Monitor and alleviate human hypoxia during short-term exposure to high altitudes: A review

Abstract

Growing numbers of lowlanders are travelling to high altitudes for occupational and recreational purposes. Hypoxia constitutes the principal physiological challenge at high altitudes, causing notable discomfort and potential life-threatening conditions. This study systematically analysed three key physiological systems during short-term high-altitude exposure and identified the most clinically relevant indicators for these systems. Six Acute Mountain Sickness (AMS) scales were summarized from a subjective monitoring perspective. Three hypoxia alleviation methods with practical implementation guidelines are presented. Based on identified limitations in current evaluation and intervention methods, we propose future research directions to improve safety protocols for high-altitude visitors and to optimize acclimatization strategies.Highlights

The relevant indicators for three key physiological systems were selected.

The key symptoms of six AMS questionnaires were analysed.

Three methods of alleviating hypoxia are summarized.

Development of an oxygen comfort assessment method is essential for mild AMS.

Thermal-oxygen coupled environment control technology is prospective.

Keywords

Short-term exposure physiological indicator acute mountain sickness alleviation method intermittent hypoxia oxygen enrichment

Introduction

With the development of society and the construction of railways, more lowlanders are exposed to high altitudes for activities, such as mountain tourism, high–altitude industries (e.g., mining) and soldiers. High altitude terms as locations higher than 2500 m above sea level. Many physiological responses of the human body start notably developing above 2500 m.¹ High-altitude regions exhibit extreme environmental conditions characterized by hypobaric hypoxia, cold temperatures, large daily temperature swings, intense UV radiation, low humidity and strong winds. Hypoxia is the primary health challenge, negatively impacting multiple physiological systems, including neurological, respiratory, sensory, haematological, digestive and musculoskeletal functions.² Physiological strain caused by hypoxia impairs normal functioning and reduces work efficiency.³ Severe cases may occur acute high-altitude illness (AHAI),⁴ the characteristics of acute mountain sickness (AMS), high-altitude pulmonary oedema (HAPE) and high-altitude cerebral oedema (HACE) are outlined in Table 1. AMS typically occurs within 4–24 h after ascent to altitudes above 2500 m. The symptoms usually resolve without the need for descent. However, individuals who persist with AMS symptoms or experience fatigue, susceptibility to cold exposure and upper respiratory tract infections, resulting in more severe AHAI, such as HAPE and HACE. Consequently, ‘people short-term exposed to high altitude’ have been the focus of concern and consideration.

Table 1.

Descriptions of acute high-altitude illness.

Name	Summary of concept and cause	The onset time and altitude	Symptoms
Acute mountain sickness, AMS	The increase in cerebral blood flow, cerebral blood volume, and the permeability of the blood-brain barrier resulting from hypoxia ultimately contributes to inadequate buffering by cerebrospinal fluid and the development of AMS.⁵	Common above 2500 m. Onset within 4–24 h after ascent.⁶	Headache, plus one or more of the following: poor appetite, nausea, vomiting, lethargy, persistent light-headedness. Normal neurologic examination and mental status.⁷
High-altitude pulmonary oedema, HAPE	HAPE is a life-threatening non-cardiogenic pulmonary oedema. It is a particular high-altitude illness that occurs in a subset of individuals who ascend to elevated altitudes for the first or second time, often as a result of hypoxia and various precipitating factors. This condition leads to increased vascular permeability, elevated pulmonary blood volume, disturbances in pulmonary circulation, and the extravasation of fluid from the microcirculation into the interstitial spaces of the lungs and the alveoli.^2,8	Above 3000 m. Onset more than 24 h after ascent.⁶	Early signs: increasing dyspnoea with activity, decreased exercise performance, dry cough. Late signs: dyspnoea with simple activities or at rest, cyanosis, cough with pink frothy sputum, respiratory distress.⁷
High-altitude cerebral oedema, HACE	The pathophysiological mechanisms underlying AMS and HACE exhibit similarities; however, HACE cannot be merely characterized as a more severe manifestation of AMS. The pathogenesis mechanism of HACE is not yet clear with the most likely cause being vasogenic oedema induced by increased cerebral blood flow. In addition, lack of ATP, cerebral autoregulation impairment, cerebral hypertension and VEGF regulation giving rise to elevated vascular permeability may also play a role in HACE pathogenesis.⁹	Unusual below 3500 m unless accompanied by HAPE. Onset within the first few days after ascent.⁷	Often preceded by symptoms of AMS. Global encephalopathy, with altered mental status, ataxia or both; focal neurologic deficits uncommon can progress to coma.⁷

Figure 1.

Time-dependent changes and related consequences of physiological responses at high altitude (modified from Burtscher et al.²⁰ and Mallet et al.¹⁵).

This research spans multiple disciplines, including medicine, exercise physiology, civil engineering and Heating, Ventilation and Air Conditioning (HVAC). Medical research investigates the effects of hypoxia, oxygen enrichment.¹⁰ and pharmacological interventions.⁷ through changes in physiological parameters.^11–13 and cognitive performance,¹⁴ and even delves into the cellular and genetic mechanisms.^15,16 Exercise physiology studies demonstrate that athletic performance can be enhanced by hypoxia.¹⁷ Civil engineering research examines oxygen diffusion dynamics in tunnel environments.¹⁸ HVAC research focuses on developing oxygen-enriched indoor environments to enhance high-altitude comfort.¹⁹ While high-altitude research traditionally focused on medical and exercise physiology, interdisciplinary approaches have recently gained prominence. Given hypoxia's systemic effects, these studies inherently integrate medical science perspectives. Thus, this study synthesizes medical evidence to systematically summarize the high-altitude exposure effect.

Current literature shows substantial variation in defining hypoxia exposure duration, ranging from acute to chronic conditions, resulting in heterogeneity in reported responses (Figure 1). Lowlanders typically experience acute exposure lasting days to weeks during high-altitude sojourns. Although Burtscher et al.²¹ define acute exposure as the initial phase of hypoxia exposure with the most pronounced (patho)physiological responses (duration from minutes to days), this diverges from observed real-world scenarios. Thus, this study adopts the definition of Song et al.²² for ‘short-term exposure’ (i.e., lowlanders staying at high altitudes for below 3 months). This study systematically investigated physiological mechanisms during short-term hypoxia exposure, evaluated subjective assessment tools and synthesized current effective hypoxia alleviation methods. It aimed to provide practical guidance for short-term high-altitude exposure and scientific insights for optimizing high-altitude adaptation strategies.

Literature search strategy

A systematic literature search was conducted to identify publications relevant to physiological responses, subjective assessment methods and alleviative methods for short-term high-altitude exposure in humans. The search was performed using electronic databases including Springer Link, Elsevier (Science Direct) and Web of Science, covering the fields of medicine, physiology, sports science and environmental engineering. The search was limited to articles published between 1950 and 2023. The search strategy, illustrated in Figure 2, was structured around three primary themes: ‘Physiological responses’, ‘Assessment’ and ‘Intervention/Outcome’. The specific search syntax was adapted to the rules of each database, using Boolean operators (AND, OR) to combine these concepts effectively. Subsequently, all retrieved articles underwent an initial screening based on eligibility criteria. Following this, the full texts of articles were carefully evaluated to select those with high relevance and significant citation impact for in-depth review.

Figure 2.

Search and selection process of literature publications.

Systemic physiological responses and monitoring indicators during short-term high-altitude exposure

Physiological indicators represent critical biomarkers for assessing systemic functions and health status. The selection of appropriate physiological indicators is essential for monitoring hypoxic exposure in lowlanders and ensuring safety during high-altitude exposure. As depicted in Figure 1, predominant responses vary across different phases of high-altitude exposure. Therefore, we analysed the physiological systems during short-term exposure and identified key monitoring indicators for each system, as listed in Table 2 (spanning systemic to cellular levels).

Table 2

The key monitoring indicators for the physiological system.

Physiological system	Indicator	Change	Non-invasive measurement	Instrument	Variation and mechanism
Respiratory system	Minute ventilation, VE.²³	↑	Y	Metabolic analyser	Activation of carotid body chemoreceptors transmits signals to specialized neurons in the nucleus tractus solitarius (NTS), activating the sympathetic nervous system-mediated acute ventilatory chemoreflex response.²¹
	Oxygen uptake, VO₂.²³	↓	Y	Metabolic analyser	The low oxygen in the environment leads to a reduction in oxygen intake.
	Carbon dioxide output, VCO₂.²³	↑	Y	Metabolic analyser	Increased ventilation elevates VCO₂, which in severe cases may result in respiratory alkalosis.²³
	End-tidal CO₂ partial pressure, PETCO₂.^24,25	↓	Y	Metabolic analyser	PETCO₂ reflects the local partial pressure in the alveoli. An increase in ventilation leads to a decrease in PETCO₂.²⁴
	End-tidal O₂ partial pressure, PETO₂.²⁵	↓	Y	Metabolic analyser	The low-oxygen environment directly leads to a decrease in the alveolar oxygen partial pressure, and PETO₂ subsequently drops.²⁵
	Peripheral oxygen saturation, SpO₂.²⁶	↓	Y	Pulse oximeter	The decrease in oxygen intake leads to a reduction in oxyhaemoglobin levels in the blood.
	Pulmonary arterial pressure, PAP.⁷	↑	Y	Echocardio graphy machine	Acute hypoxia directly stimulates pulmonary vasoconstriction, resulting in pulmonary hypertension.¹² Increased PAP with risk of reduced right-heart function or high-altitude pulmonary oedema.⁷
Cardiovascular circulation	Heart rate, HR.²⁶	↑	Y	Electrocardio graph (ECG)	Sympathetic nerve excitation with concomitant parasympathetic withdrawal.²⁷
	Heart rate variability, HRV.^23,28	-	Y	ECG	Sympathetic nerve excitation with concomitant parasympathetic withdrawal.²⁷
	Blood pressure, BP.²⁶	↑	Y	Blood pressure monitor	There is a decrease in systolic blood pressure due to hypoxic vasodilation, which is quickly (within a few hours) counteracted by an increase in sympathetic vasoconstriction, which raises systolic blood pressure above sea-level values.^12,29
	Partial pressure of arterial oxygen, PaO₂.²⁴	↓	N	Blood gas analyser	A decrease in the partial pressure of inspired oxygen directly leads to a reduction in PaO₂.
	Partial pressure of arterial carbon dioxide, PaCO₂.²⁴	↓	N	Blood gas analyser	Hyperventilation induces a reduction in PaCO₂.^15,24
	Erythropoietin, EPO	↑	N	Chemilumine scence immunoassay analyser	Hypoxia rapidly stabilizes hypoxia-inducible factor-1α (HIF-1α) within minutes, triggering transcriptional activation and subsequent production of EPO in the kidneys and liver.^30,31
	Haemoglobin concentration, Hb.²³	↑	N	Haematology analyser	EPO stimulates erythropoiesis to enhance oxygen delivery capacity.³²
	Haematocrit, Hct.^23,33	↑	N	Haematology analyser	In the early stage of hypoxia, haemoconcentration-induced Hct elevation results from dehydration caused by hyperventilation and diuresis; in the later stage, Hct further increases due to hypoxia-driven polycythemia.³³
	Red blood cell count, RBC.^33,34	↑	N	Haematology analyser	The consequence is erythrocytosis.³²
	Plasma volume.³⁵	↓	Y	Near-infrared spectroscopy (NIRS)	Dehydration results from hyperventilation and diuresis.³⁶
	Cerebral blood flow, CBF.³⁷	↑	Y	Transcranial Doppler (TCD)	CBF increased results from multiple factors, such as reduced PaO₂ and elevated cerebral lactate.^38,39
	Cerebral oxygen saturation	↓	Y	NIRS	A reduction in arterial oxygen saturation directly leads to decreased cerebral oxygen saturation.
	Cerebral lactate.³⁹	↑	N	Magnetic resonance spectroscopy (MRS)	Hypoxia-inducible factor (HIF) upregulates glycolytic enzymes (including phosphofructokinase, PFK) under hypoxia, thereby promoting lactate production.³⁹
Thermoregulatory system	Skin temperature	↓	Y	Thermistor	Reduced ambient pressure significantly alters heat exchange dynamics between the human skin surface and the surroundings. Under hypobaric conditions, the evaporation heat dissipation increases due to lower air density while convective heat transfer diminishes.⁴⁰
	Core temperature	↓	Minimally invasive	Rectal/ oesophageal probe	(1) Elevated ventilation will increase heat loss.(2) Hyperventilation hypoxia modulates central thermosensitivity, leading to the inhibition of thermogenic pathways and subsequent reductions in body temperature.⁴¹
	Skin blood flow	↓	Y	Laser Doppler flowmeter	Hypoxia activates the sympathetic nervous system (SNS), leading to norepinephrine release and subsequent cutaneous vasoconstriction.⁴²

Abbreviations: Y, yes; N, no.

Respiratory system

Respiration is a fundamental physiological process essential for sustaining normal bodily activities. The respiratory process comprises three interrelated and concurrent phases: external respiration, blood gas transport and internal respiration, as illustrated in Figure 3. During external respiration, gases diffuse through the respiratory tract and undergo gas exchange with the blood in the alveoli. Oxygenated blood subsequently perfuses tissues via systemic circulation. Internal respiration entails tissue-level gas exchange between capillaries and cells. These gas exchange processes are primarily driven by partial pressure gradients.

Figure 3.

Schematic diagram of the respiratory process.

When environmental oxygen is reduced, intake of oxygen by the body decreases, resulting in a decrease in the partial pressure of alveolar oxygen (PAO₂). This PAO₂ reduction diminishes the oxygen partial pressure gradient between the alveoli and pulmonary capillaries, thereby impeding oxygen diffusion. Consequently, blood oxygen content in pulmonary capillaries decreases, leading to the partial pressure of arterial oxygen (PaO₂). This process alters the affinity of haemoglobin for oxygen, ultimately resulting in decreased oxygen saturation and inducing hypoxic symptoms. Figure 4 illustrates the atmospheric and partial oxygen pressures at various altitudes.⁴³ To address the hypoxic condition, the human body has compensatory mechanisms. Carotid and aortic chemoreceptors of humans are activated by hypoxia, stimulating the respiratory centre to increase ventilation (hypoxic ventilatory response, HVR). HVR recruits previously non-ventilated alveoli, increasing the respiratory surface area and optimizing oxygen distribution.² This mechanism enhances alveolar gas exchange by increasing fresh air inflow. HVR also increases thoracic activity, enhances the negative pressure within the thoracic cavity, augments venous return, and promotes pulmonary blood flow as well as cardiac output.² Notably, hyperventilation decreases partial pressure of arterial carbon dioxide (PaCO₂), resulting in respiratory alkalosis. This prompts the kidneys to induce a compensatory metabolic acidosis through acid retention and increased bicarbonate (HCO₃⁻) excretion in urine.²⁴ Moreover, hyperventilation contributes to fluid loss in the respiratory system, potentially resulting in dehydration.³⁶ and haemoconcentration.

Figure 4.

Atmospheric pressure and partial oxygen pressure at different altitudes (replotted from Liu.²³)

Cardiovascular system

The cardiovascular system comprises the heart, arteries, capillaries and veins. As the central pump, the heart propels oxygenated blood through arteries to capillary networks. Within the capillaries, exchange of nutrients and gases occurs between the blood and tissue cells. The capillaries subsequently merge to form veins, which return to the heart.⁴⁴

When environmental oxygen decreases, the cardiovascular system initiates compensatory mechanisms. These mechanisms maintain consistent oxygen delivery to tissues by increased cardiac output.⁴⁵ Cardiac output (CO) depends on stroke volume (SV) and heart rate (HR). During short-term exposure to high altitudes, CO initially increases due to elevated HR without SV changes.⁴⁶ HR elevation reflects sympathetic nervous system activation. The sympathetic nervous system is excited through the central effect of the hypoxia and partly reflexes, through stimulation of chemoreceptors and possibly pulmonary arterial baroreceptors, and altered systemic baroreceptor function.¹¹ Sympathetic activation also increases blood pressure.²⁹ This masks the decrease in blood pressure that results from the endothelium-dependent and non-endothelium-dependent systemic vasodilation during subacute exposure to hypoxia,^1,12 as presented in Figure 5. This figure illustrates that system and pulmonary circulation changes during acute hypoxia, as summarized by Parati et al.¹ With prolonged acclimatization, CO normalizes to the resting level observed in high-altitude natives, accompanied by persistent HR elevation and SV reduction. Furthermore, hypoxia rapidly stabilizes hypoxia-inducible factor-1α (HIF-1α) within minutes, triggering transcriptional activation and subsequent production of erythropoietin (EPO) in the kidneys and liver.^30,31 Knaupp et al.⁴⁷ demonstrated that continuous hypoxia exposure lasting 84–120 min leads to a sustained serum EPO elevation. The glycoprotein hormone EPO enhances oxygen delivery capacity via erythropoiesis stimulation.^32,33 HIF-1 also mediates the upregulation of vascular endothelial growth factor (VEGF), thereby promoting angiogenesis.⁴⁸

Figure 5.

Effects of acute hypoxia on the system and pulmonary circulation (modified from Parati et al.¹). PaCO₂, partial pressure of arterial carbon dioxide.

As one of the core functions of the cardiovascular system, cerebral blood flow (CBF) delivers nutrients and oxygen to the brain, as well as eliminates cellular metabolic products and toxic by-products through precise regulatory mechanisms.³⁸ This is crucial for the brain, which exhibits high metabolic rates and limited energy storage capacity.

The regulation of CBF is a multifaceted process affecting pulmonary gas exchange and cardiovascular function, in addition to mediating intracranial cerebrovascular resistance. Therefore, a comprehensive understanding of CBF regulation remains challenging. The intricacies of human CBF regulation have been extensively discussed in the literature.^38,49,50 Claassen et al.³⁸ simplified CBF regulation by dividing the mechanism regulating CBF into four different components or adaptive responses, as illustrated in Table 3. These regulatory mechanisms exhibit substantial interactions and functional overlap.

Table 3.

The regulation mechanism of cerebral blood flow.³⁸

Regulation mechanism	Explanation
Autoregulation	Autoregulation relates to the response of the cerebral circulation to changes in cerebral perfusion pressure. Cerebral perfusion pressure is determined by blood pressure (BP), intrathoracic pressure (ICP) and venous pressure. Under physiological conditions, arterial BP and body posture (supine or prone vs. seated or standing in humans) primarily determine cerebral perfusion pressure, because venous BP and ICP are relatively low and normally exhibit only small changes. Lassen posits that CBF can maintain a relatively stable state across the mean arterial pressure range from 50 to 150 mmHg.
Chemoregulation	Chemoregulation is another class of vascular reactivity. This includes vascular responses to changes in CO₂ (and subsequently pH), PO₂ or O₂ content. Changes in these variables (e.g., hypocapnia and hypercapnia) elicit strong CBF responses.
Neuronal regulation	Neuronal regulation consists of the influence of nerves or neurons on CBF. This includes neurovascular coupling (NVC), the local CBF response to nearby intrinsic neuronal activation within the brain parenchyma but also includes effects of autonomic and sensory nerves (extrinsic innervation) on the extraparenchymal segments of the cerebral vasculature.
Endothelium-dependent regulation	Endothelium-dependent regulation relates to the effects of vascular endothelial cells on vascular tone and therefore CBF. In response to haemodynamic stimuli (e.g., shear stress), ions, neurotransmitters, metabolic stimuli and therapeutic agents, amongst other factors. This ability of endothelial cells to cause vasorelaxation importantly contributes to NVC.

The mammalian brain depends entirely on oxygen for the synthesis of adenosine triphosphate (ATP), making it particularly susceptible to hypoxia. Meanwhile, the brain accounts for approximately 20% of total resting oxygen consumption, establishing it as the highest oxygen-demand organ.⁵¹ Therefore, reduced environmental oxygen rapidly affects the brain, particularly evident in CBF changes. Hypoxia modulates CBF through the aforementioned four regulatory mechanisms.

As detailed previously, hypoxia notably influences the BP, PaO₂ and PaCO₂. Thus, hypoxia impacts CBF through the respiratory and cardiovascular systems, mediated by autoregulation and chemoregulation. Autoregulation maintains relatively stable CBF across the mean arterial pressure of 50–150 mmHg. Chemoregulation activates when the PaO₂ falls below approximately 50 mmHg (corresponding to SaO₂ ∼ 80%), inducing vasodilation.⁴⁹ This response also depends on the prevailing PaCO₂ levels. Hyperventilation reduces PaCO₂, increasing cerebral vascular resistance and decreasing CBF. Specifically, each 1 mmHg reduction in PaCO₂ decreases CBF by 1–3%.^38,49 In addition, the endothelium-dependent regulation significantly influences CBF through vascular endothelial factors.⁴⁸ Neuronal regulation also plays a significant role including: (1) neurovascular coupling involves retrograde signalling from neurons and glial cells responding to local tissue hypoxia; and (2) the occurrence of brain extracellular acidosis resulting from heightened anaerobic metabolism in neurons and glial cells, which subsequently induces vascular dilation.⁴⁹ The impact of hypoxia on the human body is notably intricate. While hypoxia affects CBF through multiple pathways, detailed mechanistic analysis is beyond the scope of this article.

Thermoregulatory system

Most hypoxia research focuses on the pathological implications of the human body. Since the effect of hypoxia on body temperature minimally impacts human daily life, it has received limited research consideration. However, there are still some scholars who attempt to clarify the effect of hypoxia on thermoregulation under thermal comfort, but findings remain inconsistent. Ciuha et al.⁵² observed that hypoxia did not alter rectal or mean skin temperature during bed rest, nor did it affect the thermal comfort zone. Similarly, Golja et al.⁵³ reported no significant effect of hypoxia on eardrum temperature or the human comfort zone. Conversely, Duan et al.⁵⁴ found that decreasing oxygen levels reduced mean skin temperature, particularly under colder ambient conditions. Beyond whole skin temperature, certain researchers have examined the effects of hypoxia on local skin temperature. Golja et al.⁵⁵ noted that hypoxia reduced cold sensitivity in the toes while leaving warmth perception unchanged. They suggested that this altered thermal perception might impair thermoregulatory behaviour during cold exposure at high altitudes. Supporting this, Keramidas et al.⁵⁶ proposed that hypoxia tends to blunt the sensation of coldness and thermal discomfort.

The precise mechanisms by which hypoxia on thermoregulation remain unclear, complicating the interpretation of physiological changes. Hypoxia affects the thermoregulatory system in multiple ways, ultimately altering heat dissipation, heat production and body temperature. Hypoxia increases respiratory heat loss by hyperventilation. As heat dissipation rises, heat production may decline, as supported by several animal studies. Specifically, the inhibition of brown adipose tissue (BAT) sympathetic nerve activity (SNA) triggered by peripheral chemoreceptor activation directly contributes to (or is permissive for) hypoxia-induced reductions in body temperature and oxygen consumption.⁵⁷ Hypoxia also modulates central thermosensitivity, leading to the inhibition of thermogenic pathways and subsequent decreases in body temperature.⁴¹ From a thermodynamic perspective, reduced ambient pressure significantly alters heat exchange dynamics between the human skin surface and surroundings. Under hypobaric conditions, the evaporation heat dissipation increases due to lower air density while convective heat transfer decreases.⁴⁰ These modifications have a substantial impact on thermoregulation and thermal perception.

In summary, although the effect of hypoxia on thermal comfort remains debated, biomedical evidence suggests that hypoxia potentially modulates thermoregulation. Therefore, systematic monitoring of thermoregulatory parameters is needed to clarify the mechanistic pathways of hypoxia.

Questionnaires for the measurement of AMS

Individuals may develop various hypoxic symptoms after exposing to high-altitude environments. In severe cases, AHAI (e.g., HAPE and HACE) can pose a life-threatening risk (as presented in Table 1), underscoring the importance of assessing the condition of lowlanders at high altitudes. Physiological parameters provide objective evaluations of hypoxic stress, but their practical application is limited and cannot accurately assess subjective symptoms such as headache, anorexia and nausea. Consequently, low-cost, immediate-use subjective questionnaires for assessing AMS have been extensively investigated.

AMS assessment scales

The diagnosis of AMS primarily relies on questionnaires. Six predominant assessment scales are widely used in global clinical and research settings. Table 4 summarizes these scales and respective scoring criteria. The most frequently used scales include the Lake Louise AMS Score (LLS), AMS-Cerebral score (AMS-C) and Hackett clinical score. These instruments evolved from the Environmental Symptoms Questionnaire III score. They assess symptoms through either summation or the weighted averaging methods. The Chinese AMS score (CAS) is also evaluated based on symptoms. The Visual Analogue Scale (VAS(O)) provides a continuous metric for quantifying overall disease severity. This continuous scale minimizes variations in textual interpretation by eliminating categorical thresholds.⁵⁹ The Clinical Function Score (CFS) represents the most straightforward tool, utilizing a single uncomplicated question. Amongst them, the LLS is globally recognized as an extensively quantitative benchmark. Some researchers compared the accuracy of other questionnaires with LLS. Meier et al.⁶² demonstrated that the VAS(O), AMS-C and CFS exhibited comparable diagnostic accuracy to the LLS for identifying moderate to severe AMS (LLS ≥ 5). The positive likelihood ratios for these measures ranged from 3.2 to 8.2, with specificities between 67% and 92%. Wu et al.⁶³ reported that the positive rate of AMS identified through the CAS exceeded that determined by the LLS. The ROC curve analysis indicated that the sensitivity and specificity of CAS at the optimal cut-off value of 3.5 points were 76.5% and 90.2%, respectively, demonstrating its efficacy in accurately diagnosing AMS. However, the relatively small sample size limits its generalizability and international adoption. The Hackett clinical score exhibits similar characteristics.⁶²

Table 4.

Summary of AMS diagnostic scoring systems.

	Lake Louise AMS score^a		AMS-C^b		Hackett clinical score^c		Chinese AMS score^d		VAS score^e	Clinical functional score^f
	Symptom	Value	Symptom	Weight	Symptom	Value	Symptom	Value	Symptom	Symptom	Value
Headache	Headache	0–3	Headache	0.465	Headache	1	Headache	1–7	Headache
Headache					Headache not relieved by painkillers	2
Gastrointestinal	Gastrointestinal symptoms	0–3	Loss of appetite	0.413	Nausea, anorexia, or both	1	Vomiting	2–7	Gastrointestinal symptoms
			Sick to stomach	0.347	Vomiting	2	Nausea	1
							Anorexia	1
							Abdominal distension	1
							Diarrhoea, constipation, or both	1
Neurological	Dizziness, light-headedness or both	0–3	Coordination off	0.519	Dizziness	1	Dizziness, Light-headedness, or both	1	Dizziness, light-headedness, or both
			Dim vision	0.501	Ataxia	2	Dazzling or blurred vision	1
			Light-headed	0.489			Numbness of the extremities	1
			Dizzy	0.446
			Faint	0.346
Fatigue	Fatigue, weakness or both	0–3	Feeling weak	0.387	Difficulty sleeping	1	Lethargy	1	Fatigue, weakness, or both
Fatigue	Difficulty sleeping	0–3					Insomnia	1	Trouble sleeping
Respiratory					Shortness of breath at rest	1	Palpitation	1
					Pulmonary rales 1 location	1	Shortness of breath	1
					Peripheral oedema	1	Chest distress	1
					Tachypnoea >25/min	2	Cyanosis of the lips	1
					Pulmonary rales >1 location	2
Overall	AMS Clinical Functional Score	Overall, if you had AMS symptoms, how did they affect your activities?	Feeling sick	0.692					Overall severity of AMS symptoms	No reduction of daily activity	0
	Not at all	0	Feeling hungover	0.584						Mild reduction	1
	Symptoms present, but do not force any change in activity or itinerary	1								Moderate reduction	2
	My symptoms forced me to stop the ascent or to go down on my own power	2								Severe reduction (bed rest)	3
	Have to be evacuated	3

Abbreviations: AMS, acute mountain sickness; AMS-C, AMS-Cerebral score; VAS(C), visual analogue scale-composite; VAS(O), VAS for the overall feeling of mountain sickness; VAS(I), VAS for each item of AMS.

Score requires the presence of headache (the other instruments do not) and at least 1 other symptom to establish an AMS diagnosis. Symptom grades: 0, no symptoms; 1, mild; 2, moderate; 3, severe. Final score is based on the sum of all individual symptoms (mild AMS: 3–5 points; moderate AMS: 6–9 points; severe AMS: 10–12 points). If investigators wish to assess the impact of AMS symptoms on overall function at high altitude, the ‘AMS Clinical Functional Score’ is available.⁵⁸

Score is derived from the Environmental Symptoms Questionnaire III. Respondents indicate how they were feeling that day on a scale of 0 (no symptoms) to 5 (most severe symptoms). Final score = the sum of each symptom score × the weight given each symptom/25.95 × 5. A score greater than or equal to 0.7 indicates AMS.⁵⁹

Score is derived from a clinician's assessment of each symptom. Final score is based on the sum of all individual symptoms (a score of ≥3 indicates AMS).⁶⁰

Score classifies the severity of headache with 1 (not present), 2, 4 or 7 points (severe), and the severity of vomiting from 2 points (vomiting 1–2 times per day) to 7 points (vomiting >5 times a day). The presence of other symptoms counts as 1 point each. Presence of headache, vomiting or a total score of 5 indicates AMS.⁵⁹

Similar to VAS scores used in other contexts (e.g., pain management), the patient places a single slash mark on a 100-mm-long horizontal line for each VAS (ranging from 0 [none] to 100 [severe]). This indicates either the overall severity (VAS[O]) or each symptom/item (VAS[I]), which are then combined in the composite score (VAS[C]). Various cutoffs are used depending on the different studies, as no current standard cutoff is defined. VAS(C) is mentioned for completeness but was not used in the analysis due to a lack of data.⁵⁹

CFS does not query regarding individual symptoms. Asks if the patient had any symptoms and how the symptoms affected their activity on a scale of 0 to 3 (a score of ≥2 indicates AMS).⁶¹

Assessment of short-term exposure to AMS

Current AMS assessment protocols (Table 4) primarily target severe symptom management and pathological prevention, emphasizing medical safety. However, non-severe cases need attention. Empirical studies revealed that at altitudes of 3000 m, 3600 m.⁶⁴ and 4400 m,⁶⁵ the combined prevalence of mild AMS and asymptomatic reactions reached 81.42%, 75.26% and 71.18%, respectively. These data indicate that mild AMS or subclinical hypoxic responses affect larger populations than moderate/severe AMS. Although seldom requiring medical intervention, these individuals experience discomfort that significantly impairs quality of life.

With increasing human activity in high altitudes,⁵⁴ environmental demands have transformed from survival thresholds to comfort optimization. Consequently, oxygen comfort has become a critical factor for high-altitude sojourners. Standard AMS assessment protocols lack sensitivity for mild symptoms or subtle discomfort gradation. To address this limitation, researchers have adopted 5- or 7-point scales from ISO 10551 .⁶⁶ to differentiate overall perceptions, such as oxygen sensation, comfort and acceptability.^54,67,68 Building on this approach, Cao et al.⁶⁸ further refined the evaluation by implementing a 5-level grading scale to assess symptoms associated with the respiratory, circulatory, nervous and digestive systems. Nevertheless, these classification systems remain insufficiently intuitive and clear for individuals experiencing hypoxia for the first time. In response, Song et al.²² pioneered an Oxygen Comfort Evaluation Method (OCEM). This method assesses hypoxic symptoms using both phenomenological descriptors and physiological indicators. The core component is a symptom questionnaire comprising 19 symptom indices, each rated on a five-point scale (None, Mild, Moderate, Heavier and Severe). Crucially, each grade is accompanied by specific behavioural or sensation descriptors, which significantly enhance the accuracy and consistency of subjective reporting by participants. Experimental validation demonstrated a 93% prediction accuracy for oxygen sensation and a strong agreement (weighted kappa = 0.825) for the final comfort level. Compared to LLS, OCEM detected a wider range of discomfort symptoms (76.8% were supplementary symptoms not covered by LLS), showing a stronger ability to identify subtle uncomfortable states related to oxygen comfort. The OCEM offers a novel framework to quantify oxygen sensitivity and guide indoor oxygen regulation in high-altitude buildings. Nevertheless, further empirical validation is required to establish reliability. Currently, there remains a scarcity of research focused on oxygen comfort. We advocate expanded scholarly focus on oxygen comfort to refine assessment methodologies and enhance the high-altitude experiences for short-term sojourners.

Methods of alleviating hypoxia

To ensure the safety of lowlanders exposed to high altitudes, researchers have studied pharmacological interventions, including acetazolamide, dexamethasone and sildenafil for high-altitude illness prevention.⁶⁹ Although these medications can alleviate or prevent high-altitude illnesses, they may induce side effects.⁷⁰ Therefore, the altitude alleviation methods are the most effective approach for optimizing hypoxic adjustment and maintaining physiological performance. These methods reduce AMS sensitivity, enhance physical performance and facilitate ascent to higher altitudes.^71,72 Researchers have leveraged the body's hypoxic acclimation capacity to develop various adaptation strategies.

Gradual ascent

Gradual ascent (GA) refers to taking short breaks every time ascending to a certain altitude to alleviate hypoxia. This strategy is widely used in high-altitude mountaineering. Field studies confirm its effectiveness in reducing AMS incidence and severity^73,74 and enhancing exercise performance.²⁰ Practical application guidelines have been developed across fields, as summarized in Table 5.

Table 5.

The recommended gradual ascent plans.

Author	Recommendation
The Wilderness Medical Society (WMS).⁷⁰	Above an altitude of 3000 m, individuals should not increase the sleeping elevation by more than 500 m per day and should include a rest day (i.e., no ascent to a higher sleeping elevation) every 3–4 days.
Muza and Stephen.⁷⁵	Above 2000 m, ascent should be limited to no more than 300–600 m/d, or after a rapid ascent of about 900 m, further ascent should be restricted for at least 3 d.
International Climbing and Mountaineering Federation (UIAA).⁶	Above 2500–3000 m, the next night should not be planned more than 300–500 m higher than the previous one. Have two nights at the same altitude after every 2–4 days of ascent. On this day, you may climb higher but return to sleep.
The Himalayan Rescue Association (HRA).⁷⁶	Ascending no more than 300 m/day with a rest day (no ascent in sleeping altitude) for every additional 600–900 m and no single day gain greater than 800 m.

Prolonged rest periods at moderate altitudes (2200–3000 m) during ascent enhance safety through short-term acclimatization. This approach is termed ‘stage ascent’ (SA).⁷⁰ Both GA and SA can alleviate the decline of SpO₂ and reduce the incidence and severity of AMS. These benefits derive from sufficient time to acclimate for improving ventilation and oxygenation.⁷⁷ and reducing PAP associated with HAPE.^78,79 However, the recommended GA plans are not consistent, and adhering to these requirements is challenging during actual ascent. The quantitative prediction AMS model established by Beidleman et al.⁸⁰ addresses this limitation. This approach calculated accumulated altitude exposure (AAE), which was defined as the ascent profile and was calculated by multiplying the altitude elevation (km) by the number of days (d) at that altitude before ascent to 4 km. It predicted the probability of AMS occurring ∼ 24 h after exposure to an altitude of 4 km. Figure 6 represents the changes in the prevalence of AMS at 4 km following various ascent profiles inducing various AAE (km d). The dotted line indicates the 95% confidence interval of the prediction. Although limited to a target altitude of 4 km, this method integrates the two multilevel factors of altitude increase and duration of stay into a novel indicator, providing a new perspective for future investigations into gradual ascent and holds significant milestone implications.

Figure 6.

The quantitative model of altitude acclimatization status (reprinted from Beidleman et al.,⁸⁰ Copyright (2019), with permission from Wiley).

Intermittent hypoxia exposure

Individuals engaged in activities such as travel, hiking, combat and occupational work often face temporal, financial and logistical constraints in different locations for acclimatization. Intermittent hypoxia (IH) addresses these constraints.³⁴ IH alleviates adverse effects of prolonged exposure to high altitudes, including immunosuppression,⁸¹ increased oxidative stress,⁸² elevated inflammation.⁸³ and sleep disorders. Therefore, IH is a promising non-pharmacological strategy for acclimatization. Intermittent hypoxic exposure (IHE) is defined as repeated exposure to hypoxia, ranging from seconds to hours per session, administered over several days to weeks.⁸⁴ IHE research focuses on three areas: disease treatment and prevention in sleep medicine,^85,86 exercise capacity improvement in sports medicine^84,87 and altitude acclimatization in mountain medicine.²⁰

The application of IHE mainly depends on three factors⁷⁵: altitude of exposure, duration of each treatment and total number of IH treatments. Researchers have investigated various IHE protocols, as summarized in Table 6. IHE essentially capitalizes on the body's adaptations to hypoxia. The cardiopulmonary system responds most rapidly, while the haematological system requires longer stimulation periods, as illustrated in Figure 1. Given the constraints of time and resources in pre-acclimatization, high-efficiency strategies with shorter durations are often prioritized. Accordingly, physiological changes in Table 6 primarily emphasize cardiopulmonary and cerebral parameters. However, there has been no universally accepted IH framework. Based on these empirical findings, we propose several recommendations for optimizing IHE protocols in future research. Regarding the altitude of IHE, higher altitudes should be considered. Hypoxic responses intensify with altitude elevation, whereas lower altitudes require prolonged exposure durations for equivalent acclimatization. Katayama et al.⁸⁸ and Townsend et al.⁹⁶ demonstrated that at similar IHE altitudes, significant acclimatization effects were observed only after an extended duration of IHE. Therefore, increasing the IHE altitude may enhance pre-acclimatization efficiency. However, indiscriminate increases in the altitude of IHE may lead to adverse physiological consequences. Navarrete-Opazo et al.⁸⁶ suggested that modest hypoxia (9–16% inspired O₂) and low cycle numbers (3–15 episodes per day) most often lead to beneficial effects without pathology, whereas severe hypoxia (2–8% inspired O₂) is associated with progressively pathological mechanisms. For the duration of each treatment, Katayama et al.⁹² found that equivalent HVR enhancement between 1-h and 3-h continuous IH sessions when other parameters were held constant. Wojan et al.³² observed that erythropoietin levels reached the peak at 4 h with an increase in exposure time. These findings indicate that there is a certain threshold for the physiological effects corresponding to altitudes, and longer durations are not necessarily superior. The principle also applies to the total number of IHE treatments.⁷¹ Garcia et al.⁹⁰ discovered that the HVR reached its peak at day 5, returning to the initial level by day 12. Excessive treatment may induce hypoxia adaptation, thereby diminishing the potential benefits of hypoxic stress.

Table 6.

Changes in physiological indicators after IHE.

Author	Sample (research group/control group)	Time of exposure (h/d)	Number of exposures	Exposure plan	IHE altitude (m)	Target altitude	Changes in physiological indicators	Conclusion
Katayama et al. (2007).⁸⁸	Group 1: 6/6 Group 2: 6/6	1	7	1 h/d, 1 wk	Group 1: 2500N; Group 2: 4300N	2500N	HVR→; HVR↑	Short-term IH (resting, at 4300 m) increases exercise ventilation at moderate altitude.
Wang et al. (2024).⁸⁹	50/50	2	5	2 h/d, 5 d (alternate exposure to hypoxia for 10 min and normoxia for 5 min)	3500–3800N (13%)	4500N	AMS↓SpO₂↑ICP↓	IH reduces the occurrence and severity of AMS, and these effects could be attributed to improved SpO₂, reserved ICP, and reduced inflammation and brain damage.
Garcia et al. (2000).⁹⁰	9/0	2	5/12	2 h/d; 5 d/12 d	3800N	3800N	5d: SpO₂→HVR↑ PETCO₂↑; 12d: SpO₂→HVR→ PETCO₂→	Moderate IH alters the ventilatory sensitivity to oxygen.
Schommer et al. (2010).⁹¹	20/20	—	—	1–3 week: exercise 70 min/d, 3 d/week, 2500–3500 m 4th week: rest 90 min/d, 4 d/week, 4500 m	2500–4500N	3611H; 4599H	3611H: SpO₂→AMS↓ 4599H: SpO₂→AMS→ PaCO₂→PaO₂→	The tested IH protocol prevents AMS at lower altitudes (3611 m), but not during rapid ascent to extreme altitude (4559 m).
Katayama et al. (2009).⁹²	6/6	3	7	1 h/d, 1 wk;3 h/d, 1 wk	4300N	4300N	HVR↑; HVR↑	1 h of daily exposure is as effective as 3 h of daily exposure to severe hypoxia for a short period for enhancing ventilatory chemosensitivity to hypoxia.
Gangwar et al. (2019).⁹³	20/20	4	4	4 h/d, 4 d	4500N	3250H	SpO₂↑AMS↓	IHT corroborated attenuation of hypoxia-induced inflammation and dyslipidaemia. Moderate IHT is a potential nonpharmacological strategy for high altitude acclimatization.
Zhang et al. (2024).³⁷	12/12	0.67	10	0.67 h/d (8 cycles per day: 5 min of hypoxia and 3 min of normoxia)	4500–5000N	4300N	SpO₂↑AMS↓HR→CBF↑	This simplified IHT paradigm may facilitate hypoxia acclimatization, alleviate AMS and increase CBF in multiple brain regions, and thereby ameliorate brain swelling and cognitive dysfunction.
Faulhaber et al. (2016).²³	17/15	1	7	1 h/d, 7 d	4500N	3650H	AMR→SpO₂→HVR→	This IH treatment cannot alleviate hypoxic stress.
Treml et al. (2020).⁹⁴	23/26	1	7	1 h/d, 7 d	5300N	5300N	AMS↓SpO₂→HVR→ PaCO₂→PaO₂→	This one-week IH protocol grants a reduction in AMS that lasts for at least one week.
Ricart et al. (2000).⁹⁵	9/0	2	14	2 h/d, 14 d	5000N	5000N	SaO₂↑RR→HR→ VE↑VT↑	This short-term IH effectively induces early-stage respiratory acclimatization.

Abbreviations: VE, minute ventilation; VT, tidal volume; PETCO₂, end-tidal CO₂ partial pressure; HVR, hypoxic ventilatory response; AMS, acute mountain sickness; SpO₂, peripheral oxygen saturation; SaO₂, arterial oxygen saturation; PaO₂, partial pressure of arterial oxygen; PaCO₂, partial pressure of arterial carbon dioxide; HR, heart rate; CBF, cerebral blood flow; ICP, intracranial pressure. H: hypobaric and hypoxia environment (use hypobaric chamber). N: normal atmosphere and hypoxic environment.

In addition, it should be noted that normobaric hypoxia (NH) and hypobaric hypoxia (HH) have different effects on human physiological responses. NH is widely used for convenience, but the effect of ambient pressure is ignored. HH typically induces more pronounced physiological stress than NH, attributable to differences in ventilatory patterns, alveolar gas disequilibrium and dissimilar acute hypoxic ventilatory responses.⁹⁷ These factors lead to more severe symptoms of AMS in HH, yet they may also enhance the efficacy of high-altitude acclimatization.⁹⁷

Oxygen enrichment

Lowlanders often lack sufficient time for pre-acclimatization, increasing risks during direct exposure to high altitudes. Hypoxia can be fundamentally addressed through oxygen enrichment. This method increases SpO₂, reduces HR and reduces the incidence or severity of AMS.^26,98 It is the most direct, convenient and safe method of prevention and treatment for high-altitude exposure.

Oxygen delivery methods are typically classified into two primary modalities. The first modality is nasopharyngeal oxygen delivery via nasal cannulas or masks, mostly used in emergency medical and portable hypoxia in life or work. Although achieving high oxygen utilization rates, this method causes nasal cavity discomfort.⁹⁹ and reduces work efficiency by increasing physical anxiety.¹⁰⁰ The second modality is diffusion oxygen supply, which increases ambient oxygen concentrations. This system exhibits wide applicability and excellent comfort, rendering it particularly suitable for daily living environments. West.⁹⁸ pioneered the oxygen enrichment concept, establishing that a 1% increase in oxygen concentration (e.g., from 21% to 22%) corresponds to an equivalent altitude reduction of 300 m. This seminal research substantially advanced oxygen-enriched environment comprehension. Subsequent field and laboratory studies have consistently demonstrated that oxygen enrichment benefits human physiology, psychology, cognitive performance, work efficiency and sleep quality.^26,101,102 However, the widespread adoption of oxygen enrichment has been hindered by low oxygen delivery efficiency.¹⁹ Consequently, researchers have explored alternative oxygen delivery methods (e.g., point source oxygen supply.¹⁹ and targeted oxygen supply device.¹⁰³) and distribution strategies.¹⁰⁴ to enhance efficiency. Furthermore, oxygen concentrations cannot be arbitrarily increased, even disregarding efficiency concerns. Safety standards mandate strict upper^98,105 and lower^18,106 concentration limits to prevent fire hazards while ensuring safety and comfort. The US National Fire Protection Association 99B (NFPA 99B).¹⁰⁷ stipulates that the volume fraction of O₂ must not exceed 23.5% at 101.3 kPa. Furthermore, by referencing the burning rate of filter paper at 23.5% at 101.3 kPa, this standard provides the upper concentration limits for oxygen-enriched indoor environments under different atmospheric pressures. Accordingly, West et al.⁹⁸ established equivalent altitude corresponding to the actual altitude and the oxygen concentration under U.S. National Fire Protection Association guidelines,¹⁰⁷ shown in Figure 7.

Figure 7.

Oxygen conditioning diagram (replotted from West⁹⁸).

As highlighted in the section ‘Assessment of short-term exposure to AMS’, the substantial population with oxygen comfort requirements cannot be overlooked. Consequently, determining the optimal oxygen concentration balancing delivery efficiency and safety has emerged as a critical research frontier and a societal necessity. Surprisingly, this critical aspect remains largely unexplored, with only the pioneering work by Song et al.⁶⁷ addressing this gap. Their innovative study combined subjective and objective parameters to classify lowlanders at high altitudes into three oxygen adaptation levels (high, medium, low), achieving an impressive prediction accuracy of 94.96%. Eventually, the correlation between adaptation levels and optimal indoor oxygen environment parameters was established, enabling personalized oxygen delivery strategies. This foundational research provides valuable insights for future investigations of optimal oxygen concentrations.

Challenges and future perspectives

Societal development has increased lowlanders’ exposure to high-altitude environments, and the issue of alleviating hypoxia has become a concern for the public. Based on our analysis, we propose the following strategies to enhance high-altitude experiences.

Empirically based guidance in gradual ascent

Gradual ascent is widely regarded as the most valuable approach for preventing high-altitude illnesses. However, existing ascent recommendations are inconsistent and largely rely on traditional empirical guidelines, as described in the section ‘Gradual ascent’. These recommendations lack robust physiological mechanistic support and exhibit substantial practical limitations due to individual differences, environmental variability and other multifactorial influences. The quantitative prediction AMS model established by Beidleman et al.⁸⁰ has significantly improved the objectivity and practicality of ascent recommendations. However, the model is limited to target altitudes of 4000 m, restricting its generalizability to other elevations. Future research should focus on the following directions: (1) Extending model applicability across altitude ranges to establish ascent recommendation standards suitable. (2) Integrating clinical monitoring indicators, such as resting and exercise SpO₂, PAP and HRV, to enable multimodal data fusion with the Ascent Advice Evaluation (AAE) model. This approach promises to develop a more precise and personalized risk assessment system. Ultimately, high-altitude ascent guidelines can evolve from experience-based to evidence-driven, supporting safer and more scientific mountaineering for diverse populations.

Development of a universal oxygen comfort evaluation standard

Current AMS studies primarily focus on pathophysiological mechanisms and clinical interventions within the biomedical field. However, a critical research gap exists in diagnosing mild and subclinical hypoxia manifestations. Over 70% of high-altitude sojourners experience mild or subclinical hypoxic symptoms that substantially impact quality of life despite not requiring medical intervention (as discussed in ‘Assessment of short-term exposure to AMS’). Existing assessment questionnaires lack sensitivity for grading these symptoms. Only the pioneering work by Song et al.²² has developed a multidimensional symptom severity method to comprehensively diagnose mild and subclinical hypoxia. Nevertheless, this method lacks empirical validation in heterogeneous populations, and the absence of dynamic monitoring and verification only at 3650 m.

Future research should prioritize: (1) incorporating high-risk populations (e.g., elderly and chronic disease patients) with multi-omics (genomics/metabolomics) profiling to decode individual hypoxic response variations; (2) developing dynamic oxygen prediction models through wearable device-reinforcement learning integration for personalized environmental regulation; (3) constructing multi-altitude experimental platforms with cross-cultural validation protocols; and (4) translating intelligent oxygen supply technologies into evidence-based clinical interventions and architectural guidelines, ultimately enabling a paradigm shift from pathological remediation to proactive comfort optimization in high-altitude public health strategies.

Personalized dynamic prediction of Ih protocols

The optimization of IHE protocols for pre-acclimatization faces two core challenges: (1) Unlike fixed-altitude aerobic training for athletes, IHE must account for dynamic variations in target altitudes, rendering conventional single IHE protocols inadequate; and (2) Current research focuses on verifying IHE ‘effectiveness’ while lacking mechanistic understanding of dose–response relationships and individualized response thresholds. Future studies should: (1) Develop quantitative models correlating adaptation altitudes with target altitudes to elucidate dynamic relationships between altitude gradients and exposure duration; (2) Integrate multidimensional physiological indicators (SpO₂, HRV) to establish intelligent prediction systems; and (3) Create personalized pre-acclimatization protocols based on individual characteristics (e.g., age and gender). These advancements will transform IH research from phenomenological observation to mechanistic understanding, providing scientific foundations for altitude-specific personalized pre-acclimatization.

Thermal-oxygen coupling in high-altitude environmental control

The physiological mechanisms and engineering applications of thermal-oxygen coupling remain critical knowledge gaps in high-altitude research. Current studies often examine oxygen or temperature stressors separately, neglecting their combined effects on human thermogenesis (e.g., brown adipose tissue activation) and oxygen transport efficiency (e.g., temperature-dependent haemoglobin-oxygen dissociation). Duan et al.⁵⁴ demonstrated that hypoxia discomfort decreases under thermal comfort. However, two key limitations persist: (1) Absence of quantitative models for thermal-oxygen parameter interactions, particularly regarding temperature regulation dynamics under oxygen enrichment (FiO₂ > 0.21) across altitudes; and (2) Failure to integrate individual thermal preference (e.g., inhabitants from different climatic zones) with dynamic physiological demands. Future research must develop multiphysics coupling models using computational fluid dynamics (CFD) to simulate oxygen-thermal distribution patterns, combined with reinforcement learning algorithms to optimize ‘temperature-oxygen concentration’ combinations, ultimately informing novel environmental control strategies for high-altitude eco-architecture.

Conclusion

In this article, we reviewed physiological and objective indicators associated with exposure to high altitudes. A summary of methods aimed at alleviating hypoxia was also provided.

This study systematically analysed the effects of short-term high-altitude exposure on respiratory, cardiovascular and thermoregulation systems. For each system, we have identified clinically valuable physiological indicators to provide precise assessment criteria.

Through comprehensive evaluation of six existing AMS questionnaires, we conducted comparative analyses between five representative assessment tools and the gold-standard LLS. The limitation is insufficient evaluation of subclinical or mild AMS manifestations, highlighting the need to establish a novel oxygen-comfort-oriented assessment system.

Current acclimatization methods were systematically reviewed and elaborated, including gradual ascent, intermittent hypoxia exposure and oxygen enrichment. Some specific implementation recommendations for each approach are provided.

To advance high-altitude comfort management research, we propose four key research priorities: (1) constructing a more comprehensive empirical-guided gradual ascent model, (2) establishing subjective oxygen comfort evaluation standards for subclinical or mild AMS, (3) developing personalized intermittent hypoxia exposure protocols, and (4) innovating thermal-oxygen coupled environment control technologies. These recommendations construct a comprehensive technical roadmap encompassing assessment methodologies, preventive interventions and environmental regulation, ultimately providing systematic solutions to ensure the comfort of plains populations in high-altitude environments.

Footnotes

Acknowledgements

The authors wish to thank the financial support of the National Natural Science Foundation of China (Nos. 52038009 and 52578145).

Author's contribution

Yue Hu: conceptualization, writing – original draft, writing – reviewing and editing, and visualization. Xiaoling Cao: writing – reviewing and editing. Xiaowen Su: writing – reviewing and editing. Yanping Yuan: writing – reviewing and editing, supervision, and funding acquisition. Liangliang Sun: conceptualization, writing – reviewing and editing, and funding acquisition.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Natural Science Foundation of China (grant nos. 52038009, 52578145).

ORCID iDs

Yue Hu

Xiaoling Cao

Yanping Yuan

Liangliang Sun

References

Parati

Agostoni

Basnyat

Bilo

Brugger

Coca

Festi

Giardini

Lironcurti

Luks

Maggiorini

Modesti

Swenson

Williams

Bärtsch

Torlasco

. Clinical recommendations for high altitude exposure of individuals with pre-existing cardiovascular conditions. Eur Heart J 2018; 39: 1546–1554.

Gao

Wang

Zhou

Gao

Zhang

. Altitude pathophysiology (in Chinese). Beijing: People’s Medical Publishing House, 2006.

Ando

Komiyama

Sudo

Higaki

Ishida

Costello

Katayama

. The interactive effects of acute exercise and hypoxia on cognitive performance: a narrative review. Scand J Med Sci Sports 2020; 30: 384–398.

Yin

Wang

. The association between consecutive days’ heat wave and cardiovascular disease mortality in Beijing, China. BMC Public Health 2017; 17: 223.

Basnyat

Murdoch

. High-altitude illness. Lancet 2003; 361: 1967–1974.

UIAA Medical Commission. UIAA MedCom consensus statement No. 2: Emergency field management of acute mountain sickness, high altitude pulmonary edema, and high altitude cerebral Edema. No.2, Bern: International Climbing and Mountaineering Federation (UIAA), https://www.theuiaa.org/documents/mountainmedicine/English_UIAA_MedCom_Rec_No_2_AMS_HAPE_HACE_2012_V3.3.pdf (2024).

Luks

Hackett

. Medical conditions and high-altitude travel. N Engl J Med 2022; 386: 364–373.

Korzeniewski

Nitsch-Osuch

Guzek

Juszczak

. High altitude pulmonary edema in mountain climbers. Res Physiol Neurobiol 2015; 209: 33–38.

Zhang

. Research advances in pathogenesis and prophylactic measures of acute high altitude illness. Respir Med 2018; 145: 145–152.

10.

Gerard

McElroy

Taylor

Grant

Powell

Holverda

Sentse

West

. Six percent oxygen enrichment of room air at simulated 5000 m altitude improves neuropsychological function. High Alt Med Biol 2000; 1: 51–61.

11.

Hainsworth

Drinkhill

. Cardiovascular adjustments for life at high altitude. Respir Physiol Neurobiol 2007; 158: 204–211.

12.

Riley

Gavin

. Physiological changes to the cardiovascular system at high altitude and its effects on cardiovascular disease. High Alt Med Biol 2017; 18: 102–113.

13.

Powell

Huey

Dwinell

. Central nervous system mechanisms of ventilatory acclimatization to hypoxia. Res Physiol 2000; 121: 223–236.

14.

Turner

Barker-Collo

Connell

CJW

Gant

. Acute hypoxic gas breathing severely impairs cognition and task learning in humans. Physiol Behav 2015; 142: 104–110.

15.

Mallet

Burtscher

Pialoux

Pasha

Ahmad

Millet

Burtscher

. Molecular mechanisms of high-altitude acclimatization. Int J Mol Sci 2023; 24: 1698.

16.

McGettrick

O’Neill

LAJ

. The role of HIF in immunity and inflammation. Cell Metab 2020; 32: 524–536.

17.

Levine

Stray-Gundersen

. Dose-response of altitude training: how much altitude is enough? Advances in experimental medicine and biology. Boston: MA: Springer US, 2006, pp. 233–247.

18.

Guo

Wang

Yan

Yang

Sun

. Study on oxygen supply standard for physical health of construction personnel of high-altitude tunnels. Int J Environ Res Public Health 2015; 13: 64.

19.

Liu

Song

Wang

. A novel point source oxygen supply method for sleeping environment improvement at high altitudes. Build Simul 2021; 14: 1843–1860.

20.

Burtscher

Millet

Burtscher

. Hypoxia conditioning for high-altitude pre-acclimatization. J Sci Sport Exerc 2022; 4: 331–345.

21.

Burtscher

Citherlet

Camacho-Cardenosa

Raberin

Krumm

Hohenauer

Egg

Lichtblau

Müller

Rybnikova

Gatterer

Debevec

Baillieul

Manferdelli

Behrendt

Schega

Ehrenreich

Millet

Gassmann

Schwarzer

Glazachev

Girard

Lalande

Hamlin

Samaja

Hüfner

Burtscher

Panza

Mallet

. Mechanisms underlying the health benefits of intermittent hypoxia conditioning. J Physiol 2023; 602: 5757–5783.

22.

Song

Ren

Liu

Cao

Duan

. Oxygen comfort evaluation method based on symptom index for short-term internal migrants to Tibet. Sci Total Environ 2023; 902: 166418.

23.

Faulhaber

Pocecco

Gatterer

Niedermeier

Huth

Nnwald

Menz

Bernardi

Burtscher

. Seven passive 1-h hypoxia exposures do not prevent AMS in susceptible individuals. Med Sci Sports Exerc 2016; 48: 2563–2570.

24.

Zouboules

Lafave

O’Halloran

Brutsaert

Nysten

Steinback

Sherpa

Day

Schultz

Powers

. Renal reactivity: acid-base compensation during incremental ascent to high altitude. J Physiol 2018; 596: 6191–6203.

25.

Kolb

Ainslie

Ide

Poulin

. Effects of five consecutive nocturnal hypoxic exposures on the cerebrovascular responses to acute hypoxia and hypercapnia in humans. J Appl Physiol 2004; 96: 1745–1754.

26.

Moraga

López

Morales

Soza

Noack

. The effect of oxygen enrichment on cardiorespiratory and neuropsychological responses in workers with chronic intermittent exposure to high altitude (ALMA, 5,050 m). Front Physiol 2018; 9: 187.

27.

Zeng

Wang

Chen

Zhang

Cheng

. Sex differences in time-domain and frequency-domain heart rate variability measures of fatigued drivers. Int J Environ Res Public Health 2020; 17: 8499.

28.

Allwood

Edgett

Eadie

Huber

Romanova

Millar

Brunt

Simpson

. Moderate and severe hypoxia elicit divergent effects on cardiovascular function and physiological rhythms. J Physiol 2018; 596: 3391–3410.

29.

Bilo

Caravita

Torlasco

Parati

. Blood pressure at high altitude: physiology and clinical implications. Kardiol Pol 2019; 77: 596–603.

30.

Semenza

. O₂-regulated gene expression: transcriptional control of cardiorespiratory physiology by HIF-1. J Appl Physiol 2004; 96: 1173–1177.

31.

Jelkmann

. Erythropoietin: structure, control of production and function. Physiol Rev 1992; 72: 449–489.

32.

Wojan

Stray-Gundersen

Nagel

Lalande

. Short exposure to intermittent hypoxia increases erythropoietin levels in healthy individuals. J Appl Physiol 2021; 130: 1955–1960.

33.

Vizcardo-Galindo

León-Velarde

Villafuerte

. High-Altitude hypoxia decreases plasma erythropoietin soluble receptor concentration in lowlanders. High Alt Med Biol 2020; 21: 92–98.

34.

Viscor

Torrella

Corral

Ricart

Javierre

Pages

Ventura

. Physiological and biological responses to short-term intermittent hypobaric hypoxia exposure: from sports and mountain medicine to new biomedical applications. Front Physiol 2018; 9: 814.

35.

Aldous

JWF

Chrismas

BCR

Akubat

Dascombe

Abt

Taylor

. Hot and hypoxic environments inhibit simulated soccer performance and exacerbate performance decrements when combined. Front Physiol 2016; 6: 421.

36.

Siebenmann

Robach

Lundby

. Regulation of blood volume in lowlanders exposed to high altitude. J Appl Physiol 2017; 123: 957–966.

37.

Zhang

Yang

Zhou

Cao

Yin

Fan

Zhao

Zhu

. Intermittent hypoxia training effectively protects against cognitive decline caused by acute hypoxia exposure. Pflugers Arch - Eur J Physiol 2024; 476: 197–210.

38.

Claassen

JAHR

Thijssen

DHJ

Panerai

Faraci

. Regulation of cerebral blood flow in humans: physiology and clinical implications of autoregulation. Physiol Rev 2021; 101: 1487–1559.

39.

Vestergaard

Ghanizada

Lindberg

Arngrim

Paulson

Gjedde

Ashina

Larsson

HBW

. Human cerebral perfusion, oxygen consumption, and lactate production in response to hypoxic exposure. Cereb Cortex 2022; 32: 1295–1306.

40.

Kandjov

. Heat and mass exchange processes between the surface of the human body and ambient air at various altitudes. Int J Biometeorol 1999; 43: 38–44.

41.

Tattersall

Milsom

. Hypoxia reduces the hypothalamic thermogenic threshold and thermosensitivity. J Physiol 2009; 587: 5259–5274.

42.

Kollai

. Responses in cutaneous vascular tone to transient hypoxia in man. J Auton Nerv Syst 1983; 9: 497–512.

43.

Liu

. Study on human thermal comfort within lower-pressure environment of asymptomatic altitude reaction. Doctorate thesis, Xi’an: Xi’an University of Architecture and Technology, 2008.

44.

Sun

Liu

Wang

. Human physiology (in Chinese). Beijing: Science Press, 2021.

45.

Naeije

. Physiological adaptation of the cardiovascular system to high altitude. Prog Cardiovasc Dis 2010; 52: 456–466.

46.

Vogel

Harris

. Cardiopulmonary responses of resting man during early exposure to high altitude. J Appl Physiol 1967; 22: 1124–1128.

47.

Knaupp

Khilnani

Sherwood

Scharf

Steinberg

. Erythropoietin response to acute normobaric hypoxia in humans. J Appl Physiol 1992; 73: 837–840.

48.

Mamun

Hayashi

Sakima

Sato

. Adenosine triphosphate is a critical determinant for VEGFR signal during hypoxia. Am J Physiol Cell Physiol 2016; 311: C985–C995.

49.

Willie

Tzeng

Fisher

Ainslie

. Integrative regulation of human brain blood flow. J Physiol 2014; 592: 841–859.

50.

Hamel

. Perivascular nerves and the regulation of cerebrovascular tone. J Appl Physiol 2006; 100: 1059–1064.

51.

Burtscher

Mallet

Burtscher

Millet

. Hypoxia and brain aging: neurodegeneration or neuroprotection? Ageing Res Rev 2021; 68: 101343.

52.

Ciuha

Eiken

Mekjavic

. Effects of normobaric hypoxic bed rest on the thermal comfort zone. J Therm Biol 2015; 49–50: 39–46.

53.

Golja

Kacin

Tipton

Mekjavic

. Moderate hypoxia does not affect the zone of thermal comfort in humans. Eur J Appl Physiol 2005; 93: 708–713.

54.

Duan

Song

Liu

Wang

Cao

. Can hypobaric hypoxia affect human thermal comfort? An experimental study in Tibet, China. J Cent South Univ 2022; 29: 2388–2402.

55.

Duan

Song

Liu

Wang

Suolang

. Study on the influence of hypobaric hypoxia on human thermal comfort under step change thermal environments. Energy Build 2023; 279: 112683.

56.

Keramidas

Kölegård

Mekjavic

Eiken

. Interactions of mild hypothermia and hypoxia on finger vasoreactivity to local cold stress. Am J Physiol Regul Integr Comp Physiol 2019; 317: R418–R431.

57.

Madden

Morrison

. Hypoxic activation of arterial chemoreceptors inhibits sympathetic outflow to brown adipose tissue in rats. J Physiol 2005; 566: 559–573.

58.

Roach

Hackett

Oelz

Bärtsch

Luks

Maclnnis

Baillie

and The Lake Louise AMS Score Consensus Committee. The 2018 lake louise acute mountain sickness score. High Alt Med Biol 2018; 19: 4–6.

59.

Wagner

Tatsugawa

Parker

Young

. Reliability and utility of a visual analog scale for the assessment of acute mountain sickness. High Alt Med Biol 2007; 8: 27–31.

60.

Hackett

Rennie

Levine

. The incidence, importance, and prophylaxis of acute mountain sickness. Lancet 1976; 308: 1149–1155.

61.

Roach

Bärtsch

Hackett

Oelz

and The Lake Louise AMS Scoring Consensus Committee. The lake louise acute mountain sickness scoring system. In: Sutton

Houston

Coates

, editors. Hypoxia and Molecular Medicine: Proceedings of the 8th International Hypoxia Symposium Held at Lake Louise. Canada. February 9-13, 1993. Burlington, VT: Queen City Printers, 1993, 272–274.

62.

Meier

Collet

T-H

Locatelli

Cornuz

Kayser

Simel

Sartori

. Does this patient have acute mountain sickness?: the rational clinical examination systematic review. JAMA 2017; 318: 1810.

63.

Luo

. Differences between the ‘Chinese AMS score’ and the lake louise score in the diagnosis of acute mountain sickness. Med 2016; 95: e3512.

64.

Ren

Shen

Jiang

Peng

Cui

. Incidence of high altitude illnesses among unacclimatized persons who acutely ascended to Tibet. High Alt Med Biol 2010; 11: 39–42.

65.

Wang

Yuan

Cang

. Acute mountain sickness of medical staff in real combat training. Hosp Adm J Chin People’s Liberation Army 2016; 23: 874–875.

66.

ISO 10551: 2019. Ergonomics of the physical environment-Subjective judgement scales for assessing physical environments. Geneva, Switzerland: The International Organization for Standardization, 2019.

67.

Song

Kang

Ren

Liu

. Oxygen adaptation prediction method based on objective physiological parameters for high-altitude populations. Build Environ 2025; 267: 112213.

68.

Cao

Song

Liu

Wang

. Oxygen comfort evaluation method and the oxygen adaptation level for sojourners at high altitude. In: Proceedings of the 5th International Conference on Building Energy and Environment. Montreal, QC, Canada. July 25–29, 2022. Singapore: Springer, 2023; 2343–2531. 10.1007/978-981-19-9822-5_253.

69.

Hackett

Roach

. High-Altitude illness. N Engl J Med 2001; 345: 1279–1281.

70.

Luks

Auerbach

Freer

Grissom

Keyes

Mcintosh

Rodway

Schoene

Zafren

Hackett

. Wilderness medical society practice guidelines for the prevention and treatment of acute altitude illness: 2014 update. Wilderness Environ Med 2019; 30: S3–S18.

71.

Beidleman

Muza

Fulco

Cymerman

Ditzler

Stulz

Staab

Skrinar

Lewis

Sawka

. Intermittent altitude exposures reduce acute mountain sickness at 4300 m. Clin Sci 2004; 106: 321–328.

72.

Schneider

Bernasch

Weymann

Holle

Bartsch

. Acute mountain sickness: influence of susceptibility, preexposure, and ascent rate. Med Sci Sports Exerc 2002; 34: 1886–1891.

73.

Purkayastha

Ray

Arora

Chhabra

Thakur

Bandopadhyay

Selvamurthy

. Acclimatization at high altitude in gradual and acute induction. J Appl Physiol 1995; 79: 487–492.

74.

Bloch

Turk

Maggiorini

Hess

Merz

Bosch

Barthelmes

Hefti

Pichler

Senn

Schoch

. Effect of ascent protocol on acute mountain sickness and success at Muztagh Ata, 7546 m. High Alt Med Biol 2009; 10: 25–32.

75.

Muza

. Military applications of hypoxic training for high-altitude operations. Med Sci Sports Exerc 2007; 39: 1625–1631.

76.

Zafren

. Prevention of high altitude illness. Travel Med Infect Dis 2014; 12: 29–39.

77.

Beidleman

Fulco

Muza

Rock

Staab

Forte

Brothers

Cymerman

. Effect of six days of staging on physiologic adjustments and acute mountain sickness during ascent to 4300 meters. High Alt Med Biol 2009; 10: 253–260.

78.

Baggish

Fulco

Muza

Rock

Beidleman

Cymerman

Yared

Fagenholz

Systrom

Wood

Weyman

Picard

Harris

. The impact of moderate-altitude staging on pulmonary arterial hemodynamics after ascent to high altitude. High Alt Med Biol 2010; 11: 139–145.

79.

Maggiorini

Mélot

Pierre

Pfeiffer

Greve

Sartori

Lepori

Hauser

Scherrer

Naeije

. High-Altitude pulmonary edema is initially caused by an increase in capillary pressure. Circulation 2001; 103: 2078–2083.

80.

Beidleman

Fulco

Cymerman

Staab

Buller

Muza

. New metric of hypoxic dose predicts altitude acclimatization status following various ascent profiles. Physiol Rep 2019; 7: e14263.

81.

Klokker

Kharazmi

Galbo

Bygbjerg

Pedersen

. Influence of in vivo hypobaric hypoxia on function of lymphocytes, neutrocytes, natural killer cells, and cytokines. J Appl Physiol 1993; 74: 1100–1106.

82.

Askew

. Work at high altitude and oxidative stress: antioxidant nutrients. Toxicol 2002; 180: 107–119.

83.

Gangwar

Paul

Ahmad

Bhargava

. Intermittent hypoxia modulates redox homeostasis, lipid metabolism associated inflammatory processes and redox post-translational modifications: benefits at high altitude. Sci Rep 2020; 10: 7899.

84.

Millet

Roels

Schmitt

Woorons

Richalet

. Combining hypoxic methods for peak performance. Sports Med 2010; 40: 1–25.

85.

Mateika

El-Chami

Shaheen

Ivers

. Intermittent hypoxia: a low-risk research tool with therapeutic value in humans. J Appl Physiol 2015; 118: 520–532.

86.

Navarrete-Opazo

Mitchell

. Therapeutic potential of intermittent hypoxia: a matter of dose. Am J Physiol Regul Integr Comp Physiol 2014; 307: R1181–R1197.

87.

Feng

Chen

Yan

Wang

Zhao

. Effects of various living-low and training-high modes with distinct training prescriptions on sea-level performance: a network meta-analysis. PLoS One 2024; 19: e0297007.

88.

Katayama

Sato

Hotta

Ishida

Iwasaki

Miyamura

. Intermittent hypoxia does not increase exercise ventilation at simulated moderate altitude. Int J Sports Med 2007; 28: 480–487.

89.

Wang

Zhang

Wang

Huang

. Intermittent hypoxia preconditioning can attenuate acute hypoxic injury after a sustained normobaric hypoxic exposure: a randomized clinical trial. CNS Neurosci Ther 2024; 30: e14662.

90.

Garcia

Hopkins

Powell

. Effects of intermittent hypoxia on the isocapnic hypoxic ventilatory response and erythropoiesis in humans. Respir Physiol 2000; 123: 39–49.

91.

Schommer

Wiesegart

Menold

Haas

Lahr

Buhl

Bärtsch

Dehnert

. Training in normobaric hypoxia and its effects on acute mountain sickness after rapid ascent to 4559 m. High Alt Med Biol 2010; 11: 19–25.

92.

Katayama

Ishida

Iwasaki

Miyamura

. Effect of two durations of short-term intermittent hypoxia on ventilatory chemosensitivity in humans. Eur J Appl Physiol 2009; 105: 815–821.

93.

Gangwar

Pooja

Sharma Singh

Patyal

Bhaumik

Bhargava

Sethy

. Intermittent normobaric hypoxia facilitates high altitude acclimatization by curtailing hypoxia-induced inflammation and dyslipidemia. Pflugers Arch - Eur J Physiol 2019; 471: 949–959.

94.

Treml

Kleinsasser

Hell

Knotzer

Wille

Burtscher

. Carry-Over quality of Pre-acclimatization to altitude elicited by intermittent hypoxia: a participant-blinded, randomized controlled trial on antedated acclimatization to altitude. Front Physiol 2020; 11: 531.

95.

Ricart

Casas

Pagés

Palacios

Rama

Rodríguez

Viscor

Ventura

. Acclimatization near home? Early respiratory changes after short-term intermittent exposure to simulated altitude. Wilderness Environm Med 2000; 11: 84–88.

96.

Townsend

Gore

Hahn

McKenna

Aughey

Clark

Kinsman

Hawley

Chow

. Living high-training low increases hypoxic ventilatory response of well-trained endurance athletes. J Appl Physiol 2002; 93: 1498–1505.

97.

Richard

Koehle

. Differences in cardio-ventilatory responses to hypobaric and normobaric hypoxia: a review. Aviat Space Environ Med 2012; 83: 677–684.

98.

West

. Oxygen conditioning: a new technique for improving living and working at high altitude. Physiol 2016; 31: 216–222.

99.

Zhao

Zhou

. Factors influencing nasal airway pressure and comfort in high-flow nasal cannula oxygen therapy: a volunteer study. BMC Pulm Med 2023; 23: 449.

100.

Wang

Yan

Xie

Dai

. Effects of different artificial oxygen-supply systems on migrants’ physical and psychological reactions in high-altitude tunnel construction. Build Environ 2019; 149: 458–467.

101.

Liu

Huang

Song

Wang

Suolang

Duan

. Effect of hypoxia on human cognitive ability and indoor oxygen environment demand for sojourners at high altitude. Build Environ 2021; 194: 107678.

102.

Luks

Van Melick

Batarse

Powell

Grant

West

. Room oxygen enrichment improves sleep and subsequent day-time performance at high altitude. Res Physiol 1998; 113: 247–258.

103.

Gao

Zhou

. An efficient breathing zone with targeted oxygenation for improving the sleep environment in hypoxic areas. Build Environ 2022; 222: 109371.

104.

Song

Zhao

Liu

Wang

. Distribution characteristics of indoor oxygen concentration under natural ventilation in oxygen-enriched buildings at high altitudes. Build Simul 2021; 14: 1823–1841.

105.

Yang

Liu

Shen

Liu

Zhang

Meng

. Maximum safe concentration of oxygen-enriched atmosphere in high altitude (in Chinese). J Univ Sci Technol Beijing 2009; 31: 1467–1471.

106.

GB/T 35414-2017. Requirements for oxygen conditioning for indoor oxygen diffusion in plateau areas. Beijing: Standardization Administration of China, 2017.

107.

NFPA 99B Standard for Hypobaric Facilities. (2024 ed.). National Fire Protection Association, Quincy, Massachusetts, 2024.