Fainting and Related Phenomena a Lay Review

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low blood pressure


standing up or upright

Orthostatic Intolerance (OI)

the inability to tolerate the upright stance relived by recumbence


Arrhythmia, arrhythmic

abnormal heart rhythm, irregular, too fast (tachycardia), too slow (bradycardia)



Ischemia, ischemic

too little blood


Long QT syndrome

an electrical heart abnormality that can produce dangerous arrhythmias




disease of the heart muscle


Myocardial infarction

heart attack



caused by the heart

Neurovascular, Neurally mediated, neurocardiogenic

caused by an interaction between the nervous system and the circulatory system


Vaso, Vascular, vasomotor

pertaining to blood vessels and their contraction


Vagus, vagal

a cranial nerve which when stimulated causes heart slowing (among other actions)


VasoVagal syncope

A descriptive term for syncope associated with blood vessel (vaso) dilation (widening) and heart rate slowing (bradycardia).
VVS comprises postural and p[hobic forms. The term was most famously by Sir Lewis Thomas in 1931

Autonomic nervous system

the part of the nervous system regulating many involuntary actions such as the heart rate and blood pressure. It comprises the sympathetic, parasympathetic and enteric nervous systems.



pertaining to veins

Right atrium

the part of the heart which receives blood returning from the body




the collection of blood or body fluids in dependent portions of the body



Arterial resistance (vasoconstriction)

contraction of small arteries provides resistance against which our heart pumps blood. Different vessel resistances account for redistribution of blood throughout our body



Active contraction of veins. For the most part veins empty by passive means because arteries feeding them have reduced flow. This is often called elastic recoil. The one outstanding exception is the splanchnic veins which are capable of active contraction.

Peripheral resistance

usually refers to arterial resistance in more peripheral parts of the body: e.g. limbs, skin



arterial widening

Splanchnic vascular bed

liver, spleen and digestive tract: major venous reservoir


Arterial Baroreceptors


pressure receptors intimately involved with the response to orthostasis



Cardiopulmonary reflexes

reflexes from the heart and lungs which affect vascular function; these are less involved with the normal response to orthostasis


renin-angiotensin-aldosterone, epinephrine, vasopressin

hormones involved with blood pressure regulation


cerebrovascular autoregulation

the ability of the brain to maintain its blood flow

Tilt Table test, head-up tilt, HUT

typically a motorized table with foot support which can take a patient from supine to upright or any angle in between. HUT is the de facto orthostatic stress test.



pertaining to the flow of blood



heart stopping



pumping chamber of the heart


Contractile, contractility

pertaining to the intrinsic ability of the heart to contract


low blood volume

Dysautonomia, dysautonomic

malfunction of the autonomic nervous system

Familial dysautonomia

an inherited form of autonomic failure seen only in Ashkenazi Jews


Valsalva maneuver

a simple test of overall autonomic function



postural tachycardia syndrome

Sympathetic, sympathetic nervous system

the part of the nervous system which when activated increases heart rate and blood pressure and causes vasoconstriction among other actions. Sympathetic receptors are of 2 main types designated " and $


Parasympathetic, parasympathetic nervous system


in some sense the obverse of the sympathetic system, it slows the heart rate and may have effects on blood pressure among other non-circulatory actions. The vagus nerve and the glossopharyngeal nerve are importantly involved with these actions.





Syncope (fainting) is a reasonable starting point. In principle, it is familiar to all of us because it is common. Perhaps 40% of all people will have one or more faints during their lifetime. However,  it represents a sudden change in well-being that often stimulates fear in families and discomfort among physicians. Syncope translates from the Greek as “a cutting short” (1). It is defined as a sudden transient loss of consciousness with loss of postural tone and spontaneous recovery caused by impaired blood flow to the central nervous system. Syncope may occur supine or upright and under a wide variety of conditions. It may be due to medication, cardiac disease, most commonly arrhythmic disease, or severe impairment of cardiac blood flow by mechanical pump failure or obstruction. It may be due to transient impairment of central nervous system function as in a transient ischemic attack (mild stroke) but this is less common. However, although convulsive-like movements may occur during syncope, it is distinct from a seizure disorder, and is distinct from coma in which loss of consciousness is not transient at all. (2)


Cardiac syncope is often quite serious and should be regarded as life-threatening. Although cardiac syncope is not often closely associated with orthostasis it may be. Causes of cardiac syncope include the long QT syndrome, arrhythmogenic right ventricular dysplasia, cardiomyopathies, left ventricular outflow obstruction, myocardial infarction, primary pulmonary hypertension, and most commonly ventricular tachycardia (fast heart rate), bradyarrhythmias (overly slow heart rate) and related arrhythmic events (3). The first job in evaluating syncope is to evaluate the patient for possible cardiac syncope. When specific cardiac disease is found, it is treated specifically. Thus, for example, ventricular tachycardia is treated with antiarrhythmics, bradyarrhythmias causing syncope are treated with a pacemaker, long QT syndrome with medication and a defibrillator if needed, and aortic valve disease with surgery. Cardiac syncope may first manifest during exercise, which is the best and most physiologic stressor of the myocardial circulation and overall cardiac function. Exercise related syncope should raise a “red flag” for underlying heart disease (4). Nevertheless, despite flag-waving, the large majority of exercise related syncope cases are non-cardiogenic in origin, at least for children and adolescents. Cardiogenic syncope has been well described in numerous texts including those already referenced and is not the central topic for discussion here because it accounts for a small percentage of syncope in children and of those many have previously known cardiac conditions.


Approximately 90% of syncope in children is either vasovagal or “unexplained”. Often the unexplained variety is reclassified as vasovagal  once tilt table testing has been performed (5). "Neurocardiogenic" has also been used in the place of vasovagal. Fainting is mediated through a combination of inappropriate vascular (blood vessel) and heart rate control. It is rarely fatal but it can be injurious. Some patients with VVS may have cardiac standstill ("asystole") of abrupt onset resulting in severe injuries. There is little compelling evidence for a primary role for the heart in neurocardiogenic syncope, once cardiogenic syncope has been ruled out. The term neurocardiogenic is thus somewhat misleading. Synonyms for neurocardiogenic include neurally mediated syncope and reflex syncope although the latter often includes situational syncope as well. Almost all syncope in children is  vasovagal. On the other hand adult syncope is much more likely to be cardiogenic – about a 50/50 split with neurocardiogenic syncope. Vasovagal syncope almost always occurs in the upright position, which may sometimes include sitting. Therefore it is regarded as a form of orthostatic intolerance.


Orthostatic Intolerance

Defining Characteristics    glossary

Orthostasis means standing up. Orthostatic intolerance can be defined by the inability to tolerate the upright posture because of signs and symptoms relieved by lying down . 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 (hypotension) of BP; weakness; nausea and abdominal pain; sweating; tremulousness; and exercise intolerance . 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 autoregulation may be compromised as in POTS and VVS .  CBFv may be reduced by hyperventilation and hypocapnic cerebral vasoconstriction. Involuntary postural hyperventilation, mostly hyperpnea, is observed in all VVS patients and 50% of POTS patients in my laboratory . Trigeminal, sympathetic, or parasympathetic nerve activity may also affect orthostatic CBF .

Physiology of Orthostasis       glossary

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 . Standing transfers >500ml of central blood caudally, further increasing the volume of the splanchnic pool and filling veins of the lower extremites An initial period of instability follows, denoted “initial orthostatic hypotension” (IOH)  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 are relieved by recumbency making IOH a form of orthostatic intolerance. Thereafter, HR decreases but remains 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 .  After IOH recovery, upright blood volume slowly decreases because of microvascular filtration 18 . 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 by 20mmHg . 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.

Upright posture (orthostasis) stresses regulatory capabilities of the circulatory system 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 . Upright stance causes dependent venous pooling. Muscle pumps propel blood back to the heart when upright and during exercise .  Enabling the skeletal muscle pump forms an important class of physical “countermeasures” against orthostatic intolerance .

 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 and flow dependent mechanisms , and co-transmitters neuropeptide Y and ATP 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 . Recent work indicates strong vagal influences on sympathoexcitation and important effects on nitrergic (nitric oxide containing nerves) vasodilation of the large cerebral arteries . 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 . 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 .

Patterns of Orthostatic Intolerance-Orthostatic Stress Testing and Head-up Tilt                                           glossary

Patterns of orthostatic intolerance are best defined by an orthostatic stress test – i.e. a means by which upright standing stress can be imposed in a controlled fashion and the physiological response monitored in detail. While standing can be used, individual differences and patient motion may make this difficult. Moreover, standing has only recently benn validated against upright tilt for adults and similar validation has not been performed in the young. Therefore the standard of orthostatic assessment in the young is the head-up tilt table test. Although head-up tilt was used to evoke autonomic reflexes in early NASA experiments, it was first used as a provocative agent in 1986 by Richard Sutton.. This device comprises a table driven by an electrical motor with a supportive footboard enabling positioning of a patient at varying angles of upright tilt. Although it would seem that an angle of 90o is most physiologic, this usually induces too many “false positives” (patients with no history of orthostatic intolerance who have intolerance induced during testing). Therefore lesser angles such as 60o or 70o are customarily used. Following a resting period, the patients are placed upright and their response over a period of tilt assessed – this is usually anywhere between 30-45 minutes. At a minimum, blood  pressure and continuous electrocardiography are assessed. Typically a form of continuous blood pressure assessment such as a finger plethysmography or an arterial tonometer is used and respirations are also assessed on a moment to moment basis. Other researchers have used methods to directly assess sympathetic activity (microneurograaohy). peripheral, thoracic (chest), and central nervous system blood flows which are methods still consigned to the research domain. Many laboratories use medications to enhance the fainting response, sometimes isoproterenol but more often sublingual nitroglyceron. The central purpose of a tilt table test is to reproduce symptoms of orthostatic intolerance in a setting in which hemodynamic variables (blood pressure, heart rate, blood flow) can be assessed. Most often there is correlation with changing physiological signs, but the definition of orthostatic intolerance requires symptoms. Thus for example the incidence of false positive faints during head-up tilt is high. If the complaining symptoms are not reproduced but the patient has a simple faint, the test is judged as negative. For example, my son fainted during his tenure as a HUT control patient. He has no history of fainting and the episode bore no relation to any prior complaints. This is a false positive and not a sign of orthostatic intolerance.  Other patterns of hemodynamic disturbance (see below) seem invariably associated with symptoms and are more reliable indicators of chronic impairment.


The normal response to HUT is a modest increase in heart rate (with an increased heart rate by 10-20 beats/min), a small increase in systolic BP and a larger increase in diastolic pressure. Systolic blood pressure should not fall. Abnormal tilt test responses can be used to categorize patterns of orthostatic intolerance. The overall patient assessment of chronicity and severity of impairment should be combined with these lab data to reach any conclusion concerning the nature of orthostatic intolerance in a particular patient. In addition to the normal pattern, three typical patterns of orthostatic intolerance are depicted in the figure, which shows the systolic blood pressure and heart rate in-patients during tilt.




1. I
1.1.1.Initial  stable BP, ↑HR (nl) with prominent 0.1Hz oscillations
2.Subsequent Slow and Steady ↓BP,  ↓ CO, ↑HR, ↑MSNA, ↑TPR,
3.Late rapid ↓BP,  ↓ HR, ↓TPR


This is depicted in the figure . Typically patients easily tolerate the early parts of tilt with little change in blood pressure or sensorium (phase 1). Following a variable period of time – on the order of 7 to 20 minutes, patients develop orthostatic symptoms of nausea, dizziness, heat, heavy breathing, and sweatiness initiated by a slow fall in blood pressure (phase 2).  Later,  there is an abrupt drop in blood pressure and heart rate with loss of consciousness (phase 3). Phase 1 is associated with an increase of arterial vasoconstriction but reduced cardiac output. Phase 2 with a slow fall of arterial resistance along with cardiac output. Phase 3 with arterial vasodilation and variable cardiac output.:

Blood pressure and heart rate may plummet precipitously, and asystole may occur. When this happens there is a rapid loss of central nervous system activity and often a dysinhibition of peripheral neurologic responses resulting in muscular movements mimicking a tonic-clonic seizure. This is denoted “convulsive syncope”, which might be construed as extremely brief phase 2 with immediate cardioinhibition as occurs in phase 3. There is  no true seizure activity present confirmed as early as the 1950’s by Gastaut and associates and later reconfirmed using HUT methods by Grubb and coworkers in the 1990’s . Such episodes, while relatively uncommon, are quite dramatic and such phenomena are periodically “rediscovered” by beginning practitioners of the HUT art. There are several sidebar observations on simple faint that stem from the convulsive variant

a)   If the episode occurs rapidly the patients can be injured. It is estimated that approximately 15% of patients with simple faint are injured overall during a faint. This can take relatively innocuous forms as a superficial cut while falling or can be more pernicious when a car is overturned. In the latter case it is evident that treatment for fainting is necessary. 

b)   Fainting usually is short lived; upon assuming recumbence the patient usually awakes after a few seconds. But some patients do not awake immediately and prolonged sleep-like states have occurred. These may mimic post-ictal (post seizure) states.

c)   A patient persistently maintained upright in a severe simple faint (for example proceeding to asystole) can potentially die. There is no reported pediatric death during HUT. A corollary is that such testing is potentially risky and should be performed by experienced personnel. Similar events may also occur in the real world, so called “telephone booth syncope’. This has decreased since telephone booths are largely anachronistic. However, recently one of my patients with known vasovagal syncope managed to prop herself up with impending faint and nearly required a full resuscitation. Patients should be placed supine or allowed to fall to a recumbent position. Recumbence invariably resolves all symptoms and signs.



Mechanisms for Vasovagal Faint

The most popular proposed mechanism holds that fainting results from an errant stretch reflex (aki to the Bezold=Jarisch chemoreflex) from the left ventricle. The reflex is activated by an underfilled (due to reduced venous return), overly contractile (due to sympathetic activation), left ventricle. This results in a “paradoxical reflex” mediated by unmyelinated C-fiber nerves coursing from the ventricle to the CNS and causing vagally mediated bradycardia as well as vasodilation. For the most part this explanation has become untenable. 

Bezold-Jarisch Reflex is an “an eponym for a triad of responses (apnea, bradycardia, and hypotension) following intravenous injection of veratrum alkaloids in experimental animals.” The response to mechanical stimulation is much weaker. Aviado DM, Guevara AD. The Bezold-Jarisch reflex. A historical perspective of cardiopulmonary reflexes. Ann N Y Acad Sci. 2001;940:48-58.
This mechanism was proposed despite the fact that any stimulus could only be short lived and baroreceptors would immediately be unloaded. Hainsworth R. Syncope: what is the trigger? Heart. 2003;89:123-124.
Relatively few afferent nerves were excited in the original Oberg and Thoren hemorrhaged cat model. Oberg B, Thoren P. Increased activity in left ventricular receptors during hemorrhage or occlusion of the caval veins in the cat. A possible cause of the vasovagal reaction. Acta Physiol Scand 1972;85:164–73.
VVS can occur in a ventricular denervated transplant recipient given the SNP. Scherrer U, Vissing S, Morgan BJ, Hanson P, Victor RG. Vasovagal syncope after infusion of a vasodilator in a heart-transplant recipient. N Engl J Med. 1990;322:602-604.
•The heart before syncope need not be empty nor hypercontractile. Novak V, Honos G, Schondorf R. Is the heart "empty' at syncope? J Auton Nerv Syst. 1996 Aug 27;60(1-2):83-92. Liu E et al Left ventricular geometry and function preceding neurally mediated syncope. Circulation. 2000 Feb 22;101(7):777-83.

 Other theories of fainting include epinephrine or renin surges (which would rationalize the common use of isoproterenol as adjunctive provocation). Such surges do indeed occur in those who faint and take some minutes to develop. However, it remains unclear whether these changes are the cause of the hemodynamic abnormalities or an effect of them acting as compensation for decreased blood pressure and peripheral resistance during faint. A decrease in cerebral blood flow has also been shown to occur in syncopal patients and may precede a large fall in blood pressure. However, blood flow is similarly impaired in chronic orthostatic intolerance in which hypotension (low blood pressure)  does not usually occur. Other proposed mechanisms include various changes in CNS neurotransmitters such as serotonin, norepinephrine, neuropeptide Y and substance P. Causation has not been established. In summary it is fair to say that we still have no precise understanding of the mechanics or the mechanism of simple faint. 


Treatment of Vasovagal Faint                                                                    

Without a clear mechanism there is no clear treatment. Moreover, many patients with infrequent simple faints, who do not injure themselves and who do not have convulsive syncope, may require no specific therapy above training in aversive maneuvers. The simplest of these maneuvers is lying down although leg crossing, bending at the waist, squatting and other maneuvers may also be effective. Increased fluid and salt intake is always helpful in ameliorating the initial thoracic hypovolemia of orthostasis. Lower body exercise, particularly isometric exercise, can be a genuine help by enhancing the muscle pump and by increasing venous tone in the lower extremities. Elastic support hose can be useful at times but are often unacceptable to children. Other investigators  have advocated a regimen of progressively longer quiet standing as a form of “orthostatic training”. 

·        VVS is not deadly unless in harm’s way.

·        To date, no single pharmacological intervention has been proven effective above the placebo effect in younger patients in large clinical trials . Placebo exerts 30-40% benefit in these studies.

·        Iron and even ferritin deficiency aggravates VVS .

·        Trained athletes have increased risk of VVS compared to untrained persons .

·        Salt and water supplementation can be helpful but a large amount of salt is needed .

·        Currently, compensatory physical countermaneuvers are the recommended treatment .

·        The fainting prodrome must be recognized for countermeasures to be effective. First faints are rarely countered because patients don’t understand what's happening.

·        Countermeasures: immediate lying down or squatting cause postural VVS to cease; with prolonged prodrome counterpressure such as leg-crossing, buttocks clenching, fist clenching, may be effective .

·        Once supine, the patient should not immediately stand. Instead, I suggest a 16 oz bottle 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 112;113 . Holter monitoring 24-hour is inadequate for arrhythmia determination 84

·        If total loss of consciousness is not transient, then 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.

Very frequent or extremely prolonged syncope can point to psychogenic syncope or conversion responses. These can be 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 bona fide 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 sign


2) Orthostatic Hypotension

Included in this group are patients with true “neurogenic orthostatic hypotension” defined by the American Autonomic Society to be a sustained fall in systolic blood pressure of >25 mmHg within 3 minutes of assuming the upright position . This is discussed in more detail elsewhere in this website. This group harbors patients with autonomic failure. Autonomic failure includes primary forms such as primary autonomic failure and multiple system atrophy, and more common secondary forms occurring with Parkinson’s disease and diabetes. Dysautonomia may also be drug induced. Pediatric causes are rare and include familial dysautonomia as the only “relatively” common variants (32). Acute forms may occur during infectious and inflammatory diseases or be related to peripheral nerve disease.


3) Chronic Orthostatic Intolerance and the Postural Tachycardia Syndrome

The orthostatic tachycardia syndrome is a disabling disease state described at least since 1940 (33) and is the most common reason for referral for orthostatic intolerance  in adults. It is an emerging form of orthostatic intolerance in children. Patients have day-to-day disability - a feature not shared with those with simple faint. With some exception, traditional tests of autonomic function are normal in these patients. Patients are often unable to hold jobs or attend schools. Dr. David Robertson of the Vanderbilt autonomic laboratories, 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.  He has therefore initially named the illness “Chronic Orthostatic Intolerance” (COI). Our understanding of its pathophysiology remains incomplete.  The central physical finding is upright tachycardia without concurrent hypotension. Hypotension can be induced with unusually prolonged standing. A  resting tachycardia may also be present. An operational definition of the syndrome most often called POTS for the postural tachycardia 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 greater than 120 beats per minute within 10 minutes of head-up tilt (HUT). Recent literature indicate that higher increases in HR are found in younger patients. 

Day-to-Day Symptoms of OI
Excessive Tachycardia
 (without Hypotension)
Adults Δ>30 or HR>120bpm within 10min
Adolescent – Δ>43
  (IOH a confound)?
Concurrent Symptoms of OI
during testing
Improved by Recumbence


Onset of symptoms often follows an infectious disease and may be related to inflammatory mediators (42). We reported the first pediatric cases of POTS. Our data showed that POTS physiology underlies orthostatic intolerance in the large majority of adolescents with the chronic fatigue syndrome (CFS) . POTS is common, affecting an undisclosed number of patients mostly in the age range of 12 to 50 years, mostly female (approximately 80%). There is an as yet undetermined but increasing apparent prevalence in children and adolescents (43).


POTS is caused by alterations of the autonomic nervous system, although, mild to moderate all-cause hypovolemia mimics POTS.

 Vagal Withdrawal and the Sinus Node
In some mildly ill individuals, POTS is related to loss of parasympathetic slowing of the heart with few peripheral circulatory abnormalities. Upright heart rates rarely exceed 120 bpm. Oten agents that increase cardiac parasympathetic activity such as beta blockers
, cardiac glycosides , acetylcholinesterase inhibitors (pyridostigmine) or ivabradine (not FDA approved) relieve symptoms.  

Others may have excessive beta adrenergic sensitivity of the sinus node. This condition is denoted "inappropriate sinus tachycardia" , and is regarded as distinct from POTS but less common. Supine heart rates >100bpm are observed, symptoms are less severe than in POTS, and beta blocker therapy can be efficacious.

 Neuropathic POTS and Hyperadrenergic POTS 
The remainder of patients are often partitioned among "neuropathic POTS", in which "partial dysautonomic" adrenergic denervation occurs, and "hyperadrenergic POTS", in which sympathetic overactivity prevails.  

Neuropathic POTS
As originally described, decreased adrenergic vasoconstriction in the legs causes decreased norepinephrine spillover ,  vasodilation , and increased blood flow even supine . When upright, redistributive central hypovolemia caused by leg blood pooling leads to reflex tachycardia . In another neuropathic variant decreased adrenergic vasoconstriction and redistribution of central blood to the splanchnic vasculature causes reflex tachycardia. Intense leg vasoconstriction produces acrocyanosis. Autonomic autoimmune neuropathy , presenting as POTS, causes similar reflex tachycardia. Central hypovolemia produces hyperpnea and hypocapnia in 50% of our patients . Treatment with vasoconstrictors (e.g. midodrine) and pyridostigmine can help.

 Hyperadrenergic POTS
The adrenergic synapse can be altered at pre-synaptic or post-synaptic levels. Pre-synaptic abnormalities include increased sympathetic nerve activity even when supine. While this has been reported 38 , the finding is not consistent 51 .  

Increased synaptic norepinephrine is observed in the norepinephrine transporter (NET) deficiency heterozygote , and in more prevalent epigenetic NET downregulation .  Pre-synaptic and post-synaptic adrenergic activity may be enhanced by local chemical milieu, including angiotensin-II excess caused by ACE-2 deficit and nitric oxide deficiency - a hyperadrenergic variant with tachycardia, pallor, vasoconstriction and absolute hypovolemia. Angiotensin [type 1] receptor blockers have shown benefit. Beta blockers may also help.

 Distinguishing among POTS Variants, a Matter of Opinion
Distinguishing among POTS variants may be difficult for the pediatrician (and for the OI expert) despite apparent straight forward differences. Some would say that POTS with increased upright blood pressure is hyperadrenergic, others would say that increased plasma catecholamines (or better, increased norepinephrine spillover) is required. Excessive orthostatic BP is a matter for consensus since both systolic and diastolic BP normally increase upon standing: how much is too much is unclear. As a heuristic, POTS patients with high supine HR, cool to touch and pasty white in appearance when supine, often have hyperadrenergic POTS. Standing HR is elevated to the 130-180 range during quiet standing indicating hyperadrenergic drive; vagal withdrawal alone increases HR to the 100-120 range. Those with upright HR < 120bpms are more likely neuropathic. Recent (unpublished) work with sympathetic nerve recordings have demonstrated normal sympathetic activity when supine, and supranormal activity upright. This supports adrenergic enhancement (NET deficiency, Ang-II excess) in patients with “hyperadrenergic POTS”. Confusing matters further, neuropathic patients can have increased upright catecholamines even though spillover is decreased in the lower extremities .

Gravitational Deconditioning – Caveat Bedrest! 
One confounding and alarming issue is the tendency for POTS patients to bedrest. Prolonged bedrest emulates microgravity and has deleterious effects
including OI , profound reductions in blood volume and cardiac size, redistribution of blood, osteoporosis, skeletal muscle pump atrophy and more . Vasoconstriction is impaired . Bedrest causes a self-perpetuating state of OI which can emulate or intensify POTS. It is paramount for POTS patient to leave bed and recondition. Well-structured exercise protocols are essential and must accommodate patients start off bedrested . Reconditioning invariably improves patient well-being. Recent work support the idea that POTS patients are also exercise deconditioned compared to matched volunteers . 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.


Effective treatment for chronic orthostatic intolerance is being developed but will depend on specific etiologies as these are discovered. For the moment we continue to use some of the medications outlined in the vasovagal section. Of these florinef, midodrine, beta blockers and pyridostigmine seem to be most effective with an emerging use of SSRI’s.




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Orthostatic Stress  Testing & instrumentation
Circulatory Measurements
Circulatory Autonomic Testing
Initial Orthostatic Hypotension
Research Studies
Fainting and Related Phenomena a Lay Review
Orthostatic Intolerance
Orthostatic Hypotension