What is orthostatic intolerance

Orthostatic intolerance refers to symptoms and signs caused by an upright posture, which can be relieved by lying down ¹. Orthostatic intolerance common presentations include dizziness, lightheadedness, blurred vision, headache, and fainting ². Orthostatic intolerance can also manifest as various nonspecific symptoms, such as concentration difficulties, anxiety, chest discomfort, and tremulousness ³. Orthostatic intolerance is a syndrome consisting of different clinical variants, such as orthostatic hypotension, postural orthostatic tachycardia syndrome (POTS), and vasovagal syncope ⁴. Orthostatic intolerance is a common condition in the adult population; prior studies reported the prevalence of orthostatic hypotension ranging between 14% and 30.3% and orthostatic dizziness ranging between 4.8% and 19.7% ⁵. Accumulating evidence has shown that disruption of autonomic hemodynamic regulation contributes to the mechanisms of these orthostatic intolerance subtypes with abnormal orthostatic responses ⁶. However, a considerable number of patients with orthostatic intolerance show normal orthostatic vital sign response in clinical practice. This subgroup remains undiagnosed based on the current classification system. Furthermore, little is known about the pathophysiology and treatment of orthostatic intolerance without excessive hypotension or tachycardia ². 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 ⁷.

Orthostatic intolerance causes

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 (heart attack)
• Primary pulmonary hypertension

Orthostatic intolerance symptoms

Orthostatic intolerance may be defined as “the development of symptoms while upright, during standing that are relieved by recumbency” ⁷. Dizziness and headache were the two most common symptoms complained of by patients with orthostatic intolerance.

Other symptoms of orthostatic intolerance may  include ⁸:

• Nausea
• Lightheadedness
• Concentration difficulties
• Palpitation
• Tremor in hands
• Profuse perspiration
• Blurred vision
• Chest discomfort

Orthostatic intolerance test

Orthostatic Stress Test

Perhaps the best “test” is medical history, which can often diagnose orthostatic intolerance based on symptoms relieved by recumbence. Orthostatic stress tests supplement history by evoking orthostatic intolerance in the laboratory. The predictive value of lab-induced orthostatic intolerance for real world orthostatic intolerance is unclear, at least for syncope; in adults older than 40 years, tilt tests do not predict vasovagal syncope ⁹. 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 ¹⁰. Therefore, tilt tables are used to restrict patient movement while passively placing them upright ¹¹. A recent adult study of postural orthostatic tachycardia syndrome (POTS) compared the diagnostic accuracy of standing for 10 minutes with 60o upright tilt for 10 minutes or longer ¹². 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 heart rate (HR) and blood pressure (BP) measurements were taken at 1, 3, 5, and 10 minutes. Thus, standing tests for POTS (postural orthostatic tachycardia syndrome) 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 ¹³, which best simulates hemorrhage but duplicates many orthostatic intolerance findings. A combination of lower body negative pressure with upright tilt can evoke orthostatic intolerance – 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 cardiac output, cerebral blood flow velocity , regional blood flow, blood volume, sympathetic nerve activity, synaptic norepinephrine spillover ¹⁴ and vascular biopsy ¹⁵.

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 ¹⁶. Other advanced techniques using sympathetic nerve norepinephrine spillover ¹⁴ to measure the effect of adrenergic vasoconstriction on local blood flow ¹⁷ and most recently to directly assess the integrity of norepinephrine synthesis and metabolic products by vascular biopsy ¹⁸ can be used to find the actual mechanism of orthostatic intolerance in sufferers.

Tilt table procedure

Early National Aeronautics and Space Administration (NASA) experiments used a head upright tilt table test (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 head upright tilt table test (HUT 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 head upright tilt table (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 ¹⁹. 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.

Lower body negative pressure test

The lower body negative pressure test (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 head upright tilt table (HUT) test compared with lower body negative pressure test ¹³. The lower body negative pressure test (LBNP test) resulted in splanchnic emptying, whereas the head upright tilt table (HUT) test caused splanchnic filling. Thoracic and leg volumes similarly changed when subjected to head upright tilt table (HUT) test and lower body negative pressure test (LBNP test). Currently, lower body negative pressure test (LBNP test) is a pure research tool and is, therefore, somewhat beyond the scope of this discussion.

Lower body negative pressure test (LBNP test) combined with upright tilt

Even more recently, investigators have used LBNP combined with head upright tilt table (HUT) test. 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 ¹³.

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 (central nervous system). 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 intolerance treatment

Supportive care and treatment of the underlying illness are essential. Thus, in the case of dopamine-beta-hydroxylase deficiency, droxidopa, which bypasses the missing enzyme, can provide definitive remediation ²⁰. It may also be the drug of choice for most neurogenic orthostatic hypotension since it can provide norepinephrine production through alternative pathways ²¹. Supportive therapy focuses on decreasing symptomatic orthostatic hypotension 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) ²². Defects in erythropoietin may occur as part of the denervation in autonomic failure ²³. Short-acting pressor drugs such as midodrine or drugs that enhance autonomic activity (atomoxetine, pyridostigmine) are alsoused ²⁴.

Rapid water ingestion of approximately 16 ounces deserves special mention. Studies in adults ²⁵ 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. The palliative effect of water encompasses all orthostatic intolerance including orthostatic hypotension, postural tachycardia syndrome (POTS), and vasovagal syncope (vasovagal syncope) ²⁶ 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 ²⁷. 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 ²⁸. Mestinon (pyridostigmine), 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 ²⁹. There are great expectations for Droxidopa in trials being conducted outside the United States.

Beta-blockers (ß-blockers) have been used in forms of hyperadrenergic POTS with variable success ³⁰. Innovative treatment with angiotensin 2 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 ³⁰.

Postural syncope (vasovagal syncope, acute orthostatic intolerance, 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) ³¹. Generally, enhanced salt and water intake is encouraged and has shown some efficacy in small studies employing very large amounts of salt loading ³². 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 ³³. Reports of exquisite sensitivity to midodrine are found in Chinese children ³⁴ but are not evident in other populations ³⁵. Scientists have recently shown midodrine as effective in the treatment of neuropathic, but not hyperadrenergic POTS ²⁸. 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) ³⁶. Asystolic faints have been shown to improve with pacemaker insertion ³⁷. Work into the fundamental molecular physiology of fainting is ongoing.

Vasovagal syncope

Recurrent unexplained postural syncope due to vasovagal syncope is not deadly unless the patient is in harm’s way. Trained athletes have increased risk of vasovagal syncope compared to untrained persons ³⁸. Iron and even ferritin deficiency aggravates vasovagal syncope ³⁹.

To date, no single pharmacological intervention has been proven more effective than placebo in large clinical trials of vasovagal syncope ³³. Placebo exerts 30-40% benefit in these studies. Salt and water supplementation can be helpful but a large amount of salt is needed ³².

Currently, compensatory physical countermaneuvers are the recommended treatment for vasovagal syncope ⁴⁰. 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 vasovagal syncope to cease. Prolonged prodrome counterpressure maneuvers such as leg-crossing, buttocks clenching, and fist clenching may also be effective ⁴¹. 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 ⁴².

If total loss of consciousness is not transient, it is not a faint, it is coma. vasovagal syncope 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.

Orthostatic intolerance prognosis

Cardiovascular syncope has a poor prognosis unless specifically treated. Reflex syncope has an excellent prognosis ⁴³.

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.

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