Plateau tourism is becoming increasingly popular worldwide, with Tibet alone attracting over 24 million domestic and foreign visitors from January to June 2023. In addition to tourism, many individuals engage in work, business, or sports activities at high altitudes, such as skiing, trekking, and climbing. All these people have to deal with the challenges of high altitude hypoxia which induces various mountain sicknesses and impairs the mental and physical capacity of the natives and immigrants, especially among those with acute hypoxia exposure (Netzer et al., 2013; Faulhaber et al., 2021; Forrer et al., 2021). Pharmacological prophylaxis by acetazolamide and modern preacclimatization strategies may be effective preparation options for the lowlanders to high altitude (Burtscher et al., 2023). The use of acetazolamide has been proved to be effective on preventing acute mountain sickness (AMS), while it needs the travel medicine practitioners’ professional judgment on the reasonable medication time as well as dosage to avoid adverse drug reactions (Ritchie et al., 2012; Shlim, 2020). Hypoxic preacclimatization through continuous or intermittent hypoxia exposure (CHE or IHE) is increasingly applied to enhance acclimatization to high altitude.

CHE is usually to live in a chamber simulating different high altitudes for a few days and thereafter achieve a certain degree of hypoxic acclimatization, but participants may experience AMS akin to the real ascending to high altitudes. Furthermore, this approach is time-consuming and unsuitable for emergency procedures conducted at high altitudes. IHE refers to periodic short-term and repeated exposure to hypoxic environment equivalent to a certain altitude and the acquirement of resistance to subsequent longer or more serious hypoxia injury (Viscor et al., 2018). The training method known as ‘living high, training low’ involves athletes residing in real high altitude or artificial hypoxic environment and then exercising at lower elevations. This approach has been gaining attention from the global sports community due to its positive impact on athletic performance (Inness et al., 2017; Yang et al., 2018). Currently, hypoxic preacclimatization with other IHE patterns, i.e., breathing in a hypobaric or normobaric hypoxic room, or inhaling low oxygen mixtures through masks has also been widely conducted. Although the exact mechanisms still remain unclear, it is believed that IHE can trigger compensatory physical changes primarily in oxygen metabolism pattern and the subsequent improvement of oxygen-carrying capacity (Nagel et al., 2020; Wojan et al., 2023). IHE with hypobaric chamber has been mainly used for animal researches, in which increased circulating erythropoietin levels and hypoxic ventilatory response (HVR) was observed (Logan et al., 2016; Coimbra-Costa et al., 2021). It could also trigger antioxidant defense and impact intracellular signal transduction as well as inflammatory immune response (Aguilar et al., 2018; Yan et al., 2021).

Impairment of mental and physical capacity caused by hypoxia exposure has been widely reported, and hypoxic preacclimatization may be an effective measure to mitigate such damage. Acute IHE in hypobaric chambers has shown obvious protective effects on cardiovascular system, such as the effects against hypoxic hypertension and myocardial ischemia-reperfusion injury (Cui et al., 2012; Terada et al., 2021). Chronic IHE treatment adaptively regulates cardiac autonomic activity (Shi et al., 2020) and increases antioxidant capacity in the brain (Costa et al., 2013). A recent meta-analysis concluded that exercising under hypoxic environment could significantly improve various cognitive functions, and the effect may be moderated by individual characteristics and/or hypoxic preconditioning parameters (Jung et al., 2020). Our recent study also suggests that the remote ischemic preconditioning (RIPC) treatment can notably enhance spatial memory and sleep quality in subjects exposed to acute hypoxia, potentially resulting in improved performance at high altitude (Wu et al., 2023). The effect of hypoxic preacclimatization with hypobaric chamber on cognitive function remains to be evaluated. Additionally, prior studies on IHE have recommended different schemes regarding the essential elements such as the degree of hypoxia, frequency, and duration of hypoxia exposure, and also the application of hypobaric or normobaric hypoxia (Koehle et al., 2008; Navarrete-Opazo et al., 2017), while no universally recognized standards have been established in this regard.

The protective effect of hypoxic preacclimatization with hypobaric chamber against hypoxia remains inconclusive, particularly in relation to performance in hypoxic environment. Therefore we designed this study to assess the effect of hypoxic preacclimatization combining IHE and physical exercise with hypobaric chamber on the subsequent tolerance to acute hypoxia exposure and screen the optimal schemes among the lowlanders.

We conducted a population-based study for the first time to evaluate the effect of hypoxic preacclimatization combining IHE with physical exercise in a hypobaric chamber on the subsequent tolerance to acute hypoxia among the lowlanders. IHE leads to an increase of blood oxygen saturation primarily due to effective ventilatory acclimatization (Katayama et al., 2001; Yoon et al., 2021). SpO₂ level is not only the reflection of pulmonary oxygenation function and oxygen carrying capacity of hemoglobin under hypoxic environment, but also serves as a common noninvasive parameter for monitoring exercise intensity during hypoxic trainings (Woorons and Richalet, 2021). A 7-week IHE under hypobaric pressure with mean total exposure time of 30.8 h has been reported to increase SaO₂ by 4.1% at 4570 m (Hetzler et al., 2009). We also observed an average increase of over 5 percentage points of SpO₂ among the groups with 5-day rest and 5-day physical exercise as compared with the control group. Hypoxic preacclimatization has probably resulted in an acclimatization response with shorter time than predicted. Nevertheless, it should be noted that although SpO₂ is significantly correlated with SaO₂ in most cases, it may not be reliable surrogate marker for SaO₂ in critically ill patients as well as in hypoxemia for increased bias and decreased accuracy and precision (Hassan et al., 2017; Kanz et al., 2018). HR of the subjects with 5-day rest was significantly lowered as compared with the controls, however, no matter 5-day or 3-day physical exercise in the hypobaric chamber seemed to have no obvious effect on HR. When exercising at certain intensity, the changes of HR among the subjects with IHE training are smaller than those without hypoxic training, indicating that IHE can compensate for the decrease of HR by increasing cardiac output and improve the cardiovascular function (Fukuda et al., 2010). The findings suggested that longer exposure to hypoxia for preacclimatization was more effective in increasing blood oxygen saturation and decreasing heart rate compared to engaging in more intense physical exercise.

Despite the well-established efficacy of IHE in enhancing high altitude hypoxia tolerance and the majority of findings supporting its positive effect on preventing AMS, the conclusions remain inconsistent. It has been reported that hypoxic preacclimatization for 1 h a day for 7 consecutive days had no effect on preventing AMS when entering an altitude of 4500 m. (Faulhaber et al., 2016). In this study, those with hypoxic preacclimatization of 3-day exercise in the hypobaric chamber had the lowest AMS incidence of 33.33%, while the difference was not significant. The physiological changes of cardiovascular, respiratory, and nervous systems induced in three or 5 days’ hypoxic preacclimatization may be insufficient to compensatory for the drastic decrease in ambient oxygen partial pressure.

IHE not only alleviates neurological symptoms associated with AMS, but also enhances cognitive function and uplifts mood at high altitudes (Heinrich et al., 2019; Behrendt et al., 2022). Exercise can also improve cognitive performance in both hypoxic and normoxic condition, although the beneficial effect under severe hypoxia may be attenuated (Lefferts et al., 2016; Komiyama et al., 2017; Li et al., 2017). The cognitive performance during exercising under acute hypoxia is primarily determined by alterations in cerebral blood flow, cerebral metabolism, and possibly neurotransmitter function (Ando et al., 2020). We found that 5-day IHE with physical exercise showed significant effect on perceptual speed, motor skills, and color selective reaction times. Hypoxia exposure of longer duration probably interacted positively with physical exercise of moderate intensity in improving hypoxic tolerance of the brain tissue. During this process, a variety of kinase cascades in brain cells may be initiated and induce changes in chromatin structure through epigenetic mechanisms (Rybnikova and Samoilov, 2015). The possible mechanisms also include activation of transcription factors, such as HIF and changes in expression of a variety of regulatory proteins (Qiao et al., 2014; Wu et al., 2019).

IHE enhances both V . O₂max and lactate tolerance, leading to a significant improvement in the aerobic exercise ability of athletes (Gore et al., 2007). A 9-day hypobaric hypoxia exposure at simulated altitude from 4000 m to 5500 m has significantly activated the erythropoietic response and improved the aerobic capacity (Rodriguez et al., 1999). Hypoxic preacclimatization of 5-day exercise in this study also led to a significant increase in V . O₂max. In general, prolonged exposure to hypoxia combined with moderate-intensity physical exercise is more effective in enhancing both mental and physical performance in a hypoxic environment.

The duration of each session and the fraction of inspiration O₂ (FIO2) have been considered as the most effective regimens of hypoxic preacclimatization, while the optimal schemes are still unclear and require further study (Tannheimer and Lechner, 2020). It has been implicated that the effect of hypoxic preacclimatization schemes with short duration was not different between rest and exercise while the schemes with exercise and longer duration could greatly enhance the exercise performance at high altitude (Rieger et al., 2017). In this study, we found that intermittent hypoxic training consisting of 3-h hypoxic exposure for five consecutive days combined with physical exercise was the most effective in promoting hypoxic acclimatization, especially for improvement of physical and mental capacity. The duration of hypoxia is longer than that reported in other studies (Holliss et al., 2014; Taralov et al., 2018). It implies that long duration of hypoxia and physical exercise can probably improve the effect of hypoxic preacclimatization.

This study also has several limitations. Firstly, we failed to collect the intact data on the related physiological parameters, mental and physical capacity before preacclimatization training, and we could not accurately evaluate the comparability between the control and experimental groups although they were matched in some key characteristics, such as age, sex, and history of high altitude exposure. Secondly, we did not conduct field effect evaluation at high altitude. Thirdly, we used the Chinese AMS scoring system (CAS) instead of the better known Lake Louise Score (LLS) in the present study, because the CAS is more commonly used in China, and we did not consider the use of two scoring systems in our study design. Fourthly, we failed to investigate the duration of effect maintenance, which is actually an important aspect of hypoxic preacclimatization. Lastly, as this study was conducted in Chinese Han people, the application audience was relatively limited.

Generally, hypoxic preacclimatization combining IHE with physical exercise in hypobaric chamber could significantly promote the subsequent hypoxic tolerance among the lowlanders, including improvement of SpO₂ and HR, relief of headache symptoms, and enhancement of mental and physical operation capacity. The schemes consisted of hypoxia degree simulated to the altitude of ≥4000m, duration of ≥3 days, single exposure for ≥3 h, and the total training time of ≥10 h may induce the best effect. Furthermore, longer duration of IHE combined with physical exercise of moderate intensity would be preferable for those with high altitude operations with certain intensity.