A Step Test to Evaluate the Susceptibility to Severe High-Altitude Illness in Field Conditions.

Hermand, Eric, Léo Lesaint, Laura Denis, Jean-Paul Richalet, and François J. Lhuissier. A step test to evaluate the susceptibility to severe high-altitude illness in field conditions. High Alt Med Biol. 00:000-000, 2024.-A laboratory-based hypoxic exercise test, performed on a cycle ergometer, can be used to predict susceptibility to severe high-altitude illness (SHAI) through the calculation of a clinicophysiological SHAI score. Our objective was to design a field-condition test and compare its derived SHAI score and various physiological parameters, such as peripheral oxygen saturation (SpO2), and cardiac and ventilatory responses to hypoxia during exercise (HCRe and HVRe, respectively), to the laboratory test. A group of 43 healthy subjects (15 females and 28 males), with no prior experience at high altitude, performed a hypoxic cycle ergometer test (simulated altitude of 4,800 m) and step tests (20 cm high step) at 3,000, 4,000, and 4,800 m simulated altitudes. According to tested altitudes, differences were observed in O2 desaturation, heart rate, and minute ventilation (p < 0.001), whereas the computed HCRe and HVRe were not different (p = 0.075 and p = 0.203, respectively). From the linear relationships between the step test and SHAI scores, we defined a risk zone, allowing us to evaluate the risk of developing SHAI and take adequate preventive measures in field conditions, from the calculated step test score for the given altitude. The predictive value of this new field test remains to be validated in real high-altitude conditions.

Cardiovascular physiology and pathophysiology at high altitude.

Oxygen is vital for cellular metabolism; therefore, the hypoxic conditions encountered at high altitude affect all physiological functions. Acute hypoxia activates the adrenergic system and induces tachycardia, whereas hypoxic pulmonary vasoconstriction increases pulmonary artery pressure. After a few days of exposure to low oxygen concentrations, the autonomic nervous system adapts and tachycardia decreases, thereby protecting the myocardium against high energy consumption. Permanent exposure to high altitude induces erythropoiesis, which if excessive can be deleterious and lead to chronic mountain sickness, often associated with pulmonary hypertension and heart failure. Genetic factors might account for the variable prevalence of chronic mountain sickness, depending on the population and geographical region. Cardiovascular adaptations to hypoxia provide a remarkable model of the regulation of oxygen availability at the cellular and systemic levels. Rapid exposure to high altitude can have adverse effects in patients with cardiovascular diseases. However, intermittent, moderate hypoxia might be useful in the management of some cardiovascular disorders, such as coronary heart disease and heart failure. The aim of this Review is to help physicians to understand the cardiovascular responses to hypoxia and to outline some recommendations that they can give to patients with cardiovascular disease who wish to travel to high-altitude destinations.

The Impact of COVID-19 on the Response to Hypoxia.

Louis, Alexandre, Charlotte Pröpper, Yann Savina, Corentin Tanne, Guy Duperrex, Paul Robach, Pascal Zellner, Stéphane Doutreleau, Jean-Michel Boulet, Alain Frey, Fabien Pillard, Cristina Pistea, Mathias Poussel, Thomas Thuet, Jean-Paul Richalet, and François Lecoq-Jammes. The impact of COVID-19 on the response to hypoxia. High Alt Med Biol. 24:321-328, 2023. Background: Severe high-altitude illness (SHAI) and coronavirus disease 2019 (COVID-19), while differing in most aspects of pathophysiology, both involve respiratory capacity. We examined the long-term impact of COVID-19 on response to hypoxia in individuals free of symptoms but having tested positive during the pandemic. The need for recommendations for such individuals planning a stay at high altitude are discussed. Methods: This multicenter study recruited participants from the multiSHAI cohort, all of whom had previously undergone a hypoxic exercise test. These participants were classified into two groups depending on whether they had since suffered mild-to-moderate COVID-19 (COVID+) or not (Control) and then asked to retake the test. Primary outcomes were: desaturation induced by hypoxia at exercise (ΔSpE), hypoxic cardiac response at exercise, hypoxic ventilatory response at exercise, and SHAI risk score. Results: A total of 68 participants retook the test, 36 classified in the COVID+ group. Analyses of primary outcomes showed no significant differences between groups. However, the COVID+ group showed significantly increased ventilation (VE) parameters during both hypoxic (p = 0.003) and normoxic exercise (p = 0.007). However, only the VE/oxygen consumption relationship during hypoxic exercise was significantly different. Conclusion: This study demonstrates no negative impact of COVID-19 on response to hypoxia as evaluated by the Richalet test. Clinical Trial Registration: NTC number: NCT05167357.

High-altitude pulmonary edema: the intercellular network hypothesis.

The pathophysiology of high-altitude pulmonary edema is currently attributed to exacerbated heterogeneous hypoxic pulmonary vasoconstriction. However, although other cellular mechanisms have been hypothesized, they are still poorly understood. In this review, we focused on cells of the pulmonary acinus, the distal unit for gas exchange, known to be responders to acute hypoxia, notably through many humoral or tissue factors that connect this intercellular network constituting the alveolo-capillary barrier. Hypoxia could drive alveolar edema by: 1) damaging the fluid reabsorption capacity of alveolar epithelial cells, 2) increasing the endothelial and epithelial permeability, especially by alteration of occluding junctions, 3) triggering the inflammation mainly led by alveolar macrophages, 4) increasing interstitial water accumulation by disruption of extracellular matrix architecture and tight junctions, 5) inducing pulmonary vasoconstriction through an orchestrated response of pulmonary arterial endothelial and smooth muscle cells. Hypoxia may also alter the function of fibroblasts and pericytes that contribute to the interconnection of the cells of the alveolar-capillary barrier. Due to its complex intercellular network and delicate pressure gradient equilibrium, the alveolar-capillary barrier is simultaneously affected by acute hypoxia in all its components, leading to rapid accumulation of water in the alveoli.

Strengthening Altitude Knowledge: A Delphi Study to Define Minimum Knowledge of Altitude Illness for Laypersons Traveling to High Altitude.

Berendsen, Remco R., Peter Bärtsch, Buddha Basnyat, Marc Moritz Berger, Peter Hackett, Andrew M. Luks, Jean-Paul Richalet, Ken Zafren, Bengt Kayser, and the STAK Plenary Group. Strengthening altitude knowledge: a Delphi study to define minimum knowledge of altitude illness for laypersons traveling to high altitude. High Alt Med Biol. 23:330-337, 2022. Introduction: A lack of knowledge among laypersons about the hazards of high-altitude exposure contributes to morbidity and mortality from acute mountain sickness (AMS), high-altitude cerebral edema (HACE), and high-altitude pulmonary edema (HAPE) among high-altitude travelers. There are guidelines regarding the recognition, prevention, and treatment of acute-altitude illness for experts, but essential knowledge for laypersons traveling to high altitudes has not been defined. We sought expert consensus on the essential knowledge required for people planning to travel to high altitudes. Methods: The Delphi method was used. The panel consisted of two moderators, a core expert group and a plenary expert group. The moderators made a preliminary list of statements defining the desired minimum knowledge for laypersons traveling to high altitudes, based on the relevant literature. These preliminary statements were then reviewed, supplemented, and modified by a core expert group. A list of 33 statements was then presented to a plenary group of experts in successive rounds. Results: It took three rounds to reach a consensus. Of the 10 core experts invited, 7 completed all the rounds. Of the 76 plenary experts, 41 (54%) participated in Round 1, and of these 41 a total of 32 (78%) experts completed all three rounds. The final list contained 28 statements in 5 categories (altitude physiology, sleeping at altitude, AMS, HACE, and HAPE). This list represents an expert consensus on the desired minimum knowledge for laypersons planning high-altitude travel. Conclusion: Using the Delphi method, the STrengthening Altitude Knowledge initiative yielded a set of 28 statements representing essential learning objectives for laypersons who plan to travel to high altitudes. This list could be used to develop educational interventions.

Expert group syndrome at high altitude.

During a training session for the university diploma of Mountain medicine delivered by University Sorbonne Paris Nord for medical doctors, one of the participants developed signs of maladaptation to high altitude at 3 600 m, the severity of which was incorrectly interpreted. Information was sparingly given by the patient (an anesthetist) to several of his colleagues and no one was in charge to collect clinical data, take a history, and provide appropriate treatment. The combination of the absence of designation of a supervising doctor and the difficulty of communicating with the patient led to a lack of coordinated management and to an evolution of the symptoms towards severe acute mountain sickness. Fortunately, the very rapid management of the patient and a rapid helicopter evacuation, as soon as the symptoms worsened towards the onset of a suspected high altitude cerebral and/or pulmonary edema, allowed rapid resolution without sequelae. Environmental, medical, psychological, and managerial factors led to this Expert Group Syndrome.

In Transgenic Erythropoietin Deficient Mice, an Increase in Respiratory Response to Hypercapnia Parallels Abnormal Distribution of CO2/H+-Activated Cells in the Medulla Oblongata.

Erythropoietin (Epo) and its receptor are expressed in central respiratory areas. We hypothesized that chronic Epo deficiency alters functioning of central respiratory areas and thus the respiratory adaptation to hypercapnia. The hypercapnic ventilatory response (HcVR) was evaluated by whole body plethysmography in wild type (WT) and Epo deficient (Epo-TAgh) adult male mice under 4%CO2. Epo-TAgh mice showed a larger HcVR than WT mice because of an increase in both respiratory frequency and tidal volume, whereas WT mice only increased their tidal volume. A functional histological approach revealed changes in CO2/H+-activated cells between Epo-TAgh and WT mice. First, Epo-TAgh mice showed a smaller increase under hypercapnia in c-FOS-positive number of cells in the retrotrapezoid nucleus/parafacial respiratory group than WT, and this, independently of changes in the number of PHOX2B-expressing cells. Second, we did not observe in Epo-TAgh mice the hypercapnic increase in c-FOS-positive number of cells in the nucleus of the solitary tract present in WT mice. Finally, whereas hypercapnia did not induce an increase in the c-FOS-positive number of cells in medullary raphe nuclei in WT mice, chronic Epo deficiency leads to raphe pallidus and magnus nuclei activation by hyperacpnia, with a significant part of c-FOS positive cells displaying an immunoreactivity for serotonin in the raphe pallidus nucleus. All of these results suggest that chronic Epo-deficiency affects both the pattern of ventilatory response to hypercapnia and associated medullary respiratory network at adult stage with an increase in the sensitivity of 5-HT and non-5-HT neurons of the raphe medullary nuclei leading to stimulation of f R for moderate level of CO2.

Modeling the oxygen transport to the myocardium at maximal exercise at high altitude.

Exposure to high altitude induces a decrease in oxygen pressure and saturation in the arterial blood, which is aggravated by exercise. Heart rate (HR) at maximal exercise decreases when altitude increases in prolonged exposure to hypoxia. We developed a simple model of myocardial oxygenation in order to demonstrate that the observed blunting of maximal HR at high altitude is necessary for the maintenance of a normal myocardial oxygenation. Using data from the available scientific literature, we estimated the myocardial venous oxygen pressure and saturation at maximal exercise in two conditions: (1) with actual values of maximal HR (decreasing with altitude); (2) with sea-level values of maximal heart rate, whatever the altitude (no change in HR). We demonstrated that, in the absence of autoregulation of maximal HR, myocardial tissue oxygenation would be incompatible with life above 6200 m-7600 m, depending on the hypothesis concerning a possible increase in coronary reserve (increase in coronary blood flow at exercise). The decrease in maximal HR at high altitude could be explained by several biological mechanisms involving the autonomic nervous system and its receptors on myocytes. These experimental and clinical observations support the hypothesis that there exists an integrated system at the cellular level, which protects the myocardium from a hazardous disequilibrium between O2  supply and O2 consumption at high altitude.

Editorial for Life Special Issue Book Cellular and Functional Response to Hypoxia.

Hypoxia is a current research topic in biology, physiology, and medicine [...].

Evaluation of the Lake Louise Score for Acute Mountain Sickness and Its 2018 Version in a Cohort of 484 Trekkers at High Altitude.

Richalet, Jean-Paul, Chantal Julia, and François J. Lhuissier. Evaluation of the Lake Louise Score for acute mountain sickness and its 2018 version in a cohort of 484 trekkers at high altitude. High Alt Med Biol. 22:353-361, 2021. Background: The Lake Louise Score (LLS) is widely used in field studies and chamber studies for the diagnosis of Acute Mountain Sickness (AMS). This score aggregates symptoms that are nonspecific: headache, gastrointestinal symptoms, fatigue, dizziness and sleep disturbance can be due to a variety of causes unrelated to altitude hypoxia. The objectives of this study were to (1) reevaluate the need for a headache score >0 for the diagnosis of AMS, (2) evaluate the role of sleep disturbances, in relation with other symptoms, (3) evaluate the significance of dizziness. Materials and Methods: We analyzed LLS from 484 trekkers at high altitude. Among them, 212 suffered from moderate AMS (mAMS: 3 ≤ LLS < 6) and 115 from severe AMS (sAMS: LLS ≥ 6). Results: Cluster analysis of AMS revealed three main groups presenting the following symptoms: Group 1 includes 254 subjects who had less than 2 symptoms; Group 2 includes 137 subjects who had fatigue, sleep disturbance, and headache, corresponding to mAMS; Group 3 includes 93 subjects who had headache, fatigue, dizziness and sleep disturbance, corresponding to sAMS. A headache score of zero was found in 25% of mAMS and 5% of sAMS subjects. Only the absence of headache associated with the absence of fatigue was specific of absence of sAMS. In subjects with a dizziness score > 1, end-tidal partial pressure of carbon dioxide during a hypoxic exercise test was lower than that in subjects with a dizziness score < 2. Subjects with high ventilatory response to hypoxia may develop dizziness with high altitude exposure. Conclusion: (1) An isolated headache score > 0 should not be mandatory to define AMS, (2) sleep disruption contributes to the diagnosis of AMS, (3) gastrointestinal symptoms and dizziness are weaker contributors to the LLS, (4) dizziness might be linked to a hyperresponsiveness to hypoxia and not to AMS itself.

Sub-maximal aerobic exercise training reduces haematocrit and ameliorates symptoms in Andean highlanders with chronic mountain sickness.

NEW FINDINGS: What is the central question of this study? What is the effect of sub-maximal aerobic exercise training on signs and symptoms of chronic mountain sickness (CMS) in Andean highlanders? What is the main finding and its importance? Aerobic exercise training (ET) effectively reduces haematocrit, ameliorates symptoms and improves aerobic capacity in CMS patients, suggesting that a regular aerobic ET programme might be used as a low-cost non-invasive/non-pharmacological management strategy of this syndrome. ABSTRACT: Excessive erythrocytosis is the hallmark sign of chronic mountain sickness (CMS), a debilitating syndrome associated with neurological symptoms and increased cardiovascular risk. We have shown that unlike sedentary residents at the same altitude, trained individuals maintain haematocrit within sea-level range, and thus we hypothesise that aerobic exercise training (ET) might reduce excessive haematocrit and ameliorate CMS signs and symptoms. Eight highlander men (38 ± 12 years) with CMS (haematocrit: 70.6 ± 1.9%, CMS score: 8.8 ± 1.4) from Cerro de Pasco, Peru (4340 m) participated in the study. Baseline assessment included haematocrit, CMS score, pulse oximetry, maximal cardiopulmonary exercise testing and in-office plus 24 h ambulatory blood pressure (BP) monitoring. Blood samples were collected to assess cardiometabolic, erythropoietic, and haemolysis markers. ET consisted of pedalling exercise in a cycloergometer at 60% of V̇O2peak for 1 h/day, 4 days/week for 8 weeks, and participants were assessed at weeks 4 and 8. Haematocrit and CMS score decreased significantly by week 8 (to 65.6 ± 6.6%, and 3.5 ± 0.8, respectively, P < 0.05), while V̇O2peak and maximum workload increased with ET (33.8 ± 2.4 vs. 37.2 ± 2.0 ml/min/kg, P < 0.05; and 172.5 ± 9.4 vs. 210.0 ± 27.8 W, P < 0.01; respectively). Except for an increase in high-density lipoprotein cholesterol, other blood markers and BP showed no differences. Our results suggest that reduction of haematocrit and CMS symptoms results mainly from haemodilution due to plasma volume expansion rather than to haemolysis. In conclusion, we show that ET can effectively reduce haematocrit, ameliorate symptoms and improve aerobic capacity in CMS patients, suggesting that regular aerobic exercise might be used as a low-cost non-invasive and non-pharmacological management strategy.

Exercising in Hypoxia and Other Stimuli: Heart Rate Variability and Ventilatory Oscillations.

Periodic breathing is a respiratory phenomenon frequently observed in patients with heart failure and in normal subjects sleeping at high altitude. However, until recently, periodic breathing has not been studied in wakefulness and during exercise. This review relates the latest findings describing this ventilatory disorder when a healthy subject is submitted to simultaneous physiological (exercise) and environmental (hypoxia, hyperoxia, hypercapnia) or pharmacological (acetazolamide) stimuli. Preliminary studies have unveiled fundamental physiological mechanisms related to the genesis of periodic breathing characterized by a shorter period than those observed in patients (11~12 vs. 30~60 s). A mathematical model of the respiratory system functioning under the aforementioned stressors corroborated these data and pointed out other parameters, such as dead space, later confirmed in further research protocols. Finally, a cardiorespiratory interdependence between ventilatory oscillations and heart rate variability in the low frequency band may partly explain the origin of the augmented sympathetic activation at exercise in hypoxia. These nonlinear instabilities highlight the intrinsic "homeodynamic" system that allows any living organism to adapt, to a certain extent, to permanent environmental and internal perturbations.

Impact of High Altitude on Cardiovascular Health: Current Perspectives.

Globally, about 400 million people reside at terrestrial altitudes above 1500 m, and more than 100 million lowlanders visit mountainous areas above 2500 m annually. The interactions between the low barometric pressure and partial pressure of O2, climate, individual genetic, lifestyle and socio-economic factors, as well as adaptation and acclimatization processes at high elevations are extremely complex. It is challenging to decipher the effects of these myriad factors on the cardiovascular health in high altitude residents, and even more so in those ascending to high altitudes with or without preexisting diseases. This review aims to interpret epidemiological observations in high-altitude populations; present and discuss cardiovascular responses to acute and subacute high-altitude exposure in general and more specifically in people with preexisting cardiovascular diseases; the relations between cardiovascular pathologies and neurodegenerative diseases at altitude; the effects of high-altitude exercise; and the putative cardioprotective mechanisms of hypobaric hypoxia.

Accuracy and Reliability of Pulse O2 Saturation Measured by a Wrist-worn Oximeter.

This study aims to evaluate the accuracy of the Garmin Forerunner 245 heart rate (HR) and pulse O2 saturation (SpO2) sensors compared with electrocardiogram and medical oximeter, from sea level to high altitude. Ten healthy subjects underwent five tests in normoxia and hypoxia (simulated altitudes from 3000 to 5500 m), consisting in a 5-min rest phase, followed by 5-min of mild exercise. Absolute error (±10 bpm for HR and ±3% for SpO2, around criterion) and intraclass correlations (ICC) were calculated. Error rates for HR remained under 10%, except at 3000 m, and ICCs evidenced a good reliability between Garmin and criterion. Overall SpO2 was higher than criterion (P<0.001) with a >50% error rate (>80% above 4800 m), and a poor reliability with criterion. The Garmin device displayed acceptable HR data at rest and exercise for all altitudes, but failed to provide trustworthy SpO2 values, especially at high altitude, where a pronounced arterial O2 desaturation could lead to acute mountain sickness in hypoxia-sensitive subjects, and its life-threatening complications; moreover, readings of overestimated SpO2 values might induce trekkers into further hazardous behavior by pursuing an ascent while being already at risk. Therefore, its use to assess SpO2 should be proscribed in altitude for acclimatization evaluation.

Effect of exercise training in rats exposed to chronic hypoxia: Application for Monge's disease.

Physical exercise may improve hematological conditions in high altitude dwellers suffering from Chronic Mountain Sickness (CMS), in reducing hemoglobin concentration. Therefore, the present study aimed to characterize the effects of 1-month exercise training session in a model of rats exposed to chronic hypoxia. Four groups of male rats were studied: normoxic sedentary (NS, n = 8), normoxic training (NT, n = 8), hypoxic sedentary (HS, n = 8), and hypoxic training group (HT, n = 8). Hypoxic groups were exposed to hypobaric hypoxia for one month (PB =433 Torr). Training intensity was progressively increased from a running speed of 10.4 to 17.8 m/min. Chronic hypoxia led to an increase in hematocrit (HCT) associated with a decrease in plasma volume despite an increase in water intake. Training led to a reduction in HCT (p < 0.01), with a non-significant increase in plasma volume and weight gain. Hypoxia and training had inhibitory effects on haptoglobin (NS group: 379 ± 92; HT: 239 ± 34 µg/ml, p < 0.01). Chronic hypoxia and exercise training increased SpO2 measured after acute hypoxic exposure. Training blunted the decrease in V˙ O2 peak, time of exhaustion, and maximum speed associated with chronic exposure to hypoxia. Chronic hypoxia led to a right ventricular hypertrophy, which was not corrected by 1-month exercise training. Altogether, by decreasing hematocrit, reducing body weight, and limiting performance decrease, training in hypoxia may have a beneficial effect on excessive erythropoiesis in chronic hypoxia. Therefore, regular exercise training might be beneficial to avoid worsening of CMS symptoms in high altitude dwellers and to improve their quality of life.

Cytoprotective effects of erythropoietin: What about the lung?

Erythropoietin (Epo) is a pleiotropic cytokine, essential for erythropoiesis. Epo and its receptor (Epo-R) are produced by several tissues and it is now admitted that Epo displays other physiological functions than red blood cell synthesis. Indeed, Epo provides cytoprotective effects, which consist in prevention or fight against pathological processes. This perspective article reviews the various protective effects of Epo in several organs and tries to give a proof of concept about its effects in the lung. The tissue-protective effects of Epo could be a promising approach to limit the symptoms of acute and chronic lung diseases.

The Affinity of Hemoglobin for Oxygen Is Not Altered During COVID-19.

Background: A computational proteomic analysis suggested that SARS-CoV-2 might bind to hemoglobin (Hb). The authors hypothesized that this phenomenon could result in a decreased oxygen (O2) binding and lead to hemolytic anemia as well. The aim of this work was to investigate whether the affinity of Hb for O2 was altered during COVID-19. Methods: In this retrospective, observational, single-center study, the blood gas analyses of 100 COVID-19 patients were compared to those of 100 non-COVID-19 patients. Fifty-five patients with carboxyhemoglobin (HbCO) ≥8% and 30 with sickle cell disease (SCD) were also included ("positive controls" with abnormal Hb affinity). P50 was corrected for body temperature, pH, and PCO2. Results: Patients did not differ statistically for age or sex ratio in COVID-19 and non-COVID-19 groups. Median P50 at baseline was 26 mmHg [25.2-26.8] vs. 25.9 mmHg [24-27.3], respectively (p = 0.42). As expected, P50 was 22.5 mmHg [21.6-23.8] in the high HbCO group and 29.3 mmHg [27-31.5] in the SCD group (p < 0.0001). Whatever the disease severity, samples from COVID-19 to non-COVID-19 groups were distributed on the standard O2-Hb dissociation curve. When considering the time-course of P50 between days 1 and 18 in both groups, no significant difference was observed. Median Hb concentration at baseline was 14 g.dl-1 [12.6-15.2] in the COVID-19 group vs. 13.2 g.dl-1 [11.4-14.7] in the non-COVID-19 group (p = 0.006). Among the 24 COVID-19 patients displaying anemia, none of them exhibited obvious biological hemolysis. Conclusion: There was no biological argument to support the hypothesis that SARS-CoV-2 could alter O2 binding to Hb.

Modelling the relationships between arterial oxygen saturation, exercise intensity and the level of aerobic performance in acute hypoxia.

PURPOSE: The aim of this study was to establish a model to estimate the level of arterial oxygen saturation (SpO2) and help determine the appropriate hypoxic dose in humans exercising in acute hypoxia. METHODS: SpO2 values were collected in seven untrained (UTS) and seven endurance-trained male subjects (ETS) who performed six cycle incremental and maximal tests at sea level and at simulated altitudes of 1000, 1500, 2500, 3500 and 4500 m. Oxygen uptake was continuously measured and maximal oxygen uptake ([Formula: see text]) was determined in each subject and at each altitude. Intensity was expressed as percentage of [Formula: see text]. RESULTS: There were strong non-linear relationships between altitude and SpO2 at low, moderate and high intensity both in ETS and UTS (r = 0.97, p < 0.001). SpO2 was significantly correlated to exercise intensity at sea level and at all simulated altitudes in ETS but only from 2500 m in UTS. There were inverse correlations between SpO2 and sea-level [Formula: see text] at all altitudes, which were stronger from 2500 m and with the increase in exercise intensity. The three-variable model we established predicts (p < 0.001) the SpO2 level of individuals exercising in acute hypoxia based on their sea-level [Formula: see text], the intensity of exercise and the altitude level. CONCLUSION: The model demonstrates that the drop of SpO2 during exercise in acute hypoxia is larger with the increase in both sea-level [Formula: see text] and exercise intensity. The model also highlights that the pivotal altitude from which the fall in SpO2 is exacerbated is between 2000 and 2500 m, depending on both sea-level [Formula: see text] and exercise intensity.