High Altitude Pulmonary Edema Research Articles

Acute Coronary Syndrome at Altitude: Diagnostic Dilemma on Aconcagua Using Point-of-Care Ultrasound.

At the Plaza de Mulas medical tent, located at 4300 m (14,100 ft) along the Normal Route to the 6960 m (22,837 ft) summit of Aconcagua in Argentina, a Korean male in his 50s with no known medical conditions presented with lightheadedness and shortness of breath. He had taken sildenafil and acetazolamide that morning without improvement. Vital signs on arrival were notable for oxygen saturations in the high 60s with basilar crackles on lung auscultation, concerning for high altitude pulmonary edema. The patient was started on oxygen via nasal cannula and given dexamethasone. History was limited secondary to language barriers, but on review of systems the patient noted mild chest pressure. Bedside cardiac echocardiogram was performed, which revealed a septal wall motion abnormality. The patient was therefore given aspirin and clopidogrel and was flown to a lower trailhead, where he was met by local Emergency Medical Services. A 12-lead electrocardiogram revealed an anterior ST-elevation myocardial infarction, and the patient was taken emergently to the catheterization lab in Mendoza and underwent stent placement with a full recovery.

Evaluation and Management of the Individual with Recurrent High Altitude Pulmonary Edema.

Luks AM, Grissom CK. Evaluation and Management of the Individual with Recurrent HAPE. High Alt Med Biol. 00:000-000, 2024. Individuals with a history of acute altitude illness often seek recommendations from medical providers on how to prevent such problems on future ascents to high elevation. Although many of these cases can be managed with pharmacologic prophylaxis and counseling about the appropriate rate of ascent alone, there are some situations in which further diagnostic evaluation may also be warranted. One such situation is the individual with recurrent episodes of high altitude pulmonary edema (HAPE), as one of several predisposing factors may be present that warrants additional interventions beyond pharmacologic prophylaxis and slow ascent and may even preclude future travel to high altitude. This review considers this situation in greater detail. Structured around the case of an otherwise healthy 27-year-old individual with recurrent episodes of HAPE who would like to climb Denali (6,190 m), the review examines the known risk factors for disease and then provides guidance regarding when and how to evaluate such individuals and appropriate steps to prevent HAPE on further ascents to high elevation. Except in rare circumstances, a history of recurrent HAPE does not preclude further ascent to high elevation, as a multipronged approach including pharmacologic prophylaxis, careful planning about the rate of ascent, and the degree of physical effort and other strategies, such as preacclimatization, staged ascent, and use of hypoxic tents, can be employed to reduce the risk of recurrence with future travel.

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.

Long noncoding RNA ANRIL alleviates hypoxia-induced pulmonary microvascular endothelial cell damage.

High-altitude pulmonary oedema (HAPE) is a form of noncardiogenic pulmonary oedema. Studies have found that long noncoding RNA (lncRNA) plays an important role in HAPE. ANRIL is significant in pulmonary illnesses, which implies that alterations in ANRIL expression levels may be involved in the beginning and development of HAPE. However, the specific mechanism is indistinct. The present study is meant to explore the effect and mechanism of ANRIL on hypoxic-induced injury of pulmonary microvascular endothelial cells (PMEVCs). In the hypoxic model of PMVECs, overexpression of ANRIL or knockdown of miR-181c-5p was performed to assess cell proliferation, apoptosis, and migration. Furthermore, the levels of apoptosis-related proteins, inflammatory factors, and vascular active factors were also measured. The results showed that, after 24 h of hypoxia, PMVECs proliferation and migration were suppressed in comparison to the control group, along with an increase in apoptosis, a decrease in the expression of ANRIL, and an increase in the expression of miR-181c-5p (all p < .05). The damage caused by hypoxia in PMVECs can be lessened by overexpressing ANRIL, which also inhibits the production of TNF-α, iNOS, and VEGF as well as BAX and cleaved caspase-3 (all p < .05). Further experimental results showed that overexpression of ANRIL and knockdown of miR-181c-5p had the same protection against hypoxic injury in PMVECs (all p < .05). Our study suggests that ANRIL may prevent hypoxia injury to PMVECs in HAPE through the negative regulation of miR-181c-5p.

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

BackgroundHigh-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.MethodsA 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.ResultsA 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.ConclusionFurosemide helps alleviate pulmonary edema in HAPE patients, but further research is needed to clarify its impact on prognosis.

The impact of sleeping in an elevated upper body position during acclimatization to high altitude on acute mountain sickness and pulmonary artery systolic pressure

Background: The effect of sleeping positions during acclimatization to high altitude on Acute Mountain Sickness (AMS) and High Altitude Pulmonary Edema (HAPE) is unknown. We tested whether sleeping with the upper body raised by 5° reduces prevalence and severity of symptoms of AMS as well as of elevated pulmonary artery systolic pressure (PASP) values as a risk factor of HAPE. Methods: Randomly assigning trekking tourist volunteers n = 44 (25 m, 19 f; mean age 42.9 yr) sleeping at 4280 m or 5170 m to the experimental group (upper body elevated by 5°), or to the control group. After exclusion of other reasons for AMS-like symptoms those assumed to be related to AMS were rated by Lake Louise Score questionnaire in the evening and the following morning of the study. Transthoracic echocardiography was performed on both occasions to estimate PASP. Results: In the study group, symptoms of AMS were significantly reduced in younger subjects (p = 0.021), prevalence of AMS was reduced in women (p = 0.156), and PASP values were significantly reduced in older subjects and men (p = 0.032; p = 0.031 respectively). Conclusion: Results suggest that sleeping with the upper body in elevated position during a high altitude ascent may benefit those suffering from AMS or at risk of HAPE due to elevated PASP values.

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.

Role of neutrophil myeloperoxidase in the development and progression of high-altitude pulmonary edema

BackgroundNeutrophil infiltration and hypoxic pulmonary vasoconstriction induced by hypobaric hypoxic stress are vital in high-altitude pulmonary edema (HAPE). Myeloperoxidase (MPO), an important enzyme in neutrophils, is associated with inflammation and oxidative stress and is also involved in the regulation of nitric oxide synthase (NOS), an enzyme that catalyzes the production of the vasodilatory factor nitric oxide (NO). However, the role of neutrophil MPO in HAPE's progression is still uncertain. Therefore, we hypothesize that MPO is involved in the development of HAPE via NOS. MethodsIn Xining, China (altitude: 2260 m), C57BL/6 N wild-type and mpo−/− mice served as normoxic controls, while a hypobaric chamber simulated 7000 m altitude for hypoxia. L-NAME, a nitric oxide synthase (NOS) inhibitor to inhibit NO production, was the experimental drug, and D-NAME, without NOS inhibitory effects, was the control. After measuring pulmonary artery pressure (PAP), samples were collected and analyzed for blood neutrophils, oxidative stress, inflammation, vasoactive substances, pulmonary alveolar-capillary barrier permeability, and lung tissue morphology. ResultsWild-type mice's lung injury scores, permeability, and neutrophil counts rose at 24 and 48 h of hypoxia exposure. Under hypoxia, PAP increased from 12.89 ± 1.51 mmHg under normoxia to 20.62 ± 3.33 mmHg significantly in wild-type mice and from 13.24 ± 0.79 mmHg to 16.50 ± 2.07 mmHg in mpo−/− mice. Consistent with PAP, inducible NOS activity, lung permeability, lung injury scores, oxidative stress response, and inflammation showed more significant increases in wild-type mice than in mpo−/− mice. Additionally, endothelial NOS activity and NO levels decreased more pronouncedly in wild-type mice than in mpo−/− mice. NOS inhibition during hypoxia led to more significant increases in PAP, permeability, and lung injury scores compared to the drug control group, especially in wild-type mice. ConclusionMPO knockout reduces oxidative stress and inflammation to preserve alveolar-capillary barrier permeability and limits the decline in endothelial NOS activity to reduce PAP elevation during hypoxia. MPO inhibition emerges as a prospective therapeutic strategy for HAPE, offering avenues for precise interventions.

The Value of CT Examination in the Development of Imaging Manifestations of Acute High Altitude Pulmonary Edema

This study aims to analyze the significance of CT examinations in elucidating the imaging manifestations of acute high-altitude pulmonary edema (HAPE). A cohort of 200 patients with acute HAPE, attending the clinic between January 2021 and January 2022, constituted the subjects. Employing distinct examination methods, participants were categorized into a control group (undergoing X-ray examinations, n = 100) and an observation group (undergoing CT examinations, n = 100). Comprehensive patient data were collected, facilitating a comparative analysis of examination results, diagnosis rates, imaging features, and related indicators between the two groups. No statistically significant differences were evident, signifying comparable profiles (P &gt;0.05). However, the observation group exhibited significantly superior examination outcomes compared to the control group (P &lt; 0.01). The diagnostic rate in the observation group reached 98.00%, surpassing the control group’s nursing efficiency at 92.00%. This observed superiority of the observation group was statistically significant (P &lt; 0.01). While both X-ray and CT methods detected high-altitude pulmonary edema, CT examinations provided clearer insights into specific lesions, enhancing accuracy and diagnosis rates. This study underscores the paramount significance of high-altitude pulmonary edema examinations, particularly advocating for the widespread adoption of CT technology.

Continuous Positive Airway Pressure in the Treatment of Pediatric High Altitude Pulmonary Edema: A Case Study.

Treatment of high altitude pulmonary edema (HAPE) can be challenging and is further complicated in the pediatric patient in the prehospital environment. The following case presents a decompensating pediatric patient with HAPE in the prehospital aeromedical environment. It illustrates the potential benefit of continuous positive airway pressure (CPAP) as a treatment modality in the treatment of HAPE.

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

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. This study aimed to analyze the HAPE occurrence and development mechanism and search for prospective biomarkers in peripheral blood. 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. 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. 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.

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.

Potential Candidate Molecules of Past and Present for Combating High Altitude Hypoxia Induced Maladies

Hypobaric hypoxia occurs at high altitudes where barometric pressure is low causing insufficient supply of oxygen leading to many high-altitude illnesses like acute mountain sickness (AMS), high altitude pulmonary edema (HAPE), high altitude cerebral edema (HACE) etc.Medications have been applied to treat and prevent injuries caused by HBH, showing anti-inflammatory, anti-edemagenic, and antioxidant properties. AMS symptoms, such as headache, nausea, weariness, usually go away in 1-2 days. HACE causes brain swelling, elevated intracranial pressure, resulting in confusion, stupor, ataxia, and death.Acetazolamide, dexamethasone, nifedipine are the drugs used for treatment acting oncarbonic anhydrase enzyme, calcium channels.Acetazolamide increases arterial partial pressure of oxygen.Nifedipine relaxes vascular smooth muscles and increases blood flow. Some drugscause side effects also like dizziness, diuresis, nausea, malaise, etc. Hence, a new drug search is needed to find more targeted and fewer side effects for faster relief and better health at high altitudes.

高原肺水肿中的炎症与巨噬细胞免疫作用

高原肺水肿中的炎症与巨噬细胞免疫作用

A Case of Acute Type A Aortic Dissection Complicated with High-Altitude Pulmonary Edema

A Case of Acute Type A Aortic Dissection Complicated with High-Altitude Pulmonary Edema

Asymmetric and symmetric dimethylarginine in high altitude pulmonary hypertension (HAPH) and high altitude pulmonary edema (HAPE)

Introduction: High altitude exposure may lead to high altitude pulmonary hypertension (HAPH) and high altitude pulmonary edema (HAPE). The pathophysiologic processes of both entities have been linked to decreased nitric oxide (NO) availability.Methods: We studied the effect of acute high altitude exposure on the plasma concentrations of asymmetric (ADMA) and symmetric dimethylarginine (SDMA), L-arginine, L-ornithine, and L-citrulline in two independent studies. We further investigated whether these biomarkers involved in NO metabolism were related to HAPH and HAPE, respectively. Fifty (study A) and thirteen (study B) non-acclimatized lowlanders were exposed to 4,559 m for 44 and 67 h, respectively. In contrast to study A, the participants in study B were characterized by a history of at least one episode of HAPE. Arterial blood gases and biomarker concentrations in venous plasma were assessed at low altitude (baseline) and repeatedly at high altitude. HAPE was diagnosed by chest radiography, and HAPH by measuring right ventricular to atrial pressure gradient (RVPG) with transthoracic echocardiography. AMS was evaluated with the Lake Louise Score (LLS) and the AMS-C score.Results: In both studies SDMA concentration significantly increased at high altitude. ADMA baseline concentrations were higher in individuals with HAPE susceptibility (study B) compared to those without (study A). However, upon high altitude exposure ADMA only increased in individuals without HAPE susceptibility, while there was no further increase in those with HAPE susceptibility. We observed an acute and transient decrease of L-ornithine and a more delayed but prolonged reduction of L-citrulline during high altitude exposure. In both studies SDMA positively correlated and L-ornithine negatively correlated with RVPG. ADMA was significantly associated with the occurrence of HAPE (study B). ADMA and SDMA were inversely correlated with alveolar PO2, while L-ornithine was inversely correlated with blood oxygenation and haemoglobin levels, respectively.Discussion: In non-acclimatized individuals ADMA and SDMA, two biomarkers decreasing endothelial NO production, increased after acute exposure to 4,559 m. The observed biomarker changes suggest that both NO synthesis and arginase pathways are involved in the pathophysiology of HAPH and HAPE.

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.

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

BackgroundReal-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 methodsThis 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. ResultsThe 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. ConclusionpCLE is a potential adjudicative bronchoscopic imaging technique for assessing HAPE. VAI may be acquired from quantitative parameters in the analysis of images.

Erythrocyte Nitric Oxide at High Altitude in Mountaineers Susceptible to High-Altitude Pulmonary Edema

Erythrocyte Nitric Oxide at High Altitude in Mountaineers Susceptible to High-Altitude Pulmonary Edema

Kaempferol and ginsenoside Rg1 ameliorate acute hypobaric hypoxia induced lung injury based on network pharmacology analysis

Acute hypobaric hypoxia at high altitude can cause fatal non-cardiogenic high altitude pulmonary edema. Anti-inflammatory and anti-oxidant treatments appear to be a prospective way to alleviate acute hypoxia lung injury. Kaempferol (KA) and ginsenoside Rg1 (GRg1) can be isolated and purified from ginseng with anti-inflammatory, antioxidant, anti-carcinogenic, neuroprotective, and antiaging effects. However, their effects and pharmacological mechanisms on lung injury remains unclear. Network pharmacology analyses were used to explore potential targets of KA and GRg1 against acute hypobaric hypoxia induced lung injury. Rat lung tissues were further used for animal experiment verification. Among the putative targets of KA and GRg1 for inhibition of acute hypobaric hypoxia induced lung injury, AKT1, PIK3R1, PTK2, STAT3, HSP90AA1 and AKT2 were recognized as higher interrelated targets. And PI3K-AKT signaling pathway is considered to be the most important and relevant pathway. The rat experimental results showed that KA and GRg1 significantly improved histopathological changes and decreased pulmonary edema in rats with lung injury caused by acute hypobaric hypoxia. The concentrations of IL-6, TNF-α, MDA, SOD and CAT in rats treated with KA and GRg1 were significantly ameliorated. Protein and mRNA levels of PI3K and AKTI were significantly inhibited after KA administration. KA and GRg1 can lower lung water content, improve lung tissue damage, reduce the production of pro-inflammatory cytokines and the oxidative stress level.