Space motion sickness medications: interference with biomedical parameters

The possibility that drugs administered to Skylab 3 (SL-3) and 4 (SL-4) crewmen for space motion sickness may have interfered with their biomedical evaluation in space was investigated. Healthy volunteers received combinations of Scopolamine/Dexedrine for four days in regimens similar to those used in these missions. Urine samples, heart rate, body temperature, mood and performance were analyzed for drug-related changes. Twenty-four hour urine samples were analyzed by the same procedures as those used to analyze the flight samples. Hormone concentrations determined included cortisol, epinephrine, norepinephrine, aldosterone and antidiuretic hormone (ADH). In addition, volume, specific gravity, osmolarity, sodium (Na), potassium (K), calcium (Ca), magnesium (Mg), chloride (Cl), inorganic phosphate, uric acid and creatinine were measured. Performance was not affected by the Scopolamine/Dexedrine. The drug combination increased daily mean heart rate (HR) significantly in all the subjects and daily mean rectal temperature (RT) in some of the subjects. A 2-4 hr phase shift in the HR circadian rhythm was also observed which indicates that internal circadian synchrony was disturbed by the drugs. Psychological and subjective evaluation indicated that the subjects could usually identify which days they were given the drugs by an increase in tension and anxiety, decreased patience, restlessness, decreased appetite, difficulty in sleeping and feelings of increased heart rate and body temperature. Urinary electrolytes were not changed significantly by the drug, but marked and significant changes occurred in urine volume and hormone excretion patterns. Scopolamine/Dexedrine caused consistent elevations in urinary cortisol and epinephrine and a transient elevation in ADH. Norepinephrine excretion was decreased, but there was no significant change in aldosterone excretion or in 24 hr urine volume. A comparison of these findings with the first four days of inflight data from the SL-3 and SL-4 missions leads to the conclusion that the dramatic increases in aldosterone excretion during the first three days of spaceflight probably can be directly attributed to weightlessness, whereas the antimotion sickness medication could have substantially contributed to the early increased excretion of epinephrine and cortisol during these missions.     

Ion regulatory function of the human kidney in prolonged space flights.

Ten cosmonauts, who performed 30-175-day space flights aboard Salyut-4 and Salyut-6, and over 60 test subjects who were exposed to bed rest of up to 182 days and immersion of up to 56 days, were examined. The renal excretion of potassium and calcium increased, reaching a maximum by the 4-6th weeks in prolonged space flights and simulation studies. During the load tests with potassium and calcium salt, excretion postflight was much higher than preflight. During potassium chloride load tests a positive correlation between the blood content of aldosterone and potassium excretion existed, whereas during calcium lactate load tests an increased calcium excretion was accompanied by a decrease in blood parathyroid hormone concentration. The most probable cause of the negative ion balance in weightlessness is the reduced capacity of tissues to retain electrolytes due to the decreased ion pool capacity. Different exercises have been shown to exert a beneficial effect on electrolyte metabolism.     

Characteristics of metabolism during prolonged water immersion

The effect on the organism of a 12-day stay in a water immersion medium (head on the water surface) was studied on 10 subjects. The condition of the metabolic processes in the subjects was judged from the investigation of the parameters of protein and carbohydrate metabolism, acid-base equilibrium, the activity of a number of enzymes and steroid hormones. The venous blood and diurnal urine served as the material for conducting the corresponding biochemical determinations. The stay in an immersion medium is accompanied by a significant increase in the content of residual nitrogen in the blood, by a reduction of the creatinine content in the blood and by an increase of the creatine content of the blood with the simultaneous increase of the excretion of creatinine and creatine with the urine, by a significant increase of the glucose and lactate content in the blood, by the development of acidosis of a respiratory and metabolic character, as well as by a significant increase of the activity of creatine phosphokinase and the isoenzyme fraction of lactate dehydrogenase3. In all the subjects, an expressed intensification of the glucocorticoid and androgenic functions of the adrenal cortex is noted during the experimental period.     

Fluid electrolyte excretion during different hypokinetic body positions of trained subjects

The aim of this study was to evaluate the effect of different body positions on renal excretion of fluid and electrolytes after exposure to 364 days of decreased number of steps per day (hypokinesia, HK). The studies were performed on 18 endurance trained male volunteers aged 19-24 years who had an average of VO2max 67 ml/kg body/min. All volunteers were divided into three equal groups: the 1st group subjected to 12 h orthostatic position (OP) and 12 h clinostatic position (CP)/day, the 2nd group exposed to 8 h orthostatic position and 14 h clinostatic position/day, and the 3rd group submitted to 10 h orthostatic position and 16 h clinostatic position/day for 364 days. For the simulation of the hypokinetic effect all volunteers were kept under an average of 3000 steps/day for 364 days. Diuresis and the concentrations of sodium, potassium, chloride, calcium and magnesium as well as excretion of creatine were determined in 24-h urine samples. By the end of the hypokinetic period all volunteers, regardless of their body position during HK, manifested a significant increase in renal excretion of fluid and electrolytes as compared to prehypokinetic period values. It was concluded that prolonged restriction of motor activity induced a significant increase in renal excretion of fluid and electrolytes in endurance trained subjects regardless to their body position and duration thereof per day.     

The endocrine system in space flight

Hormones are important effectors of the body's response to microgravity in the areas of fluid and electrolyte metabolism, erythropoiesis, and calcium metabolism. For many years antidiuretic hormone, cortisol and aldosterone have been considered the hormones most important for regulation of body fluid volume and blood levels of electrolytes, but they cannot account totally for losses of fluid and electrolytes during space flight. We have now measured atrial natriuretic factor (ANF), a hormone recently shown to regulate sodium and water excretion, in blood specimens obtained during flight. After 30 or 42 h of weightlessness, mean ANF was elevated. After 175 or 180 h, ANF had decreased by 59%, and it changed little between that time and soon after landing. There is probably an increase in ANF early inflight associated with the fluid shift, followed by a compensatory decrease in blood volume. Increased renal blood flow may cause the later ANF decrease. Erythropoietin (Ep), a hormone involved in the control of red blood cell production, was measured in blood samples taken during the first Spacelab mission and was significantly decreased on the second day of flight, suggesting also an increase in renal blood flow. Spacelab-2 investigators report that the active vitamin D metabolite 1 alpha, 25-dihydroxyvitamin D3 increased early in the flight, indicating that a stimulus for increased bone resorption occurs by 30 h after launch.     

Renal excretion of water in men under hypokinesia and physical exercise with fluid and salt supplementation

It has been suggested that under hypokinesia (reduced number of steps/day) and intensive physical exercise, the intensification of fluid excretion in men is apparently caused as a result of the inability of the body to retain optimum amounts of water. Thus, to evaluate this hypothesis, studies were performed with the use of fluid and sodium chloride (NaCl) supplements on 12 highly trained physically healthy male volunteers aged 19-24 years under 364 days of hypokinesis (HK) and a set of intensive physical exercises (PE). They were divided into two groups with 6 volunteers per group. The first group of subjects were submitted to HK and took daily fluid and salt supplements in very small doses and the second group of volunteers were subjected to intensive PE and fluid-salt supplements. For the simulation of the hypokinetic effect, both groups of subjects were kept under an average of 4000 steps/day. During the prehypokinetic period of 60 days and under the hypokinetic period of 364 days water consumed and eliminated in urine by the men, water content in blood, plasma volume, rate of glomerular filtration, renal blood flow, osmotic concentration of urine and blood were measured. Under HK, the rate of renal excretion of water increased considerably in both groups. The additional fluid and salt intake failed to normalize water balance adequately under HK and PE. It was concluded that negative water balance evidently resulted not from shortage of water in the diet but from the inability of the body to retain optimum amounts of fluid under HK and a set of intensive PEs.     

Fluid-electrolyte changes in physically conditioned subjects after hypokinesia and chronic hyperhydration

The aim of this study was to determine whether fluid-electrolyte changes, which are developed during prolonged hypokinesia (decreased number of km per day), can be prevented or minimized with the use of a daily intake of fluid and salt supplementation (FSS). The experiments on hypokinesia (HK) were performed for 364 days on 18 endurance-trained male volunteers in the age range of 21-23 years, with an average maximum oxygen uptake of 67 ml kg-1. All volunteers were divided into three equal groups: six volunteers were placed on a continuous regime of exercise of 14.0 km day-1 and served as control subjects. Six volunteers were subjected to continuous HK without FSS and were considered as the unsupplemented hypokinetic subjects (UHS). The remaining volunteers were under continuous HK and FSS and were considered as the supplemented hypokinetic subjects (SHS). For the simulation of the hypokinetic effect, the UHS and SHS groups were kept continuously under an average of 2.7 km day-1 for the duration of the experiment. Prior to exposure to HK, all volunteers were on the same exercise regime as the controls. During the pre-experimental period of 60 days and during the post-experimental period, urinary excretion of electrolytes and concentrations of sodium, potassium, calcium and magnesium in serum as well as serum osmolality were determined. An increased renal excretion of fluid and electrolytes and a decreased serum electrolyte concentration were observed in the SHS, while a decreased renal excretion of fluid and electrolytes and an increased serum electrolyte concentration were observed in the UHS, during the initial stages of the post-hypokinetic period. By day 30 of the post-hypokinetic period these changes were reverted back to the control levels. We concluded that chronic hyperhydration may be used to attenuate urinary and serum electrolyte changes in endurance-trained volunteers after exposure to prolonged HK.     

Cardiovascular reflexes during rest and exercise modified by gravitational stresses.

The hypotheses tested were whether variations in central venous pressure via the low pressure baroreceptors would take over or modify the arterial baroreceptor function, and further to which extent local and "whole body" hydrostatic stresses influence blood flow distribution. We investigated total forearm and skin blood flow (venous occlusion plethysmography and 133-Xe clearance) and cardiac output (rebreathing method) among other parameters. Hypo- and hyper-gravitational stresses were simulated by LBNP, LBPP, water immersion and lowering of the arm. The changes in flow distribution in the arm were ascribed to arterial baroreceptor function and not to low pressure baroreceptor activity. The enhancement of venous return during water immersion increased exercise tolerance during heat stress presumably due both to increased stroke volume and decreased venous pooling. The response to sustained handgrip exercise during LBNP and LBPP was not different from control measurements and the effects explained by arterial baroreceptor function. Application of exercise and local hydrostatic stresses in combination with gravitational stresses represent an interesting model for further study of the mechanisms behind the distribution of cardiac output to the peripheral organs.     

Fluid and salt supplementation effect on body hydration and electrolyte homeostasis during bed rest and ambulation

Bed rest (BR) induces significant urinary and blood electrolyte changes, but little is known about the effect of fluid and salt supplements (FSS) on catabolism, hydration and electrolytes. The aim was to measure the effect of FSS on catabolism, body hydration and electrolytes during BR.

Studies were done during 7 days of a pre-bed rest period and during 30 days of a rigorous bed rest period. Thirty male athletes aged, 24.6±7.6 years were chosen as subjects. They were divided into three groups: unsupplemented ambulatory control subjects (UACS), unsupplemented bed rested subjects (UBRS) and supplemented bed rested subjects (SBRS). The UBRS and SBRS groups were kept under a rigorous bed rest regime for 30 days. The SBRS daily took 30 ml water per kg body weight and 0.1 sodium chloride per kg body weight.

Plasma sodium (Na), potassium (K), calcium (Ca) and magnesium (Mg) levels, urinary Na, K, Ca and Mg excretion, plasma osmolality, plasma protein level, whole blood hemoglobin (Hb) and hematocrit (Hct) level increased significantly (p≤0.05), while plasma volume (PV), body weight, body fat, peak oxygen uptake, food and fluid intake decreased significantly (p≤0.05) in the UBRS group when compared with the SBRS and UACS groups. In contrast, plasma and urinary electrolytes, osmolality, protein level, whole blood Hct and Hb level decreased significantly (p≤0.05), while PV, fluid intake, body weight and peak oxygen uptake increased significantly (p≤0.05) in the SBRS group when compared with the UBRS group. The measured parameters did not change significantly in the UACS group when compared with their baseline control values.

The data indicate that FSS stabilizes electrolytes and body hydration during BR, while BR alone induces significant changes in electrolytes and body hydration. We conclude that FSS may be used to prevent catabolism and normalize body hydration status and electrolyte values during BR.     

Hydroelectrolytic and hormonal modifications related to prolonged bedrest in antiorthostatic position

The effects of prolonged bedrest in antiorthostatic position (-4 degrees head down) on electrolyte balance were studied in 4 young volunteers. An increase was noted in sodium excretion during the first 4 days. Plasma renin activity and plasma aldosterone varied in parallel manner during the same period. Potassium balance and creatinine clearance were not significantly modified. In light of these data we feel that prolonged bedrest in antiorthostatic position constitutes an effective way to simulate on earth metabolic and hormonal modifications occurring in man under weightlessness conditions.     

A review of the consequences of fluid and electrolyte shifts in weightlessness

This review describes the renal-endocrine mechanisms related to the early losses of fluid-electrolytes from the body during weightlessness as well as their contribution to longer term adaptation of fluid-electrolyte balance. The hypotheses presented were generated by a systematic analysis of body fluid and renal dynamics observed under conditions of actual and simulated spaceflight. These have increased our understanding of the effects of acute headward fluid shifts on renal excretion, the factors promoting excess sodium excretion and the regulation of extracellular fluid composition.     

Endocrine responses in long-duration manned space flight

The bioassay of body fluids experiment is designed to evaluate the biochemical adaptation resulting from extended exposure to space flight environment by identifying changes in hormonal and associated fluid and electrolyte parameters reflected in the blood and urine of the participating crewmen. The combined stresses of space flight include weightlessness, acceleration, confinement, restraint, long-term maintenance of high levels of performance, and possible desynchronosis. Endocrine measurements to assess the physiological cost of these stresses have been considered from two aspects. Fluid and electrolyte balance have been correlated with weight loss, changes in the excretion of aldosterone and vasopressin and fluid compartments. The second area involves the estimation of the physiological cost of maintaining a given level of performance during space flight by analysis of urinary catecholamines and cortisol. Inter-individual variability was demonstrated in most experimental indices measured; however, constant patterns have emerged which include: body weight change; increases in plasma renin activity; elevations in urinary catecholamines, ADH, aldosterone and cortisol concentrations. Plasma cortisol decreases in immediate postflight samples with subsequent increase in 24-hour urines. The measured changes are consistent with the prediction that a relative increase in thoracic blood volume upon transition to the zero-gravity environment is interpreted as a true volume expansion resulting in an osmotic diuresis. This diuresis in association with other factors ultimately results in a reduction in intravascular volume, leading to an increase in renin and a secondary aldosteronism. Once these compensatory mechanisms are effective in reestablishing positive water balance, the crewmen are considered to be essentially adapted to the null-gravity environment. Although the physiological cost of this adaptation must reflect the electrolyte deficit and perhaps other factors, it is assumed that the compensated state is adequate for the demands of the environment; however, this new homeostatic set is not believed to be without physiological cost and could, except with proper precautions, reduce the functional reserve of exposed individuals.     

Fluid electrolyte and hormonal changes in conditioned and unconditioned men under hypokinesia

It has been suggested that hypokinesia (diminished muscular activity) may induce more changes in fluid electrolyte metabolism and hormonal concentration of blood plasma in conditioned than unconditioned men. Thus, the objective of this investigation was to determine the effect of 7 days of hypokinesis (HK) on fluid-electrolyte excretion and hormonal content of blood in 12 physically healthy men aged 19-23 years. They were divided into two equal groups according to their physical conditioning. For the simulation of the hypokinetic effect the men were kept under a rigorous bed rest regime. During the background period (BGP), that is prior to the exposure to HK, and under HK, the rate of elimination of fluid, sodium and potassium, and the content of blood plasma aldosterone and cortisol was measured. The amount of excretion of fluid and electrolytes increased while blood plasma aldosterone content decreased. In the conditioned men, a greater excretion of fluid and electrolytes and a greater reduction of plasma aldosterone concentration was observed. It was concluded that hypokinesia induced substantial changes in fluid-electrolyte excretion and hormonal content of blood plasma in both conditioned and unconditioned men.     

Effect of physical fitness and training on physiological responses to hypogravity.

The studies on the orthostatic tolerance during the hypodynamics exposure seem to be significant in connection with the selection, training and health maintenance of astronauts. Using male human subjects of various physical fitness levels, fluctuations of their physical fitness through 2 weeks of vigorous athletic training were measured in many parameters. For some of the subjects, the effects of 6 hr thermal neutral water immersion exposure in head out supine position on the physical fitness parameters and orthostatic tolerability were compared before training with after training. The results obtained were as follows: (1) Before training, orthostatic tolerability before hypodynamics exposure increased, following the physical fitness levels; the value after the hypodynamics exposure decreased in all the cases, but no differences were observed between the physical fitness levels. (2) As a result of training an increase of the physical fitness capacity was observed. The increase of orthostatic tolerability before hypodynamics exposure was noticed except for athletes. (3) Before hypodynamics exposure the urinary excretion of noradrenaline on non-athlete subjects increased as the physicsl fitness level increased. The values were decreased by physical training, the more so the better the physical fitness. After hypodynamics exposure the same relation was observed. But for athletes the values remain more stable and the decrease by hypodynamics exposure was not so distinctive. Such decreased reaction to hypodynamic conditions seems to reveal the neuro hormonal mechanism for the detrimental adaptation of athletes to hypodynamics. These results suggest that stable athletes do not always have low orthostatic tolerability, but do not respond well to hypodynamic conditions, at least from the orthostatic point of view. The mechanism seems related to sympathetic nerve activity.     

A new application of LBNP to measure orthostatic tolerance before and after 0-g simulation (water immersion)

Lower body negative pressure (LBNP) remains an important device for the generation of orthostatic stress in the space flight environment as well as a tool to measure inflight and postflight changes in orthostatic response.

These applied levels of LBNP have typically not exceeded 50–60 mm Hg negative pressure. Information is incomplete as to the levels of absolute LBNP orthostatic tolerance, and the factors responsible for their variance. A better definition of the tolerance limits for males and females could be expected to aid the evaluation of lower levels of LBNP.

An LBNP device was built to study absolute orthostatic tolerance; additionally, another LBNP device was constructed to permit orthostatic tolerance testing directly after a controlled water immersion period.

Absolute LBNP orthostatic tolerance patterns are analyzed for a group of males and females (series I). A preliminary statement on the variations of LBNP orthostatic tolerance after limited periods of water immersion and bed rest is also provided (series II).     

Chronic hyperhydration and hematological changes in trained subjects during prolonged restriction of motor activity

The objective of this investigation was to evaluate the effect of a daily intake of fluid and salt supplementation (FSS) on the hemoglobin content of endurance trained athletes during hypokinesia (decreased number of steps from 10,000 to 3000 steps per day). The studies were performed on 30 long-distance runners who had a VO2max average of 66 ml kg-1 min-1 and were in the age range of 19-24 years. Prior to their exposure to hypokinesia (HK) of 364 days, all volunteers were on an average of 10,000 steps per day. All volunteers were divided into three equal groups: the first group underwent normal ambulatory life (control subjects), the second group was kept under continuous restriction of motor activity (hypokinetic subjects), and the third group was placed under continuous restriction of motor activity and consumed 26 ml water kg-1 body weight daily and 0.1 g sodium chloride kg-1 body weight in the form of supplementation (hyperhydrated subjects). For simulation of the hypokinetic effect, the number of steps taken per day by the second and third groups of volunteers was restricted to an average of 3000. During the hypokinetic period we determined reticulocytes (Rt), hemoglobin (Hb), hematocrit (Hct), plasma volume (PV), red blood cell (RBC) mass and VO2max. In hyperhydrated volunteers the content of Hb and Hct decreased significantly, while PV, RBC mass and Rt count increased significantly. In hypokinetic volunteers Hb and Hct increased, while PV, RBC and Rt decreased significantly. It was concluded that chronic hyperhydration may be used to attentuate an increase in the Hb content of physically conditioned subjects during prolonged restriction of motor activity.     

Cardiovascular effects of simulated zero-gravity in humans

Head-down and head-up [correction of heat-up] tilted bedrest (5 degrees) and head out water immersion (HOWI) for 6 hr were compared. Parameters: Cardiac output (rebreathing method), blood pressure (arm cuff), forearm blood flow (venous occlusion plethysmography), total peripheral (TPR), and forearm vascular (FVR) resistances, Hct, Hb, relative plasma volume (PV) changes, and plasma catecholamines (single-isotope assay). During HOWI there was as expected a decrement in TPR, FVR, Mean arterial pressure (MAP, from 100 to 80 mmHg), Hct, and PV, and--as a new finding--catecholamines, which were 30-50% lower compared with both +5 and -5 degrees bedrest. During head down tilt, MAP was elevated (to 100-110 mmHg) and catecholamines did not fall, while TPR and EVR slowly decreased over 6 hr. HOWI is a stronger stimulus than -5 degrees bedrest, probably because HOWI elevates central venous pressure more markedly emptying the peripheral veins, while bedrest permits a distension of veins, which induces an increase in sympathetic nervous activity.     

Mineral and nitrogen balance study: results of metabolic observations on Skylab II 28-day orbital mission

Prediction that the various stresses of flight, particularly weightlessness, would bring about significant derangements in the metabolism of the musculoskeletal system has been based on various observations of long-term immobilized or inactive bed rest. The only attempt at controlled measurement of metabolic changes in space prior to Skylab, a study during the 14-day Gemini VII flight, revealed rather modest losses of important elements. The three astronauts of Skylab II consumed a planned day-by-day, quite constant, dietary intake of major metabolic elements in mixed foods and beverages and provided virtually complete collections of excreta for 31 days preflight, during the 28 days inflight, and for 17 days postflight. Analyses showed that, in varying degree among the crewmen, urinary calcium increased gradually during flight in a pattern similar to that observed in bed-rest studies: the mean plateau peak of urinary calcium excretion in the latter part of flight was double preflight levels. Fecal calcium excretion did not change significantly, but calcium balance, owing to the urinary calcium rise, became either negative or less positive than in preflight measurement. Increased excretion and negative balance of nitrogen and phosphorus indicated appreciable loss of muscle tissue in all three crewmen. Significant losses also occurred inflight in potassium, sodium, and magnesium. Based on the similarity in pattern and degree between these observations and those in bed rest of the losses in calcium, phosphorus, and nitrogen, musculoskeletal integrity would not be threatened in space flights of up to at least 3 months. However, if similar changes occur, indicative of continuing losses of these elements, in the planned Skylab flights for considerably more than 28 days, concern for capable musculoskeletal function should be serious for flights of very many months' duration, and greater research attention will need to be given to development of protective counter-measures.