Intermittent hypoxia training effectively protects against cognitive decline caused by acute hypoxia exposure.

Intermittent hypoxia training (IHT) is a promising approach that has been used to induce acclimatization to hypoxia and subsequently lower the risk of developing acute mountain sickness (AMS). However, the effects of IHT on cognitive and cerebrovascular function after acute hypoxia exposure have not been characterized. In the present study, we first confirmed that the simplified IHT paradigm was effective at relieving AMS at 4300 m. Second, we found that IHT improved participants' cognitive and neural alterations when they were exposed to hypoxia. Specifically, impaired working memory performance, decreased conflict control function, impaired cognitive control, and aggravated mental fatigue induced by acute hypoxia exposure were significantly alleviated in the IHT group. Furthermore, a reversal of brain swelling induced by acute hypoxia exposure was visualized in the IHT group using magnetic resonance imaging. An increase in cerebral blood flow (CBF) was observed in multiple brain regions of the IHT group after hypoxia exposure as compared with the control group. Based on these findings, the simplified IHT paradigm might facilitate hypoxia acclimatization, alleviate AMS symptoms, and increase CBF in multiple brain regions, thus ameliorating brain swelling and cognitive dysfunction.

Effects of acetazolamide combined with remote ischemic preconditioning on risk of acute mountain sickness: a randomized clinical trial.

BACKGROUND: We aimed to determine whether and how the combination of acetazolamide and remote ischemic preconditioning (RIPC) reduced the incidence and severity of acute mountain sickness (AMS). METHODS: This is a prospective, randomized, open-label, blinded endpoint (PROBE) study involving 250 healthy volunteers. Participants were randomized (1:1:1:1:1) to following five groups: Ripc (RIPC twice daily, 6 days), Rapid-Ripc (RIPC four times daily, 3 days), Acetazolamide (twice daily, 2 days), Combined (Acetazolamide plus Rapid-Ripc), and Control group. After interventions, participants entered a normobaric hypoxic chamber (equivalent to 4000 m) and stayed for 6 h. The primary outcomes included the incidence and severity of AMS, and SpO2 after hypoxic exposure. Secondary outcomes included systolic and diastolic blood pressure, and heart rate after hypoxic exposure. The mechanisms of the combined regime were investigated through exploratory outcomes, including analysis of venous blood gas, complete blood count, human cytokine antibody array, ELISA validation for PDGF-AB, and detection of PDGF gene polymorphisms. RESULTS: The combination of acetazolamide and RIPC exhibited powerful efficacy in preventing AMS, reducing the incidence of AMS from 26.0 to 6.0% (Combined vs Control: RR 0.23, 95% CI 0.07-0.70, P = 0.006), without significantly increasing the incidence of adverse reactions. Combined group also showed the lowest AMS score (0.92 ± 1.10). Mechanistically, acetazolamide induced a mild metabolic acidosis (pH 7.30 ~ 7.31; HCO3- 18.1 ~ 20.8 mmol/L) and improved SpO2 (89 ~ 91%) following hypoxic exposure. Additionally, thirty differentially expressed proteins (DEPs) related to immune-inflammatory process were identified after hypoxia, among which PDGF-AB was involved. Further validation of PDGF-AB in all individuals showed that both acetazolamide and RIPC downregulated PDGF-AB before hypoxic exposure, suggesting a possible protective mechanism. Furthermore, genetic analyses demonstrated that individuals carrying the PDGFA rs2070958 C allele, rs9690350 G allele, or rs1800814 G allele did not display a decrease in PDGF-AB levels after interventions, and were associated with a higher risk of AMS. CONCLUSIONS: The combination of acetazolamide and RIPC exerts a powerful anti-hypoxic effect and represents an innovative and promising strategy for rapid ascent to high altitudes. Acetazolamide improves oxygen saturation. RIPC further aids acetazolamide, which synergistically regulates PDGF-AB, potentially involved in the pathogenesis of AMS. TRIAL REGISTRATION: ClinicalTrials.gov NCT05023941.

Using modified Fenn diagrams to assess ventilatory acclimatization during ascent to high altitude: Effect of acetazolamide.

High altitude (HA) ascent imposes systemic hypoxia and associated risk of acute mountain sickness. Acute hypoxia elicits a hypoxic ventilatory response (HVR), which is augmented with chronic HA exposure (i.e., ventilatory acclimatization; VA). However, laboratory-based HVR tests lack portability and feasibility in field studies. As an alternative, we aimed to characterize area under the curve (AUC) calculations on Fenn diagrams, modified by plotting portable measurements of end-tidal carbon dioxide ( P ETC O 2 ${P_{{\mathrm{ETC}}{{\mathrm{O}}_{\mathrm{2}}}}}$ ) against peripheral oxygen saturation ( S p O 2 ${S_{{\mathrm{p}}{{\mathrm{O}}_{\mathrm{2}}}}}$ ) to characterize and quantify VA during incremental ascent to HA (n = 46). Secondarily, these participants were compared with a separate group following the identical ascent profile whilst self-administering a prophylactic oral dose of acetazolamide (Az; 125 mg BID; n = 20) during ascent. First, morning P ETC O 2 ${P_{{\mathrm{ETC}}{{\mathrm{O}}_{\mathrm{2}}}}}$ and S p O 2 ${S_{{\mathrm{p}}{{\mathrm{O}}_{\mathrm{2}}}}}$ measurements were collected on 46 acetazolamide-free (NAz) lowland participants during an incremental ascent over 10 days to 5160 m in the Nepal Himalaya. AUC was calculated from individually constructed Fenn diagrams, with a trichotomized split on ranked values characterizing the smallest, medium, and largest magnitudes of AUC, representing high (n = 15), moderate (n = 16), and low (n = 15) degrees of acclimatization. After characterizing the range of response magnitudes, we further demonstrated that AUC magnitudes were significantly smaller in the Az group compared to the NAz group (P = 0.0021), suggesting improved VA. These results suggest that calculating AUC on modified Fenn diagrams has utility in assessing VA in large groups of trekkers during incremental ascent to HA, due to the associated portability and congruency with known physiology, although this novel analytical method requires further validation in controlled experiments. HIGHLIGHTS: What is the central question of this study? What are the characteristics of a novel methodological approach to assess ventilatory acclimatization (VA) with incremental ascent to high altitude (HA)? What is the main finding and its importance? Area under the curve (AUC) magnitudes calculated from modified Fenn diagrams were significantly smaller in trekkers taking an oral prophylactic dose of acetazolamide compared to an acetazolamide-free group, suggesting improved VA. During incremental HA ascent, quantifying AUC using modified Fenn diagrams is feasible to assess VA in large groups of trekkers with ascent, although this novel analytical method requires further validation in controlled experiments.

Assessment of Dynamic Cerebral Autoregulation During Long-Term Exposure to High Altitude in Normal Subjects by Ultrasonography.

PURPOSE: To evaluate changes in dynamic cerebral autoregulation (CA) during short-term and long-term exposure to high altitude with ultrasonography, and also study the sex differences in the response of CA to altitude. METHODS: We assessed the differences in dynamic CA and measured with Doppler ultrasound of the bilateral internal carotid artery (ICA), vertebral artery (VA), and middle cerebral artery (MCA) and the values of basic information within 48 hours and at 2 years after arrival at Tibet in 65 healthy Han young Chinese volunteers, meanwhile, we compared the resistance index (RI) and pulsatility index (PI) of the right MCA at inhale oxygen 8 minutes when a newcomer with 2 years after arrival at Tibet. RESULTS: With 2 years of altitude exposure, the SaO2 of all subjects was above 90%, the mean PEF, DAP, and HR values decreased, HGB increased compared within 48 hours in same-gender groups. Comparisons of cerebral hemodynamics between before 2 years and after 2 years within male and female groups, the mean RI and PI values of bilateral MCA after 2 years were significantly higher than before 2 years, at the same time, the mean RI and PI values of bilateral ICA were significant differences (P < .05) between male groups, with regard to female groups, showed that the mean RI and PI values of bilateral VA were significant differences (P < .05). Comparisons of Right MCA hemodynamics between after oxygen uptake 8 minutes and 2 years, the mean RI and PI values were no significant difference within male and female groups (P > .05). CONCLUSIONS: Acute mountain sickness could result from an alteration of dynamic autoregulation of cerebral blood flow, but the impaired autoregulation may be corrected with the extension of time, furthermore, the response of CA to altitude in males and females are different.

Acute mountain sickness on Jade Mountain: Results from the real-world practice (2018-2019).

Acute mountain sickness (AMS) is initiated in response to a hypoxic and hypobaric environment at a high altitude. The precise prevalence of AMS in Jade Mountain climbers remained largely unknown, particularly data obtained from real medical consultations. An overnight stay at the Pai-Yun Lodge (3402 m) is usually required before an ascent of the Jade Mountain. Since 2004, a Pai-Yun Clinic has been established in the Pai-Yun Lodge. The Pai-Yun Clinic provided regular and emergency medical service every weekend. We conducted a retrospective study by using medical records from the Pai-Yun Clinic between 2018 and 2019. A total of 1021 patients were enrolled, with 56.2 % males. Different age groups were 3.2 %, 54.5 %, 37.9 %, and 4.4 % in <20, 20-39, 40-59, and ≥60 years, respectively. There were 582 (57.0 %) patients diagnosed to have AMS (230 [39.5 %] were mild type and 352 [60.5 %] were severe type). The factors associated with AMS development included young age, absence of climbing history (>3000 m) within the last 3 months, first climbing (>3000 m) experience, taking preventive medication, low oxygen saturation, and a high Lake Louise AMS score (LLAMSS). The factors associated with AMS severity included absence of taking preventive medication, low oxygen saturation, and a high LLAMSS. Approximately 15 % of Jade Mountain climbers needed medical service, of which 60 % had AMS. 60 % of patients with AMS must require oxygen supply or medication prescription. Oxygen saturation measure and LLAMSS evaluation are reasonable tools to predict the occurrence and severity of AMS on Jade Mountain.

Inappropriate Acetazolamide Use for a Hiker Who Developed Acute Kidney Injury.

Prophylactic use of acetazolamide (ACZ) to prevent acute mountain sickness (AMS) is a common practice among high altitude travelers and mountaineers. With its use comes a possible risk of acute kidney injury (AKI). We present a case in which a 56-year-old male hiker in Grand Canyon National Park developed acute exertional rhabdomyolysis and subsequent AKI while taking prophylactic ACZ to prevent AMS. This medication was prescribed despite the hiker encountering only moderate altitude at Grand Canyon with a planned descent within <24 h. The resulting AKI was determined to be the combined result of acute exertional rhabdomyolysis and dehydration/hypovolemia, with the ACZ, a diuretic, as a contributing factor. Medical providers need to recognize the risks/benefits with ACZ use for AMS prophylaxis and avoid prescribing it to individuals whose altitude exposure and activity fall outside the clinical practice guidelines recommended for use.

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.

Application of SARIMA model in forecasting and analyzing inpatient cases of acute mountain sickness.

BACKGROUND: Acute Mountain Sickness (AMS) is typically triggered by hypoxia under high altitude conditions. Currently, rule of time among AMS inpatients was not clear. Thus, this study aimed to analyze the time distribution of AMS inpatients in the past ten years and construct a prediction model of AMS hospitalized cases. METHODS: We retrospectively collected medical records of AMS inpatients admitted to the military hospitals from January 2009 to December 2018 and analyzed the time series characteristics. Seasonal Auto-Regressive Integrated Moving Average (SARIMA) was established through training data to finally forecast in the test data set. RESULTS: A total of 22 663 inpatients were included in this study and recorded monthly, with predominant peak annually, early spring (March) and mid-to-late summer (July to August), respectively. Using the training data from January 2009 to December 2017, the model SARIMA (1, 1, 1) (1, 0, 1) 12 was employed to predict the test data from January 2018 to December 2018. In 2018, the total predicted value after adjustment was 9.24%, less than the actual value. CONCLUSION: AMS inpatients have obvious periodicity and seasonality. The SARIMA model has good fitting ability and high short-term prediction accuracy. It can help explore the characteristics of AMS disease and provide decision-making basis for allocation of relevant medical resources for AMS inpatients.

Using machine learning to determine the correlation between physiological and environmental parameters and the induction of acute mountain sickness.

BACKGROUND: Recent studies on acute mountain sickness (AMS) have used fixed-location and fixed-time measurements of environmental and physiological variable to determine the influence of AMS-associated factors in the human body. This study aims to measure, in real time, environmental conditions and physiological variables of participants in high-altitude regions to develop an AMS risk evaluation model to forecast prospective development of AMS so its onset can be prevented. RESULTS: Thirty-two participants were recruited, namely 25 men and 7 women, and they hiked from Cuifeng Mountain Forest Park parking lot (altitude: 2300 m) to Wuling (altitude: 3275 m). Regression and classification machine learning analyses were performed on physiological and environmental data, and Lake Louise Acute Mountain Sickness Scores (LLS) to establish an algorithm for AMS risk analysis. The individual R2 coefficients of determination between the LLS and the measured altitude, ambient temperature, atmospheric pressure, relative humidity, climbing speed, heart rate, blood oxygen saturation (SpO2), heart rate variability (HRV), were 0.1, 0.23, 0, 0.24, 0, 0.24, 0.27, and 0.35 respectively; incorporating all aforementioned variables, the R2 coefficient is 0.62. The bagged trees classifier achieved favorable classification results, yielding a model sensitivity, specificity, accuracy, and area under receiver operating characteristic curve of 0.999, 0.994, 0.998, and 1, respectively. CONCLUSION: The experiment results indicate the use of machine learning multivariate analysis have higher AMS prediction accuracies than analyses utilizing single varieties. The developed AMS evaluation model can serve as a reference for the future development of wearable devices capable of providing timely warnings of AMS risks to hikers.

Inflammatory gene expression during acute high-altitude exposure.

The molecular signalling pathways that regulate inflammation and the response to hypoxia share significant crosstalk and appear to play major roles in high-altitude acclimatization and adaptation. Several studies demonstrate increases in circulating candidate inflammatory markers during acute high-altitude exposure, but significant gaps remain in our understanding of how inflammation and immune function change at high altitude and whether these responses contribute to high-altitude pathologies, such as acute mountain sickness. To address this, we took an unbiased transcriptomic approach, including RNA sequencing and direct digital mRNA detection with NanoString, to identify changes in the inflammatory profile of peripheral blood throughout 3 days of high-altitude acclimatization in healthy sea-level residents (n = 15; five women). Several inflammation-related genes were upregulated on the first day of high-altitude exposure, including a large increase in HMGB1 (high mobility group box 1), a damage-associated molecular pattern (DAMP) molecule that amplifies immune responses during tissue injury. Differentially expressed genes on the first and third days of acclimatization were enriched for several inflammatory pathways, including nuclear factor-κB and Toll-like receptor (TLR) signalling. Indeed, both TLR4 and LY96, which encodes the lipopolysaccharide binding protein (MD-2), were upregulated at high altitude. Finally, FASLG and SMAD7 were associated with acute mountain sickness scores and peripheral oxygen saturation levels on the first day at high altitude, suggesting a potential role of immune regulation in response to high-altitude hypoxia. These results indicate that acute high-altitude exposure upregulates inflammatory signalling pathways and might sensitize the TLR4 signalling pathway to subsequent inflammatory stimuli. KEY POINTS: Inflammation plays a crucial role in the physiological response to hypoxia. High-altitude hypoxia exposure causes alterations in the inflammatory profile that might play an adaptive or maladaptive role in acclimatization. In this study, we characterized changes in the inflammatory profile following acute high-altitude exposure. We report upregulation of novel inflammation-related genes in the first 3 days of high-altitude exposure, which might play a role in immune system sensitization. These results provide insight into how hypoxia-induced inflammation might contribute to high-altitude pathologies and exacerbate inflammatory responses in critical illnesses associated with hypoxaemia.

High-altitude exposures and intestinal barrier dysfunction.

Gastrointestinal complaints are often reported during ascents to high altitude (>2,500 m), though their etiology is not known. One potential explanation is injury to the intestinal barrier which has been implicated in the pathophysiology of several diseases. High-altitude exposures can reduce splanchnic perfusion and blood oxygen levels causing hypoxic and oxidative stress. These stressors might injure the intestinal barrier leading to consequences such as bacterial translocation and local/systemic inflammatory responses. The purpose of this mini-review is to 1) discuss the impact of high-altitude exposures on intestinal barrier dysfunction and 2) present medications and dietary supplements which may have relevant impacts on the intestinal barrier during high-altitude exposures. There is a small but growing body of evidence which shows that acute exposures to high altitudes can damage the intestinal barrier. Initial data also suggest that prolonged hypoxic exposures can compromise the intestinal barrier through alterations in immunological function, microbiota, or mucosal layers. Exertion may worsen high-altitude-related intestinal injury via additional reductions in splanchnic circulation and greater hypoxemia. Collectively these responses can result in increased intestinal permeability and bacterial translocation causing local and systemic inflammation. More research is needed to determine the impact of various medications and dietary supplements on the intestinal barrier during high-altitude exposures.

Exercise in hypobaric hypoxia increases markers of intestinal injury and symptoms of gastrointestinal distress.

NEW FINDINGS: What is the central question of this study? What is the effect of hypobaric hypoxia on markers of exercise-induced intestinal injury and symptoms of gastrointestinal (GI) distress? What is the main finding and its importance? Exercise performed at 4300 m of simulated altitude increased intestinal fatty acid binding protein (I-FABP), claudin-3 (CLDN-3) and lipopolysaccharide binding protein (LBP), which together suggest that exercise-induced intestinal injury may be aggravated by concurrent hypoxic exposure. Increases in I-FABP, LBP and CLDN-3 were correlated to exercise-induced GI symptoms, providing some evidence of a link between intestinal barrier injury and symptoms of GI distress. ABSTRACT: We sought to determine the effect of exercise in hypobaric hypoxia on markers of intestinal injury and gastrointestinal (GI) symptoms. Using a randomized and counterbalanced design, nine males completed two experimental trials: one at local altitude of 1585 m (NORM) and one at 4300 m of simulated hypobaric hypoxia (HYP). Participants performed 60 min of cycling at a workload that elicited 65% of their NORM V̇O2max${\dot V_{{{\rm{O}}_{\rm{2}}}{\rm{max}}}}$ . GI symptoms were assessed before and every 15 min during exercise. Pre- and post-exercise blood samples were assessed for intestinal fatty acid binding protein (I-FABP), claudin-3 (CLDN-3) and lipopolysaccharide binding protein (LBP). All participants reported at least one GI symptom in HYP compared to just one participant in NORM. I-FABP significantly increased from pre- to post-exercise in HYP (708 ± 191 to 1215 ± 518 pg ml-1 ; P = 0.011, d = 1.10) but not NORM (759 ± 224 to 828 ± 288 pg ml-1 ; P > 0.99, d = 0.27). CLDN-3 significantly increased from pre- to post-exercise in HYP (13.8 ± 0.9 to 15.3 ± 1.2 ng ml-1 ; P = 0.003, d = 1.19) but not NORM (13.7 ± 1.8 to 14.2 ± 1.6 ng ml-1 ; P = 0.435, d = 0.45). LBP significantly increased from pre- to post-exercise in HYP (10.8 ± 1.2 to 13.9 ± 2.8 µg ml-1 ; P = 0.006, d = 1.12) but not NORM (11.3 ± 1.1 to 11.7 ± 0.9 µg ml-1 ; P > 0.99, d = 0.32). I-FABP (d = 0.85), CLDN-3 (d = 0.95) and LBP (d = 0.69) were all significantly higher post-exercise in HYP compared to NORM (P ≤ 0.05). Overall GI discomfort was significantly correlated to ΔI-FABP (r = 0.71), ΔCLDN-3 (r = 0.70) and ΔLBP (r = 0.86). These data indicate that cycling exercise performed in hypobaric hypoxia can cause intestinal injury, which might cause some commonly reported GI symptoms.

No effect of patent foramen ovale on acute mountain sickness and pulmonary pressure in normobaric hypoxia.

NEW FINDINGS: What is the central question to this study? Is there a relationship between a patent foramen ovale and the development of acute mountain sickness and an exaggerated increase in pulmonary pressure in response to 7-10 h of normobaric hypoxia? What is the main finding and its importance? Patent foramen ovale presence did not increase susceptibility to acute mountain sickness or result in an exaggerated increase in pulmonary artery systolic pressure with normobaric hypoxia. This suggests hypobaric hypoxia is integral to the increased susceptibility to acute mountain sickness previously reported in those with patent foramen ovale, and patent foramen ovale presence alone does not contribute to the hypoxic pulmonary pressor response. ABSTRACT: Acute mountain sickness (AMS) develops following rapid ascent to altitude, but its exact causes remain unknown. A patent foramen ovale (PFO) is a right-to-left intracardiac shunt present in ∼30% of the population that has been shown to increase AMS susceptibility with high altitude hypoxia. Additionally, high altitude pulmonary oedema (HAPE) is a severe type of altitude illness characterized by an exaggerated pulmonary pressure response, and there is a greater prevalence of PFO in those with a history of HAPE. However, whether hypoxia per se is causing the increased incidence of AMS in those with a PFO and whether a PFO is associated with an exaggerated increase in pulmonary pressure in those without a history of HAPE is unknown. Participants (n = 36) matched for biological sex (18 female) and the presence or absence of a PFO (18 PFO+) were exposed to 7-10 h of normobaric hypoxia equivalent to 4755 m. Presence and severity of AMS was determined using the Lake Louise AMS scoring system. Pulmonary artery systolic pressure, cardiac output and total pulmonary resistance were measured using ultrasound. We found no significant association of PFO with incidence or severity of AMS and no association of PFO with arterial oxygen saturation. Additionally, there was no effect of a PFO on pulmonary pressure, cardiac output or total pulmonary resistance. These data suggest that hypobaric hypoxia is necessary for those with a PFO to have increased incidence of AMS and that presence of PFO is not associated with an exaggerated pulmonary pressor response.

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

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

Matrix metalloproteinase-9 and substance-P as predictors for early-stage diagnosis of acute mountain sickness.

INTRODUCTION: Although acute mountain sickness (AMS) can be a life-threatening condition, early diagnosis is difficult due to vague and non-specific symptoms. The aim of this study is to investigate biochemical markers that can detect high-altitude diseases in advance. Eight different biomarkers (BNP, HIF-1α, NGAL, MMP-3, MMP-9, SESN2, substance P (SP), and U-II) were studied, and their relationship with AMS was investigated. METHODS: Of the 84 mountaineers who participated in the mountaineering training organized by the Turkish Mountaineering Federation in the Rize Kaçkar Mountains in 2018, 52 volunteered to participate in the study. Twelve hours after the participants reached an altitude of 2200 m (exposed to moderate hypoxia), their vital parameters were measured, and blood samples were taken for biochemistry tests. Vital signs and Lake Louise (LL) AMS scores were recorded every 24 h during the following 72 h. The participants were divided into two groups according to their LL scores: those with AMS and those without (AMS+ and AMS -), and the vital parameters and biomarker levels of both groups were compared and evaluated. RESULTS: Of the volunteers participating in the study, 35 (67.3%) were male and 17 (32.7%) were female, although there was no gender difference in terms of susceptibility to AMS. Among the investigated markers in the AMS + group, MMP-9 and SP were statistically significantly higher (p = 0.037 and p = 0.038, respectively). There were no statistical differences between AMS- and AMS+ groups with regard to heart rate, oxygen saturation, and systolic and diastolic blood pressure values (p = 0.507, p = 0.929, p = 0.955, p = 0.572, respectively). CONCLUSION: There were significant differences between the AMS- and AMS+ groups in terms of MMP-9 and SP. However, differences in physical indexes between the groups were not statistically significant. This could provide objective indexes for scanning and screening individuals susceptible to AMS in the early stages of rapid ascending.

Preliminary Evidence-Based Method of Medical Kit Design for Wilderness Expeditions Modeled by a High-Altitude Expedition to Mount Kilimanjaro.

BACKGROUND: Wilderness expeditions require extensive planning and the correct medical supplies to ensure clinical care is possible in the event of illness or injury. There are gaps in the literature regarding evidence-based methods for medical kit design. OBJECTIVES: This report describes a preliminary method for predicting medical events to determine medical supply requirements for a wilderness expedition. The performance of this method was evaluated using data from the 2017 Equal Playing Field (EPF) expedition to Mount Kilimanjaro. METHODS: Eight reports documenting medical events during wilderness expeditions were reviewed. Incidence data were consolidated into a new dataset, and a subset of data from adventure race expeditions (ARS) was created. The cumulative incidence of medical events was then predicted for the 9-day EPF expedition. The medical supply list was determined based on indication. The effectiveness of the full dataset and ARS to predict the cumulative incidence of medical events by category during the EPF expedition was evaluated using regression analysis. RESULTS: The ARS predicted a higher incidence rate of medical events than the full dataset did but underestimated the EPF expedition incidence rate. The full dataset was a weak predictor of the cumulative incidence of medical events by category during the EPF expedition, while the ARS was a strong predictor. The finalized medical kit overestimated all nonreusable supplies. CONCLUSIONS: The medical kit created using this method managed all medical events in the field. This report demonstrates the potential utility of using a tailored, evidence-based approach to design a medical kit for wilderness expeditions.

Impact of moderate altitude on lung diseases and risk of high altitude illnesses.

A large world population resides at moderate altitudes. In the Valley of Mexico (2240 m above sea level) and for patients with respiratory diseases implies more hypoxemia and clinical deterioration, unless supplementary oxygen is prescribed or patients move to sea level. A group of individuals residing at 2500 or more meters above sea level may develop acute or chronic mountain disease but those conditions may develop at moderate altitudes although less frequently and in predisposed individuals. In the valley of México, at 2200 m above sea level, re-entry pulmonary edema has been reported. The frequency of other altituderelated diseases at moderate altitude, described in skiing resorts, remains to be known in visitors to Mexico City and other cities at similar or higher altitudes. Residents of moderate altitudes inhale deeply the city's air with all pollutants and require more often supplementary oxygen.

Respiratory alkalinization and posterior cerebral artery dilatation predict acute mountain sickness severity during 10 h normobaric hypoxia.

NEW FINDINGS: What is the central question of this study? The pathophysiology of acute mountain sickness (AMS), involving the respiratory, renal and cerebrovascular systems, remains poorly understood. How do the early adaptations in these systems during a simulated altitude of 5000 m relate to AMS risk? What is the main finding and its importance? The rate of blood alkalosis and cerebral artery dilatation predict AMS severity during the first 10 h of exposure to a simulated altitude of 5000 m. Slow metabolic compensation by the kidneys of respiratory alkalosis attributable to a brisk breathing response together with excessive brain blood vessel dilatation might be involved in early development of AMS. ABSTRACT: The complex pathophysiology of acute mountain sickness (AMS) remains poorly understood and is likely to involve maladaptive responses of the respiratory, renal and cerebrovascular systems to hypoxia. Using stepwise linear regression, we tested the hypothesis that exacerbated respiratory alkalosis, as a result of a brisk ventilatory response, sluggish renal compensation in acute hypoxia and dysregulation of cerebral perfusion predict AMS severity. We assessed the Lake Louise score (LLS, an index of AMS severity), fluid balance, ventilation, venous pH, bicarbonate, sodium and creatinine concentrations, body weight, urinary pH and cerebral blood flow [internal carotid artery (ICA) and vertebral artery (VA) blood flow and diameter], in 27 healthy individuals (13 women) throughout 10 h exposures to normobaric normoxia (fraction of inspired O2 = 0.21) and normobaric hypoxia (fraction of inspired O2 = 0.117, simulated 5000 m) in a randomized, single-blinded manner. In comparison to normoxia, hypoxia increased the LLS, ventilation, venous and urinary pH, and blood flow and diameter in the ICA and VA, while venous concentrations of both bicarbonate and creatinine were decreased (P < 0.001 for all). There were significant correlations between AMS severity and the rates of change in blood pH, sodium concentration and VA diameter and more positive fluid balance (P < 0.05). Stepwise regression found increased blood pH [beta coefficient (ß) = 0.589, P < 0.001] and VA diameter (ß = 0.418, P = 0.008) to be significant predictors of AMS severity in our cohort [F(2, 20) = 16.1, R2  = 0.617, P < 0.001, n = 24], accounting for 62% of the variance in peak LLS. Using classic regression variable selection, our data implicate the degree of respiratory alkalosis and cerebrovascular dilatation in the early stages of AMS development.

Cardiorespiratory hysteresis during incremental high-altitude ascent-descent quantifies the magnitude of ventilatory acclimatization.

NEW FINDINGS: What is the central question of this study? We assessed the utility of a new metric for quantifying ventilatory acclimatization to high altitude, derived from differential ascent and descent steady-state cardiorespiratory variables (i.e. hysteresis). Furthermore, we aimed to investigate whether the magnitude of cardiorespiratory hysteresis was associated with the development of acute mountain sickness. What is the main finding and its importance? Hysteresis in steady-state cardiorespiratory variables quantifies ventilatory acclimatization to high altitude. The magnitude of cardiorespiratory hysteresis during ascent to and descent from high altitude was significantly related to the development of symptoms of acute mountain sickness. Hysteresis in steady-state chemoreflex drive can provide a simple, non-invasive method of tracking ventilatory acclimatization to high altitude. ABSTRACT: Maintenance of arterial blood gases is achieved through sophisticated regulation of ventilation, mediated by central and peripheral chemoreflexes. Respiratory chemoreflexes are important during exposure to high altitude owing to the competing influence of hypoxia and hypoxic hyperventilation-mediated hypocapnia on steady-state ventilatory drive. Inter-individual variability exists in ventilatory acclimatization to high altitude, potentially affecting the development of acute mountain sickness (AMS). We aimed to quantify ventilatory acclimatization to high altitude by comparing differential ascent and descent values (i.e. hysteresis) in steady-state cardiorespiratory variables. We hypothesized that: (i) the hysteresis area formed by cardiorespiratory variables during ascent and descent would quantify the magnitude of ventilatory acclimatization; and (ii) larger hysteresis areas would be associated with lower AMS symptom scores during ascent. In 25 healthy, acetazolamide-free trekkers ascending to and descending from 5160 m, cardiorespiratory hysteresis was measured in the partial pressure of end-tidal CO2 , peripheral oxygen saturation, minute ventilation, chemoreceptor stimulus index (end-tidal CO2 /peripheral oxygen saturation) and the calculated steady-state chemoreflex drive (SS-CD; minute ventilation/chemoreceptor stimulus index) using portable devices (capnograph, peripheral pulse oximeter and respirometer, respectively). Symptoms of AMS were assessed daily using the Lake Louise questionnaire. We found that: (i) ascent-descent hysteresis was present in all cardiorespiratory variables; (ii) SS-CD is a valid metric for tracking ventilatory acclimatization to high altitude; and (iii) the highest AMS scores during ascent exhibited a significant, moderate and inverse correlation with the magnitude of SS-CD hysteresis (rs  = -0.408, P = 0.043). We propose that ascent-descent hysteresis is a new and feasible way to quantify ventilatory acclimatization in trekkers during high-altitude exposure.

Combined methazolamide and theophylline improves oxygen saturation but not exercise performance or altitude illness in acute hypobaric hypoxia.

NEW FINDINGS: What is the central question of this study? Does the combination of methazolamide and theophylline reduce symptoms of acute mountain sickness (AMS) and improve aerobic performance in acute hypobaric hypoxia? What is the main finding and its importance? The oral combination of methazolamide (100 BID) and theophylline (300 BID) improved arterial oxygen saturation but did not reduce symptoms of AMS and impaired aerobic performance. We do not recommend this combination of drugs for prophylaxis against the acute negative effects of hypobaric hypoxia. ABSTRACT: A limited number of small studies have suggested that methazolamide and theophylline can independently reduce symptoms of acute mountain sickness (AMS) and, if taken together, can improve aerobic exercise performance in normobaric hypoxia. We performed a randomized, double-blind, placebo-controlled, cross-over study to determine if the combination of oral methazolamide and theophylline could provide prophylaxis against AMS and improve aerobic performance in hypobaric hypoxia (∼4875 m). Volunteers with histories of AMS were screened at low altitude (1650 m) and started combined methazolamide (100 mg BID) and theophylline (300 mg BID) treatment, or placebo, 72 h prior to decompression. Baseline AMS (Lake Louise Questionnaire), blood (haemoglobin, haematocrit), cognitive function, ventilatory and pulse oximetry ( SpO2 ) measures were assessed at low altitude and repeated between 4 and 10 h of exposure to hypobaric hypoxia (PB  = 425 mmHg). Aerobic exercise performance was assessed during a 12.5 km cycling time trial (TT) after 4 h of hypobaric hypoxia. Subjects repeated all experimental procedures after a 3-week washout period. Differences between drug and placebo trials were evaluated using repeated measures ANOVA (α = 0.05). The drugs improved resting SpO2 by ∼4% (P < 0.01), but did not affect the incidence or severity of AMS or cognitive function scores relative to placebo. Subjects' performance on the 12.5 km TT was ∼3% worse when taking the drugs (P < 0.01). The combination of methazolamide and theophylline in the prescribed dosages is not recommended for use at high altitude as it appears to have no measurable effect on AMS and can impair aerobic performance.