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 may be defined as "the development of symptoms during upright standing relieved by recumbency." Although the use of a term such as orthostatic intolerance logically implies the presence of findings when upright, typically, 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 apparent requiring orthostatic stress to become evident.

Standing successfully requires interplay of blood volume, physical, neurologic, humoral, and vascular factors which compensate for the effects of gravity on 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.

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 dire consequences, but no dysautonomia is noted; instead, the autonomic and other compensatory systems cannot adequately compensate for the loss of circulating blood volume.

On the other hand, a true dysautonomic cause of orthostatic intolerance, in which compensatory factors are inadequate, is pure autonomic failure; patients with this condition not only cannot easily stand and have clearly detectable autonomic abnormalities in all physical positions. Therefore, orthostatic intolerance encompasses any condition with blood flow, heart rate, and BP regulation inadequacy that are most easily demonstrable during orthostatic stress but may be present in all positions. Under such circumstances, orthostatic intolerance may be the most salient finding but is only the most obvious manifestation of a more widespread impairment in integrative neurovascular physiology.

Patterns of orthostatic intolerance are shown in the image below.

Approach Considerations

Orthostatic intolerance has 2 general distinguishable clinical variants, acute and chronic, which may be roughly divided based on patient history.

Acute Orthostatic Intolerance

Acute orthostatic intolerance usually manifests as presyncope or syncope. Syncope is a transient loss of consciousness and postural tone caused by reduced cerebral blood flow with rapid recovery. Patients with presyncope remain conscious during a transient loss of postural tone. These conditions are caused by cerebral malperfusion, usually resulting from a large and abrupt fall in BP.

Not all syncope is orthostatic. Patients with syncope may have cardiac abnormalities, particularly adults with antecedent heart disease whose sudden loss of consciousness is often caused by arrhythmias. The structural bases often, but not always, underlying these rhythm problems include muscle disease, coronary artery disease, pulmonary hypertension, and aortic stenosis. Consider cardiac syncope a life-threatening condition. Cardiac syncope may sometimes be closely associated with orthostasis; therefore, distinguishing cardiac from noncardiac syncope can be difficult.

The classic history of a simple faint, including known precipitants (eg, standing, heat, emotion) and prodromal symptoms (eg, nausea, blurred vision, headache), and postsyncopal symptoms such as fatigue and headache helps to distinguish cardiac syncope from simple faint, although differentiation is sometimes difficult. 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

Cardiologists are often involved in early evaluation of syncope because initial assessments should determine whether the condition is of cardiac or noncardiac 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 (eg, tachycardia, chest pain) indicates a search for underlying heart disease. However, exercise-related syncope in the young is most often noncardiogenic and the physiology 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 does not obviate the obvious need to evaluate such patients for potentially lethal cardiac disease. Cardiogenic syncope is well described elsewhere and is not discussed herein.

Simple faint

Patients may have simple faints, known variably as reflex syncope, neurocardiogenic syncope, neurally mediated syncope (NMS), and vasovagal syncope, referring to the original descriptive designation by Sir Thomas Lewis.^[1] Many patients with syncope have no intercurrent illness; between faints, they are well. However, some patients may have frequent enough episodes to bridge into a chronic orthostatic intolerance state.

Simple faint is extraordinarily common. Many people who faint do not consult a doctor. Hence, the prevalence of fainting is difficult to ascertain. Estimates range from 15-20% in young people (most commonly postpubertal adolescents, with a second peak in later life). Approximately 25% of elderly populations faint, which may relate to use of medications or to physiological changes. Thus, the overall lifetime incidence can approach 50%.

Although statistics are far from complete, most laboratories report a higher incidence of simple faint among highly trained athletes compared with healthy controls. This may relate to changes in cardiovascular structure and function related to improved exercise performance or to increased numbers of peripheral blood vessels. However, gravitational deconditioning, such as occurs with bedrest or microgravity, also increases the risk of all forms of orthostatic intolerance. This may relate to known changes in blood volume, reduced muscle volume and skeletal muscle pump, reduced vascular capacitance, and decreased peripheral vasoconstrictive capability.

The high incidence of fainting and related phenomena among highly trained returning astronauts is interesting (see Patterns of Orthostatic Intolerance). Currently, no consistently demonstrated specific pharmacologic treatment for simple faint in the young is recommended by adequately powered large studies. Aversive therapy, including avoidance of associated circumstances (eg, environmental heat or prolonged standing) and physical countermeasures are effective means by which to prevent syncope. Further investigations are in process.

Initial orthostatic hypotension

Many young people experience dizziness upon rapid standing. This may become a problem, especially in those with larger decreases in BP. Almost always this is a transient condition; if maintained upright, patients recover. This has been termed "initial orthostatic intolerance" by Wieling and others.^[2] This is a physiological response that is caused by rapid and large translocation of central blood volume to dependent body parts before neurovascular compensation can occur. Notably, the time it takes for compensatory neurally mediated vasoconstriction to begin is approximately 7-10 seconds, which is similar to the period of Mayer wave oscillations in normal BP.

Chronic Orthostatic Intolerance

In chronic orthostatic intolerance, patients are ill on a day-to-day basis. Chronic orthostatic intolerance may be confused with syncope because chronic illness is sometimes punctuated by acute syncopal episodes. However, this is unusual during real life (albeit common during artificial testing environments), and the author's work suggests no increase in the incidence of syncope above that in the general population. The physician should rely on the patient's history to determine whether chronic illness is present. Thus, chronic orthostatic intolerance is defined by a history of symptoms of orthostatic intolerance present on a day-to-day basis. Defining symptoms of chronic orthostatic intolerance include dizziness in all patients, with high incidence of the following conditions:

• Altered vision (blurred, "white outs", "black outs")
• Fatigue
• Exercise intolerance (frequently post-exercise malaise)
• Nausea
• Neurocognitive deficits
• Sleep problems
• Heat
• Palpitations

A large proportion of patients also experience the following symptoms:

• Headache
• Tremulousness
• Difficulty breathing or swallowing
• Sweating
• Pallor
• Other vasomotor symptoms

These symptoms are divisible into symptoms of sympathetic activation and symptoms of reduced cerebral blood flow.

Fluid Shifts with Upright Posture

Because quadrupedal mammals' cardiovascular systems are adapted to their stance, humans are the most appropriate subjects for physiological investigations of orthostasis. These studies must be performed on unrestrained and conscious subjects, making related bipeds unsuitable for study. Although some successful experiments have been performed in quadrupedal mammals, all have required justification through their relation to human physiology.

While at rest, quadrupeds have a distinct orthostatic advantage over bipedal humans because their blood reservoirs (mostly veins) are at a similar level as the brain and heart. In contrast, a human in the act of standing has approximately 750 mL of thoracic blood abruptly translocated downward. Standing fills venous blood reservoirs below the heart, impedes venous return to the heart, and reduces cerebral perfusion because of the hydrostatic change in BP. In contrast, more than 70% of a dog's vascular capacitance is situated at or above cardiac level, and the dog's brain is at a similar level to the heart.

Upright posture in humans, therefore, is a fundamental stressor, akin to hemorrhage with its loss of central blood volume. Upright posture requires rapid and effective circulatory and neurologic compensations to maintain BP, cerebral blood flow, and consciousness. Without these compensatory mechanisms, the brain's precarious position well above the neutral cardiac point (roughly at the right atrium) and the presence of large venous reservoirs below the neutral point would cause BP to decrease rapidly because of gravitational pooling of blood within the dependent veins; cerebral ischemia and loss of consciousness would rapidly follow. The largest venous reservoir is the splanchnic circulation; the legs are the next most important. Once consciousness and postural tone are lost, the resultant fall would render a person recumbent, remobilizing the blood and restoring consciousness. Evolution apparently has dictated a trade-off between manual dexterity and orthostatic competence.

Defenses Against Orthostatic Intolerance

The skeletal muscle pump, neurovascular compensation, and neurohumoral effects are the multiple levels of defense humans have to counteract orthostatic intolerance. Adequate blood volume is a prerequisite. The integrative response is the combination of compensatory responses. These defenses are somewhat redundant; when a single mechanism fails, others may partially compensate.

Muscle pump

The primary defense against venous pooling is the skeletal muscle pump. This term describes contractions of leg and gluteal muscles, which propel sequestered venous blood back to the heart, a mechanism often likened to a second heart. Muscle may also be involved in neurogenic compensation through chemoreceptors. Muscle contraction encourages blood flow through the capillaries and venous systems by reducing venous pressure, thereby increasing the pressure difference between leg arteries and leg veins. This process also has important effects on lymphatic drainage of the lower extremities. The muscle pump is partially neutralized during quiet standing and is nearly inconsequential during motionless standing. Four-legged creatures lack calf muscles, and a muscle pump is largely superfluous.

Weakened muscle pump ability is one reason astronauts are so vulnerable to orthostatic stress. During exposure to low gravity, astronauts develop rapid leg muscle atrophy and refractory lower limb pooling. Paraplegics lack an effective muscle pump.

Neurovascular compensation

Neurovascular adjustment is the second line of defense against orthostatic intolerance. Rapid changes in arterial resistance vessel tone (vasoconstriction) normally limit flow to the extremities and to the splanchnic vascular bed while promoting passive emptying. Arterial resistance increases because of vasoconstriction. Midlevel orthostatic stress corresponds roughly to a seated position. Vasoconstriction is usually associated with release of norepinephrine from nerve endings in the lower extremities, as illustrated by the work of Jacob et al that showed norepinephrine spillover at rest and with orthostasis.^[3]

Splanchnic venoconstriction occurs, further enhancing venous emptying, although little evidence suggests active venoconstriction in other vascular beds in response to orthostasis. Work from the author's laboratory indicates that the capacitance vessels' volume-pressure relations in the forearm and calf are independent of upright position. This finding indicates that active limb venoconstriction is not an important aspect of the orthostatic response.

However, veins and venules do contribute to the regulation of venous return to the heart by passive elastic properties. Elastic recoil returns blood to the heart. If inflow is curtailed by arterial vasoconstriction, the main venous reservoirs can empty. The precise process of orthostasis in humans is unclear because gravity may cause persistent venous filling despite reflex vasoconstriction. For example, in the absence of active venoconstriction, passive splanchnic venous filling is increased equally by arterial vasodilation and gravity.

Reflex compensatory mechanisms during orthostatic challenge are controlled primarily by the high-pressure arterial baroreceptors located in the carotid sinus, aortic arch, and, possibly, the proximal coronary arteries. These receptors cause vasoconstriction and heart rate changes. Low-pressure cardiopulmonary receptors within the left atrium and pulmonary vein ostia can alter renal resistance and peripheral resistance. Recent evidence suggests neither the low-pressure receptors nor the ventricular receptors make an important contribution to orthostatic adjustment. Work by Biaggioni et al in 1998 also implicated the vestibular-otolith system as afferent neurogenic postural signaling sensors.^[4]

In addition to classic autonomic mechanisms, local myogenic, metabolic, and venoarteriolar responses are important regulatory mechanisms for leg blood flow during orthostasis. Many of these highlight an evolving understanding of the role of neuropeptides, inflammatory mediators, and paracrine and autocrine signaling molecules such as nitric oxide and prostacyclin. These molecules also interact and modulate the autonomic nervous system in important ways. Moreover, many of these molecules have now been shown to occur within nonadrenergic, noncholinergic autonomic nerves (eg, nitrergic nerves), which have powerful central and peripheral trophic effects on sympathetic outflow. Local factors may also be construed as responsible for transduction of the sympathetic nerve impulse into vasoconstriction and include the norepinephrine transporter and tonic tissue levels of nitric oxide and angiotensin II.

Neurohumoral effects

During later stages of orthostasis, humoral effects certainly enhance the defense against cerebral hypoperfusion by activating the renin-angiotensin-aldosterone system, releasing epinephrine and vasopressin, and initiating central effects. However, epinephrine may have a more immediate role that increases with time. These mechanisms often have a delayed onset of at least a few minutes following orthostasis. Delayed onset makes humoral responses less important in the immediate response to postural change and more important for long-term responses. Again, tonic changes of neurohumoral activity affects tonic sympathetic vasoconstriction. Also, vagal effects may be important on a local level.

Over a longer period, humoral mechanisms can be a highly effective means for altering blood volume and sympathetic tone. Epinephrine may even have an instrumental role in mechanisms of vasovagal syncope because an epinephrine surge invariably accompanies the onset of syncope. Presently, separating cause from effect is not possible (ie, determining whether epinephrine causes fainting through vasodilation or whether increased epinephrine is a compensatory response to the fall in BP that precedes an overt faint is not possible).

Integrative response

During quiet standing, compensatory mechanisms are incomplete. These mechanisms can normally maintain systolic BP and diastolic BP, even while stroke volume is decreased, thereby ensuring cerebral and coronary artery perfusion. However, overall cardiac output decreases by an estimated 25% because of impaired heart filling only partially offset by an increased heart rate. Notably, quiet standing is associated with a normal decrease in cerebral blood flow of approximately 6-10%. Cerebral arterial pressure is decreased because of the hydrostatic column between heart and brain; therefore, cerebrovascular autoregulation is functioning near its limit when a person stands upright.

Orthostatic Stress Tests

Exercise intolerance is best demonstrated through exercise stress testing. Similarly, orthostatic intolerance is best demonstrated through orthostatic stress testing. Such tests typically impose upright stress in a controlled fashion and monitor physiologic response in detail.

The 4 standard forms of orthostatic testing are (1) standing, (2) head-upright tilt (HUT) table testing, (3) the use of lower body negative pressure (LBNP), and (4) combined HUT and LBNP. Test techniques typically involve a motionless patient to negate the effects of the muscle pump. Most investigators study the neurovascular and neurohumoral responses to positional changes and their induced orthostatic stress.

Standing test

The most physiologic stressor is clearly the standing test, although difficulties with patient movement and standardization may make standing difficult to apply and to compare cross-platform. Standing motionless can be particularly difficult for some patients with chronic orthostatic intolerance and for some children. Movement invokes the muscle pump, making measurements more difficult to perform and to interpret. Although some fundamental differences are observed between the early response to tilt and the early response to standing (especially during the first few minutes), HUT and standing tests become substantially equivalent following that early response period.

Head-upright tilt table test

The most commonly used orthostatic stress test device is the HUT table, typically using angles offset 60-90° from the horizontal for 10-45 minutes as the orthostatic stimulus (see the image below).

Some investigators administer medication during passive tilt in order to potentiate orthostatic stress. This is particularly prevalent in testing for syncope because one is seeking to duplicate the patient’s prodromal and postfaint sensations and the time course of the faint by whatever means. However, medication use produces more true-positive test results (and more false-positive results). Data suggest that so-called false positive are actually detecting patients with an increased propensity to faint but in whom skeletal muscle pump activity prevents fainting in ordinary life.^[5] Obviously, even this supposed standard test is not altogether standardized. HUT testing is best regarded as a physiologic stressor (ie, an orthostatic stress) rather than as a strictly objective test yielding clear-cut, unassailable, objective results.

In a physiologic context, positive and negative test results are less important than normal and abnormal physiologic responses during testing. The entire notion of positive or negative is easily refuted. Everyone has a response to orthostasis, which may or may not be a normal physiologic response. Fainting is often regarded as the positive endpoint, which, by exclusion, consigns much interesting and important pathophysiology to the so-called negative findings. Provocative drugs that provoke more fainting include isoproterenol, nitroglycerin, and adenosine. These are all vasoactive agents that disturb the underlying physiology. This objection may be particularly true for patients with chronic orthostatic intolerance in whom pharmacologic potentiation often leads to spurious results. Thus, testing for postural tachycardia syndrome (POTS) or true dysautonomic/orthostatic hypotension should not use medications.

Some believe epinephrine may play a key role in the onset of simple faint, making use of isoproterenol as a provocative stimulus more reasonable during syncopic investigation.^[6] In patients with chronic orthostatic intolerance, isoproterenol use is more problematic because it disturbs physiologic vasodilation and related vascular changes in these circumstances.

Some investigators have administered substances intended to improve orthostatic tolerance, such as esmolol and other beta-blockers, while performing orthostatic stress tests. Although tending to reduce syncope in those patients with acute orthostatic intolerance, preliminary data from the author's laboratory indicate a reduction in orthostatic tolerance in those with chronic orthostatic intolerance.

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 (ie, 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 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, the patient is placed upright; responses are assessed over a period of tilt, usually anywhere 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 (eg, 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 is 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.^[5] 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 a key ingredient. The authors recently demonstrated a divergent response of splanchnic volume changes induced by HUT compared with LBNP.^[7] 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.^[8]

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.

The normal heart rate and BP response to upright tilt is a modest tachycardia with an increase in heart rate of 10-30 beats per minute. Systolic BP does not fall significantly. Diastolic pressure and mean arterial pressure rise somewhat, thereby decreasing pulse pressure. These changes are caused by the rapid translocation of blood to the lower body and are a normal response. Everyone's blood pools to a greater or lesser extent and at varying rates (ie, the time blood takes to reach the lower body). However, the term pooling is reserved in this article for signs of excess blood and fluid collections in the lower body. Modest tachycardia and vasoconstriction occur as part of the normal response to orthostasis.

The imge below shows 3 common abnormal upright tilt responses.

These responses are presented as a rough guide to help organize observed heart rate and BP changes into recognizable patterns in patients with known orthostatic intolerance. The overall patient assessment, emphasizing patient history and severity of impairment, must be combined with physiologic data to reach any useful conclusion concerning the nature and treatment of orthostatic intolerance for a particular patient.

Vasovagal Syncope

Vasovagal syncope (classic simple faint) is an instance of acute orthostatic intolerance. Most patients easily tolerate the early stages of tilt with little change in systolic BP and have no symptoms. Following a period that may range from a few minutes to 20 minutes, patients develop orthostatic symptoms, often manifesting with deep inspirations and an initial slow fall in BP, evident upon close examination.

This earlier slow fall in BP (shown as a change in mean arterial pressure) is not always observed but is coincident with a decrease in vasoconstriction of the peripheral arteries, resulting in vasodilation. Active dilation may also play a complementary role to release of vasoconstriction. An abrupt and simultaneous fall in BP and heart rate occurs shortly thereafter.

Vasoconstriction occurs as part of the normal neurovascular response to orthostasis and is necessary to maintain BP during orthostasis. BP and heart rate may plummet precipitously, and asystole may occur. When these conditions occur, a rapid loss of CNS activity and often a series of peripheral neurologic responses result in muscular movements mimicking a tonic-clonic seizure. This response is termed convulsive syncope. No true seizure activity is present, a finding confirmed in the 1950s by Gastaut et al and later reconfirmed using HUT methods by Grubb et al in the 1990s.^{[9, 10]} Such episodes, although relatively uncommon, are quite dramatic and are periodically rediscovered by beginning practitioners of HUT. Although fainting may occur in chronic fatigue syndrome (CFS), it is most likely an acute punctuation of a more chronic orthostatic intolerant state.

Mechanisms for vasovagal syncope

Until recently, most research on orthostatic intolerance primarily concerned syncope, although this research has produced no consensus about mechanism.

Mosqueda-Garcia et al published an excellent review.^[11] The most popular proposed mechanism, discussed and perhaps dismissed as the mechanism for syncope, attributes fainting to a stretch reflex of the left ventricle, akin to the classic Bezold-Jarisch chemoreflex. The reflex is presumably activated when reduced venous return underfills the left ventricle. This produces sympathetic activation, enhanced contractility, and a resultant paradoxic reflex mediated by unmyelinated C-fibers coursing from the ventricle to the CNS and causing vagally mediated bradycardia and vasodilation.

Increased blood volume should help relieve underfilling, whereas negative inotropic agents should help reduce cardiac contractility; however, simply because a reflex is possible does not make it probable. Both hypercontractility and decreased ventricular stretch have been questioned. Also, patients who receive cardiac transplants retain the ability to faint, which implies that the ventricular receptor theory cannot explain all simple faints. Most significantly, animal research performed by Wright et al in 2000 convincingly demonstrated that once coronary afferents of the baroreflex are separated from ventricular receptor action, little in the way of Bezold-Jarisch–like reflex activity remains under physiologically achievable conditions.^[12]

Other theories of fainting include epinephrine or renin surges and vasopressin decreases, which would rationalize the common use of isoproterenol as adjunctive provocation. Such surges occur in those who faint and, like fainting, take minutes to develop. Yet, whether these surges are the cause of the hemodynamic abnormalities or the result of attempted compensation for decreased BP and peripheral resistance during incipient fainting remains unclear.

A decrease in cerebral blood flow also occurs in patients with syncope and may precede a large fall in BP. Some believe that cerebral syncope is independent of BP changes, but this point is moot. For example, little evidence demonstrates that cerebral autoregulation is abnormal in these patients. Therefore, extrinsic effects must alter blood flow. One such extrinsic factor is the effect of hyperventilation, which produces hypocapnia and cerebral vasoconstriction. Preliminary data suggest that the pattern of breathing becomes aberrant and is driven by sympathetic excitation and central factors. Interestingly, voluntary hyperventilation cannot produce similar changes in sensorium.

Other proposed mechanisms include changes in CNS neurotransmitters such as serotonin, norepinephrine, neuropeptide Y, calcitonin gene-related peptide (CGRP), nitric oxide, angiotensin, and substance P. Causation has not been established. Documenting such chemical alterations in patients is difficult, and findings in quadrupeds may not be applicable. In summary, a fair conclusion is that researchers lack a complete understanding of the mechanism of simple faint.

Dysautonomia

Patients with true orthostatic hypotension are defined by the American Autonomic Society as those with a persistent fall in systolic/diastolic BP of more than 20/10 mm Hg within 3 minutes of assuming the upright position.^[13] Such criteria may be overly lenient but are reasonable starting points for comparison.

As mentioned above, a transient decrease in BP associated with tachycardia is often observed just after standing up in otherwise completely healthy individuals. The dysautonomic group includes patients with autonomic failure. Autonomic failure includes primary forms such as primary pure autonomic failure, multiple system atrophy, and more common secondary forms occurring with Parkinson disease and diabetes mellitus. Dysautonomia may also be drug induced. Acute forms may occur during infectious and inflammatory diseases or may relate to peripheral neuropathies such as Guillain-Barré syndrome.

Standard tests of circulatory autonomic function, such as timed breathing and the quantitative Valsalva maneuver, demonstrate signs of circulatory autonomic dysfunction. Other manifestations of dysautonomia often include pupillary, GI, and sweating abnormalities.

Neurologic damage similar to that occurring in cerebral palsy and trauma may result in autonomic dysfunction in addition to other neurologic disability. Responses to orthostasis in such patients differ from responses of patients who are truly dysautonomic in that their compensatory mechanisms may adapt to orthostasis (eg, by increasing blood volume), a compensation that occurs less often among patients who are truly dysautonomic.

Dysautonomic orthostatic intolerance is depicted in the image below.

BP falls, and heart rate shows little change throughout the course of the tilt. The appropriate cardiac response of the baroreflex to hypotension is tachycardia, which does not occur or is blunted in these illnesses. Patients may be so brittle that they are hypertensive supine and hypotensive upright, and they may lose consciousness because of overzealous splanchnic vasodilation (or possibly cholecystokinin) after a heavy meal.

Treatments favor volume loading and midodrine, which, as noted, often results in recumbent hypertension. Specific therapy for chronic disease is largely experimental, and immediate therapy for acute illness remains specific for the specific disease and patient.

Chronic Orthostatic Intolerance and Postural Tachycardia Syndrome

With sufficient provocation, anyone can experience a simple faint. Simple fainting occurs with increased frequency in persons with chronic orthostatic intolerance and POTS, although often only under testing conditions (eg, HUT table testing). They can be made to faint but do not faint in the "real world."

POTS was defined and described by Schondorf and Low in 1993 at the Mayo Clinic, but it has been recognized under different aliases since at least 1940 and probably for hundreds of years.^[14] Synonyms abound and include hyperadrenergic orthostatic hypotension, sympathotonic orthostatic tachycardia, and idiopathic hypovolemia.

POTS, the most common reason for referral of adults with orthostatic intolerance, is now an established form of orthostatic intolerance in children. POTS is most often observed in young postmenarche women. POTS was first reported in the pediatric population by the author's laboratory. One publication has described the occurrence of various nonorthostatic symptoms that are often associated with POTS in pediatric patients.^[15]

Unlike patients with simple faint, patients with POTS often have day-to-day disability. POTS is chronic and often waxes and wanes but is always present to some extent. Results of traditional tests of autonomic function often are normal in these patients, although some degree of dysautonomia has been reported. Patients are often unable to hold jobs or to attend schools. Robertson has stated that this is the most common form of chronic orthostatic disability and is present in virtually every patient with day-to-day orthostatic intolerance.^[16]

Pathophysiology and symptoms

Understanding of POTS pathophysiology remains incomplete. The central finding is upright tachycardia with symptoms of orthostatic intolerance, although hypotension (in children) or hypertension (in adults) as well as resting tachycardia may also be present. That POTS is related to thoracic hypovolemia is well established.

An operational definition of the syndrome includes symptoms of orthostatic intolerance associated with an increase in heart rate from the supine to upright position of more than 30 beats per minute or to a heart rate of greater than 120 beats per minute within 10 minutes of HUT. These criteria are derived for adults, and larger heart rates are likely observed in children and adolescents with POTS.

POTS remains a syndrome. Reflex tachycardia due to central hypovolemia is often present and this may reflect global hypovolemia or redistribution of blood volume. However, by its definition, even dehydration might serve as a model for POTS. Indeed, a large fraction of patients with POTS have reduced blood volumes and paradoxical disturbances in the renin-angiotensin-aldosterone system. Still, other patients may have excessive adrenergic activation, often denoting hyperadrenergic POTS, whereas parasympathetic withdrawal is a key finding in others.

The disposition of gravitationally displaced blood is controlled by many factors; including regional blood flow and vascular compliance, and peripheral arterial and peripheral venous resistance (Pv). These characteristics have provided a physiologic means by which to further categorize patients with POTS.

The author's laboratory has described 3 groups of patients with POTS distinguished by differences in peripheral blood flow and peripheral arterial resistance. These groups are as follows:

• A low blood flow, high-arterial resistance, high-Pv group, which is denoted as "low-flow" POTS and is characterized by pallor and generally decreased blood flow, most notably in the dependent parts of the body. This low-flow condition is related to defects in local blood flow regulation and mild absolute hypovolemia. The authors have recently shown that this defect in local blood flow regulation is due to a reduction in neuronal nitric oxide (nNOS).^[17]
• A normal blood flow, normal arterial resistance group with normal Pv, which is denoted as "normal flow" POTS and is characterized by a normal supine phenotype, with normal peripheral resistance when supine but enhanced peripheral resistance when upright. Specific venous pooling within the splanchnic vascular bed is observed, making this a redistributive form of hypovolemia.
• A high blood flow, low arterial resistance group with normal-to-decreased Pv, which is denoted as "high-flow" POTS. It is related to a long tract neuropathy and is characterized by high cardiac output caused by inadequate peripheral vasoconstriction when supine and upright. Patients are typically acyanotic and warm to the touch with extensive filtration, resulting in dependent edema.

The changes in regional blood flow with upright tilt, comparing control subjects with those with low, normal, and high-flow POTS are shown in the image below.

This illustrates the differences in regional blood flow exhibited by each of these subgroups of POTS and, in aggregate, may explain the wide variation of symptoms exhibited by these patients.

This 3 group classification scheme incorporates various physiological parameters, such as blood flow, blood distribution, and venous compliance, to construct a dynamic model of human vascular dysfunction in POTS. It provides a framework to test hypotheses used to explain the findings of POTS and will likely evolve as more information is accumulated. Although this physiologic classification scheme has the potential to refine treatment approaches, this classification is not easily made in most clinical laboratories. Therefore, further research is needed to translate these research findings into clinical practice. Moreover, further investigations suggest that alternative ways of looking at POTS based on reflex tachycardia versus autonomic defects might serve as well or better.

One might subscribe to a definition based on reflex tachycardia, whether due to lower extremity pooling (as in high-flow POTS) or splanchnic pooling (as in one form of low-flow POTS), versus autonomic mechanisms that include abnormalities of receptors at the sinus node, central and peripheral defects in parasympathetic regulation, or central and peripheral defects in sympathetic activation, which may also include defects in transduction as occur in NET deficiency.

In the case of POTS depicted in the image below, the patient immediately became symptomatic following initiation of HUT, necessitating cessation of the test within a few minutes.

Although the patient was not hypotensive, hypotension may follow or occur with tachycardia if protracted. If hypotension does occur, it is often delayed until after the onset of the symptoms and the tachycardia, manifesting only during the artificially sustained orthostasis enforced during HUT.

The form of hypotension may be vasovagal fainting; however, in the author's experience, fainting has mainly been confined to the contrived circumstances of tilt testing. The image above shows how symptoms during testing temporally relate to a decrease in cerebral blood flow, an increase in cerebrovascular resistance, and an as-yet-unexplained hyperventilation with attendant hypocapnia, which may partly account for cerebral vasoconstriction. Current studies indicate alterations in chemoreception as well as excessive sensitivity of the aortic chemoreceptors to reductions in blood flow and blood pressure. Cerebral malperfusion correlates with neurocognitive defects in POTS.

Although onset of POTS symptoms often follows an infectious disease and may relate to inflammatory mediators, genetic and molecular causes have been found in rare instances, suggesting that long-standing deficits may be congenital. A defect in nitric oxide bioavailability is currently suspected.

The defining heart rate abnormalities in POTS have suggested a partial dysautonomia. In 1997, Freeman and Komaroff found similar abnormalities in CFS.^[18] Since their study, levels of plasma epinephrine and norepinephrine in resting patients with CFS have been reported as within the reference range to increased; these levels increase when patients are upright, fulfilling Streeten's hyperadrenergic criteria.^[19]

Streeten hypothesized that vascular abnormalities relate to decreased alpha-adrenergic function with intact cardiomotor innervation, which explains the tachycardia. This explanation has led some investigators to postulate a state of idiopathic hypovolemia that almost certainly affects a subset of patients with POTS. As in an earlier 1996 work by Streeten (on pheochromocytoma) and Anderson, a chronic state of adrenergic activation can produce reduced intravascular volume.^[20]

Conversely, reduced intravascular volume can activate the autonomic nervous system; thus, the hypovolemia may be either the cause or the effect. Similar heart rate, BP, catecholamine changes, and blood volume differences have been described in a subset of patients with POTS but not in others with relative hyporeninism. Supportive evidence from volume loading and vasoconstrictor experiments has shown transient success in remediating POTS. Similar interesting findings have also appeared in the CFS literature. Although these findings have largely been interpreted within a framework of the hypothalamus-pituitary-adrenal axis, the findings also make sense within the POTS paradigm.

Patients with POTS or CFS frequently display acrocyanosis and swelling (pooling) in their lower extremities (see image below).

The literature contains a number of potential explanations for abnormal venous pooling and fluid collection in POTS, including impaired innervation of the veins or in the veins' response to sympathetic stimulation.

Additional pathophysiological and etiologic mechanisms in postural tachycardia syndrome are discussed below.

Muscle pump defects

Physical forces comprise a primary defense against the pooling of blood in the dependent lower extremities in human beings. This occurs through the activity of the skeletal muscle pump, in which contractions of leg and gluteal muscles increase interstitial pressure and propel sequestered venous blood back to the heart. The efficacy of this pumping is augmented by the presence of one-way venous valves. Patients with incompetent venous valves or those in whom venous valves are congenitally absent suffer from severe orthostatic intolerance. Skeletal muscle may also be involved in neurogenic compensation through chemoreceptors and through local control mechanisms.

Data indicate that although the muscle pump is normal in most patients with POTS, the muscle pump is defective in patients with low-flow POTS who also have decreased resting peripheral blood flow unrelated to exercise capability but exacerbated by bed rest. Therefore, ambulation is essential for the reduction of POTS symptoms. Lower body exercise may be very helpful, but its use has not yet been examined in a systematic way.

Autonomic autoimmune neuropathy

The largest proportion of patients with POTS are said to have a mild form of peripheral autonomic autoimmune neuropathy manifested by a dysfunctional peripheral vasculature. They demonstrate increased adrenergic tone at rest and enhanced postganglionic sympathetic response to upright posture. However, serum catecholamine levels are normal or only slightly elevated when upright. This is currently attributed to an immune-mediated process because autoantibodies to the peripheral nervous system have been identified (antiganglionic antibodies). The theory that this mechanism is the cause of POTS is further supported by the frequent reports of antecedent illnesses preceding the onset of symptoms.

Histamine-related postural tachycardia syndrome

Other patients with POTS have episodic flushing and increased urinary levels of methylhistamine, a primary urinary metabolite of histamine. These patients are thought to have a coexisting mast cell activation disorder that is associated with shortness of breath, headache, lightheadedness, diarrhea, nausea, and vomiting. Patients can have a hyperadrenergic response that results in orthostatic tachycardia and hypertension. Whether mast cell activation–associated release of vasoactive mediators is the primary event or if sympathetic activation results in mast cell activation is unclear. In these patients, although beta-adrenergic antagonists may exacerbate symptoms, treatment with antihistamines (H₁ and H₂ antagonists) in combination with nonsteroidal anti-inflammatory drugs may be beneficial.

Hyperadrenergic neuropathy

Measurements of plasma norepinephrine in patients with POTS show that supine levels are often "high-normal," whereas values obtained when patients with POTS are upright can be elevated above 600 ng/mL. Accordingly, they show intact or exaggerated autonomic reflex responses. This is manifested in vigorous pressor response to the Valsalva maneuver with preservation of vagal function. These patients often complain about extreme anxiety when upright and having cold, sweaty extremities. Most patients also have true migraine headaches that include prodromes of photophobia and nausea.

Several reports have detailed patients with POTS who have a form of partial autonomic neuropathy with regional denervation of sympathetic nerves that may be autonomic autoimmune neuropathy. This appears to be somewhat paradoxical in lieu of the description of patients with POTS who had elevated plasma norepinephrine levels. Jacob et al reported patients with neuropathic POTS with normal sympathetic neuronal norepinephrine release in their arms but impaired release in their lower body.^[3]

Norepinephrine transporter protein deficiency

Another recent autonomic condition producing a complex form of POTS is NET protein deficiency. This has been reported in only a single family.^[21] Investigators have identified a single point mutation in the NET protein with both central and peripheral effects on vascular regulation. Despite its rarity, the illness has furnished an ideal monogenetic model for autonomic illness, and appropriate animal knock-out models have been constructed and investigated. An NET-deficient mouse was recently shown to have near-normal resting arterial pressure and heart rate, likely due to increased sympathoinhibition.^[22] However, when engaged in awake activities, these mice exhibited excessive tachycardia and elevated blood pressure.

The importance of active venoconstriction to the orthostatic response is uncertain. Venous capacitance properties in POTS could be abnormal because of altered vascular structure, altered muscle tone, or both. An example may occur in the Ehlers-Danlos syndrome (EDS). Perhaps paradoxically, excess lower extremity pooling seems uncommon in common variants of EDS (eg, type 3). Preliminary data also indicate no change or even a decrease in venous distensibility compared with reference ranges.

The chronic elaboration of cytokines with potent vasoactive consequences, such as interleukin (IL)-1, IL-6, and tumor necrosis factor alpha (TNF-alpha), is a potential link between altered vasoreactivity and antecedent inflammatory disease. Such a link seems established in the type of CFS in which POTS and orthostatic intolerance frequently occur.

Treatment

Medical and nonmedical treatments for POTS are available, but they are rarely curative and are often incompletely palliative. Agents that expand blood volume, such as fludrocortisone and erythropoietin, sometimes are useful by reducing the degree of thoracic hypovolemia. Vasoconstrictive agents, such as midodrine or phenylpropanolamine (recalled from US market), are sometimes useful.

Selective serotonin reuptake inhibitors have met with some success in treating CFS and orthostatic intolerance. Rapid ingestion of water has been advocated as a benign and temporarily effective means to raise BP. Support hose and physical maneuvers can reduce pooling. Exercises to add bulk to the leg muscles have a similar effect. Raising the foot of the bed at night can increase blood volume. Treatment success is sporadic because these treatments do not directly address the pathophysiology. As always, further research is needed to clarify these issues.

Mestinon (pyridostigmine) an acetylcholinesterase inhibitor has met with considerable success in the treatment of POTS and has often been used in combination with midodrine. Precise loci of effects are unclear although mestinon enhances nicotinic ganglionic transmission at sympathetic and parasympathetic ganglia and can affect muscarinic cardiac receptors.

Erythropoietin has also been used and has met with success in treating some hypovolemic patients. However, erythropoietin can adversely affect blood pressure, causing hypertension, as well as act as a procoagulant. These effects have made this unpopular with physicians treating adults with POTS.

Orthostatic intolerance is common but often misunderstood. Investigation of the condition is an evolving field of integrative physiologic study. Acute orthostatic intolerance is characterized by simple faint. Despite its ubiquity, scientists do not yet understand why particular people faint. Chronic orthostatic intolerance, characterized by postural tachycardia syndrome (POTS), has been demonstrated in adolescents. POTS, however, remains a heterogeneous entity, likely of varied etiologies. Until better understanding is achieved, treatment remains more guesswork than science.