Physiology of Orthostasis

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Compensatory Response to Orthostasis

Physical forces (muscle/abd –resp pump)

Cardiopulmonary interactions

Vascular structure  and Blood volume

Vascular regulation of O2 Delivery

Rapid

ANS–Sympathetic/Parasymp

Myogenic

Flow Mediated

Slower

Setting the tonic milieu –NO/Ang

autocrine, paracrine, endocrine

Metabolic

Standing up reduces venous return by translocating a large fraction of thoracic blood volume to the dependent body parts. Excessively decreased upright venous return (excessive thoracic hypovolemia) occurs through either absolute hypovolemia or through excessive gravitational pooling of blood and extravasated fluid within dependent veins and tissues. Such excessive pooling may be enhanced by ilnesses or pathophysiological processes which interfere with the compensatory response to orthostasis despite system redundancy. Inadequacy of the compensatory response to orthostatic stress results in orthostatic intolerance.  

Blood Volume Our "zeroth" order defense against orthostatic intolerance is therefore blood volume itself. Absolute hypovolemia is the simplest means to produce orthostatic intolerance and is familiar to all physicians in the context of dehydration. Similarly, a mismatch between vascular capacitance and blood volume could theoretically produce signs and symptoms of orthostatic intolerance but does not normally occur as capacitance appears to alter to accomodatet changing blood volumes in the long term. Fouad and Jacob have separately shown a degree of hypovolemia in patients with chronic orthostatic intolerance. Physicians are all familiar with the orthostatic intolerance which occurs with dehydration. In many respects this mimics findings in chronic orthostatic intolerance and POTS.

Muscle Pump The primary defense against excessive orthostatic pooling in man is through interstitial compression by the “skeletal muscle pump” in which contractions of leg and gluteal muscles propel sequestered venous blood back to the heart . Skeletal muscle may also be involved in neurogenic compensation through chemoreceptors and through local control mechanisms. Preliminary data show that defective muscle pump occurs in some patients with chronic orthostatic intolerance but only as a secondary effect. The muscle pump is effectively circumvented during upright tilt testing through the support afforded by the table and by instructing the patient to remain immobile throughout testing. Thus the importance of inadequate muscle pump activity is often missed during routine tilt tests.

Neurovascular Control    
Autonomic: The second line of defense against orthostatic intolerance is neurovascular compensation including rapid changes in arterial vasoconstriction limiting flow to the extremities and splanchnic vascular bed while promoting passive venous emptying. Active venoconstriction also occurs in the splanchnic circulation
. There is little evidence for venous beds other than splanchnic contributing to active orthostatic venoconstriction and recent data suggest that other veins and venules contribute to venous return by passive elastic recoil during arterial vasoconstriction . Reflex compensatory mechanisms are primarily controlled by the high-pressure arterial baroreceptors located in the carotid sinus, aortic arch, and perhaps the proximal coronary arteries . High pressure ventricular receptors, low-pressure cardiopulmonary receptors, and vestibular-otolith systems may contribute to a lesser degree . Some defects in neurovascular compensation to orthostatic stress are a major cause of chronic orthostatic intolerance by affecting sympathetic adrenergic function. Defects comprising a “long tract” peripheral neuropathy in which norepinephrine secretion is impaired and peripheral vasoconstriction to orthostasis is defective have been shown . More recently Robertson and coworkers at Vanderbilt University have identified a specific genetic defect in the norepinephrine transporter protein (NET deficiency) exerting both central and peripheral effects on vascular regulation .

Humoral: Humoral effects form a defense against orthostatic stress through the activation of the renin-angiotensin-aldosterone system, the release of epinephrine, CRF, and vasopressin, and by central effects but have onset delays on the order of minutes and therefore are less important for the immediate response to postural change.  Humoral compensations for orthostatic stress are important determinants of chronic postural tolerance.

Local Effects: Less well appreciated in the orthostatic response are contributions arising from local vasoactive responses produced by endothelial vasoactive products (i.e. NO, PGI2, endothelin, EDHF) , metabolites (adenosine, Ca++, CO2, H+ ions, lactate) , autacoids (histamine, bradykinin, 5-HT, PAF, prostaglandins) , local neurogenic mechanisms such as the axon reflex and neurogenic inflammation (CGRP, substance-P) especially within the cutaneous circulation. These may contribute to classic myogenic, metabolic and venoarteriolar flow control which may be important compensatory mechanisms in dependent extremities during orthostasis . Our preliminary data indicate a defect in local vascular compensation to orthostatic stress in a subgroup of patients with chronic orthostatic intolerance. Preliminary work suggests endothelial cell dysfunction. However local effects can have a larger impact on adrenergic synapses. Thus signaling molecules such as angiotensin-II and nitric oxide effectively modulate or, if you will, set the resting "tone" for norepinephrine mediated vasoconstriction as do various transpoter mechanisms such as the norepinelphrine transporter. 

Redundancy On a long-term basis there is redundancy built into these varied compensatory mechanisms. Thus, for example, tetraplegic individual with interrupted lower body autonomic innervation can be placed upright without fear of fainting because plasma volume is increased, circulating humoral factors are enhanced, and local effects remain inplace or are enhanced.

 

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Physiology of Orthostasis
Patterns of Orthostatic Intolerance
Acute Orthostatic Intolerance and Syncope
Chronic Orthostatic Intolerance