**1.1 Exposure to Microgravity:**

Time course of changes and adaptation to microgravity

Cardiopulmonary effects (inflight and post-flight changes,
countermeasures)

Neurovestibular effects (inflight and post-flight changes,
countermeasures) including space motion sickness

Neurosensory effects (inflight and post-flight changes, countermeasures)

Gastrointestinal effects (inflight and post-flight changes,
countermeasures)

Musculo-skeletal effects (inflight and post-flight changes,
countermeasures)

Blood, fluids and electrolytes (inflight and post-flight changes,
countermeasures)

Immunological effects (inflight and post-flight changes,
countermeasures)

Endocrinological effects (inflight and post-flight changes,
countermeasures)

Readaptation to earth\'s environment (areas of concern, equipment,
procedures, etc.)

Simulations and analogs of microgravity exposure (types, uses,
equipment, procedures, etc.) including a discussion on artificial
gravity

Medications use in microgravity (pharmacokinetics, pharmacodynamics,
routes of administration, operational safety issues, etc.)

EXPOSURE TO MICROGRAVITY

This chapter is designed to provide you with a basic understanding of
the physiological effects associated with exposure to microgravity.
Emphasis is placed on understanding the effects seen in each organ
system, as well as the time course of these adaptations. You will review
how physiological systems that evolved in a gravitational field alter
their function upon exposure to microgravity, and learn how each
readapts to the gravitational field upon return to earth. In addition,
available countermeasures will be discussed, including a description of
artificial gravity. You will be expected to identify how each body
system is affected by exposure to and return from a microgravity
environment and to understand how analog environments are used to mimic
various aspects of space travel for research purposes. Finally, the
efficacy of medications in microgravity will be described, including
altered pharmacokinetics and operational considerations.

Exposure to Microgravity

Space exploration exposes travelers to a variety of gravitational
stresses. Examples include increased acceleration forces during launch
and landing, partial gravity on extra-terrestrial locations such as the
Moon or Mars, and microgravity during orbital missions and flights
between planetary bodies. Microgravity causes changes in the
physiological processes that aerospace physicians must understand,
anticipate, and address.

Space flight environments usually have additional stressors associated
with them in addition to the lack of a gravitational vector. Isolation,
noise, radiation, toxin buildup, and operational pressures all combine
to create a uniquely stressful environment. This lesson will, however,
focus on the physiological changes specific to microgravity, leaving the
other considerations for future discussion.

It is important for the physician to recognize that, perhaps
unexpectedly, human physiological processes are largely unchanged in
microgravity. Despite early speculation about the impossibility of
physiological functioning outside of a one-g field, these concerns
proved unwarranted. However, although astronauts and cosmonauts have
demonstrated their ability to function effectively in a microgravity
environment for months at a time, there are microgravity-related effects
on their bodies. Some are more subtle than others and research into this
area is ongoing.

Several of the effects of microgravity are seen within minutes to hours
of exposure, while others require weeks or months to manifest. In part,
this can be attributed to the specific physiological systems: it is
reasonable that changes in peristalsis will occur on a different time
course than alterations in the bone marrow. Nevertheless, it is
important to understand how these changes are integrated within and
expressed throughout the entire body, so that appropriate clinical
diagnoses and decisions can be made. For example, should an astronaut be
injured upon landing and require immediate surgery, what issues -- above
and beyond the acute injury -- must be considered when planning for the
anesthesia, surgery, and recovery? Which organ systems will be most
affected and/or most vulnerable to iatrogenic complications? If
stabilizing measures can delay the need for surgical intervention,
should they be employed and for how long? Without a thorough
understanding of these issues, the aerospace physician will be unable to
provide appropriate care for his or her patient.

Time course of microgravity-related effects

The physiology of the space traveler is most labile immediately upon
exposure to, or return from, microgravity. Within a few days, the body
adapts to its new environment (as described below), but in the first 72
hours following a change to or from microgravity, most of the
physiological processes are in a state of flux.

**Short Term Effects**

Immediately upon exposure to microgravity, certain physiological systems
exhibit altered function. Many of these are associated with maintaining
moment-to-moment homeostasis and/or are directly affected by the
physical effects of microgravity. Examples of these are the baroreceptor
reflex, neurovestibular system, and gastrointestinal tract.

The majority of these systems will adapt to microgravity by resetting to
a new equilibrium state within a short time (hours to days). Upon return
to a gravitational field, the same, rapid effects may be seen in
reverse.

**Long Term Effects**

Several physiological systems exhibit microgravity-related effects on a
longer term (weeks to months). For short duration missions, these
changes may be minor or even undetectable, but on longer flights, the
effects can become more pronounced. In some cases, it is not yet clear
whether a "space normal" physiological state is ever achieved, or
whether changes continue so long as the crewmember remains in
microgravity. Examples include changes in red cell mass and bone
demineralization.

**Cardiovascular Effects**

**In-flight**

Spacecraft designers have ensured that the acceleration forces during
launch are presented in the more easily tolerated Gx direction. However,
even before launch, the space traveler's cardiovascular system is
challenged by the supine, knees up position both American and Russian
vehicles require. On the US Shuttle, crewmembers may be in a supine
position with 90 degree flexion at hip and knee for up to 4 hours prior
to launch, while crewmembers aboard the Russian Soyuz are in a somewhat
more cramped position, though generally for shorter periods. This supine
position increases preload and cardiac output, effects that are
magnified upon arrival in the microgravity environment, when the
cephalad fluid shift is further increased by the loss of the hydrostatic
gradient normally present in the vasculature.

This headward shift of approximately 1-2 L of fluid leads to
cardiovascular changes, including an increase in left ventricular
chamber volume as seen on echocardiography. This increase is perceived
by the body's regulatory mechanisms as an increase in intravascular
volume, and the body responds with decreased thirst sensation and a
possible diuresis over the first 48 hours in orbit. The fluid shift may
also be associated with the development of space motion sickness (see
below), where nausea and vomiting help the body to adjust from its
apparent "hypervolemia".

Crewmembers quickly sense the cephalad fluid shift, perceiving it as
head "fullness" or "stuffiness", jugular venous distention, visible
facial edema (which can lead to a rejuvenated appearance by erasing
wrinkles), and unusually thin calves, often called "chicken" or "stork"
legs. This increase in intrathoracic volume may also lead to transient,
clinically insignificant reductions in pulmonary compliance, such as
forced expiratory volume in one second and forced vital capacity. All of
these changes abate somewhat following the body's actions to establish a
"space normal" euvolemia, which is normally associated with
approximately a 10% decrease in total body fluid.

Concomitant with the decrease in plasma volume, the left ventricular
volume returns to near pre-flight levels.

Cardiovascular control systems, such as the baroreceptor reflex, are
also rapidly affected upon exposure to microgravity. In a gravitational
field, baroreceptors and other components of the cardiovascular control
system preserve blood flow to a biped's brain despite positionally
dependent changes in preload and afterload. In microgravity, however,
there are no orthostatic challenges associated with changes in position,
and as a result, the cardiovascular control centers do not receive
moment-to-moment stimuli. This, coupled with the cephalad fluid shift,
results in a new homeostatic set point.

There have been conflicting reports regarding microgravity-related
changes to heart rate and blood pressure.

The most recent findings would seem to suggest that heart rate and
diastolic blood pressure decrease while cardiac output increases. This
would suggest that peripheral vascular resistance is reduced, and
sympathetic tone may be similarly decreased.

Despite some early concerns to the contrary, microgravity itself does
not appear to be dysrhythmogenic. Abnormal heart patterns are not seen
at increased levels during space flight, though occasional ectopy can
occasionally be seen, as it is in terrestrial populations. Current US
regulations call for ECG monitoring only during stressful phases of
flight, such as during spacewalks (also known as an extra-vehicular
activity or EVA).

Just as skeletal muscle can become deconditioned during space flight,
there is concern that cardiac atrophy can occur as well. If so, it might
not pose a problem for a healthy crewmember in microgravity but would be
a source of concern during illness, injury, or return to a gravitational
field. Cardiac deconditioning could also be associated with increased
ectopy under these stressful periods. However, echocardiographic
research has shown no significant or sustained in-flight changes in
numerous parameters, including: ejection fraction, circumferential fiber
shortening, myocardial contractility, left ventricular wall thickness,
or myocardial mass index.

Although the majority of these cardiovascular changes appear well-suited
for healthy crewmembers, the aerospace physician must recognize that
these same microgravity-related alterations in cardiovascular physiology
could impair a compromised crewmember's ability to respond to a stress,
such as hypovolemic shock. The body's reduced plasma volume, in
conjunction with the vasculature's increased capacitance due to volume
loss, could limit volume recruitment in the event of an injury, thus
decreasing an otherwise healthy patient's ability to compensate for
hemorrhage. Management decisions must therefore take such factors into
account.

**Countermeasures**

Many of these in-flight cardiovascular changes appear to be appropriate
or neutral. As a result, relatively few countermeasures exist to reverse
or minimze the changes during the microgravity portion of the mission,
though lower body negative pressure devices (LBNP, also available
through the Russian "Chibis" suit) have been studied fairly extensively
for this purpose. In this countermeasure, crewmembers place their lower
body in a sealed container, and a negative pressure is then applied
inside the container. This pressure draws blood away from the central
circulation and into the lower extremities, thus stimulating the
baroreceptors by mimicking positional vascular changes caused by a
gravitational field.

In-flight exercise also seems to have a protective effect on post-flight
orthostatic intolerance, though the mechanism remains unclear.
Regardless of the countermeasures used during space flight, immediately
prior to return to Earth, several countermeasures are implemented to
prepare the body to cope with gravity-induced stresses such as the
resumption of the hydrostatic venous gradient. Crewmembers "fluid load"
by drinking isotonic fluids (broth or "Astro-ade", a drink modeled upon
the electrolyte replacement beverage "Gatorade") prior to reentry. In
addition, crewmembers wear a liquid cooling garment to minimize heat
stress and a G-suit which uses pressurized bladders to prevent the
pooling of blood in lower extremities. Pharmaceutical interventions are
currently under investigation, but they are not routinely used at this
time. In addition to these safeguards, astronauts and cosmonauts who
return from a long duration mission on the Shuttle are transported in a
supine, rather than a seated position.

**Post-flight**

The in-flight diuresis and new equilibrium point, while adaptive for the
microgravity environment, is profoundly maladaptive upon return to a
one-g field. Orthostatic intolerance is frequently seen during and
following landing, due to the body's inability to respond to rapid
position-related circulatory changes. The potential operational impact
of such a condition is enormous, particularly in the event of an
emergency egress. Numerous countermeasures (see above) have been
implemented in an effort to mitigate the risk to crew health and safety.
Fortunately, the system quickly readjusts to the gravitational stress,
just as it initially adapted to microgravity. Within a few days, most
crewmembers are able to mount a proper response to an orthostatic
challenge, and even following long duration flights, no irreversible
orthostatic intolerance has been noted.

Exercise capacity is also diminished post-flight, as demonstrated by a
post-flight decrease in VO2~max~. This is felt to be due in part to the
reduction in plasma volume, as well as changes in left ventricular
pressure-volume relationships. Like the other cardiovascular effects,
this too demonstrates a complete recovery over time, with return to
pre-flight values.

**Neurovestibular and Neurosensory Effects**

**In-flight**

The neurovestibular system maps head and body orientation as well
providing an internal orientation reference. During space flight,
crewmembers experience conflict between established sensory inputs
experienced all their lives and new inputs from this novel environment.
For example, the linear acceleration detectors (otolith organs) and
other sensory systems affected by position are no longer synchronized
with visual system inputs. These kinds of conflict can cause pathology.

On a "whole body" level, one of the earliest effects of these changes is
the manifestation of space motion sickness (SMS), which is the form of
motion sickness associated with microgravity, and is a subset of space
adaptation syndrome. SMS affects over 70% of space travelers, but
prediction of its occurrence (particularly in first-time flyers) is
difficult. SMS is only weakly correlated with the motion sickness
associated with ship or air travel or with symptoms elicited by exposure
to rotation or parabolic flight. The symptoms include lethargy, nausea,
vomiting, stomach awareness, headache, drowsiness, malaise, anorexia,
and poor concentration.

Although they can be debilitating, for most crewmembers symptoms rapidly
resolve within 1-2 days. In-flight SMS does not prevent subsequent
terrestrial motion sickness, and indeed crews often experience SMS
symptoms for the first few days following landing, particularly after
long duration missions. A previous occurrrence may be protective against
SMS on later space flights, as the incidence is somewhat lower among
repeat flyers than first time flyers. Motions that provoke SMS have been
identified and have led to modifications in instrument design so as to
minimize left-right head rotations and up-down arm motions.

The operational impact of SMS can be considerable. After an EVA had to
be rescheduled because of a crewmember's SMS during Apollo 9 (the first
in-flight timeline change due to a medical cause), EVAs are no longer
scheduled within the first few days of a mission.

Even after SMS has resolved, other neurovestibular and neurosensory
changes persist, including alterations in eye-head coordination, target
tracking, and optokinetic reflex function. There are related
sensorimotor changes as well, such as decrements in postural control and
locomotion, and disruption in the head-trunk coordination. These
adaptations can impair crew performance, such as the manual control of
the spacecraft or vehicle systems (e.g. the robotic arm).
Neurovestibular dysfunction has already been implicated as one of the
causes in the collision of the Russian space station Mir and a Progress
resupply vessel as well as in the "bumping" of a satellite during a
capture attempt by the Shuttle's robotic arm.

The neurovestibular system has also been suggested as a causative factor
in the correlation between Space Shuttle mission duration and the
accuracy of landing speed, position, and/or touchdown vertical velocity.
As duration increases, landing accuracy decreases, leading to concerns
about the safety of manual landings following long duration missions,
such as exploration missions to Mars.

Sensory illusions experienced in-flight include misperception of
location and directional cues due to temporary loss of spatial
orientation and motion-generated spatial and temporal visual illusions.
Some actions seem particularly provocative, such as being unrestrained
or in visually unfamiliar orientations, such as working "upside down" in
the spacecraft or relative to another adjacent crewmember. Visual
reorientation illusions, even in the absence of head movements, can
trigger SMS during the first several days in weightlessness and may
result in delayed recurrence of space sickness. Crewmembers may feel
uncomfortable working in the open Space Shuttle payload bay when the
payload bay faces the Earth, and EVA crewmembers working far out on a
structure have occasionally reported a sensation that they might "fall
off" or "fall to Earth," which has been termed *EVA acrophobia.*
Particularly during highly complex or dangerous tasks (such as an EVA),
these sensory changes could pose risks to the crew or vehicle.

Disorientation could contribute to navigation difficulties for crews
working inside a large, multi-axis space station. Some Mir crewmembers,
even after spending several months in space, reported difficulty
visualizing three-dimensional spatial relationships among the modules.
This could prove very hazardous during a spacecraft emergency,
especially if darkness or smoke compounded the problem. In response,
every module in the ISS has glow-in-the-dark directional guides and
standardized coloration of "floor" and "ceiling" surfaces.

About 80% of space flyers experience perceptual illusions during or
after flight. Several different types have been reported: illusory
self-motion (both linear and rotational), a sensation of the floor
dropping when doing a squat to stand, the sensation of things floating
in space, visual streaming (blurring), visual scene oscillation
(oscillopsia), object position distortion, visual axis distortion
(tilting or inversion), and platform stability illusion. Crewmembers
also often experience a sense of being upside down early in spaceflight.

**Countermeasures**

Firm body contact with a motionless surface can provide tactile cues and
reduce illusions and SMS in the weightless environment. As a result,
crewmembers can be educated in the use of good restraint systems,
particularly during the early days of a mission. Crewmembers can also
choose their external frame of reference, for example deciding whether
"down" is towards Earth, the vehicle "floor", or wherever their feet may
be. The aerospace physician should be aware that crewmembers using the
latter strategy ("my feet = down") seem to experience the least
disorientation when encountering an unexpected visual stimulus.
Pharmacologic intervention is widely used to prevent or treat SMS;
parenteral or rectal promethazine (25-50 mg) has proven one of the most
effective drugs and is now the recommended treatment for U.S.
crewmembers.

Research is also underway to determine if pre-flight "training" in
virtual-reality (VR) facilities can assist crewmembers in more rapidly
adjusting to the microgravity environment. Preliminary work utilizing a
VR-based microgravity analog environment seems to indicate that
adaptation time can be reduced by repeated exposure to conflicts between
the proprioceptive and visual systems. Whether these findings can be
translated to the actual microgravity environment remains to be seen
although there is encouraging anecdotal evidence to suggest that
post-flight symptomatology could be decreased by in-flight
countermeasures, such as viewing a video while exercising on the
treadmill. It is hypothesized that reaffirming "up/down" visual cues
through the video while the body experiences physical cues in a similar
orientation (e.g. heel strike) may make it easier for the
neurovestibular and neurosensory systems to readjust upon return to a
one-g field.

**Post-flight**

The nervous system demonstrates remarkable plasticity, in adaptation
both to and from microgravity. Studies on sensorimotor control have
demonstrated rapid (within 48 hours) return to pre-flight levels. Under
normal situations, then, these are of relatively minor concern and
merely lead the aerospace physician to caution against driving,
piloting, hurrying up or down stairs, changing orientation rapidly, or
other similar activities, until readaptation is complete. However, in
the event of an emergency egress or bailout over the water, in addition
to the musculoskeletal and aerobic deconditioning that may be present,
crewmembers will likely have to cope with unsteadiness, poor
coordination, vertigo, and seasickness. In routine, controlled
operations, these symptoms are mere nuisances, but in a contingency
operation, where the astronaut must complete complex tasks in a
time-dependent and hazardous environment, they are likely to impair
performance, perhaps to dangerous levels. Pharmacologic interventions
such as anti-motion sickness medications may be helpful if taken
prospectively and were used during the Skylab program. The medication
might, however, prove counterproductive if, for example, the side effect
profile included sedation.

In addition, some findings could have implications even during routine
operations, such as decreasedvisual pursuit tracking, leading to delays
in the ability of a crewmember to focus an image on his or her retina.
This has clear implications for piloting and has led to recommendations
that Shuttle commanders limit their head movements when reading
instruments during landing maneuvers.

Postflight neurovestibular and neurosensory symptoms are experienced by
most crewmembers and may include: illusory movements, clumsiness in
movements, difficulty walking a straight line, pointing errors,
dizziness, persisting sensation aftereffects, vertigo while walking or
standing, postural changes, nystagmus, nausea, and difficulty
concentrating. The majority of crewmembers report only mild symptoms,
though gait irregularities can be detected both subjectively and
objectively. Post-flight, nausea is seen more frequently in female
crewmembers, but gender has not been found to be associated with any of
the other neurovestibular symptoms seen after space flight, nor have
age, mission duration, previous space flight experience, or in-flight
SMS been associated with any postflight neurovestibular symptoms.

Space Shuttle astronauts report the perception of self or surround
motion is greatest during re-entry, followed by wheel stop on the runway
in the landing phase, and then by actual on-orbit experience. Illusions
are frequently associated with head movements (pitch or roll more than
yaw), particularly those of large amplitude or rapid speed, and
virtually all crewmembers in the postflight period experience some
gait-associated illusions. The aerospace physician must be aware of
these expected phenomena so that he or she can educate and reassure
their crews.

**Gastrointestinal Effects and Nutrition**

**In-flight**

The mechanical effects of microgravity on the GI tract, perhaps in
conjunction with other factors as yet undetermined, appear to reduce
gastric emptying and intestinal transport time. The extent of this
delay, as well as its significance, remain unclear, but potential
ramifications exist for the nutrition, drug delivery, and appetite of
the space traveler. It is known that body weight decreases during space
flight, with some of the loss due to fluid losses. In addition, muscular
atrophy, particularly in the postural muscles, plays a role. However, a
negative nitrogen balance has been consistently documented in space
travelers, suggesting that there is a persistent protein loss. Lean body
mass has been implicated as a significant portion of the in-flight
weight loss, even in short duration missions. This may be due to the
busy timelines and high stress environment that is standard for space
travelers, or it may be a consequence of the space flight environment
itself.

Crewmembers often report changes in their appetites during flight. Many
report a decreased hunger sensation, but some space travelers develop a
voracious appetite. Taste sensation is different, perhaps due to the
cephalad fluid shifts, and this may play a role as well. In addition,
time pressures associated with mission objectives may influence food
choices, with snack or "handheld" foods being preferred to full meals.

**Countermeasures**

Significant efforts are made to offer space travelers a variety of
nutritionally balanced foods, but weight loss remains a common finding.
There is currently no refrigerator for food on the ISS or Shuttle, and
the lack of fresh produce and reliance upon processed foods may be
contributing factors. Research continues into developing agricultural
methods for use on future long duration and/or exploration missions.

**Post-flight**

With the exception of the nausea related to post-flight SMS (see above),
there is no evidence of post-flight gastrointestinal changes. Space
travelers appear to recover their pre-flight weight and nutritional
balance rapidly, though it is unclear how much of a role is played by
the physical rehabilitation program undertaken for the musculoskeletal
system.

**Musculoskeletal Effects**

**In-flight**

Upon exposure to microgravity, the mechanical load upon the
musculoskeletal system lessens dramatically, leading to muscle atrophy
(particularly in the postural/antigravity muscles) and bone
demineralization (disuse osteoporosis). The reduced mechanical burden
leads to a decrease in muscle mass, architecture, and strength which, in
turn, contributes to bone demineralization. Changes are seen within the
first few days of space flight and continue throughout exposure to
microgravity. Interestingly, the gender-based differences in bone
demineralization rates that are seen terrestrially do not exist in
space; men and women lose calcium at approximately the same rate (1-2%
per month in the lower limbs).

Although the mechanism of this muscle atrophy is not well understood,
initial studies suggest that the loss of muscle mass is associated with
both a decrease in protein synthesis (approximately 15%) and an
increased rate of protein breakdown. As muscle atrophy begins, there is
a concomitant increase in the urinary excretion of nitrogen compounds ,
3-methylhistidine, creatinine, and sarcosine. Over the course of a long
duration mission, muscle mass losses of up to 50% can be seen (up to 20%
on short duration missions). These changes are readily seen in the
"chicken legs" of a space traveler; although the cephalad fluid shift
seen early in space flight can contribute to this effect, the fluid
shift is complete after the first week or so of flight, but leg volume
(particularly in the thigh area) continues to decrease throughout the
course of a mission, leading to decreases of up to 20% by the end of
three months. Leg volume measurements do not revert to pre-flight levels
immediately upon rehydration and return to earth, providing further
evidence that the changes are primarily associated with muscle atrophy
rather than fluid shifts.

Other changes in muscle morphology include decreases in muscle volume,
cross-sectional fiber area (though not in fiber number), contractile
proteins, oxidative to glyoclytic enzyme ratio, and capillary density
within muscle tissue. This contributes to a more anaerobic metabolic
profile and decreased muscle strength and endurance.

Changes in bone structure appear to be caused by increased osteoclastic
activity and are particularly pronounced in the spine and legs. Losses
of up to 20% of pre-flight bone mass have been documented and can
continue for several weeks (or months) following return to a one-g
field. The alteration in the calcium balance has effects throughout the
body, contributing to an increased risk of renal calculi as well as to
changes in hematopoeisis.

These changes in muscle structure and function have implications for the
amount and type of physical activity that can be performed in space, and
suggests that crewmembers may be at greater risk of injury. Animal
studies have demonstrated a microgravity-associated reduction in muscle
fiber regeneration and repair, which would imply that, should an injury
occur, recovery may be prolonged. Similarly, the relative reduction in
osteoblastic activity could significantly impair healing of an in-flight
fracture. Animal studies also reveal microgravity-related alterations in
the architecture of bone, leading to further doubts about the body's
ability to repair a fracture.

**Countermeasures**

The persistent diminution in bone and muscle mass is a source of great
concern for exploration class missions. Depending upon the mission
profile, travel to the destination could require several months and
crewmembers will likely be expected to engage immediately in physical
activity on the surface (specimen collection, habitation module
construction, etc). If there have been significant losses in strength
and fitness en route, injuries may occur and/or mission objectives may
be compromised. Further exacerbating any physical weaknesses will be the
neurological-associated abnormalities in balance, coordination, and gait
(see above), all of which increase the risk of falls, fractures,
dislocations, and other injuries. It is therefore critical to ensure
that space travelers will arrive in acceptable physical condition.

Towards that end, a robust countermeasures program has been initiated on
the ISS, making use of both strength and aerobic training. The ISS Crew
Health Care System includes a treadmill, cycle ergometer, and resistive
exercise device, the latter two in conjunction with vibration isolation
systems. Space station crew are currently assigned two hours per day of
exercise, in an effort to minimize microgravity-related deconditioning.
As enthusiasm for exercise (and compliance with the scheduled program)
varies from person to person, it is important for the aerospace
physician to educate space travelers about the need for regular
exercise, as well as to monitor fitness and strength levels during the
course of a mission.

Mechanical countermeasures, such as low-intensity vibrations (to
stimulate bone construction) or the Russian "penguin" suit (which makes
use of elastic bands to force use of extensor muscles), have been
studied to determine their efficacy. Unfortunately, none have as yet
proven sufficiently useful to warrant routine use. Pharmacologic and
nutritional interventions, such as bisphosphonates and other
anti-osteoclastic agents or high-calcium diets, are currently under
investigation as countermeasures, but none are (yet) routinely used. One
concern is that use of drugs to alter the calcium balance may have
unintentional effects on renal physiology and the creation of kidney
stones. Space flight is considered to be a stone-forming environment, so
concerns of this nature appear well-founded.

**Post-flight**

In the immediate post-flight period, space travelers experience muscle
weakness, fatigue, and soreness. Whether this is due to readaptation of
cellular processes (i.e. readjustment of protein synthesis and
degradation pathways), unaccustomed strain associated with reexposure to
gravity, or micro-injuries within the muscle tissue is unclear.

Muscle mass and strength tends to recover more rapidly upon return to
earth and initiation of a post-flight exercise regime. Within two weeks,
muscle strength is generally recovered, though it is unclear if there
are any associated changes to connective tissues structures (such as
tendons and ligaments). Because space travelers tend to be an extremely
fit group, the aerospace physician may find it necessary to caution
against too rapid resumption of athletic activities following space
flight, lest injuries result. This risk may be exacerbated by lingering
neurovestibular effects, as mentioned above.

Despite rigorous rehabilitation programs, recovery of pre-flight bone
mass can take years. In part this is due to the slower time course for
terrestrial mineralization (100 mg of calcium per day) compared to the
space-associated demineralization (250 mg per day), which suggests that
it will take two to three times as long to recover bone mass as to lose
it. In other words, it may take up to 18 months to recover the amount of
calcium lost from bones during a six month mission. In addition,
different parts of the skeleton lose and recover mass at different
rates. For example, demineralization of the lumbar spine has been noted
to linger for up to six months post-flight, even as other parts of the
spine were recovering and adding mass.

As a result, there is a desire to maximize bone density prior to flight,
and many crewmembers engage in pre-flight exercise programs towards that
end. Particularly for those groups at highest risk for the development
of osteoporosis (white women, positive family history, etc), the
aerospace physician may wish to work closely with athletic trainers and
physical therapists to build up bone mass prior to flight, utilize
aggressive in-flight countermeasures, and begin rehabilitation promptly
upon return.

**Blood and Electrolyte Effects**

**In-flight**

As described above, there is an in-flight loss in total body fluids,
including extracellular fluid volume, plasma volume, and circulating
blood volume. The majority of this volume loss is due to changes in
plasma volume and circulating red cell mass.

Blood sodium levels decrease in spaceflight, though the relative ratio
between sodium and potassium remains unchanged. Most of the other
electrolytes are also unaffected by exposure to space, with one major
exception: calcium. Both urine and plasma levels of calcium are
increased in conjunction with bone demineralization, while the negative
nitrogen balance and muscle atrophy lead to elevated urinary levels of
nitrogen and muscle breakdown products. Phospohorus levels mimic those
of calcium and are also felt to be secondary to changes in bone
metabolism.

Red cell mass has been found to decrease on orbit, regardless of whether
an enriched oxygen (Skylab) or sea level equivalent atmosphere (ISS) is
present. This "space anemia" appears to be due to decreased red cell
production and thus is not one of the effects seen immediately upon
exposure to microgravity. Researchers propose that the decrease in
plasma volume leads to a relative increase in hematocrit and causes the
body to decrease production of erythropoeitin and other RBC-producing
factors. As red cells are consumed in the normal life cycle, but not
replaced, the red cell mass decreases in what is felt to be an adaptive
response to the microgravity environment.

**Countermeasures**

Since the changes in blood volume, fluid status, and electrolytes are
felt to be appropriate adaptations to the space environment, there are
not countermeasures currently employed during the in-flight period.
Immediately prior to reentry, fluid loading occurs, as described in the
"Cardiovascular" section above. This is intended to re-expand the
intravascular volume and protect the crew against gravity-induced
orthostatic intolerance. Following landing, normal physiological
processes reverse the changes, returning the space traveler to a
terrestrial-euvolemic state. Some positional orthostasis may persist for
a few days, and the aerospace physician should inform his or her crew
about this possibility and provide suggestions on how to avoid it (e.g.
rise from bed slowly), similar to the cautions provided to blood donors.

**Post-flight**

Upon return to earth, the space-euvolemia is now perceived as a
terrestrial-hypovolemic state, leading to an expansion of the plasma
volume and a relative dilution in the hematocrit. This "anemia" triggers
an increase in erythropoeitin production and returns the red cell mass
to pre-flight levels. Similarly, the thirst reflex and renal system will
expand the fluid volume, thus ensuring maintenance of proper fluid and
electrolyte levels.

**Immunological Effects**

**In-flight**

Space travelers demonstrate a significant increase in the number of many
types of circulating white blood cells (neutrophils, monocytes, T-helper
cells, B-cells), but a decrease in natural killer cells. It is not clear
whether these changes are due to increased production or decreased
destruction of the cells. Studies have shown that the increase in plasma
norepinephrine levels upon landing are correlated with the increased
white blood cells, suggesting that landing stresses produce a
sympathetic redistribution of circulating leukocytes.

Although the studies to date have produced conflicting results,
anecdotal data persistently indicate that immune function is compromised
in microgravity. There have been in vitro studies which show that
lymphocytes in-flight are largely unaffected by stimulating agents,
suggesting that the white blood cells circulating in the blood, though
more numerous than terrestrial levels, will be unable to mount an
effective immune response. Changes in leukocyte morphology have also
been reported, suggesting that immune function may be impaired.

Some researchers have documented an increase in plasma cortisol levels,
which could be associated with an in vivo corticosteroid-induced
immunosuppression. Because microorganisms may be more highly
concentrated in the confined environment of a spacecraft, the issue of
immunocompetence could be important. To date, there have been reports of
(usually minor) illnesses during space flight, but no evidence that
illnesses are unusually severe or longer lasting in space. Whether the
findings to date demonstrate changes related to the microgravity
environment, or merely stress-related effects on the immune system
remain unclear, and additional research continues.

Subjects in analog environments, such as crews spending the winter in
Antarctica, often display latent viral reactivation, so it is not
unreasonable to imagine that such an effect could be present in long
duration space flight.

**Countermeasures**

Other than ensuring that space travelers are in good health and have had
all the standard vaccinations, no countermeasure program is currently in
place. The crew health care systems of the Shuttle and ISS contain
medications, including anti-biotics and anti-virals, for the treatment
of disease, and the "health stabilization program" (or quarantine
period) immediately before launch is intended to further diminish the
likelihood of communicable disease during a mission. Unfortunately, the
effects of space flight on the immune system are insufficiently
understood to permit development of appropriate countermeasures at this
time. Research continues however, and in time, other tools such as
pharmacologic agents may be used to stimulate immune cell function.

**Post-flight**

While in-flight changes to the immune system remain unclear, current
work focuses on identifying any alterations in structure and function,
along with the associated time course(s). Until these trends have been
clearly established, the aerospace physician must assume that
immunocompromise, if present in-flight, may persist in the post-flight
period. As a result, space travelers should be cautioned about the risks
of exposure to infectious diseases and the importance of seeking medical
help promptly should symptoms develop.

**Endocrinological Effects**

**In-flight**

There appears to be a down-regulation of neurohormonal receptors during
space flight. The changes in plasma volume due to the cephalad fluid
shift early in space flight, give rise to a natriuresis through both
pressure effects on the glomerulus and involvement of other factors,
including anti-diuretic hormone, the renin-angiotensin-aldosterone
system, and calcium-regulating hormones.

Among the effects of microgravity on the endocrinological system is the
establishment of a new balance between osteoblastic and osteoclastic
activity: reductions in circulating vitamin D and GSH, presumably
related to the decreased load exerted on the bones, lead to diminished
calcium absorption.

Catecholamines also exhibit some changes associated with space flight;
inflight levels of urinary norepinephrine are periodically increased,
while post-flight levels of both norepinephrine and epinephrine are
elevated compared to pre-flight values. Epinephrine is felt to reflect
stress levels, while norepi is an indication of physical activity. It is
interesting that, given the stresses of space travel (isolation, busy
schedules, etc.), in-flight levels of epinephrine are generally
unchanged from pre-flight. This could suggest that the human body adapts
relatively well to space flight and does not find microgravity, in
itself, an overly stressful environment.

There have been general increases in cortisol levels noted during space
flight, but studies into hormonal levels have demonstrated wide
variability. Differences in diet, exercise, sleep, and emotional stress
are likely contributors to the variation seen and suggest that endocrine
changes are too subtle and complex to permit easy categorization. This
is also why no countermeasures to these (generally adaptive) changes
have been developed.

**Post-flight**

Neurohormonal changes affect the cardiovascular system post-flight by
blunting the baroreceptor reflex and impairing the body's ability to
respond to an orthostatic challenge. This can contribute to the residual
orthostasis, though it should pass within a few days. Just as the body
adapts to the microgravity environment through changes in the endocrine
and nervous system, so too do the same systems facilitate the
readaptation back to the terrestrial environment.

Simulation and Analog Environments for Space Flight

**Types**

There are numerous analogs for space flight exposure, ranging from
parabolic flight to underwater operations, from the South Pole to a
bedrest laboratory. Each type mimics a different aspect of the space
flight environment and each therefore has applicability for different
studies.

Microgravity itself, i.e. free fall, can be experienced through
parabolic flight. The NASA KC-135A Reduced Gravity Research Program
makes use of a four engine turbojet aircraft to offer (typically)
alternating intervals of zero gravity (25 seconds) followed by 1.8g (20
seconds) per parabola, 40-60 parabolas per flight. Other gravitational
forces (including lunar and martian gravity) can also be simulated,
though the interval time course remains generally similar.

For muscle atrophy and "off-loading" of gravitational forces, rat models
make use of tail suspension methods, while human subjects undergo
prolonged bedrest. Head down tilt (usually 4 degrees) can be added to
the bedrest, or "dry immersion" methods can be used to create cephalid
or intrathoracic fluid shifts similar to those seen on orbit. Research
into fluid and electrolyte balances, musculoskeletal changes, and
endocrinological changes have all been studied in this way.

To investigate the effects of prolonged isolation and small group
dynamics experienced by space travelers, numerous analog environments
have been used. Examples of the latter include polar station and
submarine crews, the much publicized "Biosphere" in Arizona, NASA
Extreme Environment Mission Operations (NEEMO) projects in the Aquarius
underwater laboratory, and NASA-Haughton-Mars project on Devon Island.
Astronauts in their spacesuits can practice EVA tasks in a space analog
environment at the NASA-Johnson Space Center Neutral Buoyancy Lab (NBL).

**Uses**

Clearly each of these analogs has both benefits and limitations. No
single analog is suitable for all microgravity research, and
investigators must carefully select the model most appropriate to them.
All of these simulated microgravity analogs have shortcomings: both
water immersion and bedrest studies have proven ineffective at
predicting changes to cardiovascular parameters in space**,** the
periodic microgravity of the KC-135 is quite a different stress than the
sustained microgravity of space flight, and motion sickness aboard the
KC is not predictive of in-flight SMS. Submarines and polar stations
typically have much larger crews than those seen on space stations to
date, and even the NBL cannot entirely emulate the extra-vehicular
environment for spacewalkers because materials often behave differently
under water than they do in a vacuum. At the same time, much can be
learned from working with these analogs, so long as the differences and
confounding factors are clearly and prospectively identified.

**Artificial Gravity**

The countermeasure most avidly sought as the "solution" to many of the
most concerning microgravity-associated physiological effects is
artificial gravity (AG). This could be accomplished through rotation,
either of the entire spacecraft or an onboard centrifuge. It is
hypothesized that, through the use of AG, muscle atrophy, bone
demineralization, neurovestibular and neurosensory alterations, and many
other physiologically deconditioning effects could be avoided, thus
facilitating crewmember return to a gravitational field, whether on
Earth, the Moon, or Mars. If space travelers could use a centrifuge or
other form of AG device, combined with active head movements and
locomotion, to achieve a dual-adapted state, where they are equally
comfortable in a microgravity or full gravity state, they could
potentially avoid reentry disorientation and post-landing postural
instability. However, use of a centrifuge could also create vestibular
problems through the Coriolis effect, leading to significant motion
sickness.

A major consideration of AG is the trade-off between the radius and the
rotation rate required to achieve a desired gravity level. For example,
depending upon the radius of the rotation, Coriolis and other
nausea-inducing forces may persist and/or gravitational forces could
vary over the length of a human body. The physiological effects of
having different parts of the body at different gravitational levels is
unknown.

Even if such provocative stimuli could be avoided, there is currently
little information as to what an "adequate" gravity level might be; is
full gravity needed or would partial gravity be sufficient? In addition,
does the AG stimulus need to be continuous, or will intermittent
application (as with an onboard centrifuge) prevent the physiological
adaptations? If the latter, will the repeated shifting between
microgravity and AG cause neurovestibular difficulties? How much time
would be required in the centrifuge? Will it vary from one crewmember to
the next? How will the "AG prescription" be determined? One study flew a
short-arm centrifuge on the Shuttle (STS-90) and found that in
astronauts who were subjected to 20 minutes of 0.5-1g along the
longitudinal axis of their bodies on alternate days during the 16 day
mission experienced reduced post-flight cardiovascular deconditioning.
This is encouraging, but hardly conclusive, evidence for the value of
AG.

While it might seem simpler to subject the entire vehicle to a steady
gravitational field, there are significant barriers to the design of a
rotating spacecraft. Financial, operational, and maneuverability
challenges are enormous, and it is unlikely that they will be overcome
in the near future.

**Medication Use in Microgravity**

**Pharmacokinetics and Pharmacodynamics**

Pharmacokinetics is the study of the absorption, distribution,
utilization, and metabolism of drugs. Pharmacodynamics is the study of
drug interactions in living systems. While there is evidence that both
vary in the space flight environment (for example, one study on
in-flight use of intramuscular promethazine documented less than 5%
sedation rate, while ground-based controls had a sedation rate of over
70%, and bioavailability of certain drugs, including scopolamine and
acetominophen, have been shown to be different in-flight), relatively
little is known about microgravity-associated changes to these
parameters. In part, this is due to the small sample size and limited
opportunities for in-flight observations. Unfortunately, the analog
environments described above are largely unsuitable for pharmacologic
studies, though some work has been done using bedrest and head down tilt
models. As a result little data can be gathered from anything other than
on-orbit research.

Unfortunately, this research is often beset by confounding factors, such
as the relative hypovolemia, changes in diet and sleeping patterns, SMS,
muscle atrophy (which could have effects on drug binding by circulating
proteins), and stress levels. Other parameters, some as yet poorly
understood, can also play a role; for example, hepatic blood flow may be
altered in microgravity, and this would be expected to have a
significant impact on first pass effects and drug excretion.

**Routes of administration**

To date, numerous routes of administration have been utilized during
spaceflight, including intravenous, intramuscular, subcutaneous,
intranasal, inhaled, oral, topical, and rectal. Current ISS
resuscitation protocols call for the administration of ACLS drugs (such
as epinephrine and lidocaine) via the airway, if a peripheral IV is not
already available. Crew medical officers are trained on drug
administration through all of these routes, though generally speaking
oral and intramuscular are the routes most commonly used.

Additional research into the efficacy and bioavailability of each of
these routes is needed. Particularly, more information is needed for
exploration class missions in order to select the most appropriate
pharmacopoeia.

**Operational issues**

One of the major operational issues related to drug administration is
related to the crew medical officer training. Unless a
physician-astronaut is a member of the crew, an infrequent occurrence on
Shuttle flights and one that has not (yet) happened on ISS, the crew
medical officers are minimally trained caregivers. The training program
is both short and intermittent, with little time for hands-on training
and the development of clinical judgment. As a result, it is unlikely
that the caregiver will be experienced in either drug administration or
evaluation of drug efficacy. Even physician-astronauts have reported
unusual difficulty in obtaining intravenous access in healthy subjects
in space, and alternate methodologies (intramuscular injection, sternal
intraosseous infusion systems, etc) may be needed, especially for use in
medical contingencies when rapid access is required.

There is preliminary data to suggest that the shelf life for certain
pharmaceuticals is reduced on orbit, presumably due to the higher
radiation environment. If these findings are confirmed, supplementary
testing of all drugs intended for flight would be needed, particularly
for those being considered for exploration class missions. Without this
research, it would be impossible for the aerospace physician to know if
a patient's failure to respond to a prescribed drug was due to an
erroneous diagnosis, a worsening condition, or an inactive
pharmaceutical. This work may also result in the need for new spacecraft
designs, with additional shielding for the medication kit(s). Another
alternative might be to store drugs in powder form, and reconstitute
them as needed, as powdered forms tend to have longer shelf lives in the
terrestrial environment. However, mixing drugs during space flight poses
numerous challenges, from the inability to create injectable quality
water in-flight, to the increased training requirements for crew medical
officers, to the challenges of creating a homogeneous mixture in
microgravity. Research is currently underway in this area, but the
technical difficulties are considerable.

Prior to flight, many drugs are tested by crewmembers. This is done in
an attempt to prevent atypical reactions during the mission. While it is
virtually impossible to rule out the possibility of anaphylaxis
in-flight, testing the medications ahead of time to ensure there are no
allergic reactions is felt to be protective. In addition, it is helpful
to identify any side effects that could potentially impact the mission,
such as extreme sedation.

**[References and Suggested Readings:]{.underline}**

1\) DeHart, RL and Davis, JR. (Eds.). (2002). [Fundamentals of Aerospace
Medicine, 3^rd^ Edition.]{.underline} Philadelphia: Lippincott Williams
& Wilkins.

2\) MR Barratt and SL Pool (Eds.). (in press). [Principles of Clinical
Medicine for Space Flight.]{.underline} New York: Springer Verlag.

3\) Bacal K, Billica R, Bishop S. Neurovestibular symptoms following
space flight. *J Vestib Res* 2003; 13 (2-3): 93-102.

5\) Clement, G. (2003). [Fundamentals of Space Medicine. Space
Technology Library.]{.underline} El Segundo: Microcosm Press.

6\) Huntoon, CSL, Grigoriev, AL, Natochin, YV. (1998). [Fluid and
Electrolyte Regulation in Spaceflight. Volume 94 Science and Technology
Series.]{.underline} San Diego: American Astronautical Society.

7\) Ball, JR and Evans, CH. (Eds.). (2001). [Safe Passage: Astronaut
Care for Exploration Missions.]{.underline} Washington DC: National
Academy Press.

8\) Harding, R. (1989). [Survival in Space.]{.underline} London:
Routlege.

9\) Busby, DE. (1968). [Space Clinical Medicine.]{.underline} Dordrecht:
D. Reidel Publishing Company.

10\) Parker, JF and West, VR. (1973). [Bioastonautics Data Book, 2^nd^
Edition.]{.underline} Washington DC: NASA Scientific and Technical
Information Office.