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Risk of Orthostatic Intolerance During Re-Exposure to Gravity

Post-spaceflight orthostatic intolerance remains a significant concern to NASA. In Space Shuttle missions, astronauts wore anti-gravity suits and liquid cooling garments to protect against orthostatic intolerance during re-entry and landing, but in-flight exercise and the end-of-mission fluid loading failed to protect approximately 30% of Shuttle astronauts when these garments were not worn. The severity of the problem appears to be increased after long-duration space flight. Five of six US astronauts could not complete a 10-minutes upright-posture tilt testing on landing day following 4-5 month stays aboard the Mir space station. The majority of these astronauts had experienced no problems of orthostatic intolerance following their shorter Shuttle flights. More recently, four of six US astronauts could not complete a tilt test on landing day following approximately 6 month stays on the International Space Station. Similar observations were made in the Soviet and Russian space programs, such that some cosmonauts wear the Russian compression garments (Kentavr) up to 4 days after landing. Future exploration missions, such as those to Mars or Near Earth Objects, will be long duration, and astronauts will be landing on planetary bodies with no ground-support teams. The occurrence of severe orthostatic hypotension could threaten the astronauts' health and safety and success of the mission.

Platts, Steven↗

High Intensity Exercise Countermeasures does not Prevent Orthostatic Intolerance Following Prolonged Bed Rest

Approximately 20% of Space Shuttle astronauts became presyncopal during operational stand and 80deg head‐up tilt tests, and the prevalence of orthostatic intolerance increases after longer missions. Greater than 60% of the US astronauts participating in Mir and early International Space Station missions experienced presyncope during post‐flight tilt tests, perhaps related to limitations of the exercise hardware that prevented high intensity exercise training until later ISS missions. The objective of this study was to determine whether an intense resistive and aerobic exercise countermeasure program designed to prevent cardiovascular and musculoskeletal deconditioning during 70 d of bed rest (BR), a space flight analog, would protect against post‐BR orthostatic intolerance. METHODS Twenty‐six subjects were randomly assigned to one of three groups: non‐exercise controls (n=11) or one of two exercise groups (ExA, n=8; ExB, n=7). Both ExA and ExB groups performed the same resistive and aerobic exercise countermeasures during BR, but one exercise group received testosterone supplementation while the other received a placebo during BR in a double‐blinded fashion. On 3 d/wk, subjects performed lower body resistive exercise and 30 min of continuous aerobic exercise (≥75% max heart rate). On the other 3 d/wk, subjects performed only highintensity, interval‐style aerobic exercise. Orthostatic intolerance was assessed using a 15‐min 80 head‐up tilt test performed 2 d (BR‐2) before and on the last day of BR (BR70). Plasma volume was measured using carbon monoxide rebreathing on BR‐3 and before rising on the first recovery day (BR+0). The code for the exercise groups has not been broken, and results are reported here without group identification. RESULTS Only one subject became presyncopal during tilt testing on BR‐2, but 7 of 11 (63%) controls, 3 of 8 (38%) ExA, and 4 of 7 (57%) ExB subjects were presyncopal on BR70. Survival analysis of post‐BR tilt tests revealed no differences (p=0.77) between groups. Plasma volume (absolute or relative to body mass index) decreased (p<0.001) from pre to post‐BR, with no differences between groups. CONCLUSIONS These preliminary results corroborate previous reports that the performance of a vigorous exercise countermeasure protocol during BR, even with testosterone supplementation, does not protect against orthostatic intolerance or plasma volume loss. Preventing post‐BR orthostatic intolerance may require additional countermeasures, such as orthostatic stress during BR or end‐of‐BR fluid infusion.

Platts, Steven H.↗

Drug effects on orthostatic intolerance induced by bedrest

Effective and practical preventive procedures for postflight orthostatic intolerance are highly desirable. The current practice of attempts to expand plasma volume by ingestion of salt and fluids before reentry has proven benefits. This study evaluated alternative options using fludrocortisone (F) to expand plasma volume (PV), dextroamphetamine (Dex) to enhance norepinephrine (NE) release, and atropine (A) to reduce the effects of vagal stimulation. Seven subjects with proven post-bedrest orthostatic intolerance returned for a 7-day 6-deg head-down bedrest study. F (0.2 mg) was given at 8:00 AM and 8:00 PM the day before and 8:00 AM the day the subjects got out of bed (2 hours before standing). PV was measured before and 1 hour after the last dose of F. Dex (5 mg) and A (0.8 mg) were then taken orally 1 hour before the stand test. F expanded PV by 16 percent and caused sodium retention. Four of the 7 subjects stood for 1 hour post-bedrest and heart rate, plasma NE and plasma renin responses to standing were greatly enhanced and sustained. Although there was a narrowing of pulse pressure, the ability to overcome orthostatic intolerance with these countermeasures was largely due to vasoconstriction and sustained high heart rate.

Vernikos, J.↗

Orthostatic intolerance and the postural tachycardia syndrome: genetic and environment pathophysiologies. Neurolab Autonomic Team

Orthostatic intolerance is a common problem for inbound space travelers. There is usually tachycardia on standing but blood pressure may be normal, low or, rarely, elevated. This condition is analogous to the orthostatic intolerance that occurs on Earth in individuals with orthostatic tachycardia, palpitations, mitral valve prolapse, and light-headedness. Our studies during the Neurolab mission indicated that sympathetic nerve traffic is raised in microgravity and that plasma norepinephrine is higher than baseline supine levels but lower than baseline upright levels. A subgroup of patients with familial orthostatic intolerance differ from inbound space travelers in that they have an alanine-to-to-proline mutation at amino acid position 457 in their norepinephrine transporter gene. This leads to poor clearance of norepinephrine from synapses, with consequent raised heart rate. Clinical features of these syndromes are presented.

short duration↗

Relation of blood volume and blood pressure in orthostatic intolerance

A complex but crucial relationship exists between blood volume and blood pressure in human subjects; it has been recognized that in essential hypertension, renovascular hypertension, and pheochromocytoma, the relationship between plasma volume and diastolic blood pressure is an inverse one. This phenomenon has not been studied in individuals with low normal and reduced blood pressures. Orthostatic intolerance is a commonly encountered abnormality in blood pressure regulation often associated with tachycardia in the standing position. Most of these patients have varying degrees of reduced blood volume. We tested the hypothesis that the relationship previously found between plasma volume and diastolic blood pressure in pressor states would also hold in orthostatic intolerance. We studied 16 patients with a history of symptomatic orthostatic intolerance associated with an elevation in plasma norepinephrine in the upright posture and hypovolemia in 9 patients and normovolemia in 7 patients. Our studies demonstrate an inverse relationship between plasma volume and diastolic blood pressure in patients with orthostatic intolerance. This finding also holds for the change in diastolic blood pressure in response to upright posture. In this relationship, patients with orthostatic intolerance with high plasma norepinephrine resemble those with essential hypertension, renovascular hypertension, and pheochromocytoma. We conclude that in a variety of conditions at both ends of the blood pressure spectrum, the seemingly paradoxical association of hypovolemia and diastolic blood pressure is preserved.

NASA Discipline Regulatory Physiology↗

High Intensity Resistive and Rowing Exercise Countermeasures Do Not Prevent Orthostatic Intolerance Following 70 Days of Bed Rest

More than 60% of US astronauts participating in Mir and early International Space Station missions (greater than 5 months) were unable to complete a 10‐min 80 deg head‐up tilt test on landing day. This high incidence of post‐spaceflight orthostatic intolerance may be related to limitations of the inflight exercise hardware that prevented high intensity training. PURPOSE: This study sought to determine if a countermeasure program that included intense lower‐body resistive and rowing exercises designed to prevent cardiovascular and musculoskeletal deconditioning during 70 days of 6 deg head-down tilt bed rest (BR), a spaceflight analog, also would protect against post‐ BR orthostatic intolerance. METHODS: Sixteen males participated in this study and performed no exercise (Control, n=10) or performed an intense supine exercise protocol with resistive and aerobic components (Exercise, n=6). On 3 days/week, exercise subjects performed lower body resistive exercise and a 30‐min continuous bout of rowing (greater than or equal to 75% max heart rate). On 3 other days/week, subjects performed only high‐intensity, interval‐style rowing. Orthostatic intolerance was assessed using a 15‐min 80 deg head‐up tilt test performed 2 days (BR‐2) before and on the last day of BR (BR70). Plasma volume was measured using a carbon monoxide rebreathing technique on BR‐3 and before rising on the first recovery day (BR+0). RESULTS: Following 70 days of BR, tilt tolerance time decreased significantly in both the Control (BR‐2: 15.0 +/- 0.0, BR70: 9.9 +/- 4.6 min, mean +/- SD) and Exercise (BR‐2: 12.2 +/- 4.7, BR70: 4.9 +/- 1.9 min) subjects, but the decreased tilt tolerance time was not different between groups (Control: ‐34 +/- 31, Exercise: ‐56 +/- 16%). Plasma volume also decreased (Control: ‐0.56 +/- 0.40, Exercise: ‐0.48 +/- 0.33 L) from pre to post‐BR, with no differences between groups (Control: ‐18 +/- 11%, Exerciser: ‐15 +/-1 0%). CONCLUSIONS: These findings confirm previous reports in shorter BR studies that the performance of an exercise countermeasure protocol by itself during BR does not prevent orthostatic intolerance or plasma volume loss. This suggests that protection against orthostatic intolerance in astronauts following long‐duration spaceflight will require an additional intervention, such as periodic orthostatic stress, fluid repletion, and/or lower‐body compression garments.

Lee, Stuart M. C.↗

Contributions of MSNA and stroke volume to orthostatic intolerance following bed rest

We examined whether the altered orthostatic tolerance following 14 days of head-down tilt bed rest (HDBR) was related to inadequate sympathetic outflow or to excessive reductions in cardiac output during a 10- to 15-min head-up tilt (HUT) test. Heart rate, blood pressure (BP, Finapres), muscle sympathetic nerve activity (MSNA, microneurography), and stroke volume blood velocity (SVV, Doppler ultrasound) were assessed during supine 30 degrees (5 min) and 60 degrees (5-10 min) HUT positions in 15 individuals who successfully completed the pre-HDBR test without evidence of orthostatic intolerance. Subjects were classified as being orthostatically tolerant (OT, n = 9) or intolerant (OI, n = 6) following the post-HDBR test. MSNA, BP, and SVV during supine and HUT postures were not altered in the OT group. Hypotension during 60 degrees HUT in the post-bed rest test for the OI group (P < 0.05) was associated with a blunted increase in MSNA (P < 0.05). SVV was reduced following HDBR in the OI group (main effect of HDBR, P < 0.02). The data support the hypothesis that bed rest-induced orthostatic intolerance is related to an inadequate increase in sympathetic discharge that cannot compensate for a greater postural reduction in stroke volume.

NASA Discipline Musculoskeletal↗

Orthostatic Intolerance and Motion Sickness After Parabolic Flight

Orthostatic intolerance is common in astronauts after prolonged space flight. However, the "push-pull effect" in military aviators suggests that brief exposures to transitions between hypo- and hypergravity are sufficient to induce untoward autonomic cardiovascular physiology in susceptible individuals. We therefore investigated orthostatic tolerance and autonomic cardiovascular function in 16 healthy test subjects before and after a seated 2-hr parabolic flight. At the same time, we also investigated relationships between parabolic flight-induced vomiting and changes in orthostatic and autonomic cardiovascular function. After parabolic flight, 8 of 16 subjects could not tolerate a 30-min upright tilt test, compared to 2 of 16 before flight. Whereas new intolerance in non-Vomiters resembled the clinical postural tachycardia syndrome (POTS), new intolerance in Vomiters was characterized by comparatively isolated upright hypocapnia and cerebral vasoconstriction. As a group, Vomiters also had evidence for increased postflight fluctuations in efferent vagal-cardiac nerve traffic occurring independently of any superimposed change in respiration. Results suggest that syndromes of orthostatic intolerance resembling those occurring after space flight can occur after a brief (i.e., 2-hr) parabolic flight.

Schlegel, Todd T.↗

Space Flight Orthostatic Intolerance Protection

This paper summarizes investigations conducted on different orthostatic intolerance protection garments. This paper emphasizes on the engineering and operational aspects of the project. The current Shuttle pneumatic Anti-G Suit or AGS at 25 mmHg (0.5 psi) and customized medical mechanical compressive garments (20-30 mmHg) were tested on human subjects. The test process is presented. The preliminary results conclude that mechanical compressive garments can ameliorate orthostatic hypotension in hypovolemic subjects. A mechanical compressive garment is light, small and works without external pressure gas source; however the current garment design does not provide an adjustment to compensate for the loss of mass and size in the lower torso during long term space missions. It is also difficult to don. Compression garments that do not include an abdominal component are less effective countermeasures than garments which do. An early investigation conducted by the Human Adaptation and Countermeasures Division at Johnson Space Center (JSC) has shown there is no significant difference between the protection function of the AGS (at 77 mmHg or 1.5 psi) and the Russian anti-g suit, Kentavr (at 25 mmHg or 0.5 psi). Although both garments successfully countered hypovolemia-induced orthostatic intolerance, the Kentavr provided protection by using lower levels of compression pressure. This more recent study with a lower AGS pressure shows that pressures at 20-30 mmHg is acceptable but protection function is not as effective as higher pressure. In addition, a questionnaire survey with flight crewmembers who used both AGS and Kentavr during different missions was also performed.

Luty, Wei↗

Compression Stockings May Ameliorate Orthostatic Intolerance in Astronauts After Short-Duration Space Flight

Orthostatic intolerance following spaceflight has been observed since the early days of manned spaceflight, and no countermeasure has been 100% effective. During re-entry NASA astronauts currently wear an inflatable anti-gravity suit (AGS) which compresses the legs and abdomen, but this device is uncomfortable and loses effectiveness upon egress from the Space Shuttle. We previously reported that foot-to-thigh, gradient compression stockings were comfortable and effective during standing after Shuttle missions. More recently we showed in a ground-based model of spaceflight that the addition of splanchnic compression to the foot-to-thigh compression stockings, creating foot-to-breast high compression, improved orthostatic tolerance in hypovolemic subjects to a level similar to the AGS. Purpose: To evaluate a new three-piece, foot-to-breast high gradient compression garment as a countermeasure to post-spaceflight orthostatic intolerance. Methods: Fourteen astronauts completed this experiment (7 control, 7 treatment) following Space Shuttle missions lasting 12-16 days. Treatment subjects were custom-fitted for a three-piece, foot-to-breast high compression garment consisting of shorts and foot-to-thigh stockings. The garments were constructed to provide 55 mmHg compression at the ankle and decreased gradually to 15 mmHg over the abdomen. Orthostatic testing occurred ~30 days before flight (without garments) and ~2 hours after flight (with garments for treatment group only) on landing day. Blood pressure (BP) and heart rate (HR) were acquired for 2 minutes while the subject lay prone and then for 3.5 minutes after the subject stood. Data are reported as mean +/- SE. Results: The compression garment successfully prevented the tachycardia and hypotension typically seen post-spaceflight. On landing day, treatment subjects had a smaller change in HR (11+/-1 vs. 21+/-4 beats/min, p< or =0.05) and no decrease in systolic BP (2+/-4 vs. -9+/-2 mmHg, p< or =0.05). Garments also received good comfort ratings and were relatively easy to don. Conclusion: In this small group of astronauts, foot-to-breast high gradient compression garments seem to have prevented these negative effects of spaceflight on the cardiovascular responses to standing.

Platts, Steven H.↗

Gradient Compression Garments as a Countermeasure to Post-Space Flight Orthostatic Intolerance: Potential Interactions with the Maximum Absorbency Garment

Astronauts and cosmonauts may experience symptoms of orthostatic intolerance during re-entry, landing, and for several days post-landing following short- and long-duration spaceflight. Presyncopal symptoms have been documented in approximately 20% of short-duration and greater than 60% of long-duration flyers on landing day specifically during 5-10 min of controlled (no countermeasures employed at the time of testing) stand tests or 80 deg head-up tilt tests. Current operational countermeasures to orthostatic intolerance include fluid loading prior to and whole body cooling during re-entry as well as compression garments that are worn during and for up to several days after landing. While both NASA and the Russian space program have utilized compression garments to protect astronauts and cosmonauts traveling on their respective vehicles, a "next-generation" gradient compression garment (GCG) has been developed and tested in collaboration with a commercial partner to support future space flight missions. Unlike previous compression garments used operationally by NASA that provide a single level of compression across only the calves, thighs, and lower abdomen, the GCG provides continuous coverage from the feet to below the pectoral muscles in a gradient fashion (from approximately 55 mm Hg at the feet to approximately 16 mmHg across the abdomen). The efficacy of the GCG has been demonstrated previously after a 14-d bed rest study without other countermeasures and after short-duration Space Shuttle missions. Currently the GCG is being tested during a stand test following long-duration missions (~6 months) to the International Space Station. While results to date have been promising, interactions of the GCG with other space suit components have not been examined. Specifically, it is unknown whether wearing the GCG over NASA's Maximum Absorbency Garment (MAG; absorbent briefs worn for the collection of urine and feces while suited during re-entry and landing) will interfere with the effectiveness of the GCG or conversely whether the GCG will reduce the fluid absorption capabilities of the MAG. Methods: This operational, directed study, will (1) determine whether the effectiveness of the GCG is affected by the MAG with regard to cardiovascular responses to head-up tilt, the standard orthostatic intolerance test employed for astronauts and bed rest subjects; (2) determine whether the effectiveness of the MAG is compromised by the GCG tested by injecting a standard fluid volume (950 ml in 3 separate simulated "urine voids") at a standardized rate (30 ml/sec); and (3) determine whether comfort is affected by wearing the MAG under the GCG using a standardized questionnaire. Results from this study will guide future development and operational use of the GCG and MAG to maximize crew health, safety, and comfort.

Lee, S. M. C.↗

Marked exacerbation of orthostatic intolerance after long- vs. short-duration spaceflight in veteran astronauts

OBJECTIVE: The incidence of postflight orthostatic intolerance after short-duration spaceflight is about 20%. However, the incidence after long-duration spaceflight was unknown. The purpose of this study was to test the hypothesis that orthostatic intolerance is more severe after long-duration than after short-duration flight. METHODS: We performed tilt tests on six astronauts before and after long-duration (129-190 days) spaceflights and compared these data with data obtained during stand tests before and after previous short-duration missions. RESULTS: Five of the six astronauts studied became presyncopal during tilt testing after long-duration flights. Only one had become presyncopal during stand testing after short-duration flights. We also compared the long-duration flight tilt test data to tilt test data from 20 different astronauts who flew on the short-duration Shuttle missions that delivered and recovered the astronauts to and from the Mir Space Station. Five of these 20 astronauts became presyncopal on landing day. Heart rate responses to tilt were no different between astronauts on long-duration flights and astronauts on short-duration flights, but long-duration subjects had lower stroke volumes and cardiac outputs than short-duration presyncopal subjects, suggesting a possible decrease in cardiac contractile function. One subject had subnormal norepinephrine release with upright posture after the long flight but not after the short flight. Plasma volume losses were not greater after long flights. CONCLUSION: Long-duration spaceflight markedly increases orthostatic intolerance, probably with multiple contributing factors.

STS Shuttle Project↗

Nitric oxide in microgravity-induced orthostatic intolerance: relevance to spinal cord injury

Prolonged exposure to microgravity results in cardiovascular deconditioning which is marked by orthostatic intolerance in the returning astronauts and recovering bed-ridden patients. Recent studies conducted in our laboratories at University of California, Irvine have revealed marked elevation of nitric oxide (NO) production in the kidney, heart, brain, and systemic arteries coupled with significant reduction of NO production in the cerebral arteries of microgravity-adapted animals. We have further demonstrated that the observed alteration of NO metabolism is primarily responsible for the associated cardiovascular deconditioning. Recovery from acute spinal cord injury (SCI) is frequently complicated by orthostatic intolerance that is due to the combined effects of the disruption of efferent sympathetic pathway and cardiovascular deconditioning occasioned by prolonged confinement to bed. In this presentation, I will review the nature of altered NO metabolism and its role in the pathogenesis of microgravity-induced cardiovascular deconditioning. The possible relevance of the new findings to orthostatic intolerance in patients with acute SCI and its potential therapeutic implications will be discussed.

Review↗

Cardiac atrophy after bed-rest deconditioning: a nonneural mechanism for orthostatic intolerance

BACKGROUND: The cardiovascular adaptation to bed rest leads to orthostatic intolerance, characterized by an excessive fall in stroke volume (SV) in the upright position. We hypothesized that this large fall in SV is due to a change in cardiac mechanics. METHODS AND RESULTS: We measured pulmonary capillary wedge pressure (PCWP), SV, left ventricular end-diastolic volume (LVEDV), and left ventricular mass (by echocardiography) at rest, during lower-body negative pressure, and after saline infusion before and after 2 weeks of bed rest with -6 degrees head-down tilt (n=12 subjects aged 24+/-5 years). Pressure (P)-volume (V) curves were modeled exponentially by P=ae(kV)+b and logarithmically by P=-Sln[(Vm-V)/(Vm-V0)], where V0 indicates volume at P=0, and the constants k and S were used as indices of normalized chamber stiffness. Dynamic stiffness (dP/dV) was calculated at baseline LVEDV. The slope of the line relating SV to PCWP during lower-body negative pressure characterized the steepness of the Starling curve. We also measured plasma volume (with Evans blue dye) and maximal orthostatic tolerance. Bed rest led to a reduction in plasma volume (17%), baseline PCWP (18%), SV (12%), LVEDV (16%), V0 (33%), and orthostatic tolerance (24%) (all P<.05). The slope of the SV/PCWP curve increased from 4.6+/-0.4 to 8.8+/-0.9 mL/mm Hg (P<.01) owing to a parallel leftward shift in the P-V curve. Normalized chamber stiffness was unchanged, but dP/dV was reduced by 50% at baseline LVEDV, and cardiac mass tended to be reduced by 5% (P<.10). CONCLUSIONS: Two weeks of head-down-tilt bed rest leads to a smaller, less distensible left ventricle but a shift to a more compliant portion of the P-V curve. This results in a steeper Starling relationship, which contributes to orthostatic intolerance by causing an excessive reduction in SV during orthostasis.

NASA Discipline Cardiopulmonary↗

Midodrine prevents orthostatic intolerance associated with simulated spaceflight

Many astronauts after being weightless in space become hypotensive and presyncopal when they assume an upright position. This phenomenon, known as orthostatic intolerance, may interfere with astronaut function during reentry and after spaceflight and may limit the ability of an astronaut to exit a landed spacecraft unaided during an emergency. Orthostatic intolerance is more pronounced after long-term spaceflight and is a major concern with respect to the extended flights expected aboard the International Space Station and for interplanetary exploration class missions, such as a human mission to Mars. Fully effective countermeasures to this problem have not yet been developed. To test the hypothesis that alpha-adrenergic stimulation might provide an effective countermeasure, we conducted a 16-day head-down-tilt bed-rest study (an analog of weightlessness) using normal human volunteers and administered the alpha(1)-agonist drug midodrine at the end of the bed-rest period. Midodrine was found to significantly ameliorate excessive decreases in blood pressure and presyncope during a provocative tilt test. We conclude that midodrine may be an effective countermeasure for the prevention of orthostatic intolerance following spaceflight.

NASA Center JSC↗

Evaluation of Cutaneous Blood Flow During Lower Body Negative Pressure to Prevent Orthostatic Intolerance of Bedrest

Orthostatic tolerance is markedly impaired in most of the crewmembers during space flight and could seriously compromise crew safety during and immediately after landing. NASA investigators are studying the use of lower body negative pressure (LBNP) as a countermeasure to this intolerance. It is hypothesized that the continuously changing vascular pressure induced by sinusoidal LBNP with an additional countermeasure of salt and water will help crewmembers to be in a more acceptable physiologic condition to enter the earth's atmosphere. In ground based studies, subjects on bedrest provide the model for studying the physiologic effects of weightlessness. When subjects are treated with sinusoidal LBNP, negative pressures ranging from 0 to -60 mm/Hg are administered during a two hour period. This increases body fluids in the legs and lower body. This paper reports the results of two subjects who were placed on bedrest for six days. The subjects were randomly selected for either the control or treatment mode. The subject receiving the treatment mode ingested salt tablets and water on day 4 of the bedrest period. A ramp LBNP of two hours was next administered to this subject. The control subject did not receive anything during the bedrest period. Laser Doppler was used to measure the cutaneous blood flow of the forearm and calf to monitor vasoconstrictor effects of the baroreceptor reflex. Data indicated that skin blood flow in the treatment subject was higher than baseline in the forearm while the skin blood flow was decreased in the control subject.

Rubin, Marilyn↗

Idiopathic orthostatic intolerance and postural tachycardia syndromes

Upright posture imposes a substantial gravitational stress on the body, for which we are able to compensate, in large part because of the autonomic nervous system. Alteration in autonomic function, therefore, may lead to orthostatic intolerance. On one extreme, patients with autonomic failure caused by degenerative loss of autonomic function are severely disabled by orthostatic hypotension and may faint whenever they stand up. Fortunately, such patients are relatively rare. On the other hand, disabling orthostatic intolerance can develop in otherwise normal young people. These patients can be severely impaired by symptoms of fatigue, tachycardia, and shortness of breath when they stand up. The actual incidence of this disorder is unknown, but these patients make up the largest group of patients referred to centers that specialize in autonomic disorders. We will review recent advances made in the understanding of this condition, potential pathophysiological mechanisms that contribute to orthostatic intolerance, therapeutic alternatives currently available for the management of these patients, and areas in which more research is needed.

Review↗