In the previous article, we briefly covered some interesting medical and physiologic challenges facing the space faring human, why they matter to the development of a new space economy, and where physical medicine and rehabilitation might fit in. In this article we will delve a little more deeply into the pathophysiology — as it is understood to date — as well as some current mitigation strategies. We will focus on the aspects of spaceflight physiology that also have significant cross-over with our terrestrial populations.
As we consider the pathophysiology involved in these spaceflight-associated syndromes, remember that our entire evolutionary history and all our physiologic antecedents developed in a particular gravitational environment, which has not changed since the first forms of live emerged on Earth. Terrestrial life has always been able to rely on a constant gravitational force which provides an “up” and “down” and dictates how gas and liquid behave. Consequently, all Earth’s land-dwelling organisms who rely on a circulatory system, have one evolved with the assumption that gravity will always be there, and that “up“ and “down” are a universal constant. Similarly, when an organism requires locomotion for survival, gravitational force is assumed to represent the minimum force that its musculoskeletal system must be able to overcome in order to move about its environment and this places limits on how far and fast a creature can move. Terrestrial body plans, like that of humans, developed within a constant gravity field, with compensatory mechanisms designed to help optimize them. However, we are now on the precipice of a gravity-free setting that nullifies this force and confuses the body’s normal adaptive mechanisms. These adaptive mechanisms, which typically help our bodies respond to differing workloads (i.e. fluid shifts during changes in position), while maintaining the utmost of efficiency (catabolizing unused muscle and bone) now begin to work against us. The closest analogous state on Earth to a long duration spaceflight is prolonged bedrest. Most of our inpatients who visit inpatient PM&R have experienced this prolonged bedrest to one degree or another.
Another important thing to keep in mind when considering our knowledge of the inherent physiologic toll of long-duration spaceflight and off-planet living is that much of what we currently know about its effects had been confined to gravity-free exposure of only weeks to a few months. Humans were spending hours to days in space with the Gemini and Apollo missions, and there were a few stretches of between 4 weeks and 3 months on Skylab, with some longer times (up to 437 days) on the Russian space station MIR. Unfortunately, these missions took place between the 1970’s and 1990’s, and the quality of physiologic data at the time left much to be desired. The missions shortened again with the shuttle program, having mission durations of days to a few weeks. ISS mission started to stretch out to 4 and 6 months, then 9, with the longest to date being Scott Kelly from the USA and Mikhail Korniyenko from Russia, with ~12 months ending in 2016. However, to date — only 3 individuals have withstood a continuous year in space since humans became a space faring species. What have we learned from this, and how can we extrapolate the data to prepare ourselves for much longer durations?
Since most off-planet excursions (with the exception of lunar missions) will require transit times well beyond our current ISS mission, there are some very important and interesting unknowns that still await us. For example, a mission to the surface of Mars would take between 6–9 months in microgravity (uG) on the way there, 16–18 months on the surface at 3/8 earth standard gravity (due to the constraints of orbital mechanics on the return journey), and then another 6–9 months in uG to return to Earth.
With these realities of unprecedented uG and prolonged low-G exposure, let’s examine more closely the known and potential breakdown of these physiologic systems, and what has been done to combat this to date.
We will first revisit the musculoskeletal system, which will be presented as a unit, since many of the factors that induce their degradation are complimentary. Consequently, the mitigating strategies employed so far tend to work for reasonably well for both skeletal muscles used in posture and locomotion, and for maintenance of bone density and bone strength.
It is fairly well established that unloaded human skeletons experience 1–2.5% loss in bone mineral density (BMD) per month, depending on which skeletal site is surveyed. This holds true for both the bed-bound and the astronaut. To put this in perspective, the average postmenopausal woman loses about 1.3–1.5% of their BMD per year. So, an astronaut or completely bed bound person losses their BMD between 8 and 20 times faster than the highest-risk terrestrial population. We see an equivalent phenomenon in our patients with spinal cord injuries, who can lose bone density at a similar rate to the bed bound and astronaut populations. The theory behind this pathological adaptation lies in the notion of the mechanostat. The ’mechanostat theory‘ is a feature of our skeletons that, to date is not fully characterized, but essentially acts as a cellular mechanism that senses loading force. The sensation of this force has a central role in the activation or deactivation of the osteoblast/osteoclast system. The biomolecular and cellular mechanisms so far identified are beyond the scope of this article but suffice it to say the sensing of skeletal load directs remodeling and appears to do so in a very localized fashion. This allows bone remodeling to occur in specific areas which allow for reinforcement of bone architecture in the areas experiencing the most strain. Conversely, those areas no longer experiencing as much strain tend to break down their ’extra support’ in favor of mobilizing substrate. In complete unloading, like uG, para- or quadriparesis, and long-term bed rest, the bones’ mechanostat feature begins to work against the body. It happily mobilizes the ‘extraneous substrate‘ of skeletal calcium and phosphate that are apparently no longer needed. Unfortunately, this is happening everywhere in the skeleton not under load, except for the skull.
The well-established idea of muscle loss in the setting of disuse is a perennial problem in rehabilitation medicine, as well as for the astronaut. Our rehab patients have come out of long stays in the ICU, or after surgeries with long recoveries, and their deconditioning is a profound barrier to overcome. Now imagine if you had not endured a stay in the ICU, or had prolonged surgical recovery, yet you still developed that same level of deconditioning, merely because the gravitational environment you dwell in does not stimulate your body to maintain its natural condition. We have seen the changes in muscle fiber type composition, changes in muscle cross-sectional area, and most importantly, changes in functional capacity. The understood mechanism for this lies in the interplay between the skeletal muscle energy utilization/storage and functional capacity. When a muscle as a unit undergoes firing in response to load, it activates its cellular system for bringing in and metabolizing glucose via insulin; this also up-regulates the system’s to insulin-like growth factor IGF-1 mediated protein anabolism, in preparation for muscle repair and regeneration. Incidentally, that ’load‘ could be just the effort of walking around at a normal pace in Earth’s gravity. Conversely, when muscle is totally unloaded, it suppresses this system through insulin resistance, down-regulating protein synthesis and up-regulating catabolism.
Not only does this lead to an overall loss of muscle fiber cross-sectional area and ultimately functional strength, but this unloading can also precipitate a gradual change of fiber type predominance. In humans, fast-twitch fibers (Type II) are generally hit harder through selective degradation than type I. However importantly, Type I (slow fibers) show a type of maladaptation where their slow myosin is degraded and replaced by faster MHC isoforms, mostly IIX. This creates a new hybrid slow/fast fiber which is smaller, has less strength overall and contracts faster — therefore fatiguing more quickly. This may not seem particularly important, but our body’s proportion and distribution of muscle fibers evolved as it did due to the specific evolutionary pressures, namely, the gravity field our ancestors resided in all through their evolution. When the loss of slow twitch fibers reaches a certain point, it severely degrades endurance for even routine functions like ambulation. Finally, much like the inpatients who spend weeks at a time not fully mobilizing a joint, and then attempting to use it in a full range of motion, many astronauts experience calf and hamstring pain, as well as plantar fasciitis upon returning to Earth. Their joints and muscles having developed what amounts to essentially disuse contractures in the unloaded environment of uG. How will these effects magnify with even longer-duration space flight?
When we consider the skeletal remodeling and muscle degradation that takes place in uG environments, it is important to remember that these systems respond not just to load, but also to other critical environmental factors, like the endocrine milieu they find themselves in. Astronauts on the ISS have been shown to have elevated cortisol levels on orbit, which can independently enhance muscle and bone breakdown. Additionally, low light levels and high ambient CO2 concentrations can have a profound effect on the skeleton by lowering vitamin D levels and promoting an acidotic environment which also speeds bone density loss. Within a few days of entering weightlessness, urinary calcium excretion increases by 60–70%, similar to that of a newly quadriplegic patient. This increased calcium load can likewise cause an imbalance in protein metabolism and activate muscle catabolism.
The issue of muscle and bone loss was identified early in human spaceflight, and counter-measure programs were begun to help mitigate these changes. However, it has proven quite difficult thus far to truly stave off the effects of long term uG. At minimum, a heroic effort is required from astronauts who must become exercise fanatics upon entering uG, with current countermeasure plans requiring 2–2.5 hours of exercise 6 days a week. Even with this effort, the astronauts only manage to maintain an approximation of normal muscle strength and composition, but still had measurable losses. Variations in countermeasure programs have evolved over the years, with the first efforts being a type of cycling device, then rubber band-like devices, providing for some resistance exercises, then finally the advanced resistive exercise device (ARED), which allows for weight-lifting like maneuvers to take place in uG using a clever series of vacuum tubes and hinges. Barbells, as one might imagine, aren’t quite as useful without gravity. In addition to these exercises, other pharmacologic countermeasures have been employed for reducing bone density losses in uG, like the use of bisphosphonates. In the right combination, exercise involving heavier load bearing exercises with ARED, good nutritional support and bisphosphonates have been shown to mostly stave off bone mass losses in long duration flight.
The cardiovascular system similarly adapts to an environment that asks much less of it. Our circulatory system came into being over the countless evolutionary iterations, and it did so with the constant assumption of gravity. The strength of the pumping action of our hearts, the ability of our vasculature to dilate and contract to maintain pressure, the one-way valves in the veins of our limbs, the baroreceptors in our carotid arteries: all these features exist as a direct response to gravity as an evolutionary pressure. In uG the heart shrinks, as it no longer must pump against the same fluid column that it did on Earth. Additionally, there is a profound fluid redistribution that results in a ~15–20% loss of total intravascular volume, hypothesized to occur because there is no longer a direction of “down” pulling blood away from the brain.[3, 7] This means the vasodilation and vasocontractile feedback systems become lazy, they aren’t activated to constrict the intravascular volume when hypovolemic, or to relax in response to increased intravascular volume. This results in several unwanted consequences. Upon returning to a gravity field, (so far this only includes Earth’s G field), astronauts experience orthostatic intolerance, becoming profoundly dizzy and lightheaded with any postural change; significant, and sometimes severe, lower extremity edema; and a reduced exercise capacity. This is the case, even when maintaining an incredible 15 hours a week of dedicated exercise time. The recovery time is somewhat proportional to the time spent uG, but can be weeks before the astronaut regains a semblance of ‘normal’ functionality, and months before they can feel back to the way they were before their mission. So far, the methods of using salt tablets, aggressive hydration, and lower body compression garments can ward off the worst of the orthostatic hypotension upon returning to Earth. However, a new kink in the cardiovascular consequences of a weightless environment has only just made itself known. A recent study has shown that the uG environment has the concerning ability to allow for clot formation in the jugular vein. This thrombosis was discovered during a study looking at the vessels of the neck during spaceflight. What the study revealed was a disconcerting stasis within the jugular vein in 5 of the 11 study subjects, and in one, a clot. So far, spaceflight has not shown a greater propensity for DVT formation in the limbs, but this is unsurprising. Afterall the astronauts are performing hours of rigorous exercise daily and the skeletal muscle pumping involved is enough to ward off DVT, even when they spend the remainder of their day completely unloaded. Similarly, mere ambulation on Earth normally accomplishes this same preventative measure. There is an important difference in this case though: the vessels of the neck don’t require skeletal muscle pumping to prevent stasis on Earth, and for all of humanity’s evolutionary development, gravity ensured that there was no venous stasis in the veins of the head and neck. This is important because there is no easy countermeasure to employ, like exercise, that can remove the thrombosis risk for the veins of the head and neck in an environment that produces venous stasis. In the case of this thrombosis event, the astronaut, who was asymptomatic, was treated with the appropriate anticoagulation and removed from the study.
Acknowledging the importance of our body’s relationship to fluid columns, another potential issue is starting to take shape. Long-term uG exposure appears to be causing spaceflight associated neuro-ocular syndrome, or SANS. This is the constellation of symptoms including optic disc swelling elevated intra-ocular pressure, microvascular infarcts and globe-flattening which are presumed to be, related to if not the cause of, astronauts losing their near-distance vision. It has been known for some time that astronauts can experience decrements in their near vision in as little as a couple weeks on orbit. So much so that they often arrive on orbit with ‘space anticipation glasses’ to correct their impending near-vision loss. Now we have increasing evidence that not only does the eye change shape, but some concerning findings relating to the brain and its own fluid column of CSF are also starting to become evident. Optic disc swelling can be a sign of elevated intracranial pressure (ICP). Elevated ICP can lead to a host of other issues, as those of us used to caring for patients with brain injuries and strokes are all too familiar with. Elevated ICP’s have been measured on many astronauts upon returning from long duration flights. Noted decrements in cognitive performance after long duration missions speak to the fact that something has affected the brain in a more global sense. It is unclear if there is a relationship to these cognitive impairments with the changes seen in the brain. Recent studies show the changes in the brains of astronauts after exposure to uG where there seems to be compression leading to apparent disruption of normal CSF flow and even remodeling between pre and post-flight MRI images.[9, 10] An additional consideration not yet explored, is that if we can already see changes in the way the CSF moves around the central nervous system, this might also imply a glymphatic disruption. The glymphatic system is the recently characterized lymph-like (glia-lymph) fluid that activates on a cyclic pattern, usually during the sleep cycle, carrying away waste products like metabolites and proteins, notably beta-amyloid. Disruption of the glymphatic system is thought to play a role in many brain disorders like Alzheimer’s and other amyloidopathies. Additionally, some have hypothesized there might be a significant role of the glymphatic system in the recovery, or subsequent failure thereof, after a traumatic brain injury. All of these are promising avenues of research, with important crossover from space medicine to terrestrial care, including PM&R.
One of the candidate countermeasures so far employed for combating this fluid redistribution are some rather comical looking trousers called Chibis that look like they belong in a Wallace and Grommet movie. They are also known as lower body negative pressure devices (LBNP). These negative pressure pants do just as their name implies, they provide a negative pressure around the wearer’s legs that result in a type of forced vasodilation, like the way an old iron lung caused expansion of the chest by negative pressure around the thorax. This in turn is hypothesized to draw the fluid column away from the head by creating a net flow towards the legs. So far, this device has had mixed results, but does show some promise in the short term for alleviating some of the fluid shift. More data will be required to see if it is useful at counteracting the effects of these caudal fluid shifts in the long term and if this is protective against SANS.
These interesting pathologies associated with spaceflight are significant and important to acknowledge, but they are not insurmountable. The human tendency is to explore, continually pushing the boundaries of our current capability. This drive for exploration, for seeking the novel and the unknown “to boldly go where no one has gone before,” provides a fertile ground for innovation and the rethinking of old problems. Space exploration provides the ultimate challenge, a continually renewing frontier whose secrets bring us closer to understanding our universe. In the 3rd and final article in this series, we will explore some of the future directions and upcoming research into space medicine and physiology, the necessary innovations to enhance survivability and what it means for the viability of future, more challenging human spaceflight.
- Vico, L. and A. Hargens, Skeletal changes during and after spaceflight. Nat Rev Rheumatol, 2018. 14(4): p. 229–245.
- Gao, Y., et al., Muscle Atrophy Induced by Mechanical Unloading: Mechanisms and Potential Countermeasures. Front Physiol, 2018. 9: p. 235.
- Buckey, J.C., Space physiology Oxford University Press, 2006: p. 4.
- Fitts, R.H., D.R. Riley, and J.J. Widrick3, Functional and structural adaptations of skeletal muscle to microgravity. The Journal of Experimental Biology, 2001. 204: p. 3201–3208.
- Barret, M.R. and S.L. Pool, Principles of Clinical Medicine for Space Flight. Springer, 2008: p. 299–300.
- Nicogossian, A.E., et al., Space Physiology and Medicine From Evidence to Practice. Springer, 2016.
- Shen, M. and W.H. Frishman, Effects of Spaceflight on Cardiovascular Physiology and Health. Cardiol Rev, 2019. 27(3): p. 122–126.
- Marshall-Goebel, K., et al., Assessment of Jugular Venous Blood Flow Stasis and Thrombosis During Spaceflight. JAMA Netw Open, 2019. 2(11): p. e1915011.
- Roberts, D.R., et al., Effects of Spaceflight on Astronaut Brain Structure as Indicated on MRI. N Engl J Med, 2017. 377(18): p. 1746–1753.
- Riascos, R.F., et al., Longitudinal Analysis of Quantitative Brain MRI in Astronauts Following Microgravity Exposure. J Neuroimaging, 2019. 29(3): p. 323–330.
Luke Brane is a PGY2 in the Department of Physical Medicine and Rehabilitation at the University of Pittsburgh Medical Center (UPMC). Follow him on Twitter @LBraneMD
An Update on Regenerative Medicine
by Brandon Barndt, DO