Ranging from 64 to 8848 m above sea level, Nepal is a country rich in hilly and mountainous terrain.1 24.8% of Nepal's land area is above 3000 m, 18.9% is between 3000 and 5000 m, and 5.9% is above 5000 m.2 Hikers and trekkers are increasingly attracted to this challenging altitude and terrain, which presents risks for altitude sickness and other physical complications. Responding to medical emergencies in high-altitude areas in Nepal is highly challenging. This difficulty is often exacerbated by inclement weather, unavailability of helicopters, and poor communication regarding the location and condition of patients requiring medical attention and evacuation. High-altitude pulmonary edema (HAPE) is an illness characterized by non-cardiogenic pulmonary edema, which occurs not infrequently in individuals who rapidly ascend above 2500-3000 m in elevation,3 and which has a high mortality rate if not treated in a timely manner. Improved outcomes would be likely if skilled and equipped medical staff had better access to the sites of high-altitude expeditions in Nepal, so that life-saving interventions could be performed promptly. We report the case of a patient with HAPE who was intubated in the field at an altitude of 3600 m, and then evacuated via helicopter to a healthcare facility.

High-altitude illnesses (HAIs) result from acute exposure to high altitude/hypoxia. Numerous molecular mechanisms affect appropriate acclimatization to hypobaric and/or normobaric hypoxia and curtail the development of HAIs. The understanding of these mechanisms is essential to optimize hypoxic acclimatization for efficient prophylaxis and treatment of HAIs. This review aims to link outcomes of molecular mechanisms to either adverse effects of acute high-altitude/hypoxia exposure or the developing tolerance with acclimatization. After summarizing systemic physiological responses to acute high-altitude exposure, the associated acclimatization, and the epidemiology and pathophysiology of various HAIs, the article focuses on molecular adjustments and maladjustments during acute exposure and acclimatization to high altitude/hypoxia. Pivotal modifying mechanisms include molecular responses orchestrated by transcription factors, most notably hypoxia inducible factors, and reciprocal effects on mitochondrial functions and REDOX homeostasis. In addition, discussed are genetic factors and the resultant proteomic profiles determining these hypoxia-modifying mechanisms culminating in successful high-altitude acclimatization. Lastly, the article discusses practical considerations related to the molecular aspects of acclimatization and altitude training strategies.

Objective: To analyze the incidence and risk factors of acute mountain sickness (AMS) in grid construction personnel working at plateau. Methods: A total of 10 956 plateau construction personnel of Ali Network Project from January 1, 2019 to December 31, 2020 were included. Baseline information (including age, sex, body mass index, developmental and nutritional status, relevant clinical indicators, etc.) and follow-up data of AMS were obtained from the medical record of Ali Internet engineering staff medical station. The altitude of the residence place in early life and the working environment were obtained from the website (https://zh-cn.topographic-map.com/legal/). The incidences of overall AMS and its subgroups were calculated, and the Cox proportional hazards model was used to explore the risk factors for AMS. Results: The age of the participants was (36.1±10.5) years old at baseline, and 95.27% (10 438) of them were males. The follow-up time was (17.46±4.23) months. The altitude of the residence place in early-life and working environment were (1 959±937) m and (4 533±233) m, respectively. During the follow-up period, the incidence of AMS was 15.58% (1 707 cases), and the incidence for acute mountain sickness and high altitude pulmonary edema were 15.53% (1 702 cases) and 0.05% (5 cases), respectively. No high altitude cerebral edema patients were found. Cox proportional hazards model showed that the risk of AMS increased by 45% for every 100 m elevation in the altitude of working environment [HR (95%CI): 1.45 (1.41-1.51)]. The higher the altitude for the residence place in early-life, the lower the risk of AMS [HR (95%CI): 0.84 (0.80-0.88)]. Compared with the group with oxygen saturation during 90%-94%, the participants with oxygen saturation<75% [HR (95%CI): 1.67 (1.24-2.23)] at baseline was also associated with increased risk of AMS. Conclusions: The incidence of AMS is relatively low in grid construction workers working on plateau. The risk factors of AMS included higher working altitude, lower altitude of the residence place in early-life and oxygen saturation<75%.

High altitude pulmonary edema (HAPE) is a common respiratory disease in the high altitude area, which is rapid and harmful. We firstly conducted a case-control study to assess the potential association of CYP4F2 gene polymorphisms with HAPE susceptibility in the Chinese Han population. The study recruited 238 patients with HAPE and 230 healthy controls in Northwest China. Genomic DNA was extracted from blood samples, and gene polymorphisms were detected using the Agena MassARRAY platform. Odds ratios (ORs), 95% confidence intervals (95% CIs), and P-value were used to evaluate the relationship between HAPE risk and CYP4F2 gene polymorphisms. Multi-factor dimension reduction (MDR) was used to assess the optimal interaction of CYP4F2 gene polymorphisms on HAPE risk. We found rs3093193 was shown to reduce the risk of HAPE (OR = 0.70, 95% CI = 0.52-0.93, P = 0.014), while rs12459936 was increased the susceptibility to HAPE (OR = 2.08, 95% CI = 1.33-3.26, P = 0.001). Age stratified analysis revealed that rs3093193 and rs12459936 were correlated with HAPE risk in people at age > 32 years old, and rs3093193 and rs3093110 were correlated with the HAPE risk in people at age ≤ 32 years old. Gender stratification analysis was found that rs3093193, rs12459936, and rs3093110 were all related to HAPE risk in males. A combination of rs12459936 and rs3093110 was the best multi-loci model with the highest testing accuracy. Our study is the first to provide the association between CYP4F2 gene polymorphisms and HAPE risk in the Chinese Han population.

High-altitude polycythemia (HAPC) can occur in individuals who are intolerant to high-altitude hypoxia. In patients with HAPC, erythrocytosis is often accompanied by a decrease in platelet count. Chronic hypoxia can increase the incidence of arteriovenous thrombosis and the risk of bleeding during antithrombotic treatment due to thrombocytopenia; therefore, understanding the cause of thrombocytopenia can reduce the risk of treatment-related bleeding. In this study, we examined platelet production and apoptosis to understand the cause of thrombocytopenia in patients with HAPC. The classification of myeloid-derived megakaryocytes (MKs) in HAPC patients was mainly granular MKs rather than mature MKs, suggesting impaired differentiation and maturation. However, the total number of MKs and newly generated reticulated platelets in the peripheral blood increased, indicating sufficient platelet generation in HAPC thrombocytopenia. Increased platelet apoptosis may be one of the causes of thrombocytopenia. Platelet activation and GP1bα pathway activation induced by thrombin and von Willebrand factor can lead to platelet apoptosis. Platelet production was not reduced in patients with HAPC, whereas platelet apoptosis was associated with thrombocytopenia. These findings provide a rationale for considering the bleeding risk in HAPC patient while treating thrombotic diseases.

In the course of their missions or training, alpinists, but also mountain combat forces and mountain security services, professional miners, aircrew, aircraft and glider pilots and helicopter crews are regularly exposed to altitude without oxygen supplementation. At altitude, humans are exposed to systemic environmental hypoxia induced by the decrease in barometric pressure (<1,013 hPa) which decreases the inspired partial pressure of oxygen (PIO2), while the oxygen fraction is constant (equal to approximately 20.9%). Effects of altitude on humans occur gradually and depend on the duration of exposure and the altitude level. From 1,500 m altitude (response threshold), several adaptive responses offset the effects of hypoxia, involving the respiratory and the cardiovascular systems, and the oxygen transport capacity of the blood. Fatigue and cognitive and sensory disorders are usually observed from 2,500 m (threshold of prolonged hypoxia). Above 3,500 m (the threshold for disorders), the effects are not completely compensated and maladaptive responses occur and individuals develop altitude headache or acute altitude illness [Acute Mountain Sickness (AMS)]. The magnitude of effects varies considerably between different physiological systems and exhibits significant inter-individual variability. In addition to comorbidities, the factors of vulnerability are still little known. They can be constitutive (genetic) or circumstantial (sleep deprivation, fatigue, speed of ascent.). In particular, sleep loss, a condition that is often encountered in real-life settings, could have an impact on the physiological and cognitive responses to hypoxia. In this review, we report the current state of knowledge on the impact of sleep loss on responses to environmental hypoxia in humans, with the aim of identifying possible consequences for AMS risk and cognition, as well as the value of behavioral and non-pharmacological countermeasures.

The dramatic changes in physiology at high altitude (HA) as a result of the characteristic hypobaric hypoxia condition can modify innate and adaptive defense mechanisms of the body. As a consequence, few sojourners visiting HA with mild or asymptomatic infection may have an enhanced susceptibility to high-altitude pulmonary edema (HAPE), an acute but severe altitude sickness. It develops upon rapid ascent to altitudes above 2500 m, in otherwise healthy individuals. Though HAPE has been studied extensively, an elaborate exploration of the HA disease burden and the potential risk factors associated with its manifestation are poorly described. The present review discusses respiratory tract infection (RTI) as an unfamiliar but important risk factor in enhancing HAPE susceptibility in sojourners for two primary reasons. First, the symptoms of RTI s resemble those of HAPE. Secondly, the imbalanced pathways contributing to vascular dysfunction in HAPE also participate in the pathogenesis of the infectious processes. These pathways have a crucial role in shaping host response against viral and bacterial infections and may further worsen the clinical outcomes at HA. Respiratory tract pathogenic agents, if screened in HAPE patients, can help in ascertaining their role in disease risk and also point toward their association with the disease severity. The microbial screenings and identifications of pathogens with diseases are the foundation for describing potential molecular mechanisms underlying host response to the microbial challenge. The prior knowledge of such infections may predict the manifestation of disease etiology and provide better therapeutic options.

Pigoń, Katarzyna, Ryszard Grzanka, Ewa Nowalany-Kozielska, and Andrzej Tomasik. Severe respiratory failure developing in the course of high-altitude pulmonary edema in an alpinist with COVID-19 pneumonia: a case report. High Alt Med Biol. 23:372-376, 2022.-The case of a 38-year-old Polish alpinist, evacuated from base camp (4,200 m) under Lenin's Peak due to severe high-altitude pulmonary edema (HAPE) and symptoms of acute mountain sickness/high-altitude cerebral edema (HACE), is presented. Starting the expedition, the man was asymptomatic and had a negative COVID-19 molecular test. After a few days of trekking, he developed typical HAPE and HACE. After evacuation to the hospital in Bishkek, a diagnosis of acute bronchopneumonia was made by computed tomography (CT) imaging. A COVID-19 test was not performed at that time. After returning to Poland, a complete noninvasive cardiac and pulmonary assessment disclosed no pathology. The initial chest CT reassessment was read as demonstrating the densities typical for COVID-19 pneumonia, and a SARS-CoV-2 antibody test corroborated the diagnosis. Pre-existing lung disease increases the risk of developing HAPE. In the era of the COVID-19 pandemic, people traveling at a high altitude and unaware of the infection are at particular risk.

Hypoxic exposure makes plateau migrators susceptible to high altitude polycythemia (HAPC). Astragalus membranaceus (AM) is an edible and medicinal plant with remarkable immunomodulatory activities. The purpose of this study was to discover if AM could be a candidate for the prevention of HAPC and its mechanism. Here, network pharmacology was applied to screen active compounds, key targets, and enriched pathways of AM in the treatment of HAPC. Molecular docking evaluated the affinity between compounds and core targets. Subsequently, the mechanisms of AM were further verified using the hypoxia exposure-induced mice model of HAPC. The network pharmacology analysis and molecular docking results identified 14 core targets of AM on HAPC, which were predominantly mainly enriched in the HIF-1 pathway. In the HAPC animal models, we found that AM inhibited the differentiation of hematopoietic stem cells into the erythroid lineage. It also suppressed the production of erythrocytes and hemoglobin in peripheral blood by reducing the expression of HIF-1α, EPO, VEGFA, and Gata-1 mRNA. Furthermore, AM downregulated the expression of IL-6, TNF-α, and IFN-γ mRNA, thereby alleviating organ inflammation. In conclusion, AM supplementation alleviates hypoxia-induced HAPC in mice, and TNF-α, AKT1, HIF-1α, VEGFA, IL-6, and IL-1B may be the key targets.

Bellovary, Bryanne N., Andrew D. Wells, Zachary J. Fennel, Jeremy B. Ducharme, Jonathan M. Houck, Trevor J. Mayschak, Ann L. Gibson, Scott N. Drum, and Christine M. Mermier. Could orthostatic stress responses predict acute mountain sickness susceptibility before high altitude travel? A pilot study. High Alt Med Biol 00:000-000, 2022.- Purpose: This study assessed head-up tilt (HUT) responses in relation to acute mountain sickness (AMS)-susceptibility during hypoxic exposure. Materials and Methods: Fifteen participants completed three lab visits: (1) protocol familiarization and cycle maximal oxygen consumption (VO2max) test; (2) HUT test consisting of supine rest for 20 minutes followed by 70° tilting for ≤40 minutes; and (3) 6 hours of hypobaric hypoxic exposure (4,572 m) where participants performed two 30-minute cycling bouts separated by 1 hour at a 50% VO2max workload within the first 3 hours and rested when not exercising. During HUT, systolic blood pressure (SBP), diastolic blood pressure, heart rate (HR), and variability (blood pressure variability [BPV] and HR variability [HRV]) were measured continuously. The AMS scores were determined after 6 hours of exposure. Correlations determined relationships between HUT cardiovascular responses and AMS scores. Repeated-measures analysis of variance (ANOVA) assessed differences between those with and without AMS symptoms during HUT. Results: Higher AMS scores correlated with greater change in SBP variability (r = 0.52, p = 0.048) and blunted changes in HRV (root mean square of successive differences between normal heartbeats r = 0.81, p = 0.001, percentage of adjacent normal sinus intervals that differ by more than 50 milliseconds [pNN50] r = 0.87, p < 0.001) during HUT. A pNN50 interaction (p = 0.02) suggested elevated cardiac sympathetic activity at baseline and a blunted increase in cardiac sympathetic influence throughout HUT in those with AMS (pNN50 baseline: AMS = 26.2% ± 15.3%, no AMS = 51.0% ± 13.5%; first 3 minutes into HUT: AMS = 17.2% ± 19.1%, no AMS = 17.1% ± 10.9%; end of HUT: AMS = 6.2% ± 9.1%, no AMS 11.0% ± 10.0%). Conclusions: The results suggest autonomic responses via HUT differ in AMS-susceptible individuals. Changes in HRV and BPV during HUT may be a promising predictive measurement for AMS-susceptibility, but further research is needed for confirmation.

Ventilatory acclimatization (VA) is important to maintain adequate oxygenation with ascent to high altitude (HA). Transient hypoxic ventilatory response tests lack feasibility and fail to capture the integrated steady-state responses to chronic hypoxic exposure in HA fieldwork. We recently characterized a novel index of steady-state respiratory chemoreflex drive (SSCD), accounting for integrated contributions from central and peripheral respiratory chemoreceptors during steady-state breathing at prevailing chemostimuli. Acetazolamide is often utilized during ascent for prevention or treatment of altitude-related illnesses, eliciting metabolic acidosis and stimulating respiratory chemoreceptors. To determine if SSCD reflects VA during ascent to HA, we characterized SSCD in 25 lowlanders during incremental ascent to 4240 m over 7 days. We subsequently compared two separate subgroups: no acetazolamide (NAz; n = 14) and those taking an oral prophylactic dose of acetazolamide (Az; 125 mg BID; n = 11). At 1130/1400 m (day zero) and 4240 m (day seven), steady-state measurements of resting ventilation (V̇I ; L/min), pressure of end-tidal (PET)CO2 (Torr), and peripheral oxygen saturation (SpO2 ; %) were measured. A stimulus index (SI; PET CO2 /SpO2) was calculated, and SSCD was calculated by indexing V̇I against SI. We found that (a) both V̇I and SSCD increased with ascent to 4240 m (day seven; V̇I : +39%, p < 0.0001, Hedges' g = 1.52; SSCD: +56.%, p < 0.0001, Hedges' g = 1.65), (b) and these responses were larger in the Az versus NAz subgroup (V̇I : p = 0.02, Hedges' g = 1.04; SSCD: p = 0.02, Hedges' g = 1.05). The SSCD metric may have utility in assessing VA during prolonged stays at altitude, providing a feasible alternative to transient chemoreflex tests.

Chokes, or pulmonary decompression sickness, is a rare but severe manifestation of decompression sickness (DCS) that can be rapidly fatal even with appropriate treatment.

Ascent to high altitude (> 3000 m height above sea level or m.a.s.l) exposes people to hypobaric atmospheric pressure and hypoxemia, which provokes mountain sickness and whose symptoms vary from the mild acute mountain sickness to the life-threatening, high-altitude pulmonary edema (HAPE). This study analysed the risk factors underlying HAPE in dwellers and travellers of the Ecuadorian Andes after sojourning over 3000 m height. A group of HAPE patients (N = 58) was compared to a NO HAPE group (N = 713), through demographic (ethnicity, sex, and age), red blood cell parameters (erythrocytes counts, hematocrit, median corpuscular volume, median corpuscular haemoglobin, and median corpuscular haemoglobin concentration (MCHC)), altitude (threshold: 3000 m.a.s.l.), and health status (vital signs) variables. Analysis of Deviance for Generalised Linear Model Fits (logit regression) revealed patterns of significant associations. High-altitude dwellers, particularly children and elder people, were HAPE-prone, while women were more tolerant of HAPE than men. Interestingly, HAPE prevalence was strongly related to an increment of MCH. The residence at middle altitude was inversely related to the odds of suffering HAPE. Ethnicity did not have a significant influence in HAPE susceptibility. Elevated MCHC emerges like a blood adaptation of Andean highlanders to high altitude and biomarker of HAPE risk.

When sojourners visit to high altitude, various symptoms may appear in the body including gastrointestinal symptoms such as poor appetite or nausea, vomiting, and incapacitating. The gastrointestinal tract is a key organ involved in the development of acute mountain sickness (AMS). The intestinal epithelial lining is covered by mucus layer. Mucosal barrier is considered as first line of protection of the gut wall which not only helps in lubricating and facilitating progression of bolus but also protects intestinal epithelial lining. Gut microbes play a major role in alterations of mucus barrier and may have important role in curtailing gastrointestinal symptoms at high altitude. In our previous study, we have reported ~ 17% decrease in Akkermansia muciniphila bacteria under hypobaric hypoxia exposure in Sprague-Dawley rats. A. muciniphila is a mucin-degrading bacterium. Its presence in the human intestine is inversely associated to a number of diseases. A. muciniphila is found in the mucus layer, where it helps to maintain intestinal integrity and protects from various inflammatory diseases. Hypoxia decreases A. muciniphila bacterium in gut leading to gastrointestinal barrier injury. It could be an important probiotic that may have physiological benefits in high-altitude hypoxia induced clinical scenarios. A large-scale clinical experiments, production feasibility, and regulatory clearances need to be resolved to develop it as next generation probiotic. In this review, we have searched various databases including PubMed and Google Scholar with keywords Akkermansia muciniphila, A. muciniphila, human physiology, etc. to comprehensively highlight the importance of this gut bacterium. KEY POINTS: • High-altitude hypoxia leads to gastrointestinal barrier injury. • Hypoxia decreases Akkermansia muciniphila bacterium in gut. • A. muciniphila as probiotic may help to maintain intestinal integrity.

High-altitude pulmonary edema (HAPE) is the main cause of nontraumatic death at high altitude. HAPE development is not only related to the mode and speed of ascent and the maximum altitude reached, but also individual susceptibility plays an important role. In susceptible individuals, hypoxic pulmonary vasoconstriction leads to exaggerated elevated pulmonary arterial pressures and capillary leakage in the lungs. Thus, this review provides an overview of studies investigating the genetic background in HAPE susceptibles by focusing on specific variants, entire genes, genome-wide signatures, or family studies.

High altitude hypoxia stress is the key cause of high-altitude pulmonary edema and spleen contraction. The molecular mechanism of immune response of various tissue systems to hypoxia stress remains lacking. In this study, we applied proteomics combined with metabolomics to explore the key molecular profilings involved in high altitude hypoxia response in the spleen of mice. The results showed that 166 proteins were significantly up-regulated, and only 39 proteins were down-regulated. Bioinformatics analysis showed that mineral absorption, neuroactive ligand-receptor interaction, arachidonic acid metabolism, IL-17 signaling pathway and NOD-like preceptor signaling pathway were significantly enriched in the list of 166 upregulated differentially expressed proteins (DEPs). Among these metabolic pathways, the former three pathways were co-identified in KEGG terms from LC-MS/MS based metabolic analysis. We further found that both arachidonate 15-lipoxygenase and hematopoietic prostaglandin D synthase were upregulated by around 30% and 80% for their protein levels and mRNA levels, respectively. Most downstream metabolites were upregulated accordingly, such as prostaglandin A2 and D2. This study provides important evidence that arachidonic acid metabolism potentially promotes spleen hypoxia response through a combined analysis of proteomics and metabolism, which could bring new insights for the spleen targeted rational design upon arachidonic acid metabolism of new therapies.

In chronic mountain sickness (CMS), increased blood oxygen (O2)-carrying capacity due to excessive erythrocytosis (EE, [Hb] ≥ 21 g/dL) could be offset, especially during exercise by both impaired cardiac output (Q̇t) and O2 diffusion limitation in lungs and muscle. We hypothesized that EE results in reduced peak V̇o2 despite increased blood O2-carrying capacity, and that isovolumic hemodilution (IVHD) improves exercise capacity. In 14 male residents of Cerro de Pasco, Peru (4,340 m), six with and eight without EE, we measured peak cycle-exercise capacity, V̇o2, Q̇t, arterial blood gas parameters, and (resting) blood volume. This was repeated for participants with EE after IVHD, reducing hematocrit by 20% (from 67% to 53%). From these data, we quantified the major O2 transport pathway components (ventilation, pulmonary alveolar-capillary diffusion, Q̇t, and blood-muscle mitochondria diffusion). Participants with EE had similar peak V̇o2, systemic O2 delivery, and O2 extraction as non-EE controls, however, with lower Q̇t and higher arterial [O2]. After IVHD, peak V̇o2 was preserved (but not enhanced), with lower O2 delivery (despite higher Q̇t) balanced by greater O2 extraction. The considerable variance in exercise capacity across the 14 individuals was explained essentially completely by differences in both pulmonary and muscle O2 diffusional conductances and not by any differences in ventilation, [Hb], nor Q̇t. In conclusion, EE does not result in lower peak V̇o2 in Andean males, and IVHD maintains, but does not enhance, exercise capacity.NEW & NOTEWORTHY Male Andean highlanders with and without excessive erythrocytosis (EE) have similar peak V̇o2 at 4,340 m, with higher arterial [O2] in EE and lower cardiac output (Q̇t), thus maintaining similar O2 delivery. Peak V̇o2 in participants with EE was unaffected by isovolumic hemodilution (hematocrit reduced from 67% to 53%), with lower O2 delivery balanced by slightly increased Q̇t and greater O2 extraction. Differences in lung and muscle diffusing capacity, and not hematocrit variation, accounted for essentially all interindividual variance in peak V̇o2.