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    Drugs & Diseases>Neurology

    Orthostatic Intolerance

    Updated: Nov 13, 2019
    • Author: Julian M Stewart, MD, PhD; more...
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    Overview

    Background

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

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

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

    Pathophysiology

    Normal orthostatic regulation

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

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

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

    Immediate Orthostatic Hypotension (IOH) upon standImmediate Orthostatic Hypotension (IOH) upon standing. There is a short-lived decrease in blood pressure (BP - upper panel) and increase in heart rate (HR - lower panel). The fall in BP is resolved within 20 seconds. The patient experienced transient lightheadedness.
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    After IOH recovery, sympathetic nerve activity increases while upright blood volume slowly decreases because of microvascular filtration. [89] Decreased venous return decreases central blood volume and cardiac output (CO) by 20% despite baroreflex mediated vasoconstriction, increased cardiac contractility, and increased HR. Cerebral blood flow velocity (CBFv) decreases by 3-12% partly because of reduced cerebral perfusion pressure of 20mmHg. [90] Cerebral autoregulation (unchanged CBF despite changing BP) is blunted during orthostasis. Unless the muscle pump is evoked, standing still places us at risk for decreased CO and CBF. The normal orthostatic response to tilt is shown in the image below.

    Hemodynamic and neurovascular changes during uprigHemodynamic and neurovascular changes during upright tilt in a representative healthy volunteer. The left panel shows from top to bottom: arterial pressure, muscle sympathetic nerve activity (MSNA) from the peroneal nerve, heart rate (HR) and cardiac output. The right panel shows from top to bottom: total peripheral resistance (TPR), cerebral blood flow velocity (CBFv) by transcranial Doppler ultrasound, stroke volume and a vagal index calculated from the respiratory sinus arrhythmia component of the frequency spectrum of HR variability. During upright tilt at 275 seconds (s), systolic, diastolic and arterial pressures increase slightly, while pulse pressure is decreased with a decrease in stroke volume by approximately 40%. HR increases so that cardiac output is only decreased by 20% because of the increase in HR. CBFv decreases by 5-10%. Both total peripheral vascular resistance and muscle sympathetic nerve activity increase, while the vagal index decreases, reflecting, respectively, sympathetic activation and parasympathetic withdrawal.
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    Etiology

    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

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    Epidemiology

    Statistics

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

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

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

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

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

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    Prognosis

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

    Mortality/morbidity

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

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    Patient Education

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

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