Adapting nitric oxide: A review of its foundation, uses in austere medical conditions, and emerging applications.

Nitric oxide was first identified as a novel and effective treatment for persistent pulmonary hypertension of the newborn (PPHN), and has since been found to be efficacious in treating acute respiratory distress syndrome (ARDS) and pulmonary hypertension. Physicians and researchers have also found it shows promise in resource-constrained settings, both within and outside of the hospital, such as in high altitude pulmonary edema (HAPE) and COVID-19. The treatment has been well tolerated in these settings, and is both efficacious and versatile when studied across a variety of clinical environments. Advancements in inhaled nitric oxide continue, and the gas is worthy of investigation as physicians contend with new respiratory and cardiovascular illnesses, as well as unforeseen logistical challenges.

High-Altitude Pulmonary Edema in Two Pediatric Patients with Pre-Existing Lung Disease.

BACKGROUND: The illnesses associated with changes in barometric pressure can be classified into three types: acute mountain sickness, high-altitude pulmonary edema (HAPE), and high-altitude cerebral edema. HAPE is a rare form of pulmonary edema that occurs in susceptible individuals after arriving at altitudes over 2500 m above sea level (m). Only a few studies have reported classical HAPE among children with underlying cardiopulmonary comorbidities. In this study, we report two pediatric cases of classical HAPE that occurred immediately upon arriving at Abha city (with an average elevation of 2270 m above sea level). Notably, both patients possessed underlying chronic lung diseases, raising crucial questions about susceptibility factors and the early onset manifestations of HAPE. CASE: Two pediatric cases of HAPE are presented. The first patient, with a medical history of repaired right congenital diaphragmatic hernia and subsequent right lung hypoplasia, developed HAPE following their ascent to a high altitude. The second patient, diagnosed with diffuse lung disease of unknown etiology, experienced HAPE after a rapid high-altitude ascent. Both patients resided in low-altitude areas prior to ascent. The initial emergency room assessment revealed that both patients had severe hypoxia with respiratory distress that mandated the initiation of respiratory support and 100% oxygen therapy. They required intensive care unit admission, improved after 5 days of hospitalization, and were sent home in good condition. CONCLUSION: HAPE is a complex, potentially life-threatening high-altitude illness with diverse clinical presentations and variable risk factors. This case report sheds light on a potential predisposition factor-pre-existing lung disease-in children experiencing severe HAPE. While further validation is crucial, this valuable insight opens doors for improved preventative strategies and informed medical decisions for children with pre-existing lung conditions traveling to high altitudes.

Effect of furosemide in the treatment of high-altitude pulmonary edema.

BACKGROUND: High-altitude pulmonary edema (HAPE) refers to the onset of breathlessness, cough, and fever at rest after arriving at high altitudes. It is a life-threatening illness caused by rapid ascent to high altitudes. Furosemide is controversial in HAPE treatment but is routinely used in China. Further research is needed to assess its efficacy and impact on HAPE management and prognosis. The aim of this study is to determine the effectiveness of furosemide for HAPE. METHODS: A retrospective was conducted to analysis of patients with HAPE admitted to the People's Hospital of Shigatse City from January 2018 to September 2023. Patients were divided into furosemide group and non-furosemide group for further analysis. Clinical variables including demographic information, comorbidities, vital signs, inflammatory markers, biochemical analysis, CT severity score and prognostic indicators were collected. RESULTS: A total of 273 patients were enrolled, with 209 patients in the furosemide group and 64 patients in the non-furosemide group. The furosemide group showed a significantly decrease in CT severity scores compared to the non-furosemide group. Subgroup analysis showed that the longer the duration of furosemide use, the more pronounced the improvement in lung CT severity scores. But there were no significant differences in length of hospital stay and in-hospital mortality between the two groups. CONCLUSION: Furosemide helps alleviate pulmonary edema in HAPE patients, but further research is needed to clarify its impact on prognosis.

Hypobaric hypoxia modulated structural characteristics of circulating cell-free DNA in high-altitude pulmonary edema.

The utility of cell-free (cf) DNA has extended as a surrogate or clinical biomarker for various diseases. However, a more profound and expanded understanding of the diverse cfDNA population and its correlation with physiological phenotypes and environmental factors is imperative for using its full potential. The high-altitude (HA; altitude > 2,500 m above sea level) environment characterized by hypobaric hypoxia offers an observational case-control design to study the differential cfDNA profile in patients with high-altitude pulmonary edema (HAPE) (number of subjects, n = 112) and healthy HA sojourners (n = 111). The present study investigated cfDNA characteristics such as concentration, fragment length size, degree of integrity, and subfractions reflecting mitochondrial-cfDNA copies in the two groups. The total cfDNA level was significantly higher in patients with HAPE, and the level increased with increasing HAPE severity (P = 0.0036). A lower degree of cfDNA integrity of 0.346 in patients with HAPE (P = 0.001) indicated the prevalence of shorter cfDNA fragments in circulation in patients compared with the healthy HA sojourners. A significant correlation of cfDNA characteristics with the peripheral oxygen saturation levels in the patient group demonstrated the translational relevance of cfDNA molecules. The correlation was further supported by multivariate logistic regression and receiver operating characteristic curve. To our knowledge, our study is the first to highlight the association of higher cfDNA concentration, a lower degree of cfDNA integrity, and increased mitochondrial-derived cfDNA population with HAPE disease severity. Further deep profiling of cfDNA fragments, which preserves cell-type specific genetic and epigenetic features, can provide dynamic physiological responses to hypoxia.NEW & NOTEWORTHY This study observed altered cell-free (cf) DNA fragment patterns in patients with high-altitude pulmonary edema and the significant correlation of these patterns with peripheral oxygen saturation levels. This suggests deep profiling of cfDNA fragments in the future may identify genetic and epigenetic mechanisms underlying physiological and pathophysiological responses to hypoxia.

Clinical and Pathophysiological Features of High-altitude Pulmonary Edema in the Japanese Population: A Review of Studies on High-altitude Pulmonary Edema in Japan.

High-altitude pulmonary edema (HAPE) is a life-threatening, noncardiogenic pulmonary edema that occurs in unacclimatized individuals rapidly ascending to high altitudes above 2,500 m above sea level. Until the entity of HAPE was first identified in a case report published in Japan in 1966, the symptoms of severe dyspnea or coma occurring in climbers of the Japan Alps were incorrectly attributed to pneumonia or congestive heart failure. The Shinshu University Hospital serves as the central facility for rescuing and treating patients with HAPE in the region. Over the past 50 years, a series of studies have been conducted at Shinshu University to gain a better understanding of the characteristics of HAPE. This review summarizes the major achievements of these studies, including their clinical features, management, and pathogenesis of HAPE, particularly in the Japanese population.

B2M is a Biomarker Associated With Immune Infiltration In High Altitude Pulmonary Edema.

BACKGROUND: High altitude pulmonary edema (HAPE) is a serious mountain sickness with certain mortality. Its early diagnosis is very important. However, the mechanism of its onset and progression is still controversial. AIM: This study aimed to analyze the HAPE occurrence and development mechanism and search for prospective biomarkers in peripheral blood. METHODS: The difference genes (DEGs) of the Control group and the HAPE group were enriched by gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and then GSEA analysis was performed. After identifying the immune-related hub genes, QPCR was used to verify and analyze the hub gene function and diagnostic value with single-gene GSEA and ROC curves, and the drugs that acted on the hub gene was found in the CTD database. Immune infiltration and its association with the hub genes were analyzed using CIBERSORT. Finally, WGCNA was employed to investigate immune invasion cells' significantly related gene modules, following enrichment analysis of their GO and KEGG. RESULTS: The dataset enrichment analysis, immune invasion analysis and WGCNA analysis showed that the occurrence and early progression of HAPE were unrelated to inflammation. The hub genes associated with immunity obtained with MCODE algorithm of Cytoscape were JAK2 and B2M.. RT-qPCR and ROC curves confirmed that the hub gene B2M was a specific biomarker of HAPE and had diagnostic value, and single-gene GSEA analysis confirmed that it participated in MHC I molecule-mediated antigen presentation ability decreased, resulting in reduced immunity. CONCLUSION: Occurrence and early progression of high altitude pulmonary edema may not be related to inflammation. B2M may be a new clinical potential biomarker for HAPE for early diagnosis and therapeutic evaluation as well as therapeutic targets, and its decrease may be related to reduced immunity due to reduced ability of MCH I to participate in antigen submission.

Pressure-sensitive multivesicular liposomes as a smart drug-delivery system for high-altitude pulmonary edema.

Changes in bodily fluid pressures, such as pulmonary artery pressure, play key roles in high-altitude pulmonary edema (HAPE) and other disorders. Smart delivery systems releasing a drug in response to these pressures might facilitate early medical interventions. However, pressure-responsive delivery systems are unavailable. We here constructed hydrostatic pressure-sensitive multivesicular liposomes (PSMVLs) based on the incomplete filling of the internal vesicle space with neutral lipids. These liposomes were loaded with amlodipine besylate (AB), a next-generation calcium channel inhibitor, to treat HAPE on time. AB-loaded PSMVLs (AB-PSMVLs) were destroyed, and AB was released through treatment under hydrostatic pressure of at least 25 mmHg. At 25 mmHg, which is the minimum pulmonary artery pressure value in HAPE, 38.8% of AB was released within 1 h. In a mouse HAPE model, AB-PSMVLs concentrated in the lung and released AB to diffuse into the vascular wall. Intravenously injected AB-PSMVLs before HAPE modeling resulted in a stronger protection of lung tissues and respiratory function and lower occurrence of pulmonary edema than treatment with free drug or non-pressure-sensitive AB-loaded liposomes. This study offers a new strategy for developing smart drug delivery systems that respond to changes in bodily fluid pressures.

Wilderness Medical Society Clinical Practice Guidelines for the Prevention, Diagnosis, and Treatment of Acute Altitude Illness: 2024 Update.

To provide guidance to clinicians about best practices, the Wilderness Medical Society (WMS) convened an expert panel to develop evidence-based guidelines for prevention, diagnosis, and treatment of acute mountain sickness, high altitude cerebral edema, and high altitude pulmonary edema. Recommendations are graded based on the quality of supporting evidence and the balance between the benefits and risks/burdens according to criteria put forth by the American College of Chest Physicians. The guidelines also provide suggested approaches for managing each form of acute altitude illness that incorporate these recommendations as well as recommendations on how to approach high altitude travel following COVID-19 infection. This is an updated version of the original WMS Consensus Guidelines for the Prevention and Treatment of Acute Altitude Illness published in Wilderness & Environmental Medicine in 2010 and the subsequently updated WMS Practice Guidelines for the Prevention and Treatment of Acute Altitude Illness published in 2014 and 2019.

High-Altitude Pulmonary Edema Combined with Spontaneous Pneumomediastinum: A Case Report.

Background: High-altitude pulmonary edema (HAPE) is a serious life-threatening disease that occurs after rapid ascent to high altitude; its main early-stage presentations include fatigue, headache, low-grade fever, dyspnea, and cough. X-ray and computed tomography (CT) images show pulmonary shadows and patches, which may be localized (initial right lung field predomination) or generalized to the bilateral lung base. Case Presentation: In this report, we present a case of a 25-year-old man diagnosed with HAPE combined with spontaneous pneumomediastinum. After a quick descent and effective medical treatment, this patient made a full recovery. The case may provide helpful information for the prevention and treatment of this disease since an increased number of people, especially young men, currently travel and work at high altitudes. Conclusion: After accurate clinical diagnosis with the help of CT or X-ray, immediate descent and appropriate oxygen supplementation are the most effective treatments for HAPE at high altitude.

Probe-based confocal laser endomicroscopy for evaluating high-altitude pulmonary edema in canines.

Background: Real-time assessment of high-altitude pulmonary edema (HAPE) remains a challenge. Probe-based confocal laser microscopy (pCLE) allows a real-time in vivo visualization of the alveoli. This study aimed to develop a new non-invasive method for analyzing microscopic images in a canine model of HAPE using pCLE. Materials and methods: This was a prospective, controlled animal study in adult male beagle dogs randomized to control and HAPE groups. The HAPE group was exposed to a high altitude of 6000 m for 48 h. The blood gas levels, lung morphological changes, infectious factors, and lung wet-to-dry ratio were analyzed in different groups. The pCLE images were described based on the volume air index (VAI), which applies an integral over specific signal intensities. Results: The lung wet-to-dry weight ratio and injury scores in the HAPE group were significantly increased compared with those of the control group. The levels of infectious factors interleukin-1 beta, tumor necrosis factor-alpha, and interleukin-6 were significantly increased in the HAPE group compared with those in the control group. VAI was significantly decreased in the HAPE group. Conclusion: pCLE is a potential adjudicative bronchoscopic imaging technique for assessing HAPE. VAI may be acquired from quantitative parameters in the analysis of images.

High-Altitude Pulmonary Edema in Women: A Scoping Review-UIAA Medical Commission Recommendations.

Pichler Hefti, Jacqueline, Dominique Jean, Alison Rosier, Mia Derstine, David Hillebrandt, Lenka Horakova, Linda E. Keyes, Kaste Mateikaite-Pipiriene, Peter Paal, Marija Andjelkovic, Beth Beidlemann, and Susi Kriemler. High-altitude pulmonary edema in women: a scoping review-UIAA Medical Commission Recommendations. High Alt Med Biol. 24:268-273, 2023. Background: High-altitude pulmonary edema (HAPE) can occur >2,500-3,000 m asl and is a life-threatening medical condition. This scoping review aims to summarize the current data on sex differences in HAPE. Methods: The International Climbing and Mountaineering Federation (UIAA) Medical Commission convened an international author team to review women's health issues at high altitude. Pertinent literature from PubMed and Cochrane was identified by keyword search combinations (including HAPE), with additional publications found by hand search. The primary search focus was for original articles that included minimum one woman and at least a rudimentary subgroup analysis. Results: The literature search yielded 7,165 articles, 416 of which were relevant for HAPE, and 7 of which were ultimately included here. Six were case series, consistently reporting a lower HAPE prevalence in women. The one retrospective case-control study reported male HAPE prevalence at 10/100,000 and female at 0.74/100,000. No studies were identified that directly compared sex differences in the prevalence of HAPE. No published data was found for topics other than epidemiology. Conclusions: Few studies and associated methodological limitations allow few conclusions to be drawn. Incidence of HAPE may be lower in women than in men. We speculate that besides physiological aspects, behavioral differences may contribute to this potential sex difference.

Notoginsenoside R1 protects against hypobaric hypoxia-induced high-altitude pulmonary edema by inhibiting apoptosis via ERK1/2-P90rsk-BAD ignaling pathway.

High-altitude pulmonary edema (HAPE) is a potentially fatal disease. Notoginsenoside R1 is a novel phytoestrogen with anti-inflammatory, antioxidant and anti-apoptosis properties. However, its effects and underlying mechanisms in the protection of hypobaric hypoxia-induced HAPE rats remains unclear. This study aimed to explore the protective effects and underlying mechanisms of Notoginsenoside R1 in hypobaric hypoxia-induced HAPE. We found that Notoginsenoside R1 alleviated the lung tissue injury, decreased lung wet/dry ratio, and reduced inflammation and oxidative stress. Additionally, Notoginsenoside R1 ameliorated the changes in arterial blood gas, decreased the total protein concentration in bronchoalveolar lavage fluid, and inhibited the occurrence of apoptosis caused by HAPE. In the process of further exploration of the mechanism, it was found that Notoginsenoside R1 could promote the activation of ERK1/2-P90rsk-BAD signaling pathway, and the effect of Notoginsenoside R1 was attenuated after the use of ERK1/2 inhibitor U0126. Our study indicated that the protective effects of Notoginsenoside R1 against HAPE were mainly related to the inhibition of inflammation, oxidative stress, and apoptosis. Notoginsenoside R1 may be a potential candidate for preventing HAPE.

Protective effects of Eleutheroside E against high-altitude pulmonary edema by inhibiting NLRP3 inflammasome-mediated pyroptosis.

Eleutheroside E (EE) is a primary active component of Acanthopanax senticosus, which has been reported to inhibit the expression of inflammatory genes, but the underlying mechanisms remain elusive. High-altitude pulmonary edema (HAPE) is a severe complication of high-altitude exposure occurring after ascent above 2500 m. However, effective and safe preventative measures for HAPE still need to be improved. This study aimed to elucidate the preventative potential and underlying mechanism of EE in HAPE. Rat models of HAPE were established through hypobaric hypoxia. Mechanistically, hypobaric hypoxia aggravates oxidative stress and upregulates (pro)-inflammatory cytokines, activating NOD-like receptor protein 3 (NLRP3) inflammasome-mediated pyroptosis, eventually leading to HAPE. EE suppressed NLRP3 inflammasome-mediated pyroptosis by inhibiting the nuclear translocation of nuclear factor kappa-Β (NF-κB), thereby protecting the lung from HAPE. However, nigericin (Nig), an NLRP3 activator, partially abolished the protective effects of EE. These findings suggest EE is a promising agent for preventing HAPE induced by NLRP3 inflammasome-mediated pyroptosis.

Lung diffusing capacity after different modalities of exercise at sea level and hypobaric simulated altitude of 4.000 m / Capacidad de difusión pulmonar bajo diferentes modalidades de ejercicio a nivel del mar y en hipoxia hipobárica simulada de 4.000 m

Introduction: Lung diffusion capacity of carbon monoxide (DLCO) provides a measure of gas transfer in the lungs, which increase in relation to exercise and decrease in the presence of lung interstitial disease. The aim of this study is to evaluate the changes in lung diffusion after anaerobic and aerobic exercise in a cycle ergometer. Material and method: The participants were 9 healthy active subjects, including six females and three males (age: 24.3 ± 3.1 years). Lung diffusion capacity for carbon monoxide (DLCO) was studied under two different protocols: In the first day, DLCO was measured at SL at rest (SL-R), after 30-s maximal exercise (SL-ANA), and after 15-min moderate continuous exercise (SL-AER). In the second day, DLCO was evaluated at rest at SL, and then at HA (4,000 m) at rest (HA-R) and after 30-min of moderate interval exercise (HA-AER). Results: There was an increase in DLCO from rest to after SL-ANA (32.5 ± 6.4 to 40.3 ± 11.6 mL·min-1·mmHg-1, P = 0.027). In the second day, DLCO was evaluated at rest at SL, and then at HA (4,000 m) at rest (HA-R) and after 30-min of moderate interval exercise (HA-AER). During HA exposure, there was no changes in DLCO, either at HA-R, or after HA-AER. Conclusions: Lung diffusion capacity largely increased after 30-s maximal exercise in a cycle ergometer, although the O2-dependence is small during this type of anaerobic exercise. Thus, exercise intensity may be a key modulator of the changes in lung diffusing capacity in relation to exercise.(AU)

Introducción: La difusión pulmonar para el monóxido de carbono (DLCO) proporciona una medida de la transferencia de gas en los pulmones, que aumenta con relación al ejercicio y disminuye en presencia de una lesión intersticial pulmonar. El objetivo de este estudio es fue evaluar los cambios en la difusión pulmonar después de un ejercicio aeróbico y anaeróbico en cicloergómetro. Material y método: Los participantes fueron 9 sujetos físicamente activos, incluyendo seis mujeres (edad: 24,6 ± 3,6 años) y tres hombres (edad: 23,7 ± 1,5 años). La DLCO se estudió bajo dos protocolos diferentes: El primer día, la DLCO fue medida a nivel del mar en reposo (SL-R), después de un esfuerzo máximo de 30 segundos (SL-ANA), y después de un ejercicio moderado continuo de 15-min (SL-AER). El segundo día, la DLCO fue evaluada a nivel del mar en reposo (SL-R, y luego en altitud (4.000 m) en reposo (HA-R) y después de un ejercicio interválico de 30 minutos (HA-AER). Resultados: Se produjo un aumento de la DLCO de la SL-R a la SL-ANA (32,5 ± 6,4 a 40,3 ± 11,6 mL·min-1·mmHg-1, p = 0,027). En el segundo día, la DLCO no se modificó después de la exposición en altitud, ya sea en reposo a 4.000 m (HA-R) o después del ejercicio interválico moderado a dicha intensidad (HA-AER). Conclusiones: La difusión pulmonar aumentó ampliamente después de un esfuerzo máximo de 30 segundos en cicloergómetro, aunque la dependencia del oxígeno en este tipo de esfuerzos es pequeña. La intensidad del esfuerzo es un modulador determinante en las modificaciones de la difusión pulmonar con relación al ejercicio.(AU)

Dry Powder Formulations for Inhalation Require a Smaller Aerodynamic Diameter for Usage at High Altitude.

BACKGROUND: High Altitude Pulmonary Edema (HAPE) seriously threatens the health of people at high altitudes. There are drug treatments for HAPE, and dry powder formulations (DPFs) represent a rapid and accessible delivery vehicle for these drugs. However, there are presently no reports on the inhalability of DPFs in low-pressure environments. Given the reduced atmospheric pressure typical at high altitudes, conventional DPFs might not be suitable for inhalation. Therefore, it is necessary to elucidate the deposition behaviors of dry powder in the respiratory tract at low pressure, as well as to improve their pulmonary deposition efficiency via adjustments to their formulation and design. METHODS: The effect of air pressure, inspiratory velocity, and particle properties (such as size, density, and aerodynamic diameter) on pulmonary deposition of DPFs was calculated by a computational fluid dynamics (CFD)-coupled discrete phase model. DPFs of various aerodynamic diameters were prepared by spray drying, and the inhalability of these DPFs in a low-pressure environment was evaluated in mice. Finally, a mouse model of HAPE was established, and the treatment of HAPE by nifedipine-loaded DPFs with small aerodynamic diameter was validated. RESULTS: CFD results showed that low pressure decreased the deposition of DPFs in the lungs. At 0.5 standard atmosphere, DPFs with aerodynamic diameter of ∼2.0 µm could not enter the lower respiratory tract; however, a decrease in the physical diameter, density, and, consequently, the aerodynamic diameter of the DPFs was able to enhance pulmonary deposition of these powders. To validate the CFD results, three kinds of dry powder with aerodynamic diameters of 0.66, 0.98, and 2.00 µm were prepared by spray drying. Powders with smaller aerodynamic diameter could be inhaled into the lungs of mice more effectively, and, consequently could ameliorate the progression of HAPE more effectively than conventional powders. These results were consistent with the CFD results. CONCLUSIONS: Low atmospheric pressure can prevent the pulmonary deposition of DPFs at high altitudes. Compared with conventional DPFs, powders with smaller aerodynamic diameter can be effectively inhaled at these pressures and thus might be more suitable for the treatment the HAPE.

Low-dose of caffeine alleviates high altitude pulmonary edema via regulating mitochondrial quality control process in AT1 cells.

Backgrounds: High-altitude pulmonary edema (HAPE) is a life-threatening disease without effective drugs. Caffeine is a small molecule compound with antioxidant biological activity used to treat respiratory distress syndrome. However, it is unclear whether caffeine plays a role in alleviating HAPE. Methods: We combined a series of biological experiments and label-free quantitative proteomics analysis to detect the effect of caffeine on treating HAPE and explore its mechanism in vivo and in vitro. Results: Dry and wet weight ratio and HE staining of pulmonary tissues showed that the HAPE model was constructed successfully, and caffeine relieved pulmonary edema. The proteomic results of mice lungs indicated that regulating mitochondria might be the mechanism by which caffeine reduced HAPE. We found that caffeine blocked the reduction of ATP production and oxygen consumption rate, decreased ROS accumulation, and stabilized mitochondrial membrane potential to protect AT1 cells from oxidative stress damage under hypoxia. Caffeine promoted the PINK1/parkin-dependent mitophagy and enhanced mitochondrial fission to maintain the mitochondria quality control process. Conclusion: Low-dose of caffeine alleviated HAPE by promoting PINK1/parkin-dependent mitophagy and mitochondrial fission to control the mitochondria quality. Therefore, caffeine could be a potential treatment for HAPE.

Whole-exome sequencing in searching for novel variants associated with the development of high altitude pulmonary edema.

BACKGROUND: High altitude pulmonary edema (HAPE) is a high-altitude idiopathic disease with serious consequences due to hypoxia at high altitude, and there is individual genetic susceptibility. Whole-exome sequencing (WES) is an effective tool for studying the genetic etiology of HAPE and can identify potentially novel mutations that may cause protein instability and may contribute to the development of HAPE. MATERIALS AND METHODS: A total of 50 unrelated HAPE patients were examined using WES, and the available bioinformatics tools were used to perform an analysis of exonic regions. Using the Phenolyzer program, disease candidate gene analysis was carried out. SIFT, PolyPhen-2, Mutation Taster, CADD, DANN, and I-Mutant software were used to assess the effects of genetic variations on protein function. RESULTS: The results showed that rs368502694 (p. R1022Q) located in NOS3, rs1595850639 (p. G61S) located in MYBPC3, and rs1367895529 (p. R333H) located in ITGAV were correlated with a high risk of HAPE, and thus could be regarded as potential genetic variations associated with HAPE. CONCLUSION: WES was used in this study for the first time to directly screen genetic variations related to HAPE. Notably, our study offers fresh information for the subsequent investigation into the etiology of HAPE.

Preliminary screening of biomarkers in HAPE based on quasi-targeted metabolomics.

High altitude pulmonary edema (HAPE) is a serious threat to the physical and mental health of people who quickly enter high plateaus, deserves more attention and in-depth research. In our study, through the detection of various physiological indexes and other phenotypes in a HAPE rat model, the HAPE group showed a significant decrease in oxygen partial pressure and oxygen saturation, and a significant increase in pulmonary artery pressure and lung tissue water content. The lung histomorphology showed characteristics such as pulmonary interstitial thickening and inflammatory cell infiltration. We applied quasi-targeted metabolomics to compare and analyze the components of metabolites in arterial-veinous blood in control rats and HAPE rats. Using kyoto Encyclopedia of Genes Genomes (KEGG) enrichment analysis and two machine algorithms, we speculate that after hypoxic stress and comparing arterial blood and venous blood products in rats, the metabolites were richer, indicating that normal physiological activities, such as metabolism and pulmonary circulationhad a greater impact after hypoxic stress; D-mannoseDOWN, oxidized glutathioneDOWN, glutathione disulfideDOWN, and dehydrocholic acidDOWN in arterial blood play key roles in predicting the occurrence of HAPE; in venous blood, L-leucineDOWN, L-thyroxineDOWN, and cis-4-hydroxy- D-prolineDOWN may have key roles, which can be considered biomarkers of HAPE. This result provides a new perspective for the further diagnosis and treatment of plateau disease and lays a strong foundation for further research.

Clinical characteristics of venous thromboembolism onset from severe high altitude pulmonary edema in plateau regions.

BACKGROUND: To investigate venous thromboembolism (VTE) in hospitalized patients with severe high altitude pulmonary edema (HAPE), we performed a single center retrospective study to evaluate its clinical characteristics, prognosis, and potential thromboprophylaxis strategies in a large referral and treatment center in plateau regions. METHODS: We studied a total of 18 patients with severe HAPE from January 1, 2012 to December 31, 2021. Demographic and clinical data, laboratory data, including ultrasound scans of the lower extremities and cardiac ultrasound, and computed tomographic pulmonary angiography (CTPA) variables were obtained, and comparisons were made between groups with and without VTE. RESULTS: Of the 18 patients hospitalized with severe HAPE (age 43 (range, 34-54) years, 14 [77.8%] men), 7 patients developed VTE (38.9%), including 5 with deep vein thrombosis (DVT) and pulmonary embolism (PE), 2 of whom had DVT only. Eighteen patients are all firstly rapid ascent to high altitudes which the mean altitude was 3700 m (3656-4050 m). Compared with patients who did not have VTE, patients with VTE had a longer time in hospital (13 [11, 19] versus 9 [7, 12]; P = 0.027), respiratory failure (6 [85.7%] versus 2 [18.2%]; P = 0.013), the shortened APTT (21.50 [19.00, 27.50] versus 26.30 [24.80, 30.10]; P = 0.044) and the higher level of D-dimer (7.81 [4.62, 9.60] versus 2.90 [1.75, 3.37]; P = 0.003). The proportion of thromboprophylaxis is too low in our cohort which 2 of 18 (11.1%) patients were given VTE prophylaxis. There was no statistically significant difference between the VTE and non-VTE groups (0 [0.0%] versus 2 [18.2%]; P = 0.497). CONCLUSIONS: The prevalence of VTE is high in hospitalized patients with severe high altitude pulmonary edema (HAPE). Prophylaxis for venous thromboembolism may be protective in severe HAPE patients after admission. Our data seem to suggest that VTE is probably an additional prognostic factors in patients with severe HAPE.

Hyperbaric oxygen preconditioning for prevention of acute high-altitude diseases: Fact or fiction?

Acute high-altitude diseases, including acute mountain sickness (AMS), high-altitude cerebral edema (HACE), and high-altitude pulmonary edema (HAPE), have been recognized as potentially lethal diseases for altitude climbers. Various preconditioning stimuli, including hyperbaric oxygen (HBO), have been proposed to prevent acute high-altitude diseases. Herein, we reviewed whether and how HBO preconditioning could affect high-altitude diseases and summarized the results of current trials. Evidence suggests that HBO preconditioning may be a safe and effective preventive method for acute high-altitude diseases. The proposed mechanisms of HBO preconditioning in preventing high-altitude diseases may involve: 1) protection of the blood-brain barrier and prevention of brain edema, 2) inhibition of the inflammatory responses, 3) induction of the hypoxia-inducible factor and its target genes, and 4) increase in antioxidant activity. However, the optimal protocol of HBO preconditioning needs further exploration. Translating the beneficial effects of HBO preconditioning into current practice requires the "conditioning strategies" approach. More large-scale and high-quality randomized controlled studies are needed in the future.