Hemodynamic effects of midodrine after spaceflight in astronauts without orthostatic hypotension.

INTRODUCTION: Orthostatic hypotension and presyncope are common and potentially serious risks for astronauts returning from space. Susceptible subjects fail to generate an adequate adrenergic response to upright posture. The alpha-1 adrenergic agonist, midodrine, may be an effective countermeasure. We tested the hypothesis that midodrine would have no negative hemodynamic effect on healthy astronauts returning from space. METHODS: Five male astronauts participated in preflight and post-flight tilt testing on a control flight as well as on the test flights, where midodrine (10 mg, orally) was administered after landing approximately 1 h before testing. RESULTS: None of these astronauts exhibited orthostatic hypotension or presyncope before or after either flight. Midodrine did not cause any untoward reactions in these subjects before or after flight; in fact, a modest beneficial effect was seen on postflight tachycardia (p = 0.036). DISCUSSION: These data show that midodrine protected against post-spaceflight increases in heart rate without having any adverse hemodynamic effects on non-presyncopal, male astronauts. Among these subjects, midodrine was a safe cardiovascular countermeasure.

Plasma volume restoration with salt tablets and water after bed rest prevents orthostatic hypotension and changes in supine hemodynamic and endocrine variables.

Head-down bed rest changes the values of many cardiovascular and endocrine variables and also elicits significant hypovolemia. Because previous studies had not controlled for hypovolemia, it is unknown whether the reported changes were primary effects of bed rest or secondary effects of bed rest-induced hypovolemia. We hypothesized that restoring plasma volume with salt tablets and water after 12 days of head-down bed rest would result in an absence of hemodynamic and endocrine changes and a reduced incidence of orthostatic hypotension. In 10 men, we measured changes from pre-bed-rest to post-bed-rest in venous and arterial pressures; heart rate; stroke volume; cardiac output; vascular resistance; plasma norepinephrine, epinephrine, vasopressin, renin activity (PRA), and aldosterone responses to different tilt levels (0 degrees, -10 degrees, 20 degrees, 30 degrees, and 70 degrees); and plasma volume and platelet alpha2- and lymphocyte beta2-adrenoreceptor densities and affinities (0 degrees tilt only). Fluid loading at the end of bed rest restored plasma volume and resulted in the absence of post-bed-rest orthostatic hypotension and changes in supine hemodynamic and endocrine variables. Fluid loading did not prevent post-bed-rest increases in beta2-adrenoreceptor density or decreases in the aldosterone-to-PRA ratio (P = 0.05 for each). Heart rate, epinephrine, and PRA responses to upright tilt after bed rest were increased (P < 0.05), despite the fluid load. These results suggest that incidents of orthostatic hypotension and many of the changes in supine hemodynamic and endocrine variables in volume-depleted bed-rested subjects occur secondarily to the hypovolemia. Despite normovolemia after bed rest, beta2-adrenoreceptors were upregulated, and heart rate, epinephrine, and PRA responses to tilt were augmented, indicating that these changes are independent of volume depletion.

Midodrine prescribed to improve recurrent post-spaceflight orthostatic hypotension.

Many astronauts exhibit post-spaceflight orthostatic hypotension due to inadequate norepinephrine release when in an upright posture. We hypothesized that an alpha1-adrenergic agonist, midodrine, would be an effective countermeasure. A female astronaut, who had problems with postflight orthostatic hypotension after a previous flight, consumed 10 mg midodrine after a subsequent flight, prior to her tilt test. Hemodynamic variables were compared between the two flights. Midodrine prevented severe falls in stroke volume, cardiac output and systolic pressure, and severe increases in heart rate without increasing vascular resistance, thus preventing orthostatic hypotension. This is the first report showing that midodrine has the potential to improve post-spaceflight orthostatic hypotension and suggesting that reduced venous return contributes to the etiology.

Mechanisms of postspaceflight orthostatic hypotension: low alpha1-adrenergic receptor responses before flight and central autonomic dysregulation postflight.

Although all astronauts experience symptoms of orthostatic intolerance after short-duration spaceflight, only approximately 20% actually experience presyncope during upright posture on landing day. The presyncopal group is characterized by low vascular resistance before and after flight and low norepinephrine release during orthostatic stress on landing day. Our purpose was to determine the mechanisms of the differences between presyncopal and nonpresyncopal groups. We studied 23 astronauts 10 days before launch, on landing day, and 3 days after landing. We measured pressor responses to phenylephrine injections; norepinephrine release with tyramine injections; plasma volumes; resting plasma levels of chromogranin A (a marker of sympathetic nerve terminal release), endothelin, dihydroxyphenylglycol (DHPG, an intracellular metabolite of norepinephrine); and lymphocyte beta(2)-adrenergic receptors. We then measured hemodynamic and neurohumoral responses to upright tilt. Astronauts were separated into two groups according to their ability to complete 10 min of upright tilt on landing day. Compared with astronauts who were not presyncopal on landing day, presyncopal astronauts had 1). significantly smaller pressor responses to phenylephrine both before and after flight; 2). significantly smaller baseline norepinephrine, but significantly greater DHPG levels, on landing day; 3). significantly greater norepinephrine release with tyramine on landing day; and 4). significantly smaller norepinephrine release, but significantly greater epinephrine and arginine vasopressin release, with upright tilt on landing day. These data suggest that the etiology of orthostatic hypotension and presyncope after spaceflight includes low alpha(1)-adrenergic receptor responsiveness before flight and a remodeling of the central nervous system during spaceflight such that sympathetic responses to baroreceptor input become impaired.

Pressor response to intravenous tyramine is a marker of cardiac, but not vascular, adrenergic function.

Intravenous injections of the indirect sympathetic amine, tyramine, are used as a test of peripheral adrenergic function. The authors measured the time course of increases in ejection fraction, heart rate, systolic and diastolic pressure, popliteal artery flow, and greater saphenous vein diameter before and after an injection of 4.0 mg/m(2) body surface area of tyramine in normal human subjects. The tyramine caused moderate, significant increases in systolic pressure and significant decreases in total peripheral resistance. The earliest changes were a 30% increase in ejection fraction and a 16% increase in systolic pressure, followed by a 60% increase in popliteal artery flow and a later 11% increase in greater saphenous vein diameter. There were no changes in diastolic pressure or heart rate. These results suggest that pressor responses during tyramine injections are primarily due to an inotropic response that increases cardiac output and pressure and causes a reflex decrease in vascular resistance. Thus, tyramine pressor tests are a measure of cardiac, but not vascular, sympathetic function.

Postspaceflight orthostatic hypotension occurs mostly in women and is predicted by low vascular resistance.

About 20% of astronauts suffer postspaceflight presyncope. We studied pre- to postflight (5- to 16-day missions) cardiovascular responses to standing in 35 astronauts to determine differences between 1) men and women and 2) presyncopal and nonpresyncopal groups. The groups were presyncopal women, presyncopal men, and nonpresyncopal men based on their ability to stand for 10 min postflight. Preflight, women and presyncopal men had low vascular resistance, with the women having the lowest. Postflight, women experienced higher rates of presyncope (100 vs. 20%; P = 0.001) and greater losses of plasma volume (20 vs. 7%; P < 0.05) than men. Also, presyncopal subjects had lower standing mean arterial pressure (P < or = 0.001) and vascular resistance (P < 0.05), smaller increases in norepinephrine (P < or = 0.058) and greater increases in epinephrine (P < or = 0.058) than nonpresyncopal subjects. Presyncopal subjects had a strong dependence on plasma volume to maintain standing stroke volume. These findings suggest that postflight presyncope is greatest in women, and this can be ascribed to a combination of inherently low-resistance responses, a strong dependence on volume status, and relative hypoadrenergic responses. Conversely, high vascular resistance and postflight hyperadrenergic responses prevent presyncope.