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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.
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 Orthostatic Intolerance