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.     

Cardiovascular deconditioning during weightlessness simulation and the use of lower body negative pressure as a countermeasure to orthostatic intolerance

The cardiovascular function is one of the main disturbed by weightlessness: it is particularly affected by the astronaut's return to Earth, where symptoms linked to the cardiovascular deconditioning syndrom appear in the following forms: (1) orthostatic intolerance with its risk of syncope: (2) higher submaximal oxygen consumption for an equivalent work load. Lower Body Negative Pressure (LBNP) is intended to stimulate the venous system of the lower limbs; however, the specific effects of periodical LBNP sessions on the orthostatic intolerance have never been studied. With this objective in mind, 5 volunteers took part in two recent antiorthostatic bedrest experiments for 30 days. In the first experiment 3 subjects were submitted to several sessions of LBNP experiment per day and 2 others were controls; in the second experiment the LBNP group of the 1st one became controls and vice-versa. Two orthostatic investigations were performed: (1) 5 days before the bedrest; (2) at the end of the 30 day bedrest period. The results showed: (1) when the subjects were control, a high orthostatic intolerance post bedrest with 3 syncopes and one presyncopal state during the first minutes of the tilt test; (2) when the subjects were submitted to LBNP sessions, no orthostatic intolerance.     

Status of vestibular function after prolonged bedrest.

6 young, healthy, male volunteers were submitted to one week of head down (-4 degrees) bedrest. This position simulates the cerebral hemodynamic conditions in weightlessness. Measurements of vestibular equilibrium and of oculomotor system function were made before and after the prolonged bedrest. Analysis of the results indicates that vestibular responses, as measured by the maximal speed of the slow phase of the provoked nystagmus (caloric and sinusoidal rotatory stimulations), are decreased after prolonged bedrest. This statistically significant diminution requires confirmation with a greater number of cases. The reflex conflicting or interacting with the cervico-ocular and optokinetic reflexes on the one hand and the foveal vision on the other, is one of several possible explanations for the observed changes.     

A mathematical and experimental simulation of the hematological response to weightlessness

Two ground-based methods of weightlessness simulation--a computer model of erythropoiesis feedback regulation and bedrest--were used to investigate the mechanisms which lead to loss of red cell mass during spaceflight. Both methods were used to simulate the first Skylab mission of 28 days. Human bedrest subjects lose red cell mass linearly with time and in this study the loss was 6.7% at the end of four weeks (compared to 14% in Skylab). Postbedrest recovery of red cell mass was delayed for two weeks during which time a further decline in this quantity was noted. This is consistent with the first Skylab mission but not with the two longer flights of two and three months. Hemoconcentration, observed early in the study, was essentially maintained despite red cell loss because of continued loss of plasma volume. The computer model, using the time-varying hematocrit data to estimate red cell production rates, predicted dynamic behavior of plasma volume and red cell mass that was in close agreement with the measured values. The results support the hypothesis that red cell loss during supine bedrest is a normal physiological feedback process in response to hemoconcentration enhanced tissue oxygenation and suppression of red cell production. In contrast, the delayed postbedrest recovery of red cell mass was more difficult to explain, especially in the light of enhanced reticulocyte indices observed at the onset on ambulation. Model simulation suggested the possibilities, still to be experimentally demonstrated, that this period was marked by some combination of increased oxygen-hemoglobin affinity, small reductions in mean red cell life span, ineffective erythropoiesis, or abnormal reticulocytosis. The question of whether hemoconcentration is the sole contributor to spaceflight red cell losses also remains to be resolved.     

Fluid volumes changes induced by spaceflight

The blood volume (BV), plasma volume (PV), and extracellular fluid volume changes produced in crewmembers during spaceflights of 11-84 days were compared to changes after 14 or 28 days of bedrest. Spaceflight and bedrest produce approximately equal BV changes but the recorded PV change after spaceflight was less. However, the diurnal change in PV may explain the smaller decreases recorded after spaceflight. The cardiovascular deconditioning caused by spaceflight and bedrest was compared using the mean heart rate response to lower body negative pressure (LBNP) testing at -50 mmHg pressure. These tests show approximately equal LBNP produced heart rate changes after bedrest and spaceflight. A countermeasure which includes 4 hr of LBNP treatment at -30 mmHg and the ingestion of one l. of saline was studied and found capable of returning the heart rate response and the PV of bedrested subjects to control (prebedrest) levels suggesting that it would be useful to the crewmembers after a spaceflight.     

Evaluation of spontaneous baroreflex response after 28 days head down tilt bedrest

The spontaneous baroreflex response was evaluated during supine rest and head up tilt (60 degrees) before and immediately after a 28 day 6 degrees HDT bedrest in 6 healthy adult men (age 30-42 years). Sequences of 3 or more beats where RR-interval and systolic blood pressure changed in the same direction were used to evaluate baroreflex response slope (BRS). Prior to bedrest, the mean BRS and RR-interval were 18.0 +/- 3.9 ms/mm Hg and 926 +/- 61 ms at rest and 10.5 +/- 2.5 ms/mm Hg and 772 +/- 63 ms during the first 10 min of 60 degrees tilt. Following bedrest, these values changed to 15.6 +/- 2.7 ms/mm Hg and 780 +/- 53 ms at rest, and to 6.5 +/- 1.2 ms/mm Hg and 636 +/- 44 ms during tilt. Thus, (1) the spontaneous baroreflex can be evaluated in human subjects during experiments of orthostatic stress; (2) the baroreflex slope was reduced on going from supine to the head up tilt position; and (3) 28 days of bedrest reduced the spontaneous baroreflex slope.     

Effect on the cardiac function of repeated LBNP during a 1-month head down tilt

Cardiovascular assessment by ultrasound methods was performed during two long duration (1 month) Head Down Tilt (HDT) on 6 healthy volunteers. On a first 1 month HDT session, 3 of the 6 subjects (A, B, C) had daily several lower body negative pressure tests (LBNP), whereas the 3 subjects remaining (D, E, F) rested without LBNP. On a second 1 month HDT session subjects D, E, and F had daily LBNP tests and the A, B and C subjects did not. The cardiac function was assessed by Echocardiography, (B mode, TM mode). On all the "6 non LBNP" subjects the left ventricule diastolic volume (LVDV), the stroke volume (SV) and the cardiac output (CO) increase (+10%, -15%) after HDT then decrease and remain inferior (-5%, -5%) or equal to the basal value during the HDT. Immediately after the end of the HDT the heart rate (HR) increase (+10%, +30%) whereas the cardiac parameters decrease weakly (-5%, -10%) and normalize after 3 days of recovery. On the "6 LBNP" subjects the LVDV, SV and CO increase (+10%, 15%) after 1 h HDT as in the previous group then decrease but remain superior (+5%, +15%) or equal to the basal value. After the HDT session, the HR is markedly increased (+20%, +40%) the LVDV and SV decrease (-15%, -20%) whereas the CO increases or decreases depending on the amplitude of the HR variations. These parameters do not completely normalize after 3 day's recovery. Repeated LBNP sessions have a significant effect on the cardiovascular function as it maintains all cardiac parameters above the basal value. The LBNP manoeuvre can be considered as an efficient countermeasure to prevent cardiac disadaptation induced by HDT position and probably microgravity.     

Psychomotor performance during a 28 day head-down tilt with and without lower body negative pressure

Several factors may affect psychomotor performance in space: sensory-motor changes, sleep disturbances, psychological modifications induced by the social isolation and confinement. However, psychomotor performance is difficult to assess. A battery of standardized and computerized tests, so-called "Automated Portable Test System" (APTS) was devised to ascertain the cognitive, perceptive and motor abilities and their possible fluctuations according to environmental effects. Antiorthostatic bedrest, often used to simulate weightlessness, (particularly cardiovascular modifications) also constitutes a situation of social confinement and isolation. During two bedrest experiments (with head-down tilt of -6 degrees) of 28 days each, we intended to assess psychomotor performance of 6 males so as to determine whether: on the one hand, it could be altered by remaining in decubitus; on the other, the Lower Body Negative Pressure sessions, designed to prevent orthostatic intolerance back on Earth, could improve the performance. To accomplish this, part of the APTS tests as well as an automated perceptive attention test were performed. No downgrading of psychomotor performance was observed. On the contrary, the tasks were more accurately performed over time. In order to assess the experimental conditions on the acquisition phase, the learning curves were modelled. A beneficial effect of the LBNP sessions on simple tests involving the visual-motor coordination and attention faculties can only be regarded as a mere trend. Methods used in this experiment are also discussed.     

Bright light as a chronobiological countermeasure for shiftwork in space

Work-rest schedules during long duration space missions involve several factors which could disrupt sleep and circadian temporal organisation: (1) displacement of sleep due to two-shift operations; (2) planned or unplanned schedule changes due to operational requirements; (3) social and light Zeitgebers different from those on earth; (4) changes in the gravitational exposure. Timed bright light treatment has the potential to accelerating adaptation to schedule changes. Four male subjects were exposed to two sessions of 11 d of simulated microgravity (6 ° head down tilt bedrest) with 6-h extensions of the wake period on 2 days (12-h phase delay). In a blind crossover design, subjects were exposed to bright light (> 3500 lux) for 5 h on each of the 2 shift days and the following day, at times either expected to accelerate the adjustment to the phase delay (experimental condition) or to have no phase shifting effect (control condition). Sleep was recorded polygraphically, the circadian system was monitored by recordings of heart rate and body temperature, and by collection of urine (electrolyte and hormone excretion). Only the rhythms of 6-hydroxymelatoninsulphate and potassium excretions showed significantly enhanced adjustment under the experimental condition. Different rhythms Actapted to the 12-h delay at different rates, comparable to those observed after time zone shifts. Sleep was shorter in simulated weightlessness than in normal ambulatory age-matched subjects, consistent with the shorter sleep durations characteristic of space flight. These results confirm the disruptive effects of wake-rest schedule shifts on sleep and circadian rhythms. Contrary to our initial hypothesis, 5-h exposures to bright light finishing at the time of the circadian temperature minimum were not more effective at accelerating adjustment to a 12-h schedule delay than exposures coinciding with the temperature maximum. We conclude that, while bright light may accelerate adjustment to work-rest schedule delays, any such effect seems to be largely independent from the timing of the light exposure.     

Effectiveness of centrifuge-induced artificial gravity with ergometric exercise as a countermeasure during simulated microgravity exposure in humans

To test the effectiveness of centrifuge-induced artificial gravity with ergometric exercise, 12 healthy young men (20.7 +/- 1.9 yr) were exposed to simulated microgravity for 14 days of -6 degrees head-down bedrest. Half the subjects were randomly selected and loaded 1.2 G artificial gravity with 60 W (four out of six subjects) or 40 W (two out of six subjects) of ergometric workload on days 1, 2, 3, 5, 7, 9, 11, 12, 13, 14 (CM group). The rest of the subjects served as the control. Anti-G score, defined as the G-load x running time to the endpoint, was significantly elongated by the load of the centrifuge-ergometer. Plasma volume loss was suppressed (-5.0 +/- 2.4 vs. -16.4 +/- 1.9%), and fluid volume shift was prevented by the countermeasure load. Elevated heart rate and muscle sympathetic nerve activity after bedrest were counteracted, and exaggerated response to head-up tilt was also suppressed. Centrifuge-induced artificial gravity with exercise is effective in preventing cardiovascular deconditioning due to microgravity exposure, however, an effective and appropriate regimen (magnitude of G-load and exercise workload) should be determined in future studies.     

Mechanisms of spinal motoneurons survival in rats under simulated hypogravity on earth

It was previously shown that different cell types in vivo and in vitro may die via apoptosis under weightlessness conditions in space as well as in simulated hypogravity on the Earth. We assessed survivability of spinal motoneurons of rats after 35-day antiorthostatic hind limb suspension. Following weight bearing, unloading the total protein content in lumbar spinal cord is dropped by 21%. The electrophysiological studies of m. gastrocnemius revealed an elevated motoneurons’ reflex excitability and conduction disturbances in the sciatic nerve axons. The number of myelinated fibers in the ventral root of experimental animals was insignificantly increased by 35-day of antiorthostatic hind limb suspension, although the retrograde axonal transport was significantly decreased during the first week of simulated hypogravity. The results of the immunohistochemical assay with antibodies against proapoptotic protein caspase 9 and cytotoxicity marker neuron specific nitric oxide synthase (nNOS) and the TUNEL staining did not reveal any signs of apoptosis in motoneurons of suspended and control animals. To examine the possible adaptation mechanisms activated in motoneurons in response to simulated hypogravity we investigated immunoexpression of Hsp25 and Hsp70 in lumbar spinal cord of the rats after 35-day antiorthostatic hind limb suspension. Comparative analysis of the immunohistochemical reaction with anti-Hsp25 antibodies revealed differential staining of motoneurons in intact and experimental animals. The density of immunoprecipitate with anti-Hsp25 antibodies was substantially higher in motoneurons of the 35-day suspended than control rats and the more intensive precipitate in this reaction was observed in motoneuron neuritis. Quantitative analysis of Hsp25 expression demonstrated an increase in the Hsp25 level by 95% in experimental rats compared to the control. The immunoexpression of Hsp70 found no qualitative and quantitative differences in control and experimental lumbar spinal cords. Taken together our results show that (1) rat motoneurons survived after 35-day antiorthostatic hind limb suspension and the changes in neurons had a mostly functional character, and (2) the increased immunoexpression of Hsp25 can be considered as the anti-apoptotic factor.     

Pre-adaptation to shiftwork in space

Astronauts are often required to work in shift schedules. To test pre-mission adaptation strategies and effects on the circadian system, a study was performed using microgravity simulation by head-down bedrest. Eight male subjects were studied over 4 control days, and 7 days each for pre-mission adaptation, bedrest, and readjustment. The circadian system was assessed by monitoring ECG and temperature, and by collecting urine for determination of hormones and electrolytes. Rhythms did not achieve complete adjustment within the adaptation period when the sleep-wake cycle was shortened by 1 h/day, but resynchronization continued during bedrest. After the bedrest period when the time shift was reversed by a 7-h delay within 2 days, resynchronization was achieved satisfactorily only within 7 days. From the results it is concluded that a sleep-wake cycle advance as used in this study is insufficient to keep the circadian system in pace. Under operational conditions the circadian system of astronauts may become longer and more destabilized than under controlled laboratory conditions.     

Leg venous hemodynamics and leg volumes during a 42 day -6 degrees head-down bedrest

Seven healthy subjects were submitted to a 42-day head down bedrest, where leg venous compliance (venous distensibity index VDI) and leg volumes were assessed by mercury strain gauge plethysmography with venous occlusion and optoelectronic plethysmography, respectively. Plethysmographic and volometric measurements were made, before, during (at days 1, 4, 7, 14, 21, 26, 34 and 41), and after bedrest (days 1, 4, 7, 11 and 30 of the recovery period). Results showed a continuous decrease in leg volumes throughout bedrest, when VDI increased until day 26 of bedrest, and then decreased afterwards. The recovery period was characterized by a rapid return of VDI to prebedrest levels while leg volumes progressively normalised. These results showed that leg venous compliance changes are not always dependant upon skeletal muscle changes, and that factors other than size of muscle compartment are able to determine increases in leg venous compliance during long-term bedrest.     

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.     

Influence of graviceptives cues at different level of visual information processing: the effect of prolonged weightlessness

We evaluated the influence of prolonged weightlessness on the performance of visual tasks in the course of the Russian-French missions ANTARES, Post-ANTARES and ALTAIR aboard the MIR station. Eight cosmonauts were subjects in two experiments executed pre-flight, in-flight and post-flight sessions.

In the first experiment, cosmonauts performed a task of symmetry detection in 2-D polygons. The results indicate that this detection is locked in a head retinal reference frame rather than in an environmentally defined one as meridional orientations of symmetry axis (vertical and horizontal) elicited faster response times than oblique ones. However, in weightlessness the saliency of a retinally vertical axis of symmetry is no longer significantly different from an horizontal axis. In the second experiment, cosmonauts performed a mental rotation task in which they judged whether two 3-D objects presented in different orientations were identical. Performance on this task is basically identical in weightlessness and normal gravity.     

The prevention of adverse physiological change in Space Station crewmembers

Various physiological countermeasures, consisting primarily of isotonic and isometric exercises but also including prescribed nutrient intake, have been used in all manned spaceflights exceeding about one month in duration. So consistent has been this practice that the effects of weightlessness on the human, unconfounded by the use of countermeasures, are difficult to discern. Equally elusive, in the absence of control studies conducted in weightlessness, is an accurate assessment of the efficacy of the countermeasures themselves. Changes in body composition occurring during and following flights from Gemini through Shuttle, when compared with changes during and following bedrest, demonstrate certain mitigating effects that may be attributable to countermeasures and which provide some rationale for the choice of countermeasures in the Space Station.     

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.     

Cardiovascular system and microgravity simulation and inflight results.

Main results of cardiovascular investigation, performed with ultrasound methods during the common French/Soviet flight aboard Salyut VII in June 1982, are compared to variations of the same parameters studied during ground-based simulations on the same subject or observed by other investigators during various ground-based experiences. The antiorthostatic bed rest simulation partly reproduces microgravity conditions and seems to be better adaptated to cardiac hemodynamics, despite some differences, and to the cerebral circulation, than to the inferior limb circulation.     

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.     

Immobilization induces a very rapid increase in osteoclast activity

We studied in a randomized, strictly controlled cross-over design, the effects of 6 days 6 degrees head-down tilt bed rest (HDT) in eight male healthy subjects in our metabolic ward. The study consisted of two periods (phases) of 11 days each in order to allow for the test subjects being their own controls. Both study phases were identical with respect to environmental conditions, study protocol and diet. Two days before arriving in the metabolic ward the subjects started with a diet. The diet was continued in the metabolic ward. The metabolic ward period (1l days) was divided into three parts: 4 ambulatory days, 6 days either HDT or control and 1 recovery day. Continuous urine collection started on the first day in the metabolic ward to analyze calcium excretion and bone resorption markers. On the 2nd ambulatory day in the metabolic ward and on the 5th day in HDT or control blood was drawn to analyze serum calcium, parathyroid hormone, and bone formation markers. Urinary calcium excretion was, as early as the first day in immobilization, increased (p<0.01). CTX- and NTX-excretion stayed unchanged in the first 24 h in HDT compared to the control. But already on the 2nd day of immobilization, both bone resorption markers significantly increased. We conclude from these results--pronounced rise of bone resorption markers--that already 24 h of immobilization induce a significant rise in osteoclast activity in healthy subjects. Thus, it appears possible to use short-term bed rest studies as a first step for the development of countermeasures to immobilization.