Peripheral skin cooling during Hypergravity: Neuroendocrine, leucocytic and hematological reactions

Peripheral skin cooling during Hypergravity: Neuroendocrine, leucocytic and hematological reactions | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Peripheral skin cooling during Hypergravity: Neuroendocrine, leucocytic and hematological reactions Michael Nordine, Niklas Kagelmann, Jan Kloka, Hanns-Christian Gunga, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3750578/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Jul, 2025 Read the published version in npj Microgravity → Version 1 posted 9 You are reading this latest preprint version Abstract Introduction: Optimal neuroendocrine responses, particularly noradrenergic responses, are critical during hypergravity (+ Gz) exposure. Peripheral skin cooling (PSC) has the potential to enhance noradrenergic function, which could improve + Gz resiliency and may also affect leukocyte and hematologic factors. We predicted that PSC would augment cumulative + Gz stress index (CGSI) neuroendocrine, leukocyte and hematologic activity compared to controls, and that CGSI would shift to a noradrenergic dependency in PSC compared to controls. Methods 18 men in a cross-over design underwent a graded + Gz profile. PSC was applied using Arctic Sun cooling pads around the thighs with 8°C water infusion. Neuroendocrine parameters and a complete blood profile with differential were obtained before and after + Gz. CGSI was calculated as + Gz * seconds. Pre / post comparisons were made within the groups with paired t-tests and between groups with independent t-tests. Pearson's correlation analysis was performed between CGSI and neuroendocrine/leukocyte/hematological parameters. Results CSGI did not differ between groups. In both groups, all neuroendocrine, leukocyte and hematological factors changed significantly from pre to post + Gz, except for serum osmolality, which increased only in PSC (p = 0.03). In PSC, CGSI correlated with noradrenaline (p < 0.01, r = 0.71), metanephrine (p = 0.02, r = -0.54), neutrophiles (p = 0.03, r = 0.51), and thrombocytes (p = 0.04, r = 0.48), while in controls, CGSI correlated with metanephrine (p = 0.02, r = -0.54). Pre + Gz metanephrine correlated with CGSI in both groups. Discussion PSC did not confer a higher CGSI nor induce a greater neuroendocrine, leukocytic or hematologic response compared to controls. However, the increase in serum osmolality may indicate increased vasopressin activity. The strong correlations between CGSI and norepinephrine in PSC suggest that despite equal average serum levels, the responsiveness of norepinephrine is enhanced. This may serve as an optimal cardio-protective countermeasure for manned space missions and possible ICU patients. The correlations between neutrophiles and thrombocytes in PSC suggest a leukocytic and hematologic involvement in CSGI. In addition, this is the first study to demonstrate that baseline serum metanephrine may serve as a potential neuroendocrine parameter to assess + Gz resilience. Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Introduction Exposure to hypergravity (+ Gz) is an environmental challenge encountered during human spaceflight, and occurs during launch, orbital re-entry, and aerobraking maneuvers 1 . Crucially, the physiological impact of + Gz are most pronounced during the return to normal or partial gravity following periods in microgravity, where cardiovascular deconditioning — characterized by decreases in blood volume, cardiac systolic function, systemic vascular resistance and baroreflex activity 2 — compromises + Gz resilience 3 . During launch and re-entry, crews may experience + 3Gz 4 for extended periods During these critical phases, cerebral and cardiac perfusion may be at risk due to the cranial to caudal blood volume shift 5 . This effect resides until the body has been fully re-adapted to planetary gravity. Future space missions, potentially landing astronauts in challenging environments on other celestial bodies, underscore the need for fast-acting, non-invasive and effective countermeasures, ensuring astronauts safety and operative capacity 6 . The resilience to + Gz hinges on optimal neuroendocrine functioning, particularly through noradrenergic and adrenergic pathways. In response to + Gz, noradrenaline release from the postsynaptic cleft enhances systemic vascular resistance, inotropic cardiac activity and coronary tone. Additionally, renal vasoconstriction activates the renin-angiotensin system and vasopressin release. The adrenergic response, works in tandem with noradrenergic pathways to preserve cerebral perfusion via heart rate increases and facilitating vasodilation in specific organ systems 7 . Dysregulation of these responses can lead to physiological instability, posing a threat to mission success. Research indicates that reduced + Gz resilience or orthostatic intolerance, often stems from inadequate noradrenaline-mediated vasoconstriction in the lower extremities and splanchnic area 3 . This condition is linked to suboptimal increases in total peripheral resistance and more prevalent after longer International Space Station missions and in female astronauts 8 – 10 . Orthostatic intolerance can even manifest even after short parabolic flights, and is attributed to an ineffective total peripheral resistance response 11 . Peripheral Skin Cooling (PSC) emerges as a promising countermeasure to augment total peripheral resistance: PSC dramatically boost noradrenergic activity with minimal impact on adrenergic activity 7 , inducing a blood shift from the periphery to the core. This shift results in elevated mean arterial pressure, cardiac output, stroke volume, and systemic vascular resistance 12 . Notably, PSC also induces significant celiac, mesenteric, and renal vasoconstriction. These shifts are highlighted by changes in the balance between noradrenaline and adrenaline, as well as pro-inflammatory markers 13 , 14 . PSC has also been effectively used to augment orthostatic stability in tilt-table test 15 and lower body negative pressure (LBNP) studies 16 – 21 . These studies showcase the efficacy and potential of PSC in improving orthostatic tolerance and hemodynamics during orthostatic stress conditions. However, PSC and its impact on + Gz resilience, neuroendocrine, leucocytic and hematological parameters remains unclear. We hypothesized that PSC will enhance the cumulative + Gz stress index (CGSI) and noradrenaline levels during graded + Gz exposures in a Short Arm Human Centrifuge (SAHC). We also anticipate that the increase in noradrenergic activity induced by PSC will affect leukocytic and hematological factors, shifting the CGSI towards a noradrenergic-dominant response. This study aims to evaluate PSC's potential as a neuroendocrine and hematologic modulator in + Gz environments, a relatively unexplored area in aerospace medicine. Methods SAHC + Gz Protocol and Participant Randomization This study was conducted at the SAHC facililty at the German Aerospace Institute (DLR) in Cologne, Germany. Eighteen healthy, male civilian volunteers were recruited after a comprehensive pre-+Gz medical examination. Written informed consent was obtained prior to beginning the study. The experiment was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of the Medical Council North Rhine. The participants, secured in the SAHC in a supine position with their heads toward the gantry center. The ambient temperature was maintained at 23°C – 25°C, and continuous communication was facilitated with the aerospace physician via a microphone and three cameras. Run termination criteria included pre-syncope / syncope symptoms, arrhythmia and/or narrowing pulse pressure. Alternatively, participants were able to stop the experiment at any point using an emergency stop button available for immediate use. A randomized cross-over design was implemented, with participants divided into two groups (A and B). Group A first underwent a + Gz run without PSC, followed by a PSC + Gz run. Group B completed the study in the reverse order. The minimal + Gz washout period was three days. The SAHC + Gz protocol began with a 10-minute baseline phase at + 1Gz and a recovery phase. Then it progressed to a step profile acceleration from + 1Gz to + 4Gz in 3-minute increments. A detailed graphical description of the + Gz protocol has been previously published 22 . PSC Application PSC was administered using the Arctic Sun 5000™ (C.R. Bard, Inc., United States), consisting of a main cooling device and bilateral thigh cooling pads with circulating water at 8°C. To minimize bias, non-cooled pads were used in the control group. PSC commenced during the 10-minute rest period and continued throughout the graded + Gz protocol. Neuroendocrine, Leukocyte, and Hematological Parameters Blood samples for neuroendocrine and complete blood count parameters were collected pre and post + Gz. Neuroendocrine analyses included noradrenaline, adrenaline, normetanephrine, and metanephrine in plasma, as well as serum osmolality (measured in ng/L and mosmol/kg, respectively). The complete blood count, including total leukocyte, neutrophile, lymphocyte, monocyte, erythrocyte, and thrombocyte counts among others, was performed by Axon Lab AG (Switzerland). Plasma and red blood cell volumes pre/post + Gz were calculated using the following formulas: total blood volume in mililiters * hematocrit/100 [red blood cell volume] and total blood volume in mililters * (1-hematocrit/100) [plasma volume]. Total blood volume was calculated according to Nadler 23 . Statistical Analysis Within-group comparisons of pre and post + Gz values were made using two-tailed paired t-tests, while between-group comparisons were conducted using independent two-tailed t-tests on absolute and percentage changes from pre + Gz values. A Pearson´s correlation analysis between CGSI and all neuroendocrine, leucocytic and hematological paramaters was performed to assess the relationships of pre and post + Gz for both groups independently. Additionally post + Gz noradrenaline and adrenaline levels were correlated to leukocyte and hematological counts in both PSC and control groups using Pearson's correlation analysis. Alpha error was set at p < 0.05. Statistical analyses were conducted using JASP Version 0.17.2.1 (JASP Team, 2023), with values reported as mean ± SD. Correlation values included p and t values. Graphical data representation was created using DataGraph Version 5.11 (Visual Data Tools, Inc.). Results All 18 participants successfully completed both the PSC and CTL + Gz runs. Consistency in cohort demographics was maintained, as reflected in (Table 1 ), due to the study's cross-over design. The mean CGSI was comparable between the groups, with values of 1158 ± 327 for PSC and 1116 ± 335 for CTL (p = 0.7). Post + Gz, significant increases in noradrenaline, adrenaline, normetanephrine, and metanephrine levels were noted in both groups. Notably, serum osmolality showed a significant increase only in the PSC group. Further details on these neuroendocrine and hematological changes are provided. (Fig. 1 ) / (Supplement Table 2 ) Table 1 Anthropometric parameters, entire cohort Parameter Mean Value and SD Age (years) 28 ± 6.4 Height (cm) 180 ± 7.4 Weight (kg) 80 ± 6.9 Body surface area, BSA (m2) 2.01 ± 0.12 Body mass index, BMI (kg/m2) 24.7 ± 1.6 Lean body weight, LBW (kg) 62.7 ± 5.0 Total body volume, TBV (L) 5.34 ± 0.4 Leukocyte and hematological responses post + Gz revealed notable patterns. Absolute leukocyte counts demonstrated an equivalent increase across all parameters in both PSC and CTL groups. (Fig. 2 ). In contrast, the percentage distribution of leukocytes showed a significant shift in both groups. (Fig. 3 ) There was a marked decrease in the percentage of neutrophiles and monocytes, coupled with an increase in lymphocytes. The magnitude of monocyte increase was significantly greater in the PSC group, suggesting a differential impact of PSC on specific leukocyte subtypes. (Supplement Table 2 ) Hematological parameters, increased in both groups in general, reflecting a consistent hematological response to + Gz. (Fig. 4 ) However, an exception was observed in the mean platelet volume, which increased significantly only in the CTL group. Correlation Analysis: CGSI and Neuroendocrine / Leukocytic / Hematological Factors Pearson's correlation analysis provided distinct insights for the PSC and CTL groups. In the PSC group, CGSI showed significant correlations with several parameters: pre + Gz metanephrine and post + Gz noradrenaline, metanephrine, neutrophiles, and thrombocytes. This suggests a multifaceted influence of PSC on neuroendocrine and hematological responses under + Gz conditions. In contrast, the CTL group's CGSI correlated solely with pre and post + Gz metanephrine, indicating a more limited neuroendocrine response to + Gz without PSC. Notably, pre + Gz anthropometrics, along with leukocytic and hematological values, did not demonstrate significant correlations with CGSI in either group, underscoring the specificity of the observed correlations. (Fig. 5 + 6) Correlation Analysis: Neuroendocrine Factors and Leukocytic/Hematological Factors Further analysis revealed distinct correlations between neuroendocrine and leukocytic / hematological factors, especially post + Gz. In the PSC group, post + Gz noradrenaline was significantly correlated with total leukocytes, neutrophiles, and thrombocytes, highlighting the interplay between neuroendocrine activation and leukocyte dynamics. Additionally, a notable correlation was observed between post + Gz adrenaline and plasma volume. (Fig. 7 + 8) In the CTL group, however, the sole significant correlation was found between post + Gz noradrenaline and monocytes. (Fig. 9 ) This highlights a more selective neuroendocrine influence on leukocyte subtypes in the absence of PSC. Discussion Main Findings This study found that PSC using a bilateral femoral cold-water infusion system did not significantly improve the CGSI or enhance neuroendocrine parameters compared to the CTL during graded + Gz exposure. The neuroendocrine reactions were nearly identical in both groups, except for a notable increase in serum osmolality in the PSC group. Both absolute and percentage counts of leukocytes were consistent across groups, with PSC showing a uniquely greater increase in monocyte count. This shift indicates a notable change in leukocyte subtype distribution in response to + Gz exposure. Hematological factors were similarly consistent, though CTL exhibited a large increase in mean platelet volume. This differential response might indicate a unique impact of PSC on platelet dynamics under + Gz conditions. The key finding of this study was the significant correlation between CGSI with noradrenaline in the PSC group, which was not observed in the CTL group. This is further underlined by the significant correlations between neutrophiles and thrombocytes with CGSI in PSC, indicating a synergistic noradrenergic influence. These significant correlations suggest that PSC may augment noradrenaline function as well as optimizing its physiological responsiveness during + Gz. Furthermore, this study is the first to demonstrate a correlation between metanephrine levels and CGSI in both groups. The correlations in the PSC group however, suggest that PSC may shift + Gz resilience towards a noradrenergic pathway rather than relying on a lower adrenergic tone. These correlations are particularly relevant for enhancing + Gz resilience in human space flight and clinical settings, where PSC's noradrenaline-mediated cardio-protective properties could be beneficial for longer term missions under medium + Gz conditions. Further, PSC be an important translational finding for supporting the management of hemodynamically unstable ICU patients 24 – 27 . Univariate Parameter Analysis Comparative Analysis of PSC and CTL Our findings show that CGSI in PSC group was comparable to the CTL, diverging from LBNP studies that reported enhanced orthostatic stress tolerance with PSC. This difference might stem from the smaller proportion of body surface area covered by PSC in this study, potentially influencing the overall physiological impact on neuroendocrine activity. Furthermore, LBNP and + Gz exert different types of stress: LBNP induces hydrostatic stress, whereas + Gz creates a gravitational gradient along the body, limiting direct comparisons 22 , 28 . Neuroendocrine Response to Graded + Gz Profile The graded + Gz profile led to an increase in all neuroendocrine parameters, irrespective of the intervention (PSC or CTL). This uniform response could result from the overwhelming effect of + Gz stress, potentially overshadowing any distinct impacts of PSC. The only directly comparable + Gz study investigating neuroendocrine parameters pre/post + Gz without PSC found a significant increase only in noradrenaline, and a non-significant increase in adrenaline amongst a women and men participants 29 . Earlier research suggested an immediate increase in noradrenaline following PSC application, but this effect diminishes over time 30 . It's plausible that noradrenaline levels peaked during the initial phases of + Gz in the PSC group. Additionally, studies indicate that during prolonged orthostatic stress, adrenaline becomes the dominant catecholamine, but its vasodilative effect undermines orthostatic stability 31 , 32 . In contrast, our study observed significant increases in both noradrenaline and adrenaline, which might be attributed to the study's unique participant profile (male-only) or the intensity of the + Gz profile exceeding + 3Gz. Exploring Inactive Catecholamine Metabolites Notably, this study also examined plasma normetanephrine and metanephrine, which are inactive metabolites of noradrenaline and adrenaline 33 . These metabolites offer insights into the extraneuronal inactivation of active catecholamines 34 . A previous study involving orthostatic and cold stress reported increases in active catecholamines surpassing those of their inactive counterparts 35 . Our findings partially confirm this, marking the first time these metabolites have been analyzed in relation to + Gz exposure. Serum Osmolality and Hemodynamic Implications A distinct observation within the PSC group was the strong increase in serum osmolality, which has also been observed in previous studies 13 , 36 , 37 . This increase in serum osmolality, which can lead to a rapid elevation in vasopressin levels and and subsequently blood pressure, might be beneficial for space crews and ICU patients. The initial hemodynamic results suggest that the higher systolic blood pressure trends in PSC could be indicative of vasopressin activation 38 . Leukocytic and Hematological Reactions There was no marked difference regarding leukocytic and hematological responses between PSC and CTL groups, aside from the magnitude of monocyte change and mean platelet volume. The PSC group indicated a lower change in monocytes. A decrease in mean platelet volume only appeared in CTL. These observations might suggest increased physiological stress in CTL, underlined by the trends in lymphocyte percentages. Consistent with other + Gz studies 39 – 42 , our study observed leukocytosis and hemoconcentration in both groups. However, the extent of plasma volume reduction was not as pronounced as in other studies 43 . The leukocytosis observed was likely catecholamine-induced due to splenic release and leukocyte mobilization. Correlation Analysis Adrenergic Activation and CGSI Correlation The correlation analysis revealed strong negative correlations between pre + Gz metanephrine and CGSI in both PSC and CTL groups. Metanephrine was sampled before PSC activation and reflects adrenergic activation independet of PSC’s effects. High metanephrine levels, were associated with lower CGSI. This observation aligns with a previous study suggesting that high baseline catecholamine levels do not predict tolerance to negative pressures up to -50 mmHg LBNP 44 . Conversely, lower renin concentration, often associated with less noradrenaline activation, correlates with reduced orthostatic tolerance 45 . Here, higher baseline levels could equal a lower residual capacity to increased catecholamine or renin levels and therefore a reduced capability to react to increased orthostatic stress. This pattern suggests that metanephrine could be a potential marker for assessing + Gz resilience, warranting further investigation. Noradrenaline's Role in PSC Group A strong correlation between CGSI and noradrenaline in the PSC group points to a unique physiological shift induced by PSC. Despite similar noradrenaline increases in both groups, the correlation suggests a heightened responsiveness or susceptibility to noradrenaline in the PSC group. This implies that PSC might enhance the cardio-protective effects of noradrenaline, potentially beneficial for prolonged use in space missions and in critical care settings. Immune and Hematological Pathway Interactions Noteworthy correlations were found in the PSC group between CGSI, neutrophiles, and platelets, indicating an interplay between noradrenaline activation and these hematological and immune pathways, which has been previously documented 46 – 48 . While noradrenaline typically increases neutrophiles, adrenaline usually elevates lymphocytes 40 , 49 — a correlation not observed in our study. The CTL group showed a distinct pattern, with noradrenaline correlating with monocytes. These differences suggest PSC may amplify neutrophilic responses to + Gz, while CTL links more with monocytic pathways. Such findings resonate with astronaut data, where catecholamine increases post-re-entry correlated with a rise in white blood cells, mainly neutrophiles 4 , 49 . Neuroendocrine Activation and Volume Homeostasis Additional correlations in PSC between adrenaline and plasma volume suggest that reductions in plasma volume are crucial for adrenaline release. Cross-talk between neutrophiles, platelets, and plasma volume indicates an interaction between platelet mobilization and volume changes. The correlation between metanephrine and serum osmolality hints at a potential link with the renin-angiotensin-aldosterone system. These results suggest that neuroendocrine activation under PSC leads to a complex cascade of responses involving leukocytic, hematological, and volume homeostasis pathways, underscoring the need for further investigations. Study Limitations The use of a SAHC in this study to simulate + Gz conditions may not accurately mimic spaceflight associated gravitational transitions, which tend to be longer and less intense. This difference could have influenced the findings, particularly regarding the physiological impacts of PSC on neuroendocrine parameters. The inconsistency in + Gz run durations due to varying maximal tolerance among participants further complicates the uniformity of the experimental conditions. Subjective decisions by flight physicians to abort + Gz runs introduced variability, especially with a change in physicians midway through the study. This potentially led to different assessments of + Gz tolerance. This subjectivity may have affected the comparability of the PSC and CTL groups. The water-based PSC system was limited under + Gz conditions due to potential gravitational effects on water flow. Furthermore, limiting PSC application to the bilateral thighs may not have captured the full potential impact of PSC. Covering a larger body surface area could yield more pronounced physiological effects 50 . The study did not include dopamine analysis which is also a key neuroendocrine parameter influencing hemodynamic activity during stress. PSC may have had an impact on this pathway, and future studies should include this analysis. Additionally, the methodology of blood sampling only pre and post + Gz, and exclusively from venous blood does not provide a complete picture of the neuroendocrine reactions. This is especially true for neuroendocrine reactions post-PSC activation where reactions may have been more pronounced, or longer-term effects after + Gz exposure, which may have yielded valuable information. Venous blood sampling may also not accurately represent total serum catecholamine levels due to rapid uptake by organ systems and potential local release effects on noradrenaline levels 51 . Conclusion This study's findings reveal that using water-based PSC on the bilateral thighs during graded + Gz exposure did not result in a higher CGSI or a more pronounced neuroendocrine response compared to CTL, with an exception for an increase in serum osmolality. This increase may suggest enhanced vasopressin activity under PSC. Additionally, no differences between PSC and CTL in leukocytic and hematological responses were observed. However, PSC did lead to a noradrenaline-dependent CGSI. This implyies that while average noradrenaline levels were similar in both groups, its physiological effectiveness during + Gz was enhanced under PSC. The observed correlations between CGSI, neutrophiles, and thrombocytes in the PSC group suggest an amplification of immune-based stress responses. These findings indicate that PSC usage during physiological stress may lead to a more cardio-protective response, beneficial for manned space crews. Additionally, PSC might have stabilizing effects on hemodynamics in clinically unstable patients. Given these results, future research is warranted to further explore PSC's impacts using different simulation models like SAHC, parabolic flight, or LBNP. Studies should consider employing alternative PSC systems and extending the application to a larger body surface area. Such research is crucial as non-invasive counter-measure systems will play a key role in the success of human spaceflight and planetary colonization. Declarations Author contributions MN composed the manuscript and performed primary data analysis. NK performed the study. NK, JK, VH, and NP co-wrote and revised the manuscript. H-C.G, OO, and TB revised the manuscript, devised the study, and procured funding. Competing interest All authors declare no financial or non-financial competing interests. Funding This study was supported by the DLR (German Aerospace Center, Bonn, Germany) grant number 50WB1832. Data availability The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. References Wade, C. E. Responses across the Gravity Continuum: Hypergravity to Microgravity. in Advances in Space Biology and Medicine vol. 10 225–245 (Elsevier, 2005). Komorowski, M., Fleming, S. & Kirkpatrick, A. W. Fundamentals of Anesthesiology for Spaceflight. J. Cardiothorac. Vasc. Anesth. 30 , 781–790 (2016). Jordan, J., Limper, U. & Tank, J. 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Physiol. 101 , 1265–1275 (2016). Lorenzi, G., Fuchs-Bislin, P. & Cogoli, A. Effects of hypergravity on ‘whole-blood’ cultures of human lymphocytes. Aviat. Space Environ. Med. 57 , 1131–1135 (1986). Benschop, R. J., Rodriguez-Feuerhahn, M. & Schedlowski, M. Catecholamine-Induced Leukocytosis: Early Observations, Current Research, and Future Directions. Brain. Behav. Immun. 10 , 77–91 (1996). Limper, U. et al. Simulated Hypergravity Activates Hemostasis in Healthy Volunteers. J. Am. Heart Assoc. 9 , e016479 (2020). Gasiorowska, A. et al. Hemodynamic and neuroendocrine predictors of lower body negative pressure (LBNP) intolerance in healthy young men. J. Physiol. Pharmacol. Off. J. Pol. Physiol. Soc. 56 , 179–193 (2005). Greenleaf, J. E. et al. Low LBNP tolerance in men is associated with attenuated activation of the renin-angiotensin system. Am. J. Physiol.-Regul. Integr. Comp. Physiol. 279 , (2000). Silverman, M. N., Heim, C. M., Nater, U. M., Marques, A. H. & Sternberg, E. M. Neuroendocrine and Immune Contributors to Fatigue. PM&R 2 , 338–346 (2010). Hartmann, C., Radermacher, P., Wepler, M. & Nußbaum, B. Non-Hemodynamic Effects of Catecholamines. Shock 48 , 390–400 (2017). Kozyreva, T. V., Tkachenko, E. Ya., Eliseeva, L. S., Kozaruk, V. P. & Polyakova, E. V. A possible mechanism for noradrenaline involvement in the effector responses to cold exposure. J. Therm. Biol. 26 , 505–512 (2001). Mills, P. J., Meck, J. V., Waters, W. W., D’Aunno, D. S. & Ziegler, M. G. Peripheral leukocyte subpopulations and catecholamine levels in astronauts as a function of mission duration. Psychosom. Med. 63 , 886–890 (2001). Alvarez, G. E., Zhao, K., Kosiba, W. A. & Johnson, J. M. Relative roles of local and reflex components in cutaneous vasoconstriction during skin cooling in humans. J. Appl. Physiol. 100 , 2083–2088 (2006). Kjeldsen, S. E., Westheim, A., Aakesson, I., Eide, I. & Leren, P. Plasma adrenaline and noradrenaline during orthostasis in man: The importance of arterial sampling. Scand. J. Clin. Lab. Invest. 46 , 397–401 (1986). Additional Declarations (Not answered) Supplementary Files SupplementaryMaterial.docx Cite Share Download PDF Status: Published Journal Publication published 02 Jul, 2025 Read the published version in npj Microgravity → Version 1 posted Editorial decision: revise 10 Jul, 2024 Review # 2 received at journal 28 Jun, 2024 Review # 1 received at journal 08 Jun, 2024 Reviewer # 2 agreed at journal 07 Jun, 2024 Reviewer # 1 agreed at journal 20 May, 2024 Reviewers invited by journal 02 Feb, 2024 Editor assigned by journal 15 Dec, 2023 Submission checks completed at journal 15 Dec, 2023 First submitted to journal 13 Dec, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3750578","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":270665690,"identity":"adb61361-cdf3-4530-9463-e7406fb91678","order_by":0,"name":"Michael Nordine","email":"data:image/png;base64,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","orcid":"","institution":"University Hospital Frankfurt","correspondingAuthor":true,"prefix":"","firstName":"Michael","middleName":"","lastName":"Nordine","suffix":""},{"id":270665691,"identity":"e28202c6-5148-4d22-a109-edc8c3cf529d","order_by":1,"name":"Niklas Kagelmann","email":"","orcid":"","institution":"Charité-Medical University","correspondingAuthor":false,"prefix":"","firstName":"Niklas","middleName":"","lastName":"Kagelmann","suffix":""},{"id":270665692,"identity":"53651869-71c8-4038-90b4-30e2844cc416","order_by":2,"name":"Jan Kloka","email":"","orcid":"","institution":"University Hospital Frankfurt","correspondingAuthor":false,"prefix":"","firstName":"Jan","middleName":"","lastName":"Kloka","suffix":""},{"id":270665693,"identity":"2dec4ce8-4f6f-4609-85c3-07d12b48c643","order_by":3,"name":"Hanns-Christian Gunga","email":"","orcid":"https://orcid.org/0000-0002-0145-179X","institution":"Charité – Universitätsmedizin Berlin","correspondingAuthor":false,"prefix":"","firstName":"Hanns-Christian","middleName":"","lastName":"Gunga","suffix":""},{"id":270665694,"identity":"e2a788b2-7549-49ba-8d52-a5965879f9c4","order_by":4,"name":"Viktor Heinz","email":"","orcid":"https://orcid.org/0009-0002-5363-793X","institution":"Charité Medical University","correspondingAuthor":false,"prefix":"","firstName":"Viktor","middleName":"","lastName":"Heinz","suffix":""},{"id":270665695,"identity":"e628d73c-8bfd-4557-b6c8-0d768f07ec97","order_by":5,"name":"Niklas Pilz","email":"","orcid":"","institution":"Charité Medical University","correspondingAuthor":false,"prefix":"","firstName":"Niklas","middleName":"","lastName":"Pilz","suffix":""},{"id":270665696,"identity":"599a2ff5-6ff0-4291-84fa-558608367d05","order_by":6,"name":"Oliver Opatz","email":"","orcid":"https://orcid.org/0000-0003-4746-9343","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Oliver","middleName":"","lastName":"Opatz","suffix":""},{"id":270665697,"identity":"b977f41b-bb9f-4118-9ee7-a57ad675395a","order_by":7,"name":"Tomas Bothe","email":"","orcid":"","institution":"Charite Medical University","correspondingAuthor":false,"prefix":"","firstName":"Tomas","middleName":"","lastName":"Bothe","suffix":""}],"badges":[],"createdAt":"2023-12-13 23:40:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3750578/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3750578/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41526-025-00486-9","type":"published","date":"2025-07-02T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":50745674,"identity":"22f3c788-d971-4f43-8c22-26485f760390","added_by":"auto","created_at":"2024-02-06 17:03:37","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":47527,"visible":true,"origin":"","legend":"\u003cp\u003eNeuroendocrine parameters, pre / post +Gz for PSC (Blue) and CTL (red) as Tukey style box plots. *=p \u0026lt; 0.05.\u003c/p\u003e","description":"","filename":"Figure1Neuroendo.png","url":"https://assets-eu.researchsquare.com/files/rs-3750578/v1/7723f9c8486d1a71995610d8.png"},{"id":50745667,"identity":"058c3835-7255-403c-9ae8-176a591c5b24","added_by":"auto","created_at":"2024-02-06 17:03:36","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":42279,"visible":true,"origin":"","legend":"\u003cp\u003eAbsolute Leucocyte parameters, pre / post +Gz for PSC (Blue) and CTL (red) as Tukey style box plots. *=p \u0026lt; 0.05.\u003c/p\u003e","description":"","filename":"Figure2AbsoluteLeucocytes.png","url":"https://assets-eu.researchsquare.com/files/rs-3750578/v1/3caa0535d8e9330d7f8a61c6.png"},{"id":50745666,"identity":"e4ae5503-6d83-47e7-8089-b864aa6618f6","added_by":"auto","created_at":"2024-02-06 17:03:36","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":43060,"visible":true,"origin":"","legend":"\u003cp\u003ePercentage of leucocyte parameters, pre / post +Gz for PSC (Blue) and CTL (red) as Tukey style box plots. *=p \u0026lt; 0.05.\u003c/p\u003e","description":"","filename":"Figure3PercLeucocytes.png","url":"https://assets-eu.researchsquare.com/files/rs-3750578/v1/f20f034e947119a322ec2164.png"},{"id":50745668,"identity":"a8c94b97-ee76-429c-8198-ed8a013369c7","added_by":"auto","created_at":"2024-02-06 17:03:36","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":42421,"visible":true,"origin":"","legend":"\u003cp\u003eHematological parameters, pre / post +Gz for PSC (Blue) and CTL (red) as Tukey style box plots. *=p \u0026lt; 0.05.\u003c/p\u003e","description":"","filename":"Figure4Hematological.png","url":"https://assets-eu.researchsquare.com/files/rs-3750578/v1/57075e97e8c89c4708cd660b.png"},{"id":50745675,"identity":"663d36d5-912f-4213-868d-3b5f27cd0150","added_by":"auto","created_at":"2024-02-06 17:03:38","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":61977,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003ePearson's Correlation analysis pre/post +Gz between neuroendocrine, leucocytic and hematological parameters with CGSI for PSC. Denoted are p and r values.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure5PSCCorr.png","url":"https://assets-eu.researchsquare.com/files/rs-3750578/v1/04aacccaab2806ecd123efae.png"},{"id":50745670,"identity":"52b3d74b-b751-4a84-af59-a06b171288fc","added_by":"auto","created_at":"2024-02-06 17:03:37","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":33007,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003ePearson's correlation analysis pre/post +Gz between neuroendocrine, leucocytic and hematological parameters with CGSI for CTL. Denoted are p and r values.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure6CTLCorr.png","url":"https://assets-eu.researchsquare.com/files/rs-3750578/v1/cb7a7d3b3c9b09270b0aa629.png"},{"id":50745672,"identity":"feaaa209-ceec-4fd8-95ea-29c7e99d7bbb","added_by":"auto","created_at":"2024-02-06 17:03:37","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":37124,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003ePearson's correlation analysis post +Gz between noradrenaline, leucocytic and hematological parameters for PSC. Denoted are p and r values.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure7NAPSC.png","url":"https://assets-eu.researchsquare.com/files/rs-3750578/v1/0f4d4e6fc75d77d1a5736f74.png"},{"id":50745673,"identity":"d9ca8baf-2f5d-4a36-afb1-52def73c5805","added_by":"auto","created_at":"2024-02-06 17:03:37","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":19421,"visible":true,"origin":"","legend":"\u003cp\u003ePearson's correlation analysis post +Gz between adrenaline and plasma volume for PSC\u003c/p\u003e","description":"","filename":"Figure8ADPSC.png","url":"https://assets-eu.researchsquare.com/files/rs-3750578/v1/76c0a52c6232efd5945435b7.png"},{"id":50745669,"identity":"e49b6223-5eaf-41c0-a44a-0e8818c461f9","added_by":"auto","created_at":"2024-02-06 17:03:37","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":18998,"visible":true,"origin":"","legend":"\u003cp\u003ePearson's correlation analysis post +Gz between noradrenaline and monocytes for CTL\u003c/p\u003e","description":"","filename":"Figure9NACTL.png","url":"https://assets-eu.researchsquare.com/files/rs-3750578/v1/03c0da2daff45edabfd43ffd.png"},{"id":85917921,"identity":"483982f9-b490-4fe7-82e2-2f1525eca6e4","added_by":"auto","created_at":"2025-07-03 07:16:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1251101,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3750578/v1/f1098056-bacb-45c8-b38b-2831045346b2.pdf"},{"id":50745671,"identity":"81b99e32-ff5f-4e61-8478-6ca3398fcf54","added_by":"auto","created_at":"2024-02-06 17:03:37","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":21417,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-3750578/v1/c09edc33628da0b19c7884a9.docx"}],"financialInterests":"(Not answered)","formattedTitle":"\u003cp\u003ePeripheral skin cooling during Hypergravity: Neuroendocrine, leucocytic and hematological reactions\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eExposure to hypergravity (+\u0026thinsp;Gz) is an environmental challenge encountered during human spaceflight, and occurs during launch, orbital re-entry, and aerobraking maneuvers\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Crucially, the physiological impact of +\u0026thinsp;Gz are most pronounced during the return to normal or partial gravity following periods in microgravity, where cardiovascular deconditioning \u0026mdash; characterized by decreases in blood volume, cardiac systolic function, systemic vascular resistance and baroreflex activity\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e \u0026mdash; compromises\u0026thinsp;+\u0026thinsp;Gz resilience\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eDuring launch and re-entry, crews may experience\u0026thinsp;+\u0026thinsp;3Gz\u003csup\u003e4\u003c/sup\u003e for extended periods During these critical phases, cerebral and cardiac perfusion may be at risk due to the cranial to caudal blood volume shift\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. This effect resides until the body has been fully re-adapted to planetary gravity. Future space missions, potentially landing astronauts in challenging environments on other celestial bodies, underscore the need for fast-acting, non-invasive and effective countermeasures, ensuring astronauts safety and operative capacity\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe resilience to +\u0026thinsp;Gz hinges on optimal neuroendocrine functioning, particularly through noradrenergic and adrenergic pathways. In response to +\u0026thinsp;Gz, noradrenaline release from the postsynaptic cleft enhances systemic vascular resistance, inotropic cardiac activity and coronary tone. Additionally, renal vasoconstriction activates the renin-angiotensin system and vasopressin release. The adrenergic response, works in tandem with noradrenergic pathways to preserve cerebral perfusion via heart rate increases and facilitating vasodilation in specific organ systems\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Dysregulation of these responses can lead to physiological instability, posing a threat to mission success.\u003c/p\u003e \u003cp\u003eResearch indicates that reduced\u0026thinsp;+\u0026thinsp;Gz resilience or orthostatic intolerance, often stems from inadequate noradrenaline-mediated vasoconstriction in the lower extremities and splanchnic area\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. This condition is linked to suboptimal increases in total peripheral resistance and more prevalent after longer International Space Station missions and in female astronauts\u003csup\u003e\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Orthostatic intolerance can even manifest even after short parabolic flights, and is attributed to an ineffective total peripheral resistance response\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003ePeripheral Skin Cooling (PSC) emerges as a promising countermeasure to augment total peripheral resistance: PSC dramatically boost noradrenergic activity with minimal impact on adrenergic activity\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e, inducing a blood shift from the periphery to the core. This shift results in elevated mean arterial pressure, cardiac output, stroke volume, and systemic vascular resistance\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Notably, PSC also induces significant celiac, mesenteric, and renal vasoconstriction. These shifts are highlighted by changes in the balance between noradrenaline and adrenaline, as well as pro-inflammatory markers\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. PSC has also been effectively used to augment orthostatic stability in tilt-table test\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003eand lower body negative pressure (LBNP) studies\u003csup\u003e\u003cspan additionalcitationids=\"CR17 CR18 CR19 CR20\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. These studies showcase the efficacy and potential of PSC in improving orthostatic tolerance and hemodynamics during orthostatic stress conditions. However, PSC and its impact on +\u0026thinsp;Gz resilience, neuroendocrine, leucocytic and hematological parameters remains unclear.\u003c/p\u003e \u003cp\u003eWe hypothesized that PSC will enhance the cumulative\u0026thinsp;+\u0026thinsp;Gz stress index (CGSI) and noradrenaline levels during graded\u0026thinsp;+\u0026thinsp;Gz exposures in a Short Arm Human Centrifuge (SAHC). We also anticipate that the increase in noradrenergic activity induced by PSC will affect leukocytic and hematological factors, shifting the CGSI towards a noradrenergic-dominant response. This study aims to evaluate PSC's potential as a neuroendocrine and hematologic modulator in +\u0026thinsp;Gz environments, a relatively unexplored area in aerospace medicine.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSAHC\u0026thinsp;+\u0026thinsp;Gz Protocol and Participant Randomization\u003c/h2\u003e \u003cp\u003eThis study was conducted at the SAHC facililty at the German Aerospace Institute (DLR) in Cologne, Germany. Eighteen healthy, male civilian volunteers were recruited after a comprehensive pre-+Gz medical examination. Written informed consent was obtained prior to beginning the study. The experiment was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of the Medical Council North Rhine. The participants, secured in the SAHC in a supine position with their heads toward the gantry center. The ambient temperature was maintained at 23\u0026deg;C \u0026ndash; 25\u0026deg;C, and continuous communication was facilitated with the aerospace physician via a microphone and three cameras. Run termination criteria included pre-syncope / syncope symptoms, arrhythmia and/or narrowing pulse pressure. Alternatively, participants were able to stop the experiment at any point using an emergency stop button available for immediate use.\u003c/p\u003e \u003cp\u003eA randomized cross-over design was implemented, with participants divided into two groups (A and B). Group A first underwent a\u0026thinsp;+\u0026thinsp;Gz run without PSC, followed by a PSC\u0026thinsp;+\u0026thinsp;Gz run. Group B completed the study in the reverse order. The minimal\u0026thinsp;+\u0026thinsp;Gz washout period was three days. The SAHC\u0026thinsp;+\u0026thinsp;Gz protocol began with a 10-minute baseline phase at +\u0026thinsp;1Gz and a recovery phase. Then it progressed to a step profile acceleration from +\u0026thinsp;1Gz to +\u0026thinsp;4Gz in 3-minute increments. A detailed graphical description of the +\u0026thinsp;Gz protocol has been previously published\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003ePSC Application\u003c/h2\u003e \u003cp\u003ePSC was administered using the Arctic Sun 5000\u0026trade; (C.R. Bard, Inc., United States), consisting of a main cooling device and bilateral thigh cooling pads with circulating water at 8\u0026deg;C. To minimize bias, non-cooled pads were used in the control group. PSC commenced during the 10-minute rest period and continued throughout the graded\u0026thinsp;+\u0026thinsp;Gz protocol.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eNeuroendocrine, Leukocyte, and Hematological Parameters\u003c/h2\u003e \u003cp\u003eBlood samples for neuroendocrine and complete blood count parameters were collected pre and post\u0026thinsp;+\u0026thinsp;Gz. Neuroendocrine analyses included noradrenaline, adrenaline, normetanephrine, and metanephrine in plasma, as well as serum osmolality (measured in ng/L and mosmol/kg, respectively). The complete blood count, including total leukocyte, neutrophile, lymphocyte, monocyte, erythrocyte, and thrombocyte counts among others, was performed by Axon Lab AG (Switzerland). Plasma and red blood cell volumes pre/post\u0026thinsp;+\u0026thinsp;Gz were calculated using the following formulas: total blood volume in mililiters * hematocrit/100 [red blood cell volume] and total blood volume in mililters * (1-hematocrit/100) [plasma volume]. Total blood volume was calculated according to Nadler\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eWithin-group comparisons of pre and post\u0026thinsp;+\u0026thinsp;Gz values were made using two-tailed paired t-tests, while between-group comparisons were conducted using independent two-tailed t-tests on absolute and percentage changes from pre\u0026thinsp;+\u0026thinsp;Gz values. A Pearson\u0026acute;s correlation analysis between CGSI and all neuroendocrine, leucocytic and hematological paramaters was performed to assess the relationships of pre and post\u0026thinsp;+\u0026thinsp;Gz for both groups independently. Additionally post\u0026thinsp;+\u0026thinsp;Gz noradrenaline and adrenaline levels were correlated to leukocyte and hematological counts in both PSC and control groups using Pearson's correlation analysis. Alpha error was set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. Statistical analyses were conducted using JASP Version 0.17.2.1 (JASP Team, 2023), with values reported as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD. Correlation values included p and t values. Graphical data representation was created using DataGraph Version 5.11 (Visual Data Tools, Inc.).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eAll 18 participants successfully completed both the PSC and CTL\u0026thinsp;+\u0026thinsp;Gz runs. Consistency in cohort demographics was maintained, as reflected in (Table \u003cspan\u003e1\u003c/span\u003e), due to the study\u0026apos;s cross-over design. The mean CGSI was comparable between the groups, with values of 1158\u0026thinsp;\u0026plusmn;\u0026thinsp;327 for PSC and 1116\u0026thinsp;\u0026plusmn;\u0026thinsp;335 for CTL (p\u0026thinsp;=\u0026thinsp;0.7). Post\u0026thinsp;+\u0026thinsp;Gz, significant increases in noradrenaline, adrenaline, normetanephrine, and metanephrine levels were noted in both groups. Notably, serum osmolality showed a significant increase only in the PSC group. Further details on these neuroendocrine and hematological changes are provided. (Fig. \u003cspan\u003e1\u003c/span\u003e) / (Supplement Table \u003cspan\u003e2\u003c/span\u003e)\u003c/p\u003e\n\u003cdiv\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 1\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eAnthropometric parameters, entire cohort\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eParameter\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMean Value and SD\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e28\u0026thinsp;\u0026plusmn;\u0026thinsp;6.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHeight (cm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e180\u0026thinsp;\u0026plusmn;\u0026thinsp;7.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWeight (kg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e80\u0026thinsp;\u0026plusmn;\u0026thinsp;6.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBody surface area, BSA (m2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.01\u0026thinsp;\u0026plusmn;\u0026thinsp;0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBody mass index, BMI (kg/m2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e24.7\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLean body weight, LBW (kg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e62.7\u0026thinsp;\u0026plusmn;\u0026thinsp;5.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTotal body volume, TBV (L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.34\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv\u003e\u003cbr\u003e\u003c/div\u003e\n\u003cp\u003eLeukocyte and hematological responses post\u0026thinsp;+\u0026thinsp;Gz revealed notable patterns. Absolute leukocyte counts demonstrated an equivalent increase across all parameters in both PSC and CTL groups. (Fig.\u0026nbsp;\u003cspan\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eIn contrast, the percentage distribution of leukocytes showed a significant shift in both groups. (Fig.\u0026nbsp;\u003cspan\u003e3\u003c/span\u003e)\u003c/p\u003e\n\u003cp\u003eThere was a marked decrease in the percentage of neutrophiles and monocytes, coupled with an increase in lymphocytes. The magnitude of monocyte increase was significantly greater in the PSC group, suggesting a differential impact of PSC on specific leukocyte subtypes. (Supplement Table\u0026nbsp;\u003cspan\u003e2\u003c/span\u003e)\u003c/p\u003e\n\u003cp\u003eHematological parameters, increased in both groups in general, reflecting a consistent hematological response to +\u0026thinsp;Gz. (Fig.\u0026nbsp;\u003cspan\u003e4\u003c/span\u003e)\u003c/p\u003e\n\u003cp\u003eHowever, an exception was observed in the mean platelet volume, which increased significantly only in the CTL group.\u003c/p\u003e\n\u003cdiv id=\"Sec8\"\u003e\n \u003ch2\u003eCorrelation Analysis: CGSI and Neuroendocrine / Leukocytic / Hematological Factors\u003c/h2\u003e\n \u003cp\u003ePearson\u0026apos;s correlation analysis provided distinct insights for the PSC and CTL groups. In the PSC group, CGSI showed significant correlations with several parameters: pre\u0026thinsp;+\u0026thinsp;Gz metanephrine and post\u0026thinsp;+\u0026thinsp;Gz noradrenaline, metanephrine, neutrophiles, and thrombocytes. This suggests a multifaceted influence of PSC on neuroendocrine and hematological responses under +\u0026thinsp;Gz conditions. In contrast, the CTL group\u0026apos;s CGSI correlated solely with pre and post\u0026thinsp;+\u0026thinsp;Gz metanephrine, indicating a more limited neuroendocrine response to +\u0026thinsp;Gz without PSC. Notably, pre\u0026thinsp;+\u0026thinsp;Gz anthropometrics, along with leukocytic and hematological values, did not demonstrate significant correlations with CGSI in either group, underscoring the specificity of the observed correlations. (Fig.\u0026nbsp;\u003cspan\u003e5\u003c/span\u003e\u0026thinsp;+\u0026thinsp;6)\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eCorrelation Analysis: Neuroendocrine Factors and Leukocytic/Hematological Factors\u003c/h3\u003e\n\u003cp\u003eFurther analysis revealed distinct correlations between neuroendocrine and leukocytic / hematological factors, especially post\u0026thinsp;+\u0026thinsp;Gz. In the PSC group, post\u0026thinsp;+\u0026thinsp;Gz noradrenaline was significantly correlated with total leukocytes, neutrophiles, and thrombocytes, highlighting the interplay between neuroendocrine activation and leukocyte dynamics. Additionally, a notable correlation was observed between post\u0026thinsp;+\u0026thinsp;Gz adrenaline and plasma volume. (Fig.\u0026nbsp;\u003cspan\u003e7\u003c/span\u003e\u0026thinsp;+\u0026thinsp;8) In the CTL group, however, the sole significant correlation was found between post\u0026thinsp;+\u0026thinsp;Gz noradrenaline and monocytes. (Fig.\u0026nbsp;\u003cspan\u003e9\u003c/span\u003e) This highlights a more selective neuroendocrine influence on leukocyte subtypes in the absence of PSC.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eMain Findings\u003c/h2\u003e \u003cp\u003eThis study found that PSC using a bilateral femoral cold-water infusion system did not significantly improve the CGSI or enhance neuroendocrine parameters compared to the CTL during graded\u0026thinsp;+\u0026thinsp;Gz exposure. The neuroendocrine reactions were nearly identical in both groups, except for a notable increase in serum osmolality in the PSC group. Both absolute and percentage counts of leukocytes were consistent across groups, with PSC showing a uniquely greater increase in monocyte count. This shift indicates a notable change in leukocyte subtype distribution in response to +\u0026thinsp;Gz exposure. Hematological factors were similarly consistent, though CTL exhibited a large increase in mean platelet volume. This differential response might indicate a unique impact of PSC on platelet dynamics under +\u0026thinsp;Gz conditions.\u003c/p\u003e \u003cp\u003eThe key finding of this study was the significant correlation between CGSI with noradrenaline in the PSC group, which was not observed in the CTL group. This is further underlined by the significant correlations between neutrophiles and thrombocytes with CGSI in PSC, indicating a synergistic noradrenergic influence. These significant correlations suggest that PSC may augment noradrenaline function as well as optimizing its physiological responsiveness during +\u0026thinsp;Gz. Furthermore, this study is the first to demonstrate a correlation between metanephrine levels and CGSI in both groups. The correlations in the PSC group however, suggest that PSC may shift\u0026thinsp;+\u0026thinsp;Gz resilience towards a noradrenergic pathway rather than relying on a lower adrenergic tone.\u003c/p\u003e \u003cp\u003eThese correlations are particularly relevant for enhancing\u0026thinsp;+\u0026thinsp;Gz resilience in human space flight and clinical settings, where PSC's noradrenaline-mediated cardio-protective properties could be beneficial for longer term missions under medium\u0026thinsp;+\u0026thinsp;Gz conditions. Further, PSC be an important translational finding for supporting the management of hemodynamically unstable ICU patients\u003csup\u003e\u003cspan additionalcitationids=\"CR25 CR26\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eUnivariate Parameter Analysis\u003c/h2\u003e \u003cdiv id=\"Sec13\" class=\"Section3\"\u003e \u003ch2\u003eComparative Analysis of PSC and CTL\u003c/h2\u003e \u003cp\u003eOur findings show that CGSI in PSC group was comparable to the CTL, diverging from LBNP studies that reported enhanced orthostatic stress tolerance with PSC. This difference might stem from the smaller proportion of body surface area covered by PSC in this study, potentially influencing the overall physiological impact on neuroendocrine activity. Furthermore, LBNP and +\u0026thinsp;Gz exert different types of stress: LBNP induces hydrostatic stress, whereas +\u0026thinsp;Gz creates a gravitational gradient along the body, limiting direct comparisons\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e,\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eNeuroendocrine Response to Graded\u0026thinsp;+\u0026thinsp;Gz Profile\u003c/h2\u003e \u003cp\u003eThe graded\u0026thinsp;+\u0026thinsp;Gz profile led to an increase in all neuroendocrine parameters, irrespective of the intervention (PSC or CTL). This uniform response could result from the overwhelming effect of +\u0026thinsp;Gz stress, potentially overshadowing any distinct impacts of PSC. The only directly comparable\u0026thinsp;+\u0026thinsp;Gz study investigating neuroendocrine parameters pre/post\u0026thinsp;+\u0026thinsp;Gz without PSC found a significant increase only in noradrenaline, and a non-significant increase in adrenaline amongst a women and men participants\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. Earlier research suggested an immediate increase in noradrenaline following PSC application, but this effect diminishes over time\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. It's plausible that noradrenaline levels peaked during the initial phases of +\u0026thinsp;Gz in the PSC group. Additionally, studies indicate that during prolonged orthostatic stress, adrenaline becomes the dominant catecholamine, but its vasodilative effect undermines orthostatic stability\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e,\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. In contrast, our study observed significant increases in both noradrenaline and adrenaline, which might be attributed to the study's unique participant profile (male-only) or the intensity of the +\u0026thinsp;Gz profile exceeding\u0026thinsp;+\u0026thinsp;3Gz.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eExploring Inactive Catecholamine Metabolites\u003c/h2\u003e \u003cp\u003eNotably, this study also examined plasma normetanephrine and metanephrine, which are inactive metabolites of noradrenaline and adrenaline\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. These metabolites offer insights into the extraneuronal inactivation of active catecholamines\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. A previous study involving orthostatic and cold stress reported increases in active catecholamines surpassing those of their inactive counterparts\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. Our findings partially confirm this, marking the first time these metabolites have been analyzed in relation to +\u0026thinsp;Gz exposure.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eSerum Osmolality and Hemodynamic Implications\u003c/h2\u003e \u003cp\u003eA distinct observation within the PSC group was the strong increase in serum osmolality, which has also been observed in previous studies\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e,\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e. This increase in serum osmolality, which can lead to a rapid elevation in vasopressin levels and and subsequently blood pressure, might be beneficial for space crews and ICU patients. The initial hemodynamic results suggest that the higher systolic blood pressure trends in PSC could be indicative of vasopressin activation\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eLeukocytic and Hematological Reactions\u003c/h2\u003e \u003cp\u003eThere was no marked difference regarding leukocytic and hematological responses between PSC and CTL groups, aside from the magnitude of monocyte change and mean platelet volume. The PSC group indicated a lower change in monocytes. A decrease in mean platelet volume only appeared in CTL. These observations might suggest increased physiological stress in CTL, underlined by the trends in lymphocyte percentages. Consistent with other\u0026thinsp;+\u0026thinsp;Gz studies\u003csup\u003e\u003cspan additionalcitationids=\"CR40 CR41\" citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e, our study observed leukocytosis and hemoconcentration in both groups. However, the extent of plasma volume reduction was not as pronounced as in other studies\u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e. The leukocytosis observed was likely catecholamine-induced due to splenic release and leukocyte mobilization.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eCorrelation Analysis\u003c/h2\u003e \u003cdiv id=\"Sec19\" class=\"Section3\"\u003e \u003ch2\u003eAdrenergic Activation and CGSI Correlation\u003c/h2\u003e \u003cp\u003eThe correlation analysis revealed strong negative correlations between pre\u0026thinsp;+\u0026thinsp;Gz metanephrine and CGSI in both PSC and CTL groups. Metanephrine was sampled before PSC activation and reflects adrenergic activation independet of PSC\u0026rsquo;s effects. High metanephrine levels, were associated with lower CGSI. This observation aligns with a previous study suggesting that high baseline catecholamine levels do not predict tolerance to negative pressures up to -50 mmHg LBNP\u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e. Conversely, lower renin concentration, often associated with less noradrenaline activation, correlates with reduced orthostatic tolerance\u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e. Here, higher baseline levels could equal a lower residual capacity to increased catecholamine or renin levels and therefore a reduced capability to react to increased orthostatic stress. This pattern suggests that metanephrine could be a potential marker for assessing\u0026thinsp;+\u0026thinsp;Gz resilience, warranting further investigation.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eNoradrenaline's Role in PSC Group\u003c/h2\u003e \u003cp\u003eA strong correlation between CGSI and noradrenaline in the PSC group points to a unique physiological shift induced by PSC. Despite similar noradrenaline increases in both groups, the correlation suggests a heightened responsiveness or susceptibility to noradrenaline in the PSC group. This implies that PSC might enhance the cardio-protective effects of noradrenaline, potentially beneficial for prolonged use in space missions and in critical care settings.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eImmune and Hematological Pathway Interactions\u003c/h2\u003e \u003cp\u003eNoteworthy correlations were found in the PSC group between CGSI, neutrophiles, and platelets, indicating an interplay between noradrenaline activation and these hematological and immune pathways, which has been previously documented\u003csup\u003e\u003cspan additionalcitationids=\"CR47\" citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e. While noradrenaline typically increases neutrophiles, adrenaline usually elevates lymphocytes\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e,\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e \u0026mdash; a correlation not observed in our study. The CTL group showed a distinct pattern, with noradrenaline correlating with monocytes. These differences suggest PSC may amplify neutrophilic responses to +\u0026thinsp;Gz, while CTL links more with monocytic pathways. Such findings resonate with astronaut data, where catecholamine increases post-re-entry correlated with a rise in white blood cells, mainly neutrophiles\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003eNeuroendocrine Activation and Volume Homeostasis\u003c/h2\u003e \u003cp\u003eAdditional correlations in PSC between adrenaline and plasma volume suggest that reductions in plasma volume are crucial for adrenaline release. Cross-talk between neutrophiles, platelets, and plasma volume indicates an interaction between platelet mobilization and volume changes. The correlation between metanephrine and serum osmolality hints at a potential link with the renin-angiotensin-aldosterone system. These results suggest that neuroendocrine activation under PSC leads to a complex cascade of responses involving leukocytic, hematological, and volume homeostasis pathways, underscoring the need for further investigations.\u003c/p\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003eStudy Limitations\u003c/h2\u003e \u003cp\u003eThe use of a SAHC in this study to simulate\u0026thinsp;+\u0026thinsp;Gz conditions may not accurately mimic spaceflight associated gravitational transitions, which tend to be longer and less intense. This difference could have influenced the findings, particularly regarding the physiological impacts of PSC on neuroendocrine parameters. The inconsistency in +\u0026thinsp;Gz run durations due to varying maximal tolerance among participants further complicates the uniformity of the experimental conditions.\u003c/p\u003e \u003cp\u003eSubjective decisions by flight physicians to abort\u0026thinsp;+\u0026thinsp;Gz runs introduced variability, especially with a change in physicians midway through the study. This potentially led to different assessments of +\u0026thinsp;Gz tolerance. This subjectivity may have affected the comparability of the PSC and CTL groups.\u003c/p\u003e \u003cp\u003eThe water-based PSC system was limited under +\u0026thinsp;Gz conditions due to potential gravitational effects on water flow. Furthermore, limiting PSC application to the bilateral thighs may not have captured the full potential impact of PSC. Covering a larger body surface area could yield more pronounced physiological effects\u003csup\u003e\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe study did not include dopamine analysis which is also a key neuroendocrine parameter influencing hemodynamic activity during stress. PSC may have had an impact on this pathway, and future studies should include this analysis. Additionally, the methodology of blood sampling only pre and post\u0026thinsp;+\u0026thinsp;Gz, and exclusively from venous blood does not provide a complete picture of the neuroendocrine reactions. This is especially true for neuroendocrine reactions post-PSC activation where reactions may have been more pronounced, or longer-term effects after +\u0026thinsp;Gz exposure, which may have yielded valuable information. Venous blood sampling may also not accurately represent total serum catecholamine levels due to rapid uptake by organ systems and potential local release effects on noradrenaline levels\u003csup\u003e\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study's findings reveal that using water-based PSC on the bilateral thighs during graded\u0026thinsp;+\u0026thinsp;Gz exposure did not result in a higher CGSI or a more pronounced neuroendocrine response compared to CTL, with an exception for an increase in serum osmolality. This increase may suggest enhanced vasopressin activity under PSC. Additionally, no differences between PSC and CTL in leukocytic and hematological responses were observed.\u003c/p\u003e \u003cp\u003eHowever, PSC did lead to a noradrenaline-dependent CGSI. This implyies that while average noradrenaline levels were similar in both groups, its physiological effectiveness during +\u0026thinsp;Gz was enhanced under PSC. The observed correlations between CGSI, neutrophiles, and thrombocytes in the PSC group suggest an amplification of immune-based stress responses. These findings indicate that PSC usage during physiological stress may lead to a more cardio-protective response, beneficial for manned space crews. Additionally, PSC might have stabilizing effects on hemodynamics in clinically unstable patients.\u003c/p\u003e \u003cp\u003eGiven these results, future research is warranted to further explore PSC's impacts using different simulation models like SAHC, parabolic flight, or LBNP. Studies should consider employing alternative PSC systems and extending the application to a larger body surface area. Such research is crucial as non-invasive counter-measure systems will play a key role in the success of human spaceflight and planetary colonization.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAuthor contributions\u003c/p\u003e\n\u003cp\u003eMN composed the manuscript and performed primary data analysis. NK performed the study. \u0026nbsp; NK, JK, VH, and NP co-wrote and revised the manuscript. H-C.G, OO, and TB revised the manuscript, devised the study, and procured funding.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCompeting interest\u003c/p\u003e\n\u003cp\u003eAll authors declare no financial or non-financial competing interests.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis study was supported by the DLR (German Aerospace Center, Bonn, Germany) grant number 50WB1832.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eData availability\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWade, C. E. Responses across the Gravity Continuum: Hypergravity to Microgravity. in \u003cem\u003eAdvances in Space Biology and Medicine\u003c/em\u003e vol. 10 225\u0026ndash;245 (Elsevier, 2005).\u003c/li\u003e\n\u003cli\u003eKomorowski, M., Fleming, S. \u0026amp; Kirkpatrick, A. W. 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Invest.\u003c/em\u003e \u003cstrong\u003e46\u003c/strong\u003e, 397\u0026ndash;401 (1986).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"npj-microgravity","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"npjmgrav","sideBox":"Learn more about [npj Microgravity](http://www.nature.com/npjmgrav/)","snPcode":"41526","submissionUrl":"https://submission.springernature.com/new-submission/41526/3","title":"npj Microgravity","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-3750578/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3750578/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eIntroduction:\u003c/h2\u003e \u003cp\u003eOptimal neuroendocrine responses, particularly noradrenergic responses, are critical during hypergravity (+\u0026thinsp;Gz) exposure. Peripheral skin cooling (PSC) has the potential to enhance noradrenergic function, which could improve\u0026thinsp;+\u0026thinsp;Gz resiliency and may also affect leukocyte and hematologic factors. We predicted that PSC would augment cumulative\u0026thinsp;+\u0026thinsp;Gz stress index (CGSI) neuroendocrine, leukocyte and hematologic activity compared to controls, and that CGSI would shift to a noradrenergic dependency in PSC compared to controls.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003e18 men in a cross-over design underwent a graded\u0026thinsp;+\u0026thinsp;Gz profile. PSC was applied using Arctic Sun cooling pads around the thighs with 8\u0026deg;C water infusion. Neuroendocrine parameters and a complete blood profile with differential were obtained before and after +\u0026thinsp;Gz. CGSI was calculated as +\u0026thinsp;Gz * seconds. Pre / post comparisons were made within the groups with paired t-tests and between groups with independent t-tests. Pearson's correlation analysis was performed between CGSI and neuroendocrine/leukocyte/hematological parameters.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eCSGI did not differ between groups. In both groups, all neuroendocrine, leukocyte and hematological factors changed significantly from pre to post\u0026thinsp;+\u0026thinsp;Gz, except for serum osmolality, which increased only in PSC (p\u0026thinsp;=\u0026thinsp;0.03). In PSC, CGSI correlated with noradrenaline (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01, r\u0026thinsp;=\u0026thinsp;0.71), metanephrine (p\u0026thinsp;=\u0026thinsp;0.02, r = -0.54), neutrophiles (p\u0026thinsp;=\u0026thinsp;0.03, r\u0026thinsp;=\u0026thinsp;0.51), and thrombocytes (p\u0026thinsp;=\u0026thinsp;0.04, r\u0026thinsp;=\u0026thinsp;0.48), while in controls, CGSI correlated with metanephrine (p\u0026thinsp;=\u0026thinsp;0.02, r = -0.54). Pre\u0026thinsp;+\u0026thinsp;Gz metanephrine correlated with CGSI in both groups.\u003c/p\u003e\u003ch2\u003eDiscussion\u003c/h2\u003e \u003cp\u003ePSC did not confer a higher CGSI nor induce a greater neuroendocrine, leukocytic or hematologic response compared to controls. However, the increase in serum osmolality may indicate increased vasopressin activity. The strong correlations between CGSI and norepinephrine in PSC suggest that despite equal average serum levels, the responsiveness of norepinephrine is enhanced. This may serve as an optimal cardio-protective countermeasure for manned space missions and possible ICU patients. The correlations between neutrophiles and thrombocytes in PSC suggest a leukocytic and hematologic involvement in CSGI. In addition, this is the first study to demonstrate that baseline serum metanephrine may serve as a potential neuroendocrine parameter to assess\u0026thinsp;+\u0026thinsp;Gz resilience.\u003c/p\u003e","manuscriptTitle":"Peripheral skin cooling during Hypergravity: Neuroendocrine, leucocytic and hematological reactions","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-06 17:03:27","doi":"10.21203/rs.3.rs-3750578/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2024-07-10T12:38:51+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-06-28T14:46:25+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-06-08T16:16:26+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-06-07T10:00:59+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-05-20T06:44:50+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2024-02-02T13:58:29+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-12-15T06:45:34+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-12-15T06:45:28+00:00","index":"","fulltext":""},{"type":"submitted","content":"npj Microgravity","date":"2023-12-13T23:39:28+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"npj-microgravity","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"npjmgrav","sideBox":"Learn more about [npj Microgravity](http://www.nature.com/npjmgrav/)","snPcode":"41526","submissionUrl":"https://submission.springernature.com/new-submission/41526/3","title":"npj Microgravity","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8886b695-27dc-473a-ad86-14ed1a6cd21f","owner":[],"postedDate":"February 6th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-07-03T07:16:35+00:00","versionOfRecord":{"articleIdentity":"rs-3750578","link":"https://doi.org/10.1038/s41526-025-00486-9","journal":{"identity":"npj-microgravity","isVorOnly":false,"title":"npj Microgravity"},"publishedOn":"2025-07-02 04:00:00","publishedOnDateReadable":"July 2nd, 2025"},"versionCreatedAt":"2024-02-06 17:03:27","video":"","vorDoi":"10.1038/s41526-025-00486-9","vorDoiUrl":"https://doi.org/10.1038/s41526-025-00486-9","workflowStages":[]},"version":"v1","identity":"rs-3750578","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3750578","identity":"rs-3750578","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}