservoir.[85] Standing transfers >500ml of central blood caudally, further increasing the volume of the splanchnic pool and filling veins of the lower extremities.[86] An initial period of instability follows, denoted “initial orthostatic hypotension”[87] (see the image below), during which BP can decrease by 30% or more, reaching its nadir at 10-20 seconds after standing. Reflex tachycardia occurs. BP is restored within 30-60 seconds. IOH results from the normal delay of arterial baroreflex detection and response to gravitational blood volume redistribution. Lightheadedness, postural instability, and occasionally brief loss of consciousness occur and can be relieved by recumbency making IOH by far the single most common and innocuous form of orthostatic intolerance. Thereafter, HR decreases butremains elevated compared to supine, and BP is restored by arterial vasoconstriction, by elastic recoil of venous blood in dependent veins, and by active venoconstriction in splanchnic veins.[88]

After IOH recovery, sympathetic nerve activity increases while upright blood volume slowly decreases because of microvascular filtration.[89] Decreased venous return decreases central blood volume and cardiac output (CO) by 20% despite baroreflex mediated vasoconstriction, increased cardiac contractility, and increased HR. Cerebral blood flow velocity (CBFv) decreases by 3-12% partly because of reduced cerebral perfusion pressure of 20mmHg.[90] Cerebral autoregulation (unchanged CBF despite changing BP) is blunted during orthostasis. Unless the muscle pump is evoked, standing still places us at risk for decreased CO and CBF. The normal orthostatic response to tilt is shown in the image below.

Ventricular tachycardia, bradyarrhythmias, and related arrhythmic events are the most common causes of cardiac syncope, but other possible causes include the following:

• Long QT syndrome

• Arrhythmogenic right ventricular dysplasia

• Brugada syndrome

• Cardiomyopathies

• Left ventricular outflow obstruction

• Acute or subacute aortic regurgitation (especially postsurgical or endocarditis-related)

• Myocardial infarction

• Primary pulmonary hypertension

Statistics

Approximately 40% of people will faint during their lives; half of these presenting during adolescence. The peak age for first faint is 15 years old.[91] .

Sex-, age-, and race-related differences in incidence

POTS: Females predominate 3:1, and onset is usually from menarche to menopause.

Non-neurogenic OH is relatively common in the young while neurogenic OH is rare in young people but associated with diabetes, amyloidosis, primary autonomic failure, and Parkinson's disease in older patients.[10] NOH may occur in up to 17% in adults older than 65 years old.[14]

To date, there have been no studies describing the distribution of fainting by racial groups.

Cardiovascular syncope has a poor prognosis unless specifically treated. Reflex syncope has an excellent prognosis.[45] .

Mortality/morbidity

The mortality/morbidity associated with syncope is difficult to evaluate because of its wide range of causes. Patients with cardiogenic syncope accompanying complete heart block, ventricular tachycardia, acute aortic dissection, or pulmonary embolisms are at much greater risk than those with, say, vasovagal syncope. Appropriate clinical evaluations of the cause of syncope are therefore necessary and appropriate.

In many instances, patients with postural syncope experience a prodrome of symptoms. When these occur, patients should be instructed to employ so-called physical countermaneuvers to obviate postural effects. These include the use of bilateral handgrip for 15 seconds before rising as this forestalls IOH by evoking the exercise pressor reflex, which can substantially increase blood pressure. Lower body muscle contraction while seated (e.g., pumping calf muscles) can also help as a preemptive maneuver. Also, lower body muscle tensing of legs, buttocks, and abdomen particularly attenuates the transient arterial blood pressure decrease once standing has occurred and can be potentiated by handgrip. Recumbence and squatting are general measures used to remediate all forms of orthostatic intolerance. Recommendations for patients to increase salt and water intake may also be of help.

Postural tachycardia syndrome (POTS)

Quality of life can be severely compromised in patients suffering from POTS. A few features are common to all variants.

The onset often follows a flu-like illness. Illness may occasionally represent a self-limited autoimmune disease.[13] The role of immune and epigenetic factors remains ill-defined. Some patients have an insidious onset over years, sometimes with a past history of vasovagal syncope (VVS). Some patients have joint hypermobility syndromes.[92] While supine or seated, some patients appear well while others appear pasty and pale. Many patients are unable to remain upright for long periods of time and experience symptoms similar to the prodrome of VVS. BP is typically well maintained and may increase when upright in hyperadrenergic individuals. Prolonged laboratory tilt may provoke VVS.

Cognitive deficits and exercise intolerance are prominent complaints[93] and gastrointestinal symptoms such as dysmotility are reported.[94] Young women may be underweight, and POTS must be differentiated from eating disorders, which can produce POTS-like OI in early stages.

Environmental heat reroutes blood to the skin and makes patients worse. Air conditioning may be required and standing in hot showers untenable. School work may be impaired, and home schooling is common. Colleges are often accommodating because of adaptive scheduling and improved logistics.

A wide variety of pharmacologic therapies are recommended with variable effects including beta ß-blockade, a-1 agonists (midodrine), acetylcholinesterase inhibitors (pyridostigmine), and fludrocortisone acetate (florinef).

Water ingestion is a useful short-lived palliation.[95] Effects are through TRPV4 receptors in the splanchnic vasculature,[96] and ingestion of 16 ounces of water and waiting 20-30 minutes yields benefit for hours. Salt and water loading can help but are often difficult to accomplish.

Even when the cause is known (e.g., NET deficiency) pharmacologic treatment is rarely curative. Most young people improve over time; in others POTS persists.

Postural syncope (vasovagal syncope, acute OI, simple faint)

The initial evaluation of a patient presenting with syncope comprises a detailed history, physical examination, including orthostatic BP measurements, and an electrocardiogram to look for QT prolongation, pre-excitation, and arrhythmia. Obtaining a detailed history is paramount. Historical details that point towards reflex syncope[54] include a history of similar recurrent episodes, whether episode(s) occur exclusively when upright or with change in position, whether they are related to activity such as urination, defecation, deglutition, hair-grooming, or stretch, whether there are predisposing factors such as fear, noxious stimuli, environmental heat, immobilization, whether they follow exercise and whether they are preceded by the prodrome of OI (e.g., nausea, seating, pallor) – a more gradual onset (many seconds to minutes) favors reflex syncope as does a post-drome of pallor, fatigue, and confusion. History that favors an increased likelihood of cardiac syncope include antecedent heartdisease, family history of sudden death, known arrhythmia or arrhythmia risk such as long QT syndrome or pre-excitation, an arrhythmogenic medication history, palpitations preceding the episode, and episodes that occur abruptly, during exercise, or when supine.

Some patients with postural tachycardia syndrome (POTS) may appear pale and malperfused. The majority have a normal appearance as do patients suffering from vasovagal syncope (VVS). A POTS patient, on average, has an increased heart rate. Blood pressure should be normal for age although reports of patients with constitutional low blood pressure exist and can potentially relate to epigenetic down-regulation of tyrosine hydroxylase synthesis. A 10-minute standing test following prolonged recumbency has been validated in adults with POTS but not in children and adolescents. It is important to note that the HR change on orthostasis should not be used alone as the criterion for POTS; symptoms must be present. A 3-minute standing BP test for neurogenic orthostatic hypotension (NOH) has been validated across ages.

Perhaps the best “test” is medical history, which can often diagnose OI based on symptoms relieved by recumbence. Orthostatic stress tests supplement history by evoking OI in the laboratory. The predictive value of lab-induced OI for real world OI is unclear, at least for syncope; in adults older than 40 years, tilt tests do not predict vasovagal syncope (VVS).[97] . Controlled studies have not been performed in younger patients. There is no reference standard for orthostatic testing. Standing without movement may be the most physiologic orthostatic stress, but is complicated by muscle pump activity.[98] Therefore, tilt tables are used to restrict patient movement while passively placing them upright.[99] A recent adult study of POTS compared the diagnostic accuracy of standing for 10 minutes with 60o upright tilt for 10 minutes or longer.[100] Results showed that standing after being supine for 1 hour was at least as good as 10 minute tilt; longer tiltsintroduced excessive numbers of false positives. Standing HR and BP measurements were taken at 1, 3, 5, and 10 minutes. Thus, standing tests for POTS require prior supine rest. In our hands >20 min is needed to reach fluid equilibrium. More dramatic results can be obtained by lower body negative pressure (LBNP),[101] which best simulates hemorrhage but duplicates many OI findings. A combination of LBNP with upright tilt can evoke OI - usually syncope – in everyone. Tests always include measurements of BP, HR, and rhythm, and are supplemented in research laboratories by measurements of beat-to-beat CO, CBFv, regional blood flow, blood volume, sympathetic nerve activity, synaptic norepinephrine spillover,[102] and vascular biopsy.[28]

Instrumentation that measures BP, heart rate and cardiac rhythm, cardiac output (e.g., indicator dilution, inert gas rebreathing), regional blood flow (e.g., ultrasound, venous occlusion plethysmography, impedance plethysmography), and blood volume have all been bundled with clinical tilts. Studies of sympathetic control of orthostasis in conscious humans began in earnest with the use of microneurography to measure peripheral sympathetic nerve activity.[103] Other advanced techniques using sympathetic nerve norepinephrine spillover[102] to measure the effect of adrenergic vasoconstriction on local blood flow[104] and most recently to directly assess the integrity of norepinephrine synthesis and metabolic products by vascular biopsy[105, 28] can be used to find the actual mechanism of OI in sufferers.

Tilt table procedure

Early National Aeronautics and Space Administration (NASA) experiments used a HUT test to evoke autonomic reflexes and vascular responses. This device was first used in 1986 as a clinical testing agent to evaluate syncope. The tilt table is often driven by an electrical motor (although manual tables are also available) and has a supportive footboard; this enables positioning of patients at varying angles of upright tilt. Although an angle of 90° would seem most physiologic, this usually induces excessive false-positive results (i.e., patients with no history of orthostatic intolerance who have orthostatic intolerance induced during testing). Lesser angles such as 60° or 70° are customarily used.

Clinically, the HUT table test is not a particularly accurate or repeatable test for syncope. Even without excessive angles of tilt and without pharmacologic potentiation, about 25% of adolescents with no prior fainting history faint during testing. Moreover, among people who habitually faint, approximately 25-30% do not faint during the test on a given day. Results are not repeatable in the sense that a positive or negative result on one day does not ensure a positive or negative result on another day, although some patients consistently faint. As a test for fainting, the tilt table test is fraught with error; as a stressor, it is excellent and controllable. Interestingly, and in contrast to fainters, patients with postural tachycardia syndrome (POTS) often have repeatable orthostatic stress test results. The American Heart Association now regards tilt table testing as a secondary to history and physical exam and routine cardiology testing in diagnosing simple faint.

Following a resting period, a patient is placed upright; responses are assessed over the period of tilt, usually up to 30-45 minutes, as tolerated. Often, if orthostatic tachycardia is the diagnosis sought, a 10-minute tilt is sufficient. At a minimum, BP and continuous ECG are assessed. Typically, a form of continuous BP assessment is used (e.g., finger plethysmography, arterial tonometry). Respiration is also continuously assessed and often end-tidal carbon dioxide (ETCO2). In addition, researchers have used techniques to assess peripheral, thoracic, and cerebral blood flow.

The central clinical purpose of HUT testing is to reproduce symptoms of orthostatic intolerance in a setting where hemodynamic variables can be assessed, although this is not the only purpose. Symptoms and changing physiologic signs often correlate, but the definition of orthostatic intolerance requires symptoms. If the patient's defining symptoms are not reproduced but the patient has a simple faint, the test results are often regarded as false-positive and not a sign of genuine orthostatic intolerance because healthy control subjects with no prior history of fainting may faint during testing.

Data suggest the physiology of false-positive results is itself interesting and that strict use of the term negative applied to these patients' findings may be incorrect.[15] Other patterns of hemodynamic disturbance, such as postural tachycardia and the dysautonomic response, invariably seem associated with symptoms and are more reliable indicators of chronic impairment.

LBNP test

The LBNP test, developed by NASA scientists and others as a research tool, simulates many features of orthostasis by using external negative pressure on the legs, buttocks, and lower abdomen under well-controlled conditions. Actually, LBNP most closely duplicates the findings of hemorrhages that bear similarities to orthostatic intolerance, in that central hypovolemia is induced. The authors recently demonstrated a divergent response of splanchnic volume changes induced by HUT compared with LBNP.[101] LBNP resulted in splanchnic emptying, whereas HUT caused splanchnic filling. Thoracic and leg volumes similarly changed when subjected to HUT and LBNP. Currently, LBNP is a pure research tool and is, therefore, somewhat beyond the scope of this discussion.

LBNP combined with upright tilt

Even more recently, investigators have used LBNP combined with HUT. By additively combining these stressors, virtually all subjects were made to experience some form of orthostatic intolerance. The amount of negative pressure and tilt used then defines a susceptibility to orthostatic stress.[101]

Tests as Research Tools

All of these tests have a related function as research tools to evoke the orthostatic response, which is a complex interplay among arterial baroreflex, vasculature, local factors, and the CNS. The tilt table test, therefore, is not a "black box" apparatus with positive or negative responses. Everyone responds physiologically to orthostatic challenge.

The black box approach has been popular among cardiologists using a descriptive paradigm as a way to categorize patients who faint. These cardiologists sought to compare patterns of syncope during upright tilt with cardiogenic syncope caused by electrical or mechanical events. Thus, they designated positive responses associated with primary bradycardia as cardioinhibitory, positive responses associated with primary hypotension but not bradycardia as vasodepressor, and vasovagal episodes in which both heart rate and BP fell in concert as mixed.

With input from neurologists and integrative physiologists studying a wider range of orthostatic intolerance, this paradigm for the orthostatic stress response has largely been superseded by a physiologic approach that emphasizes the responses of neurovascular and neurohumoral circulatory control mechanisms to orthostatic stress.

Orthostatic hypotension

Supportive care and treatment of the underlying illness are essential. Thus, in the case of dopamine-beta-hydroxylase (DBH) deficiency, droxidopa, which bypasses the missing enzyme, can provide definitive remediation.[106] It may also be the drug of choice for most neurogenic orthostatic hypotension (NOH) since it can provide norepinephrine production through alternative pathways.[107] Supportive therapy focuses on decreasing symptomatic OH and syncope. Such therapy would include physical countermaneuvers including compression garments, and dietary changes (increased salt, rapid water drinking). Supportive drug therapy often aims to increase blood volume by promoting salt and water retention (fludrocortisone) or by increasing red blood cell mass (recombinant erythropoietin).[10] Defects in erythropoietin may occur as part of the denervation in autonomic failure.[108] Short-acting pressor drugs such as midodrine or drugs that enhance autonomic activity (atomoxetine, pyridostigmine) are alsoused.[109, 10]

Rapid water ingestion of approximately 16 ounces deserves special mention. Studies in adults have demonstrated that intake of water free of solute can increase blood pressure and improve sympathetic vasoconstriction after a sufficient time has elapsed for the water to reach the small intestine, say 20 minutes.[95] The palliative effect of water encompasses all OI including OH, postural tachycardia syndrome (POTS), and vasovagal syncope (VVS)[110] and can be successfully used to prevent blood phobic vasovagal syncope. Effects last for several hours. The mechanism is dependent on osmolarity and may depend on TRPV4 C-fiber receptors within the portal system.[96] This is a very important, simple, and effective palliation that is not often considered by clinicians.

Postural tachycardia syndrome (POTS)

Therapy for neuropathic postural tachycardia syndrome (POTS) includes general supportive measures such as physical countermaneuvers, increased salt and water intake, and exercise. Pharmacotherapy has focused on improving sympathetic vasoconstriction, which unfortunately uses medications with widespread systemic effects. Midodrine, an a-1 adrenergic agonist, can be helpful and has few side effects apart from piloerection.[111, 112] Mestinon (pyridostigmine),[113] an acetylcholinesterase inhibitor, alone or in combination with midodrine, can be very helpful through its potentiation of cholinergic ganglionic nerve activity and through its muscarinic effects. There are great expectations for Droxidopa in trials being conducted outside the United States.

ß-blockers have been used in forms of hyperadrenergic POTS with variable success.[114, 115] Innovative treatment with angiotensin II receptor blockers (ARBs) is under investigation. Exercise has always been a mainstay of rehabilitation in these patients. Recent work indicates that gravitational deconditioning (e.g., bedrest) is a frequent concomitant of the illness and that a graded exercise program can be very effective in improving overall patient well-being.[114, 116]

Postural syncope (vasovagal syncope, acute OI, simple faint)

First time postural noncardiogenic fainting with no sequelae probably requires no treatment. The first time fainter rarely knows what is happening. Once suitably apprised, countermeasures can be employed. These include avoidance of precipitants and physical countermaneuvers; the most effective countermaneuvers are lying down with legs up or squatting. Both propel blood from the lower body below the diaphragm back into the central circulation. Other countermaneuvers include those that enhance the skeletal muscle pump (e.g., leg crossing) or activate the exercise pressor reflex (isometric hand grip).[73, 117, 75] Generally, enhanced salt and water intake is encouraged and has shown some efficacy in small studies employing very large amounts of salt loading.[118] Rapid water ingestion offers an effective palliative effect. Thus, once syncope patients have staved off the faint with physical maneuvers, they are counseled to consume 16 ounces of water before attempting to stand up. In olderpatients, confounding use of antihypertensives or diuretics need to be considered. Pharmacotherapy (atenelol or fludrocortisone) has not been shown to be more effective than placebo in younger patients in large multicenter studies.[119] Reports of exquisite sensitivity to midodrine are found in Chinese children[120] but are not evident in other populations.[121] We have recently shown midodrine as effective in the treatment of neuropathic, but not hyperadrenergic POTS.[112] Other pharmacologic strategies tested in small studies include selective serotonin reuptake inhibitors (SSRIs) including paroxetine, which showed efficacy in a double-blind randomized study of a select patient subset (n=68).[122] Asystolic faints have been shown to improve with pacemaker insertion.[123] Work into the fundamental molecular physiology of fainting is ongoing in our laboratory and in others. Our hope is to determine specific therapy based upon specific pathophysiology.

Vasovagal syncope (VVS)

Recurrent unexplained postural syncope due to vasovagal syncope (VVS) is not deadly unless the patient is in harm’s way. Trained athletes have increased risk of VVS compared to untrained persons.[116] Iron and even ferritin deficiency aggravates VVS.[124]

To date, no single pharmacological intervention has been proven more effective than placebo in large clinical trials of VVS.[125, 119] Placebo exerts 30-40% benefit in these studies. Salt and water supplementation can be helpful but a large amount of salt is needed.[118]

Currently, compensatory physical countermaneuvers are the recommended treatment for VVS.[76] The fainting prodrome must be recognized for countermeasures to be effective. First faints are rarely countered because patients don’t understand what's happening.

Countermaneuvers including immediate lying down or squatting cause postural VVS to cease. Prolonged prodrome counterpressure maneuvers such as leg-crossing, buttocks clenching, and fist clenching may also be effective.[126, 127] Once supine, the patient should not immediately stand. Instead, the patient should drink 16 ounces of water and remaining supine for >20 minutes following the episode.

If there is no prodrome or if there is abrupt onset with injury, then consider asystolic vasovagal faint or an arrhythmia and evaluate by loop recording electrocardiography.[54, 128]

If total loss of consciousness is not transient, it is not a faint, it is coma. VVS is less than 2 minutes of total loss of consciousness, as a matter of consensus. Rarely, fainting promotes an underlying seizure disorder via cerebral ischemia.

Enhanced salt and water intake is the common wisdom. However, evidence-based literature has only shown effect with ingestion of large quantities of salt. Research may now show a considerable effect of diet on the presence of vasoactive substances including the ingestion of excess nitrates and nitrites, but studies remain largely anecdotal.

One confounding and alarming issue is the tendency for POTS patients to become bedrested. Prolonged bedrest emulates microgravity and has deleterious effects,[129] including OI[130] reductions in blood volume and cardiac size, redistribution of blood, osteoporosis, skeletal muscle pump atrophy, and more.[131] Vasoconstriction is impaired,[132] and bedrest causes a self-perpetuating state of OI that can emulate or intensify POTS. It is paramount for POTS patients to leave bed and recondition. Well-structured exercise protocols are essential and must accommodate patients who start off bedrested.[114] Reconditioning invariably improves patient well-being. Recent work support the idea that POTS patients are also exercise deconditioned compared to matched volunteers.[133] While exercise deconditioning may or may not be causal in POTS, it is clear that exercise reconditioning is beneficial and should be advocated for all POTS patients.

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Class Summary

These agents improve the hemodynamic status by increasing myocardial contractility and heart rate, resulting in increased cardiac output. They also increase peripheral resistance by causing vasoconstriction. Increased cardiac output and increased peripheral resistance lead to increased blood pressure.

Droxidopa (Northera)

Droxidopa is a synthetic amino acid analog directly metabolized to norepinephrine by dopadecarboxylase. Increases blood pressure by inducing peripheral arterial and venous constriction.

Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Fludrocortisone

Fludrocortisone may increase blood volume by promoting salt and water retention.

Class Summary

These agents are hormones that stimulate the production of red cells from the erythroid tissues in the bone marrow.

Epoetin alfa (Procrit, Epogen)

Purified glycoprotein produced from mammalian cells modified with gene coding for human erythropoietin (EPO). Amino acid sequence is identical to that of endogenous EPO. Biological activity mimics human urinary EPO, which stimulates division and differentiation of committed erythroid progenitor cells and induces release of reticulocytes from bone marrow into the blood stream. By increasing red blood cell mass it may increase blood volume.

Class Summary

These agents raise the concentration of acetylcholine, by inhibiting the degradation of Ach, at the myoneural junction and increase the chance of activating the acetylcholine receptor.

Pyridostigmine bromide (Mestinon)

Pyridostigmine bromide acts in smooth muscle, CNS, and secretory glands where it blocks the action of ACh at parasympathetic sites. It may enhance autonomic activity.

Class Summary

These drugs are used to treat orthostatic hypotension that is refractory to nonpharmacologic recommendations.

Midodrine

Midodrine is a selective alpha1-adrenergic agonist used for the treatment of hypotension.