Introduction

The human body undergoes numerous adaptations during spaceflight, many of which are sustained following return to Earth1. Without gravitational force providing axial head-to-toe loading, astronauts experience thoraco-cephalic fluid redistribution, autonomic nervous system dysregulation, muscle atrophy, and bone demineralisation1. Persistent adaptations to spaceflight last for inter-individually variable periods following return to Earth. Some of these adaptations include: orthostatic intolerance2, changes in resting heart rate and heart rate variability3, exercise intolerance4, decreases in postural stability, and changes in gait5. Spaceflight induced physiological deconditioning puts astronaut health at risk as well as potentially affecting their performance in completing mission-related tasks1,6. Understanding spaceflight deconditioning and its mitigation is of the utmost importance with the onset of exploration-class missions where astronauts will be exposed to longer periods of microgravity followed by variable gravitational environments without access to large medical care and support facilities or resources. Upon landing on a planetary surface, stringent mission timelines, limited access to rehabilitation exercise equipment as well as unknown responses to rehabilitation in hypogravity environments may limit mid-mission rehabilitation efforts. Autonomous functioning of deconditioned astronauts following prolonged hypogravity exposure could threaten both life and mission. Dangerous physiologic effects following spaceflight such as presyncope, perhaps from impaired cerebral blood flow autoregulation7,8, could lead to disastrous consequences following transit to the lunar surface. Moreover, it is not known how the human body will react to being exposed to hypogravity after prolonged exposure times to microgravity as foreseen in the current ARTEMIS and Lunar Gateway mission profiles. During the Apollo era, astronauts had only ~3 days of microgravity exposure before they landed on the lunar surface, yet some fell, stumbled, and had other mishaps during their lunar surface EVAs. Current Artemis missions foresee much longer exposure times to microgravity in lunar orbit and it is not known how this will affect crewmembers' orthostatic tolerance and balance when re-exposed to hypogravity on the moon. The moon itself may serve as an effective spaceflight analogue to further research spaceflight deconditioning and can be used as testbed for countermeasures in preparation for further missions to Mars and beyond9.

Various countermeasures have been developed and employed by space agencies in order to reduce the risk to astronaut health and increase mission success1. Space agencies employ exercise programmes to counteract some of the cardiopulmonary and musculoskeletal effects of microgravity during missions to the International Space Station (ISS)10,11. However, exercise as a countermeasure is constrained by mechanical failures, as well as technical, mass and space limitations on space vessels11. Pre-establishing in-space and on-surface countermeasure equipment has been postulated as a potential solution to overcome these limitations. However, establishment and use of this equipment comes with its own set of limitations including equipment failure and wear. Added technical complexity to mission planning such as map** exact trajectories in order to allow for docking of crewmember-containing vessels to orbiting rehabilitation-centres increases the risk of error as well as potentially increasing mission duration. Moreover, evidence suggests that exercise equipment for sustained habitation on the Moon or Mars could be relatively basic to compensate for the “lack” of gravity as simple exercises like rope skip** could be applied to provide a very potent stimulus to maintain musculoskeletal and cardiovascular integrity12,13.

Currently, exercise is the primary countermeasure modality used on the ISS. Although it significantly counteracts bone and muscle loss as well as cardiovascular deconditioning in hypogravity—the countermeasure has not been seen to completely ameliorate the adverse cardiopulmonary or musculoskeletal effects of microgravity on the human body14,15. A level of acceptable deconditioning will likely need to be established for future exploration-class missions such as the NASA Artemis program16. Optimally, this level would allow for safe and efficient completion of mission tasks whilst using the least number of resources and time necessary to achieve. Increased effort and resources have been allocated towards develo** effective countermeasures to micro-gravity induced deconditioning for LDSMs on the horizon. Passive countermeasures may have a greater probability of ensuring astronaut health and supporting mission success by maintaining levels of acceptable deconditioning during exploration-class missions which exercise alone may not be able to accomplish.

In this systematic review, passive countermeasures are defined as those wherein the individual using the countermeasure does not need to exert effort for its intended use. Nutritional countermeasures are excluded from this definition as those are examined in a separate dedicated systematic review17. To our knowledge, no previous review exists which has evaluated the effectiveness of passive countermeasures as stand-alone means of ameliorating physiologic deconditioning in microgravity. Passive countermeasures are generally used in concert with other types of countermeasures. However, the use of multiple types of countermeasures makes it difficult to discern which countermeasure is affecting measured outcomes and to what efficacy. In order to best establish passive countermeasure effectiveness, they must be examined as standalone measures.

Thus, the aim of this review is to examine the effectiveness of standalone passive countermeasures in preventing cardiopulmonary and musculoskeletal deconditioning in humans due to gravitational unloading in both spaceflight and ground-based analogue studies.

Results

Results by passive countermeasure

Although many passive countermeasures have been developed over the last few decades, this review identified five passive countermeasures which have been tested in space analogue studies and were of sufficient quality to be included. Briefly, they include:

Human centrifugation

Centrifugation involves replacing lost axial loading by gravitational force which humans experience on Earth with induced centripetal force, a countermeasure termed “artificial gravity (AG)”18. This force is created through the rotation of an arm at constant velocity around an axis. Space flight size constraints limit short arm centrifuges to a radius of 2 m19. In order to create sufficient centrifugal forces to mimic 1-g at the heart using such a short radius, a high rotation rate must be accomplished as the amplitude of centripetal acceleration is directly related to axis arm length18. Due to the high spin-rate, there is an increased risk of astronauts experiencing Coriolis cross-coupled illusion which can lead to disorientation and motion sickness20. Long-axis centrifuges have the potential to decrease the risk of Coriolis cross-couples illusion as lower spin rates are required to achieve 1 g as compared to their short-axis counterparts. However, many limitations exist which limit these centrifuges’ operational viability. Due to their mass and size, these centrifuges will likely have to be external to the vessel. Additionally, a large external centrifuge will impact navigational trajectory which must be compensated for through expenditure of increased amounts of fuel and added complexity to navigation.

Lower body negative pressure (LBNP)

LBNP is designed to counteract the thoraco-cephalic fluid shifts experienced in microgravity by simulating gravitational fluid shifts experienced on Earth21. The countermeasure also simulates some of the mechanical loading experienced terrestrially and which is lost during spaceflight22. Suits that provide LBNP during spaceflight have been used by Russian cosmonauts on the ISS21 and a National Aeronautics and Space Administration (NASA)-supported research team has recently developed a mobile LBNP suit for potential use during exploration-class missions23.

Thigh cuffs

Thigh cuffs (aka “bracelets”) apply about 30–40 mmHg of pressure to the thighs in order to reduce venous return to the heart from the lower extremities during spaceflight in order to reduce thoraco-cephalic fluid shift24. These devices have been used by Russian cosmonauts for many years, initially to counter the so-called “puffy-face-bird-leg” syndrome24.

Skin surface cooling

Skin surface cooling (SSC) may improve orthostatic tolerance through activation of the sympathetic nervous system, reduction in skin blood flow, increase in mean arterial pressures and preservation of cerebral blood flow velocity. Currently, astronauts wear water-cooled suits only for re-entry or for research purposes25.

Whole body vibration (WBV)

WBV consists of providing 15–45 Hz of sinusoidal vibration to the bottom of the feet through a vibrational platform26. The countermeasure works to preserve postural stability by limiting the sensorimotor adaptations which occur in microgravity due to the lack of tactile inputs which normally occur during ambulation on Earth6. In those muscles integral for postural stability, these inputs may lead to strength retention as they serve as a surrogate to normal terrestrial muscle loading 26.

Notably, there are numerous limitations to consider regarding the operational implementation of WBV for LDSMs. Firstly, WBV may impact microgravity research on crystalline structures through unintended vibrational disruption of these structures27. Current Microgravity Vibration Isolation Mounts such as those used on the ISS may be insufficient to attenuate the much larger levels of vibration transmitted through the vessel during WBV. Low amplitude vibration also increases the number of corrective saccadic eye movements needed to visually track a point stimulus28. Increasing vibrational exposure of crewmembers could therefore impact vision and coordination during LDSMs. Lastly, the energy dissipated through vibration could impact and damage electronics, further elucidating the importance of isolating vibrational instrumentation.

Characteristics of reviewed studies

Of the 16 included studies, 9 were randomised control trials (RCTs)19,25,26,29,30,19.

Muscle strength

Neither centrifugation19,33 nor WBV were found to have significant effects on muscle strength-related outcome measures26.

Gait

LBNP was not found to have a significant effect on gait37.

Balance

Whole Body Vibration was found to have a significant positive effect on many balance-related outcome measures such as anterior-posterior root mean squared velocity with eyes closed at 90 days post-BR; but with no significant effect on others such as anterior-posterior root mean squared velocity with eyes open at 90 days post-BR26. Lower Body Negative Pressure was not found to have any significant effect on balance37.

Skeletal anthropometrics

Effect sizes comparing control and countermeasure groups for skeletal anthropometric outcome measures are summarised in Table 3.

Bone Mineral Density

Whole body vibration was found to only have a significant positive effect on ultrasound velocity when baseline data was compared to day 60 data6. These adaptations may occur due to the lack of somatosensory input which humans are accustomed to on Earth6. Tactile inputs are important for the preparatory activations which allow for maintenance of postural stability6. In astronauts, the absence of these tactile inputs results in alterations in sensitivity to high and low frequency vibrations to their feet, which causes postural instability and alterations in walking6. In this way WBV can significantly improve balance-related outcome measures as seen in this review26. However, this positive effect was not ubiquitous across all the study conditions. It seems that comparisons of baseline data with BR-day 90 data more often showed no significant effect of the countermeasure. Whereas baseline data vs. BR-day 60 data showed more instances of significant positive effect. This may be due to maximal deterioration in postural stability occurring within 60 days as well as further muscle and endurance deteriorations as the study period progressed26. Eyes closed conditions also generally favoured the intervention while eyes open conditions more often showed no significant effect. The authors of the reviewed study postulate that this is due to the importance of visual cues in maintaining balance26. Therefore, in the eyes closed conditions, visual cues could not be used by the body to compensate for deteriorations in postural stability caused by deconditioning26. Although OT may play a role in balance, it does not appear to be significant as LBNP-induced improvements in OT did not correlate with significant effects on balance nor gait37. Therefore, sensorimotor pathways may play a larger role preserving postural stability as opposed to fluid-balance and cardiovascular remodelling. Likely, the sensorimotor adaptation which occurs in microgravity cannot be compensated for with improvements in other systems through LBNP6.

Significant muscle atrophy is seen in even short duration space flight56. Weight-bearing muscles and those used for gait such as the quadriceps femoris, hamstrings, sartorius, gracilis and triceps surae have been seen to significantly decrease in volume following spaceflight, most likely due to atrophy from the absence of axial loading57. The positive benefits previously seen using WBV on plantar flexor and dorsiflexor muscle strength58 were not seen in this review26. Centrifugation also seems to not provide sufficient loading to preserve muscle strength19,33 nor preserve jump-related outcome measures19. In the absence of gait and continuous loading by gravity, lower limb muscles will undergo substantial atrophy as loading cannot be sufficiently mimicked with short sessions of centrifugation nor loading through WBV.

Similar to muscle atrophy caused by unloading, disuse osteopenia presents a significant threat to astronaut health during exploration-class missions4). These keywords were combined with Boolean logic as shown in Table 4. The main and specific categories as well as the overall search strategy were defined by the European Astronaut Centre space physiology and space medicine operations experts. Articles in English from the following databases were included: Pubmed, Web of Science, Embase, Institute of Electrical and Electronics Engineers (IEEE) database, the ESA’s “Erasmus Experiment Archive”, the NASA “Life Science Data Archive” and “Technical Reports Server” and the German Aerospace Centre’s (DLR) database.

Table 4 ESA Space Medicine Team search strategy 2017 taken from Sandal et al. 17
Full size table

In May of 2021, an updated search was performed for databases which had produced the majority of the relevant articles during the 2017 search: Pubmed, Web of Science, and Embase. For this update, the search strategy was modified to only include articles examining passive countermeasures. Keywords used to search for active and nutritional countermeasure studies were not included (search numbers 6, 8 and 9 in Table 4). Exclusion of these keywords required adjustment in Boolean operators (#9 was replaced with #7 in search #14 within Table 4).

In 2017, Fiebig and colleagues screened the titles and abstracts of n = 2695 unique records which the initial search yielded17. n = 433 unique records pertaining to passive countermeasures were identified to meet inclusion criteria based on title/abstract screening. These records were rescreened in 2021. The updated 2021 search yielded n = 286 results. All records (n = 647 following duplicate removal) were screened using established PICOS as defined in Sandal et al.17: “Population: Healthy humans; Interventions: Space flights and ground-based space flight analogues with a duration of ≥5 days with a stand-alone passive countermeasure; Control: Space flights and ground-based space flight analogues with a duration of ≥5 days without any form of countermeasure; Outcomes: Studies must contain cardiopulmonary/vascular and/or musculoskeletal/biomechanical outcome measures; and, Study designs: Randomized control trials (RCT) and controlled clinical trial (CT)”. The PRISMA flow diagram for the updated search is shown below (Fig. 2).

Fig. 2: PRISMA.
figure 2

Diagram map** the number of records identified for inclusion in this review following the 2021 updated search.

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Data collection and analysis

Double blinded screening of articles was accomplished through use of the online software tool Rayyan72. Two screeners independently decided if articles met established inclusion criteria. A third screener resolved any disagreements. As detailed above, in 2017, two independent reviewers screened for ground-based analogue and spaceflight studies that examined countermeasures grouped into active, passive, nutritional and mixed countermeasures17. In 2021, an updated search was completed through the Pubmed, Web of Science and Embase databases. Following this search, two other independent reviewers did the abstract and title screening for passive countermeasure studies using records that passed title/abstract screening in 2017 in addition to records found through the updated search (Fig. 2). Full text versions of the resulting articles following title and abstract screening were obtained and screened further using the PICOS inclusion criteria. A third independent reviewer resolved any disagreements amongst the other two with regards to inclusion or exclusion as required. It should be noted that although spaceflight studies were screened, none met inclusion criteria due to risk of confounding as study participants concurrently used exercise and/or other countermeasures during study durations. Therefore, it would have been difficult to truly assess the effectiveness of passive countermeasure being studied as standalone measures.

Data extraction

The ASMRG Data Extraction and Analysis form was used to extract data from the included studies71. This form was created by the ASMRG as a tool to standardise data extraction and analysis for systematic reviews in aerospace medicine completed by the group. Means and standard deviations of control vs. countermeasure groups pre- and post- BR protocol were extracted from included studies and entered into the AMSRG form in order to calculate effect sizes.

Quality assessment

The lead author assessed the risk of bias for each of the included studies using one of two tools depending on whether the included articles were RCTs or CTs. For RCTs, a risk of bias tool curated by the Space Biomedicine SR Methods Group was utilised17. For non-randomised CTs, the Risk of Bias Assessment for Non-Randomised Studies (RoBANS) was used to evaluate risk of bias73.

Bed rest transferability

The ASMRG bed-rest (BR) transferability tool allows for ground-based analogue studies using BR to be assessed on their ability to mimic microgravity conditions on the human body as experienced during actual human spaceflight74. The tool is used to evaluate each study on 8 different criteria with points awarded if a criterion is met. These criteria were developed from the International Academy of Aeronautics’ (IAA) Guidelines for Standardization of Bed Rest Studies in the Spaceflight Context75. The more criteria which are met, the higher the score and therefore the greater the transferability of the study to human space flight74. Transferability is ranked from 1 (poor) to 8 (excellent). The 8 criteria are as follows: (1) Was 6° head-down tilt utilised?; (2) Was diet controlled?; (3) Were sleep-wake cycles controlled?; (4) Were BR phases standardised?; (5) Was horizontal positioning uninterrupted throughout the BR period?; (6) Was sunlight exposure controlled?; (7) Were measurements scheduled to take place at the same time each day?; and (8) Was the duration of the BR period stated?

Data analysis

A full meta-analysis could not be performed due to the heterogeneity of the extracted data. Means and standard deviations were extracted from the included studies in order to calculate effect sizes based on mean differences of control vs. countermeasure groups pre- and post- BR. Due to the small sample sizes of the included studies, Hedge’s G method was used for correction of bias wherein the quotient of the difference of means is taken from the pooled standard deviation17. As in Sandal et al.17, data were presented in effect size plots with 95% confidence interval bars. Outcomes were grouped by the broad grou**s reflecting those used in the search strategy: “cardiopulmonary,” “musculoskeletal performance” and “skeletal anthropometric”. Outcomes were then further grouped by specific variables being measured. The cardiopulmonary grou** included: heart rate (HR), orthostatic tolerance (OT), VO2max and peak power. The musculoskeletal performance grou** included: balance, gait, muscle strength and jump performance. Finally, the skeletal anthropometric grou** included bone mineral density (BMD).

Reporting summary

Further information on research design is available in the Nature Research Reporting Summary linked to this article.