Orthostatic Intolerance (OI) In the Young (orthostasis = standing) (OI= Can’t remain standing)
Gravitational Blood Distribution in Man and Beast Unconstrained Pooling Causes Rapid Loss of BP
Circulatory Responses to Orthostasis • Physical forces (muscle/abd –resp pump) • Vascular structure and Blood volume • Vascular regulation of O 2 Delivery • Rapid • ANS–Sympathetic/Parasymp • Myogenic Most of OI= • Flow Mediated Abnormalities in adrenergic regulation • Slower and the modulation of • Setting the tonic milieu –NO/Ang adrenergic • autocrine, paracrine, endocrine vasoconstriction in humans • Metabolic • Gene expression -> Epigenetics
Normal Circulatory Response to Orthostasis
Impose Orthostatic Stress ~Model for Standing ↓ Skeletal Muscle Pump ≠ 100% Syncope in Syncopizers http://www.standingwave.ca/Support.html LBNP=Surrogate Hemorrhage
Orthostatic Intolerance: defined by inability to tolerate the upright posture relieved by recumbence • Loss of Consciousness • Lightheadedness-Dizziness cerebral • Neurocognitive Deficit perfusion abnormalities • Headache despite cerebral autoregulation • Fatigue – worst post-ictal • Orthostatic Hypotension/Hypertension • Weakness – peripheral malperfusion? ↓↑ Adrenergic • Nausea/abdominal pain vasoconstriction • Sweating, tremulousness Parasympathetic ↓↑ • Exercise Intolerance
Variants of Orthostatic Intolerance •Initial Orthostatic Hypotension •Gravitational Deconditioning •Orthostatic Hypotension •Chronic Orthostatic Intolerance Postural Tachycardia Syndrome (POTS) Other •Postural Vasovagal Syncope •Newer variants –Hyperpnea, Cerebral Dysreg
Initial Orthostatic Hypotension Standing 200 Arterial Pressure (mmHg) AP 100 g) g) 200 200 ressure ( mmH ressure ( mmH AP AP 0 100 100 rt eri al P rt eri al P 0 20 A A 0 0 0 0 20 20 40 40 M A M A P ( mmH P ( mmH g) g) Time (sec) 150 150 at e ( bpm) at e ( bpm) 100 100 HR HR eart R eart R H H 50 50 0 0 20 20 40 40 M A M A P ( mmH P ( mmH g) g) g) 200 ressure ( mmH AP 100 rt eri al P A 0 0 20 40 M A P ( mmH g) 150 at e ( bpm) 100 HR eart R H 50 0 20 40 M A P ( mmH g)
Gravitational Deconditioning • Reduced blood volume • Cardiovascular remodeling • Different Regional blood volume redistribution • Reduction in the response to norepinephrine/MSNA (and other pressors)
Orthostatic Hypotension (OH) •OH is defined as a sustained reduction of systolic BP> 20 mmHg or diastolic BP>10 mmHg within 3 min of standing or head-up tilt to ≥ 60 o 120 Arterial Pressure (mmHg) AP 80 •Non-neurogenic OH Drugs, 40 0 0 100 200 300 400 •hypovolemia (pheochromocytoma, HR 150 Heart Rate (bpm) •Addison Disease ) 100 50 0 100 200 300 400 Time (sec) •Neurogenic OH is identified with Autonomic vasoconstrictor failure due to inadequate release of norepinephrine from sympathetic vasomotor neurons.
Chronic Orthostatic Intolerance: Postural Tachycardia Syndrome (POTS) Day-to-Day Symptoms of OI + + 150 HR Heart Rate (bpm) 120 Excessive Tachycardia 90 60 ( without Hypotension) 30 0 0 100 200 300 400 500 600 Adults Δ >30 or HR>120bpm within 10min Time (sec) Adolescent – Δ >43 120 MAP MAP (mmHg) (IOH a confound)? 100 80 + 60 Concurrent Symptoms of OI 40 0 100 200 300 400 500 600 Time (sec) during testing Schondorf and Low. Idiopathic postural orthostatic tachycardia syndrome: an Improved by Recumbence attenuated form of acute pandysautonomia? Neurology 1995;43:132-137
What’s This? Tilt down 140 120 Heart Rate (BPM) HR Tilt up 100 80 60 40 0 120 240 360 480 600 IOH BP 150 Blood Pressure (bpm) 100 50 0 0 100 200 300 400 500 600 Time (seconds)
Well, so what! Maybe POTS patients Faint? Incremental tilt
The Tachycardia of POTS • Sinoatrial Sinoatrial Node Tachycardia • Node Tachycardia •Hypovagal Hypovagal POTS Parasympathetic • POTS due to cholinergic Parasympathetic due to cholinergic and nitrergic (NO) mechanisms. Channelopathy Channelopathy. . and nitrergic (NO) mechanisms. Hyperadrenergic POTS” ” ( ↑ ↑ adrenergic activity) adrenergic activity) “ Hyperadrenergic POTS ( •“ • •I I ncreased sympathetic nerve activity • ncreased sympathetic nerve activity •Increased peripheral transduction (NET, NPY, Increased peripheral transduction (NET, NPY, • receptors, β β - -1 receptors, Ang, NO deficit) 1 receptors, Ang, NO deficit) receptors, •Postural Hyperpnea • Postural Hyperpnea – – Hypocapnic Hypocapnic sympathoexcitation sympathoexcitation
The Tachycardia of POTS • Reflex Reflex (Neuropathic) Neuropathic) Central • ( Central Hypovolemia with Hypovolemia with baroreflex mediated tachycardia (intact cardiac ANS) baroreflex mediated tachycardia (intact cardiac ANS) Absolute Hypovolemia Absolute Hypovolemia • • •Regional Redistribution Regional Redistribution “ “Neuropathic POTS Neuropathic POTS” ” • ↓ regional adrenergic vasoconstriction ↓ regional adrenergic vasoconstriction •Legs Legs • •Splanchnic Splanchnic •
Neuropathic - Splanchnic Blood Pooling Control POTS 20 * 10 0 -10 -20 * -30 Thorax Splanchnic Pelvic Leg
POTS Factoids • Female Female • Rx Beta Blocker? Rx Beta Blocker? α α 1 agonist • • 1 agonist • Prior Inflammation Prior Inflammation • Volume load, fludrocortisone Volume load, fludrocortisone • • • EDS EDS • Acetylcholinesterase Inhibitors Acetylcholinesterase Inhibitors • • • Defects in Cerebral Defects in Cerebral • AT1R antagonists AT1R antagonists • • Autoregulation Autoregulation • Statin drugs Statin drugs • • Cognitive Deficits/Exercise Cognitive Deficits/Exercise • • Water Palliation Water Palliation • Intolerance Intolerance • Salt? Salt? – – in very large amounts • in very large amounts • Association with low BMI Association with low BMI • • IV saline/oral rehydration IV saline/oral rehydration – – yes • yes • BP maintained BP maintained • • Variable pale appearance Variable pale appearance •
Syncope Transient loss of consciousness and postural tone due to global cerebral hypoperfusion and characterized by rapid onset, short duration, and spontaneous recovery. Often the result of systemic hypotension Very Common (~40%)
Syncope (nasty)
Peds ‒ Hair-grooming, stretch Syncope (not so nasty?) But then there is asystolic syncope. 30 EKG 20 mV 10 0 0 6 12 18 24 30 Time (sec) 150 AP 120 BP (mmHg) 90 60 30 0 0 6 12 18 24 30 Time (sec) And being in harm’s way.
Postural Vasovagal Syncope in the Young Mechanism Remains Elusive 150 1 2 3 HR 120 Heart Rate (bpm) 90 60 Tilt Up Tilt Down 30 0 0 300 600 900 1200 1500 Time (sec) 120 MAP Slow ↓ 100 BP MAP (mmHg) 80 Rapid 60 ↓ BP 40 0 300 600 900 1200 1500 Time (sec)
Hemodynamics are Similar to Hemorrhage with impaired Adrenergic Vasoconstriction Reduced response to NE reversed with NOS inhibitors Response to step increments of NE Szabo C, Thiemermann C. Role of Nitric Oxide in Hemorrhagic, Traumatic and anaphylactic shock and thermal injury. Shock 2(2):145, 1994 • Barcroft, H., J. McMichael 0. G. Edholm, and E. P. Sharpey-Schafer. Posthaemorrhagic fainting. Study by cardiac output and forearm flow. Lancet 1: 489-491, 1944.
How do you explain Stage 2 gradual hypotension MAP = CO x SVR
VVS in the Old vs Young: ↓ CO vs ↓ TPR Older Younger
Excessive ↓ Central Blood Volume ↑ Splanchnic Blood Volume splanchnic volume/Kg body weight trunk volume/Kg body weight Fainters bsl 1m early mid late faint 900 Splanchnic Healthy Normalized change Normalized change Thorax 750 -150 600 -400 450 300 -650 150 Fainters 0 -900 0 l n d e t s y n t i i b m l m a i Healthy r a a l 1 f e pelvic volume/Kg body weight volume leg/Kg body weight Fainters Fainters 125 600 Healthy Healthy Normalized change Normalized change 500 100 400 75 300 50 Pelvic Leg 200 25 100 0 0 0 n d t 0 l n d e t l e s y n s y n i i t i i t b b m l m a i m l m a i r r a a a l a l f 1 f 1 e e Head uptilt 70 Head uptilt 70
Or even
How do you explain Hypotension-Bradycardia? Hyperpneic Hyperventilation Loss of Cerebral Autoregulation Baroreflex Failure We do not know the mechanism
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