Human hypoxia models in aerospace medicine: Potential applications for human pharmacological research.

Aerospace medicine required controlled terrestrial models to investigate influences of altered atmosphere conditions, such as hypoxia, on human health and performance. These models could potentially be expanded to encompass disease conditions or treatment targets regulated through hypoxia or hypercapnia. Hypoxia, a condition in which the body is deprived of adequate oxygen supply, profoundly affects human physiology at multiple levels and contributes to the pathogenesis of various diseases. Experimental exposure to hypoxic conditions has gained recognition as a model for studying diseases such as pulmonary hypertension, chronic obstructive pulmonary disease, obstructive sleep apnoea, migraine and kidney disease. This approach may be particularly useful in mechanism-oriented early-stage clinical studies. This review discusses the ability of hypoxia models from space medicine research to mimic or induce these conditions in a controlled laboratory setting as a tool for testing the efficacy and safety of new pharmaceutical interventions.

High expression of L-GILZ transcript variant 1 (GILZ TV 1) is associated with increased 30-day sepsis mortality, and a high expression ratio possibly contraindicates hydrocortisone administration.

BACKGROUND: Sepsis presents a challenge due to its complex immune responses, where balance between inflammation and anti-inflammation is critical for survival. Glucocorticoid-induced leucine zipper (GILZ) is key protein in achieving this balance, suppressing inflammation and mediating glucocorticoid response. This study aims to investigate GILZ transcript variants in sepsis patients and explore their potential for patient stratification and optimizing glucocorticoid therapy. METHODS: Sepsis patients meeting the criteria outlined in Sepsis-3 were enrolled, and RNA was isolated from whole blood samples. Quantitative mRNA expression of GILZ transcript variants in both sepsis patient samples (n = 121) and the monocytic U937 cell line (n = 3), treated with hydrocortisone and lipopolysaccharides, was assessed using quantitative PCR (qPCR). RESULTS: Elevated expression of GILZ transcript variant 1 (GILZ TV 1) serves as a marker for heightened 30-day mortality in septic patients. Increased levels of GILZ TV 1 within the initial day of sepsis onset are associated with a 2.2-[95% CI 1.2-4.3] fold rise in mortality, escalating to an 8.5-[95% CI 2.0-36.4] fold increase by day eight. GILZ TV1 expression is enhanced by glucocorticoids in cell culture but remains unaffected by inflammatory stimuli such as LPS. In septic patients, GILZ TV 1 expression increases over the course of sepsis and in response to hydrocortisone treatment. Furthermore, a high expression ratio of transcript variant 1 relative to all GILZ mRNA TVs correlates with a 2.3-fold higher mortality rate in patients receiving hydrocortisone treatment. CONCLUSION: High expression of GILZ TV 1 is associated with a higher 30-day sepsis mortality rate. Moreover, a high expression ratio of GILZ TV 1 relative to all GILZ transcript variants is a parameter for identifying patient subgroups in which hydrocortisone may be contraindicated.

The Association between the rs3747406 Polymorphism in the Glucocorticoid-Induced Leucine Zipper Gene and Sepsis Survivals Depends on the SOFA Score.

The variability in mortality in sepsis could be a consequence of genetic variability. The glucocorticoid system and the intermediate TSC22D3 gene product-glucocorticoid-induced leucine zipper-are clinically relevant in sepsis, which is why this study aimed to clarify whether TSC22D3 gene polymorphisms contribute to the variance in sepsis mortality. Blood samples for DNA extraction were obtained from 455 patients with a sepsis diagnosis according to the Sepsis-III criteria and from 73 control subjects. A SNP TaqMan assay was used to detect single-nucleotide polymorphisms (SNPs) in the TSC22D3 gene. Statistical and graphical analyses were performed using the SPSS Statistics and GraphPad Prism software. C-allele carriers of rs3747406 have a 2.07-fold higher mortality rate when the sequential organ failure assessment (SOFA) score is higher than eight. In a multivariate COX regression model, the SNP rs3747406 with a SOFA score ≥ 8 was found to be an independent risk factor for 30-day survival in sepsis. The HR was calculated to be 2.12, with a p-value of 0.011. The wild-type allele was present in four out of six SNPs in our cohort. The promoter of TSC22D3 was found to be highly conserved. However, we discovered that the C-allele of rs3747406 poses a risk for sepsis mortality for SOFA Scores higher than 6.

[Damage Control Resuscitation and Damage Control Surgery]. / Damage Control Resuscitation und Damage Control Surgery.

Trauma triggers complex physiological responses with primary and secondary effects vital to understanding and managing trauma impact. "Damage Control" (DC), a concept adapted from naval practices, refers to abbreviated initial surgical care focused on controlling bleeding and contamination, critical for the survival of severely compromised patients. This impacts anaesthesia procedures and intensive care. "Damage Control Resuscitation" (DCR) is an interdisciplinary approach aimed at reducing mortality in severely injured patients, despite potentially increasing morbidity and ICU duration. Current medical guidelines incorporate DC strategies.DC is most beneficial for patients with severe physiological injury, where surgical trauma ("second hit") poses greater risks than delayed treatment. Patient assessment for DC includes evaluating injury severity, physiological reserves, and anticipated surgical and treatment strain. Inadequate intervention can worsen trauma-induced complications like coagulopathy, acidosis, hypothermia, and hypocalcaemia.DCR focuses on rapidly restoring homeostasis with minimal additional burden. It includes rapid haemostasis, controlled permissive hypotension, early blood transfusion, haemostasis optimization, and temperature normalization, tailored to individual patient needs."Damage Control Surgery" (DCS) involves phases like rapid haemostasis, contamination control, temporary wound closure, intensive stabilization, planned reoperations, and final wound closure. Each phase is crucial for managing severely injured patients, balancing immediate life-saving procedures and preparing for subsequent surgeries.Intensive care post-DCS emphasizes stabilizing patients hemodynamically, metabolically, and coagulopathically while restoring normothermia. Decision-making in trauma care is complex, involving precise patient assessment, treatment prioritization, and team coordination. The potential of AI-based decision support systems is noted for their ability to analyse patient data in real-time, aiding in decision-making through evidence-based recommendations.

A case of recurring perioperative circulatory arrest: mind the autonomic nervous system.

We report the case of an elderly woman who developed recurring episodes of unexplained cardiocirculatory arrest. The index event appeared during surgery to fix a fracture of the ankle and consisted of bradypnea, hypotension and asystole, coherent with a Bezold-Jarisch-like cardioprotective reflex. Classical signs of acute myocardial infarction were absent. Yet, occlusion of the right coronary artery (RCA) was observed and successfully revascularized, whereupon circulatory arrests vanished. We discuss several differential diagnoses. Unexplainable circulatory failure, with sinus bradycardia and arterial hypotension, despite lack of ECG signs of ischemia or significant troponin levels, suggest the action of cardioprotective reflexes of the autonomic nervous system. Coronary artery disease is a common source. Attention to cardioprotective reflexes should be taken in the case of unexplained cardiac arrest without overt reasons. We recommend performing coronary angiography to exclude significant coronary stenosis.

Space Omics and Tissue Response in Astronaut Skeletal Muscle after Short and Long Duration Missions.

The molecular mechanisms of skeletal muscle adaptation to spaceflight are as yet not fully investigated and well understood. The MUSCLE BIOPSY study analyzed pre and postflight deep calf muscle biopsies (m. soleus) obtained from five male International Space Station (ISS) astronauts. Moderate rates of myofiber atrophy were found in long-duration mission (LDM) astronauts (~180 days in space) performing routine inflight exercise as countermeasure (CM) compared to a short-duration mission (SDM) astronaut (11 days in space, little or no inflight CM) for reference control. Conventional H&E scout histology showed enlarged intramuscular connective tissue gaps between myofiber groups in LDM post vs. preflight. Immunoexpression signals of extracellular matrix (ECM) molecules, collagen 4 and 6, COL4 and 6, and perlecan were reduced while matrix-metalloproteinase, MMP2, biomarker remained unchanged in LDM post vs. preflight suggesting connective tissue remodeling. Large scale proteomics (space omics) identified two canonical protein pathways associated to muscle weakness (necroptosis, GP6 signaling/COL6) in SDM and four key pathways (Fatty acid ß-oxidation, integrin-linked kinase ILK, Rho A GTPase RHO, dilated cardiomyopathy signaling) explicitly in LDM. The levels of structural ECM organization proteins COL6A1/A3, fibrillin 1, FBN1, and lumican, LUM, increased in postflight SDM vs. LDM. Proteins from tricarboxylic acid, TCA cycle, mitochondrial respiratory chain, and lipid metabolism mostly recovered in LDM vs. SDM. High levels of calcium signaling proteins, ryanodine receptor 1, RyR1, calsequestrin 1/2, CASQ1/2, annexin A2, ANXA2, and sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA1) pump, ATP2A, were signatures of SDM, and decreased levels of oxidative stress peroxiredoxin 1, PRDX1, thioredoxin-dependent peroxide reductase, PRDX3, or superoxide dismutase [Mn] 2, SOD2, signatures of LDM postflight. Results help to better understand the spatiotemporal molecular adaptation of skeletal muscle and provide a large scale database of skeletal muscle from human spaceflight for the better design of effective CM protocols in future human deep space exploration.

Brain structure and neurocognitive function in two professional mountaineers during 35 days of severe normobaric hypoxia.

BACKGROUND AND PURPOSE: Animal studies suggest that exposure to severe ambient hypoxia for several days may have beneficial long-term effects on neurodegenerative diseases. Because, the acute risks of exposing human beings to prolonged severe hypoxia on brain structure and function are uncertain, we conducted a pilot study in healthy persons. METHODS: We included two professional mountaineers (participants A and B) in a 35-day study comprising an acclimatization period and 14 consecutive days with oxygen concentrations between 8% and 8.8%. They underwent cerebral magnetic resonance imaging at seven time points and a cognitive test battery covering a spectrum of cognitive domains at 27 time points. We analysed blood neuron specific enolase and neurofilament light chain levels before, during, and after hypoxia. RESULTS: In hypoxia, white matter volumes increased (maximum: A, 4.3% ± 0.9%; B, 4.5% ± 1.9%) whilst gray matter volumes (A, -1.5% ± 0.8%; B, -2.5% ± 0.9%) and cerebrospinal fluid volumes (A, -2.7% ± 2.4%; B, -5.9% ± 8.2%) decreased. Furthermore, the number (A, 11-17; B, 26-126) and volumes (A, 140%; B, 285%) of white matter hyperintensities increased in hypoxia but had returned to baseline after a 3.5-month recovery phase. Diffusion weighted imaging of the white matter indicated cytotoxic edema formation. We did not observe changes in cognitive performance or biochemical brain injury markers. DISCUSSION: In highly selected healthy individuals, severe sustained normobaric hypoxia over 2 weeks elicited reversible changes in brain morphology without clinically relevant changes in cognitive function or brain injury markers. The finding may pave the way for future translational studies assessing the therapeutic potential of hypoxia in neurodegenerative diseases.

Cardiovascular autonomic nervous system responses and orthostatic intolerance in astronauts and their relevance in daily medicine.

BACKGROUND: The harsh environmental conditions during space travel, particularly weightlessness, impose a major burden on the human body including the cardiovascular system. Given its importance in adjusting the cardiovascular system to environmental challenges, the autonomic nervous system has been in the focus of scientists and clinicians involved in human space flight. This review provides an overview on human autonomic research under real and simulated space conditions with a focus on orthostatic intolerance. METHODS: The authors conducted a targeted literature search using Pubmed. RESULTS: Overall, 120 articles were identified and included in the review. CONCLUSIONS: Postflight orthostatic intolerance is commonly observed in astronauts and could pose major risks when landing on another celestial body. The phenomenon likely results from changes in volume status and adaptation of the autonomic nervous system to weightlessness. Over the years, various non-pharmacological and pharmacological countermeasures have been investigated. In addition to enabling safe human space flight, this research may have implications for patients with disorders affecting cardiovascular autonomic control on Earth.

The thrombotic risk of spaceflight: has a serious problem been overlooked for more than half of a century?

The first ever venous thrombotic condition associated with spaceflight, an internal jugular vein thrombus requiring anticoagulation, has recently been reported. Systematic investigation of space travel-associated thrombotic risk has not been conducted. Cellular, animal, and human studies performed in ground-based models and in actual weightlessness revealed influences of weightlessness and gravity on the blood coagulation system. However, human study populations were small and limited to highly selected participants. Evidence in individuals with medical conditions and older persons is lacking. Evidence for thrombotic risk in spaceflight is unsatisfactory. This issue deserves further study in heterogeneous, high risk populations to find prevention strategies and to enable safe governmental and touristic human spaceflight.

[Treatment of thermal injuries in adults : Update of the S2k guidelines from 1 February 2021]. / Behandlung thermischer Verletzungen des Erwachsenen : Update der S2k-Leitlinie vom 01.02.2021.

The current S2k guidelines on treatment of thermal injuries in adults are summarized in this article from the perspective of anesthesiology, emergency medicine and intensive care medicine. The guidelines were prepared under the auspices of the German Society for Burn Medicine with the participation of other professional societies and interest groups and were published last year in revised form by the AWMF.

Beet on Alps: Time-course changes of plasma nitrate and nitrite concentrations during acclimatization to high-altitude.

Nitric oxide seems to be involved in the altitude acclimatization process due to its ability to regulate pulmonary, cardiovascular and muscular responses to hypoxia. In this study, we investigated the plasma nitrate (NO3-) and nitrite (NO2-) response to hypobaric hypoxia in two groups of lowlanders exposed at different altitudes. For seven days, fourteen subjects were evaluated at Casati Hut (3269 m a.s.l. M.CEVEDALE) and eleven individuals were studied at Capanna Regina Margherita (4554 m a.s.l. M.ROSA). Before expeditions and at different time points during high-altitude sojourn, plasma NO3- and NO2- concentrations were measured by chemiluminescence. Resting peripheral arterial oxygen saturation (SpO2), heart rate (HR) and mean arterial blood pressure (MAP) were monitored during the experimental period. Possible confounding factors such as dietary NO3- intake, physical activity and altitude changes were controlled. Sea level plasma NO3- and NO2- concentrations significantly increased at altitude in both M.CEVEDALE group (+26.2 µM, p ≤ 0.0001, 95% CI [+17.6, +34.8] and +559.2 nM, p ≤ 0.0001, [+332.8, +785.6]) and M.ROSA group (+18.7 µM, p ≤ 0.0001, [+10.8, +26.5] and +463.7 nM, p ≤ 0.0001, [+314.3, +613.0]). Average peak value in NO metabolites concentration occurred earlier in M.CEVEDALE group vs M.ROSA group (NO3-, day 3 vs day 5, p = 0.007; NO2-, day 3 vs day 5, p = 0.019). In both groups, resting SpO2, HR and MAP values changed according to altitude levels. This study shows that exposure to hypobaric hypoxia affects nitric oxide metabolites, resulting in a significant increase in plasma NO3- and NO2- concentrations from sea level values. Interestingly, the higher the altitude reached, the longer the time taken to reach a peak in plasma concentrations of nitric oxide metabolites.

[Target Temperature Control in Patients with Burns]. / Zieltemperaturkontrolle beim Patienten mit Verbrennungen.

Severe burns lead to a persistent hypermetabolic response of the organism with significantly increased resting energy turnover, multi-organ dysfunction, muscle breakdown and increased risk of infection. Elevated core and skin temperatures are characteristic. A further increase in the metabolic rate can be triggered by heat losses, for which these patients are particularly predisposed due to high heat dissipation via evaporation of moisture and impairment of the thermoregulatory and insulating properties of the burnt skin. This is especially true in all treatment situations with exposure to large, uncovered skin surfaces, such as primary care, dressing changes in the intensive care unit and surgery with extensive sterile operating field. It has been shown that hypothermia is associated with numerous risks for the burn patient. Consistent heat management with measurement of the core body temperature and application of external and internal heat protection measures is recommended. Traditionally, an increase in room temperature is used here. However, this effective measure is limited by the resilience of the intensive care practitioners and the surgeons. To avoid perioperative hypothermia, strict surgical planning with limitation of the duration of surgery and close intraoperative communication about the risk of hypothermia are of particular importance.The differentiation between accepted temperature increase and infectious fever is often only possible by the inclusion of further examination findings. The criterion for sepsis is a temperature above 39 °C or below 36.5 °C.

Modeling human orthostatic responses on the Moon and on Mars.

PURPOSE: Since manned missions to the Moon and Mars are planned, we conducted active standing tests with lunar, Martian, terrestrial, and 1.8 loads of inertial resistance (+Gz) modeled through defined parabolic flight maneuvers. We hypothesized that the cardiovascular response to active standing is proportional to the +Gz load. METHODS: During partial-+Gz parabolic flights, 14 healthy test subjects performed active stand-up maneuvers under 1 +Gz, lunar (0.16 +Gz), Martian (0.38 +Gz), and hyper inertial resistance (1.8 +Gz) while heart rate and finger blood pressure were continuously monitored. We quantified amplitudes and timing of orthostatic response immediately following standing up. RESULTS: The maximum early heart rate increase was 21 (SD ± 10) bpm with lunar, 23 (± 11) bpm with Martian, 34 (± 17) bpm with terrestrial +Gz, and 40 (± 11) bpm hyper +Gz. The time to maximum heart rate increased gradually with increasing loads of inertial resistance. The transient blood pressure reduction was most pronounced with hyper +Gz but did not differ significantly between lunar and Martian +Gz. The mean arterial pressure nadir was reached significantly later with Martian and lunar compared to 1 +Gz. Paradoxically, the time for blood pressure to recover was shortest with terrestrial +Gz. CONCLUSION: While load of inertial resistance directly affects the magnitude of the transient blood pressure reduction and heart rate response to active standing, blood pressure stabilization is most rapidly attained during terrestrial +Gz. The observation might suggest that the human cardiovascular system is tuned to cope with orthostatic stress on earth.