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Pichler Hefti, Jacqueline, Dominique Jean, Alison Rosier, Mia Derstine, David Hillebrandt, Lenka Horakova, Linda E. Keyes, Kastė Mateikaitė-Pipirienė, 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. [ABSTRACT FROM AUTHOR]

Horakova, Lenka, Peter Paal, Jacqueline Pichler Hefti, Marija Andjelkovic, Beth A. Beidleman, Mia Derstine, David Hillebrandt, Dominique Jean, Kastė Mateikaitė-Pipirienė, Alison J. Rosier, Susi Kriemler, and Linda E. Keyes. Women's health at high altitude: An introduction to a 7-part series by the International Climbing and Mountaineering Federation Medical Commission. High Alt Med Biol. 24:243–246, 2023. Background: Women have been traveling to high altitude since the inception of modern mountaineering. Although there are distinct female-specific features such as menstruation and menopause relevant to adaptation to and performance at high altitude, very little data exist on women's high-altitude health. To summarize what is known to date, the Medical Commission of the International Climbing and Mountaineering Federation (UIAA) has created a series of articles on women's health, high altitude illness, and performance at high altitude. Methods: Assembling an international author team, two types of manuscripts were developed: (1) reviews on female-specific topics such as pregnancy; (2) reviews on sex differences in high-altitude related illnesses, nutrition, cold injuries, and mortality. Results: The literature search yielded 7,165 articles, with 482 studies meeting the inclusion criteria for full-text review. The authors of individual chapters reviewed these articles and performed additional hand searches. Conclusions: Some important questions on women sojourning and exercising at high altitude have been studied, but many are still awaiting a qualified and evidence-based response. Our seven reviews, to be published in future issues of this journal, summarize what is known about lowland women sojourning at high altitude, provide recommendations, and highlight knowledge gaps in high altitude women's medicine. [ABSTRACT FROM AUTHOR]

Background: In May 2015, the results of the SERVE-HF trial - addressing adaptive servoventilation (ASV) in chronic congestive heart failure (CHF) patients with central sleep apnea (CSA) - prompted a field safety notice. It was recommended to identify CHF patients treated with ASV and to advise the discontinuation of the treatment. We aimed to analyze the identification process and effect of ASV discontinuation on affected patients.Methods: 126 patients treated with ASV on May 13th, 2015 at our institution were retrospectively analyzed. Treatment decisions, effect of ASV discontinuation and clinical course were followed for a year. Patients on ASV with CHF were compared to those without CHF.Results: The risk criteria of the safety notice were fulfilled by 10.3% of patients (13/126). Additional echocardiographies were performed in 38%. ASV was discontinued in 93% of patients without adverse events (emergency hospitalization in n = 1). CSA reappeared immediately. Day- or nighttime symptoms were reported by 61%. Symptomatic patients were started on alternative treatments. CHF and non-CHF patients differed in cardiac function and type of SDB. CHF patients had shorter overall treatment duration. Compliance to ASV was similar in both groups with a median usage of 412 min (269; 495)/night in the CHF group and 414.5 min (347; 480) in the non-CHF group.Conclusion: Identification of patients "at risk" is feasible but outcome of discontinuation of ASV cannot be evaluated based on these data. ASV withdrawal in patients with stable chronic CHF and CSA leads to an immediate return of sleep disordered breathing. Symptomatic patients may ask for alternative treatment options. [ABSTRACT FROM AUTHOR]

Purpose: Hypoxia and oxidative stress affect endothelial function. Endothelial microparticles (MP) are established measures of endothelial dysfunction and influence vascular reactivity. To evaluate the effects of hypoxia and antioxidant supplementation on endothelial MP profiles, a double-blind, placebo-controlled trial, during a high altitude expedition was performed.Methods: 29 participants were randomly assigned to a treatment group (n = 14), receiving vitamin E, C, A, and N-acetylcysteine daily, and a control group (n = 15), receiving placebo. Blood samples were obtained at 490 m (baseline), 3530, 4590, and 6210 m. A sensitive tandem mass spectrometry method was used to measure 8-iso-prostaglandin F2α and hydroxyoctadecadienoic acids as markers of oxidative stress. Assessment of MP profiles including endothelial activation markers (CD62+MP and CD144+MP) and cell apoptosis markers (phosphatidylserine+MP and CD31+MP) was performed using a standardized flow cytometry-based protocol.Results: 15 subjects reached all altitudes and were included in the final analysis. Oxidative stress increased significantly at altitude. No statistically significant changes were observed comparing baseline to altitude measurements of phosphatidylserine expressing MP (p = 0.1718) and CD31+MP (p = 0.1305). Compared to baseline measurements, a significant increase in CD62+MP (p = 0.0079) and of CD144+MP was detected (p = 0.0315) at high altitudes. No significant difference in any MP level or oxidative stress markers were found between the treatment and the control group.Conclusion: Hypobaric hypoxia is associated with increased oxidative stress and induces a significant increase in CD62+ and CD144+MP, whereas phosphatidylserine+MP and CD31+MP remain unchanged. This indicates that endothelial activation rather than an apoptosis is the primary factor of hypoxia induced endothelial dysfunction. [ABSTRACT FROM AUTHOR]

Background: Findings of cerebral cortical atrophy, white matter lesions and microhemorrhages have been reported in high-altitude climbers. The aim of this study was to evaluate structural cerebral changes in a large cohort of climbers after an ascent to extreme altitudes and to correlate these findings with the severity of hypoxia and neurological signs during the climb. Methods: Magnetic resonance imaging (MRI) studies were performed in 38 mountaineers before and after participating in a high altitude (7126m) climbing expedition. The imaging studies were assessed for occurrence of new WM hyperintensities and microhemorrhages. Changes of partial volume estimates of cerebrospinal fluid, grey matter, and white matter were evaluated by voxel-based morphometry. Arterial oxygen saturation and acute mountain sickness scores were recorded daily during the climb. Results: On post-expedition imaging no new white matter hyperintensities were observed. Compared to baseline testing, we observed a significant cerebrospinal fluid fraction increase (0.34% [95% CI 0.10–0.58], p = 0.006) and a white matter fraction reduction (-0.18% [95% CI -0.32–-0.04], p = 0.012), whereas the grey matter fraction remained stable (0.16% [95% CI -0.46–0.13], p = 0.278). Post-expedition imaging revealed new microhemorrhages in 3 of 15 climbers reaching an altitude of over 7000m. Affected climbers had significantly lower oxygen saturation values but not higher acute mountain sickness scores than climbers without microhemorrhages. Conclusions: A single sojourn to extreme altitudes is not associated with development of focal white matter hyperintensities and grey matter atrophy but leads to a decrease in brain white matter fraction. Microhemorrhages indicative of substantial blood-brain barrier disruption occur in a significant number of climbers attaining extreme altitudes. [ABSTRACT FROM AUTHOR]

Objectives Exposure to high altitudes is associated with oxidative cellular damage due to the increased level of reactive oxygen and nitrogen species and altered activity of antioxidant systems. Subjects were submitted to prolonged hypoxia, to evaluate changes in mitochondrial enzyme activities of monocytes and their attenuation by supplementation with antioxidants. Methods Twelve subjects were randomly assigned to receive antioxidant supplements or placebo prior to and during an expedition to Pik Lenin (7145 m). Monocytes were isolated from blood samples to determine the activity of mitochondrial enzymes cytochrome c oxidase and citrate synthase at 490 m (baseline) and at the altitudes of 3550 m, 4590 m, and 5530 m. Results An increase in citrate synthase activity at all altitudes levels was observed. Hypoxia induced an increase in the activity of cytochrome c oxidase only at 4590 m. Neither citrate synthase activity nor cytochrome c oxidase activity differed between the subjects receiving antioxidant supplements and those receiving placebo. Conclusions Hypoxia leads to an increase in citrate synthase activity of monocyte mitochondria as a marker of mitochondrial mass, which is not modified by antioxidant supplementation. The increase in mitochondrial mass may represent a compensatory mechanism to preserve oxidative phosphorylation of monocytes at high altitudes. [ABSTRACT FROM AUTHOR]

Pichler Hefti, Jacqueline, Philipp Hoigné-Perret, and Raimund Kottke. Extensive microhemorrhages of the cerebellar peduncles after high-altitude cerebral edema. High Alt Med Biol. 18:182-184, 2017.-Neuromagnetic resonance imaging (MRI) of subjects who suffered from high-altitude cerebral edema (HACE) typically shows cerebral microhemorrhages (MH) of the corpus callosum, in particular the splenium, and supratentorial white matter. This is a case report of a 43-year-old male, who suffered from unusually prolonged severe ataxia and amnesia after having been rescued during the ascent to Mount Everest at 6400 m. MRI of the brain 63 days after the incident showed the typical MH in the corpus callosum, but, in addition, extensive MH were found in the middle cerebellar peduncles. These infratentorial MH might reflect the pronounced atactic gait disorder. This case describes the first HACE-associated MH in the cerebellar peduncles in a high-altitude mountaineer indicating a potential vulnerability of infratentorial brain areas to hypobaric hypoxia. [ABSTRACT FROM AUTHOR]

AbstractPichler Hefti, Jacqueline, Denise Sonntag, Urs Hefti, Lorenz Risch, Otto D. Schoch, Alexander J. Turk, Thomas Hess, Konrad E Bloch, Marco Maggiorini, Tobias M. Merz, Klaus M. Weinberger, and Andreas R. Huber. Oxidative stress in hypobaric hypoxia and influence on vessel-tone modifying mediators. High Alt Med Biol.14:273–279, 2013.—Increased pulmonary artery pressure is a well-known phenomenon of hypoxia and is seen in patients with chronic pulmonary diseases, and also in mountaineers on high altitude expedition. Different mediators are known to regulate pulmonary artery vessel tone. However, exact mechanisms are not fully understood and a multimodal process consisting of a whole panel of mediators is supposed to cause pulmonary artery vasoconstriction.We hypothesized that increased hypoxemia is associated with an increase in vasoconstrictive mediators and decrease of vasodilatators leading to a vasoconstrictive net effect. Furthermore, we suggested oxidative stress being partly involved in changement of these parameters.Oxygen saturation (Sao2) and clinical parameters were assessed in 34 volunteers before and during a Swiss research expedition to Mount Muztagh Ata (7549 m) in Western China. Blood samples were taken at four different sites up to an altitude of 6865 m.A mass spectrometry-based targeted metabolomic platform was used to detect multiple parameters, and revealed functional impairment of enzymes that require oxidation-sensitive cofactors. Specifically, the tetrahydrobiopterin (BH4)-dependent enzyme nitric oxide synthase (NOS) showed significantly lower activities (citrulline-to-arginine ratio decreased from baseline median 0.21 to 0.14 at 6265 m), indicating lower NO availability resulting in less vasodilatative activity. Correspondingly, an increase in systemic oxidative stress was found with a significant increase of the percentage of methionine sulfoxide from a median 6% under normoxic condition to a median level of 30% (p<0.001) in camp 1 at 5533 m. Furthermore, significant increase in vasoconstrictive mediators (e.g., tryptophan, serotonin, and peroxidation-sensitive lipids) were found.During ascent up to 6865 m, significant altitude-dependent changes in multiple vessel-tone modifying mediators with excess in vasoconstrictive metabolites could be demonstrated. These changes, as well as highly significant increase in systemic oxidative stress, may be predictive for increase in acute mountain sickness score and changes in Sao2. [ABSTRACT FROM AUTHOR]

Andjelkovic, Marija, Peter Paal, Susi Kriemler, Kaste Mateikaite-Pipiriene, Alison Rosier, Beth Beidleman, Mia Derstine, Jacqueline Pichler Hefti, David Hillebrandt, Lenka Horakova, Dominique Jean, and Linda E. Keyes. Nutrition in women at high altitude: a scoping review—UIAA Medical Commission recommendations. High Alt Med Biol. 25:9–15, 2024. Background: Nutritional concerns such as food composition, energy intake, and nutrient absorption are essential for performance at high altitude and may differ between men and women. We performed a scoping review to summarize what is currently known on nutrition for women during short-term, high-altitude, physically active sojourns. Methods: The UIAA Medical Commission convened an international team to review women's health issues at high altitude and to publish updated recommendations. Pertinent literature from PubMed and Cochrane was identified by keyword search combinations (including nutrition, metabolism, energy composition, micronutrients) with additional publications found by hand search. Results: We found 7,165 articles, of which 13 original articles assessed nutritional aspects in physically active women on short-term high-altitude sojourns, with other articles found by hand search. We summarize the main findings. Conclusions: Data on women's nutrition at altitude are very limited. Reduction in energy intake plus increased energy expenditure at high altitude can lead to unbalanced nutrition, negatively influencing high-altitude adaptation and physical performance. Therefore, adequate dietary and fluid intake is essential to maintaining energy balance and hydration at high altitude in women as in men. Iron supplementation should be considered for women with iron depletion before travel. [ABSTRACT FROM AUTHOR]

Derstine, Mia, Dominique Jean, Beth A. Beidleman, Jacqueline Pichler Hefti, David Hillebrandt, Lenka Horakova, Susi Kriemler, Kasté Mateikaité–Pipiriené, Peter Paal, Alison Rosier, Marija Andjelkovic, and Linda E. Keyes. Acute mountain sickness and high altitude cerebral edema in women: A scoping review—UIAA Medical Commission recommendations. High Alt Med Biol. 24:259–267, 2023. Background: Acute mountain sickness (AMS) and high-altitude cerebral edema (HACE) are illnesses associated with rapid ascent to altitudes over 2,500 m in unacclimatized lowlanders. The aim of this scoping review is to summarize the current knowledge on sex differences in the epidemiology, pathophysiology, symptomatology, and treatment of AMS and HACE, especially in women. Methods and Results: The UIAA Medical Commission convened an international author team to review women's health issues at high altitude and to publish updated recommendations. Pertinent literature from PubMed and Cochrane was identified by keyword search combinations (including AMS, HACE, and high altitude), with additional publications found by hand search. The primary search focus was for articles assessing lowland women sojourning at high altitude. Results: The literature search yielded 7,165 articles, 37 of which were ultimately included. The majority of publications included did not find women at increased risk for AMS or HACE. There was extremely limited sex-specific data on risk factors or treatment. Conclusions: There is a limited amount of data on female-specific findings regarding AMS and HACE, with most publications addressing only prevalence or incidence with regard to sex. As such, general prevention and treatment strategies for AMS and HACE should be used regardless of sex. [ABSTRACT FROM AUTHOR]

Kriemler, Susi, Kastė Mateikaitė-Pipirienė, Alison Rosier, Linda E. Keyes, Peter Paal, Marija Andjelkovic, Beth A. Beidleman, Mia Derstine, Jacqueline Pichler Hefti, David Hillebrandt, Lenka Horakova, and Dominique Jean; for the UIAA MedCom Writing Group on Women's Health in the Mountains. Frostbite and mortality in mountaineering women: a scoping review—UIAA Medical Commission recommendations. High Alt Med Biol. 24:247–258, 2023. Background: The harsh environment of high altitudes (HA) poses many serious health risks for mountaineers, including cold injuries and death. The aim of this work was to review whether female mountaineers are at special risk for frostbite or death at HA compared with their male counterparts. Methods: The UIAA Medical Commission convened an international author team to review women's health issues at HA and to publish updated recommendations. Pertinent literature from PubMed and Cochrane was identified with additional publications found by hand search. The primary search focus was for articles assessing cold injuries and death in women mountaineers at HA. Results: We reviewed the literature and identified 20 relevant studies: 2 studies on frostbite at HA, plus 7 studies and 1 report for death at HA. An additional 10 studies about frostbite at low altitude were included. We found that female mountaineers at HA were at lower risk of death than their male counterparts, but sex differences in frostbite were inconclusive. Conclusions: The frequency of cold injuries and mortality in female mountaineers is not yet well studied, and the studies that have been published tend to lack precise exposure data. More studies and registries with sex-differentiated data are needed. [ABSTRACT FROM AUTHOR]

Key points: A physiological response to increase microcirculatory oxygen extraction capacity at high altitude is to recruit capillaries.In the present study, we report that high altitude‐induced sublingual capillary recruitment is an intrinsic mechanism of the sublingual microcirculation that is independent of changes in cardiac output, arterial blood pressure or systemic vascular hindrance.Using a topical nitroglycerin challenge to the sublingual microcirculation, we show that high altitude‐related capillary recruitment is a functional response of the sublingual microcirculation as opposed to an anatomical response associated with angiogenesis.The concurrent presence of a low capillary density and high microvascular reactivity to topical nitroglycerin at sea level was found to be associated with a failure to reach the summit, whereas the presence of a high baseline capillary density with the ability to further increase maximum recruitable capillary density upon ascent to an extreme altitude was associated with summit success. A high altitude (HA) stay is associated with an increase in sublingual capillary total vessel density (TVD), suggesting microvascular recruitment. We hypothesized that microvascular recruitment occurs independent of cardiac output changes, that it relies on haemodynamic changes within the microcirculation as opposed to structural changes and that microcirculatory function is related to individual performance at HA. In 41 healthy subjects, sublingual handheld vital microscopy and echocardiography were performed at sea level (SL), as well as at 6022 m (C2) and 7042 m (C3), during ascent to 7126 m within 21 days. Sublingual topical nitroglycerin was applied to measure microvascular reactivity and maximum recruitable TVD (TVDNG). HA exposure decreased resting cardiac output, whereas TVD (mean ± SD) increased from 18.81 ± 3.92 to 20.92 ± 3.66 and 21.25 ± 2.27 mm mm−2 (P < 0.01). The difference between TVD and TVDNG was 2.28 ± 4.59 mm mm−2 at SL (P < 0.01) but remained undetectable at HA. Maximal TVDNG was observed at C3. Those who reached the summit (n = 15) demonstrated higher TVD at SL (P < 0.01), comparable to TVDNG in non‐summiters (n = 21) at SL and in both groups at C2. Recruitment of sublingual capillary TVD to increase microcirculatory oxygen extraction capacity at HA was found to be an intrinsic mechanism of the microcirculation independent of cardiac output changes. Microvascular reactivity to topical nitroglycerin demonstrated that HA‐related capillary recruitment is a functional response as opposed to a structural change. The performance of the vascular microcirculation needed to reach the summit was found to be associated with a higher TVD at SL and the ability to further increase TVDNG upon ascent to extreme altitude. Key points: A physiological response to increase microcirculatory oxygen extraction capacity at high altitude is to recruit capillaries.In the present study, we report that high altitude‐induced sublingual capillary recruitment is an intrinsic mechanism of the sublingual microcirculation that is independent of changes in cardiac output, arterial blood pressure or systemic vascular hindrance.Using a topical nitroglycerin challenge to the sublingual microcirculation, we show that high altitude‐related capillary recruitment is a functional response of the sublingual microcirculation as opposed to an anatomical response associated with angiogenesis.The concurrent presence of a low capillary density and high microvascular reactivity to topical nitroglycerin at sea level was found to be associated with a failure to reach the summit, whereas the presence of a high baseline capillary density with the ability to further increase maximum recruitable capillary density upon ascent to an extreme altitude was associated with summit success. [ABSTRACT FROM AUTHOR]

Case Presentation: A 58-year-old man with idiopathic pulmonary fibrosis, who had received a right-sided single-lung transplant 2 years earlier, was referred to the sleep clinic for the assessment of nocturnal position-dependent episodes of dyspnea and frequent arousals when lying on his right side. There was no subjective worsening of daytime respiratory symptoms, but he complained of fatigue and unrefreshing sleep. His Epworth Sleepiness Scale score was 12/24. After lung transplantation he had a favorable course while receiving immunosuppression with prednisolone, everolimus, and mycophenolate mofetil. In addition, he had received diagnoses of stable coronary artery disease and moderate chronic kidney failure. [ABSTRACT FROM AUTHOR]

AbstractBrill, Anne-Kathrin, Alexander Kunz, Sebastian Robert Ott, Thomas Geiser, and Jacqueline Pichler Hefti. When “High” Is Not Very High: High Altitude Pulmonary Edema as First Manifestation of Sarcoidosis-Related Pulmonary Hypertension. High Alt Med Biol13:285–287, 2012.—High altitude pulmonary edema (HAPE) is a life-threatening complication of high altitude stay, which may occur above altitudes of 2500?m. This is a case report of a healthy 41-year-old man, presenting with recurrent HAPE at moderate altitude. Medical work-up revealed an idiopathic pulmonary artery hypertension (PAH), and specific vasoactive treatment was started. Despite treatment with an endothelin receptor antagonist, the patient deteriorated clinically. Subsequent medical reevaluation showed a significant progress of mediastinal lymphadenopathy. Due to the histological proof of sarcoidosis, the initial diagnosis of PAH had to be changed to sarcoidosis-related pulmonary hypertension. Initiation of immunosuppressive therapy with corticosteroids led to significant and clinically relevant decrease in pulmonary artery pressure, even allowing episodes of asymptomatic re-exposure to moderate altitude. This case describes HAPE as first manifestation of a sarcoidosis–related pulmonary hypertension with a very unusual and early presentation of the underlying disease in an apparently healthy mountaineer. [ABSTRACT FROM AUTHOR]