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20 July 2023: Review Articles  

Understanding Acute Respiratory Distress Syndrome in High-Altitude Environments: A Comprehensive Review of Diagnosis and Treatment

Litao Guo1ABEF*, Jingjing Sun1CEF, Zongzhao He2BF, Qingdong Shi1AEF, Siqing Ma2ADFG

DOI: 10.12659/MSM.939935

Med Sci Monit 2023; 29:e939935




ABSTRACT: Approximately 2% of the global population lives above 1500 m, where low atmospheric pressure, decreased oxygen levels, harsh cold and dry conditions, strong radiation, and the effects of climate change present significant health challenges. Residents of these high-altitude areas display physiological adaptions, including smaller body size, enlarged ribs, improved oxygen delivery in hypoxic conditions, and adjustments in oxygen utilization and metabolism. Both acute and chronic hypoxia prevalent in such regions can trigger various diseases by stimulating hypoxia-inducible factors, boosting inflammatory responses, and impairing mitochondrial function.Acute Respiratory Distress Syndrome (ARDS) - a critical respiratory condition associated with high morbidity and mortality - occurs more frequently among the health risks in these environments. Hypoxia is a critical predisposing and aggravating factor for high-altitude ARDS. Despite similarities with its low-altitude counterpart, ARDS in high-altitude areas displays unique pathophysiology and clinical manifestations due to the specific environmental conditions.This review aims to shed light on how high-altitude environments influence the diagnosis and treatment of ARDS, providing a comprehensive understanding of the distinct challenges inherent to these regions.

Keywords: COVID-19, Extracorporeal Membrane Oxygenation, Respiration, Artificial, respiratory distress syndrome, Humans, Altitude, Environment, Hypoxia, Oxygen


Acute respiratory distress syndrome (ARDS) is a common critical respiratory disease in the intensive care unit (ICU). ARDS clinically presents as respiratory distress and intractable hypoxemia [1,2], with a high rate of morbidity and in-hospital mortality of 35% to 40% [2,3]; thus, this condition has received extensive attention from clinicians and researchers.

Studies have shown that patients can have lower partial pressure of oxygen (PaO2) and arterial oxygen saturation (SaO2) values at altitudes >1500 m than at sea level [4]. Some studies have measured pulmonary arterial pressure in patients at an altitude of 1600 meters and found that 45% of the patients had a mean pulmonary arterial pressure ≥18 mmHg [5], which was significantly higher from that of patients in lower-altitude areas. Therefore, a height of 1500 m above sea level has been proposed as the boundary between physiological and pathological altitude conditions [6]. As altitude increases, atmospheric pressure and oxygen content in the air gradually decrease; therefore, patients living in high-altitude areas present different respiratory physiology and pathology than patients living in low-altitude areas [2]. In our study, high altitude was defined as altitudes >1500 m above sea level.

Globally, approximately 2% of the population lives at an altitude >1500 m [7]. High altitude, low atmospheric pressure, low atmospheric oxygen, a dry and cold environment, strong radiation, and climate change significantly impact human health [2,6]. People living at high altitude exhibit adaptive physiological responses to these conditions through developmental plasticity and natural selection [8]. Developmental plasticity is a long-term process in which individuals adapt to environmental conditions over time through growth and maturation [8]. Natural selection is an evolutionary force through which specific genotypes and phenotypes confer survival and reproductive advantages in specific environments over many generations. The offspring also develop a similar phenotype during growth under the same conditions [8]. Many physiological and anatomical features allow humans to successfully inhabit high-altitude areas; for example, a small body, large ribs, enhanced oxygen delivery under hypoxic conditions, and changes in tissue oxygen utilization and metabolism [8,9] allow the reduction of hypoxia adverse effects at high altitude. This enables humans to combat hypoxia by protecting their bodies’ physiological systems, and therefore to perform their daily activities in agriculture and livestock. People living at altitudes above 2500 m have been found to have very low COVID-19 mortality and to be less likely to develop severe effects [10,11]. It has been demonstrated that the expression level of angiotensin converting enzyme 2 (ACE2) in lung epithelial cells is positively correlated with the infection rate of the first SARS-CoV-2 variant [11]. ACE2 levels are reduced in the lungs (and other tissues) of highlanders (ie, people living under chronic exposure to hypoxic conditions) [11]. Available epidemiological data analyses have suggested that physiological acclimatization/adaptation to counteract the hypoxic environment at high altitude may protect against the severe effects of SARS-CoV-2 acute viral infection [10,11]. The potential underlying mechanisms include: (1) impaired viral half-life caused by high-altitude environments (drastic diurnal temperature changes, dry air, and high levels of ultraviolet radiation); and (2) hypoxia-mediated down-regulation of ACE2 [10,11].

Furthermore, acute and chronic hypoxia in high-altitude areas can induce various diseases by activating hypoxia-inducible factor, enhancing inflammatory responses, and impairing mitochondrial function [7,9]. Severe hypoxia is a predisposing and aggravating factor for high-altitude ARDS. The incidence of ARDS increases significantly in hypoxic environments at high altitudes [2,12]. Compared with living in low-altitude areas, long-term living in high-altitude, hypobaric, and hypoxic environments results in differences in the pathophysiology and clinical manifestations of ARDS [2,6,7]. Therefore, this article aims to review the effects of high altitude on the diagnosis and treatment of ARDS.


Pathophysiological changes in patients with high-altitude ARDS differ from those in patients with low-altitude ARDS. Atmospheric pressure gradually decreases with increasing altitude, and the PaO2 in the air gradually decreases; therefore, the oxygen content of inhaled air decreases significantly. Owing to the decrease in atmospheric pressure, the partial alveolar oxygen pressure, partial alveolar-arterial oxygen pressure difference, and diffusion rate of oxygen in the alveolar capillaries decrease, resulting in oxygen exchange disorders [2,6]. Studies have shown that the arterial PaO2 of healthy adults in plateau areas is significantly lower than that of healthy adults of the same age in plain areas [1,13]. Hypoxia causes a compensatory increase in the number of red blood cells, hemoglobin level, and blood volume. The patient’s breathing increases, the sympathetic nervous system is activated, and cardiac output increases. Hypoxia also causes pulmonary vasoconstriction, which leads to the development and exacerbation of pulmonary hypertension, damage to the right heart, and pulmonary vascular permeability [14,15]. At the same time, long-term residents of plateau areas have good tolerance to hypoxia. Therefore, patients with high-altitude ARDS experience rapid disease progression, more obvious hypoxemia, and more complex clinical manifestations, and their condition often combines with multiple organ distress syndrome; therefore, they have a worse prognosis. The diagnostic criteria for high-altitude ARDS also differ from those for low-altitude ARDS [16].

ARDS is a clinical syndrome characterized by refractory hypoxemia resulting from intrapulmonary and/or extrapulmonary causes. Therefore, PaO2 is important in the diagnosis of ARDS. In 1992, the Joint American and European Consensus Conference (AECC) on ARDS proposed the concept of acute lung injury (ALI), that is, a PaO2/fraction of inspired oxygen (FiO2) of 300 mmHg (39.7 kPa) indicates an early or ALI stage of ARDS. PaO2/FiO2 ≤200 mmHg (26.6 kPa) can be used to diagnose ARDS, which is a severe manifestation of ALI [17]. Although the AECC criteria are helpful in diagnosing ARDS, they do not consider the particularity of patients living at high altitudes and therefore are not suitable for diagnosing high-altitude ARDS [2]. In 2001, Chinese researchers, including Zhang et al, proposed the “Diagnostic Criteria for ALI/ARDS at High Altitudes in Western China” [6]. In their proposed criteria, Zhang et al pointed out that, although it has the same etiology, pathology, and physiology as low-altitude ARDS, high-altitude ARDS is influenced by an increase in the altitude gradient, the partial drop of oxygen pressure, and the environmental factors of high altitudes, resulting in more significant differences in pathophysiological changes, clinical signs and symptoms, and blood gas parameters [6].

According to the criteria described by Zhang et al, the primary causes of ALI/ARDS include acute onset status, cardiogenic etiology, and high-altitude pulmonary edema (HAPE). Other causes of ventilatory dyspnea can be excluded, and any of the following clinical criteria and any 2 blood gas criteria that meet this gradient can be used to diagnose high-altitude ALI/ARDS. The clinical criteria include the following: (1) breathing frequency ≥30 breaths/min (ALI), ≥40 breaths/min (ARDS), rapid onset, dyspnea, distress, and significant cyanosis; (2) dry or moist rales or wheezing sounds (ALI) that can be heard in the chest, or a large amount of foamy viscous and pink sputum (ARDS) being coughed up; and (3) chest radiographs showing blurred lung markings (ALI) and patchy or confluent shadows (ARDS) in one or both lung fields. Blood gas standards are listed in Table 1.

Although the criteria of Zhang et al were based on AECC diagnostic criteria and applied to different altitudes, they were revised for high-altitude ALI/ARDS to account for misdiagnoses of ARDS in such areas. However, Zhang et al’s criteria have been abandoned because of the limitations of the AECC diagnostic criteria in terms of onset time and positive end-expiratory pressure (PEEP) selection; thus, these cannot be used to diagnose and treat high-altitude ARDS [2]. Currently, the internationally recognized diagnostic criteria for ARDS are the Berlin criteria proposed in 2012 [1], which include mainly 4 aspects: (1) onset time; (2) origin of pulmonary edema; (3) chest radiograph infiltration; and (4) PaO2/FiO2 ratio (Table 2). In addition to focusing on the onset time, the Berlin criteria proposed the stratification of ARDS into mild, moderate, and severe based on the PaO2/FiO2 ratio, which currently is a widely used factor in diagnosing ARDS. Moreover, the PaO2/FiO2 ratio has been shown to have high diagnostic sensitivity and specificity, providing a basis for treatment and prognosis [18].

For altitudes >1000 m above sea level, the Berlin criteria proposed a correction factor for the calculation of the PaO2/FiO2 ratio used to classify the severity of ARDS, namely (PaO2/FiO2 × [barometric pressure/760]). High-altitude ARDS severity grades according to the corrected PaO2/FiO2 are presented in Table 3. For patients in high-altitude areas, using an uncorrected PaO2/FiO2 ratio results in false-positives in the severity stratification of high-altitude ARDS [2]. Unfortunately, this dramatic difference caused by altitude changes has not attracted the attention of high-altitude intensivists, resulting in a low success rate of high-altitude ARDS treatment.

Some studies [2] have compared the standard Berlin definition [1] (ie, PaO2/FiO2 is not corrected with altitude), the PaO2/FiO2 altitude-adjusted Berlin criteria [1], and Zhang et al’s criteria [6] in Xining in the Qinghai province (altitude 2261 m) in terms of the application value of ARDS. The results showed that 253 patients met the Berlin definition criteria, 229 met the PaO2/FiO2 altitude-adjusted Berlin criteria, and 204 satisfied Zhang et al’s criteria [2]. Comparison of the area under the receiver operating characteristic (ROC) curve of the 3 different ARDS criteria for the death rate in the ICU did not show any statistically significant differences. However, in high-altitude regions, clinicians using Zhang et al’s criteria failed to identify the severity of ARDS in some patients, leading to a delayed diagnosis. On the other hand, using the Berlin definition criteria led to an overdiagnosis of ARDS in many patients, leading to overtreatment [2]. In contrast, the PaO2/FiO2 altitude-adjusted Berlin criteria correctly identified the severity of ARDS at high altitudes and seemed better suited than the other 2 criteria for diagnosing high-altitude ARDS [2]. This calibration standard has also been shown to be applicable for treating patients with COVID-19 complicated by ARDS [19]. Regardless of which criteria are used to diagnose high-altitude ARDS, it is necessary to differentiate it from HAPE [20,21].

Currently, there is a problem with diagnosing high-altitude ARDS using the PaO2/FiO2 calibration standard according to altitude [22]. Furthermore, a high-flow nasal cannula (HFNC) has become an important treatment method for patients with respiratory failure in the ICU [23,24]. Clinical practice guidelines also recommend HFNC for treating patients with respiratory failure [25]. However, none of the diagnostic criteria for high-altitude ARDS include how to diagnose high-altitude ARDS under HFNC treatment [2,6]. If high-altitude ARDS was still diagnosed according to the original standard, the clinical application of HFNC would delay the diagnosis of high-altitude ARDS. Therefore, the diagnostic criteria for high-altitude ARDS remain controversial. The Berlin criteria have not been updated for 10 years, and there is still no unified standard for diagnosing and treating high-altitude ARDS. Therefore, further clinical research is required.

Differentiation Between Plateau-Related ARDS and HAPE

HAPE is a life-threatening non-cardiogenic lung edema with clinical manifestations similar to ARDS manifestations, but the etiology, pathophysiology, course development, and prognosis of the 2 conditions are different to some extent [15,20] (Table 4). HAPE is an overreaction of the body to high-altitude hypoxia and is a serious disease caused by rapid entry into a high-altitude hypoxic environment [20,21]. HAPE can progress to ARDS in the following situations [15,20,21]: (1) deteriorating condition due to an inadequate diagnosis and treatment; (2) severe diffuse exudation in both lungs (white lung), with the lesions progressing rapidly; (3) secondary severe pulmonary infection or concurrent intestinal infection and sepsis; and (4) mixed pulmonary/cerebrospinal edema. Early detection and appropriate pharmacological and nonpharmacological prophylaxis can significantly prevent further disease progression [21]. Our study found that surfactant protein D has a protective effect on ARDS secondary to high altitude pulmonary edema, and is worthy of further investigation and study. Once HAPE is secondary to ARDS or multiple organ distress syndrome, its treatment should be actively included in the management strategy of critically ill patients to prevent serious complications.



In addition to common infection, aspiration, trauma, and shock [3], chronic hypoxia is a predisposing factor for ARDS in individuals living in high-altitude areas [6,26]. High-altitude hypobaric hypoxia contributes to the progression of high-altitude ARDS by stimulating the release of inflammatory mediators and inducing the development of HAPE and pulmonary hypertension [6,20,26]. Moreover, high-altitude hypobaric hypoxia is associated with a poor prognosis [27]. Control of the primary disease is the most critical factor affecting treatment. Therefore, when treating the primary cause of high-altitude ARDS, patient exposure to hypobaric and hypoxic environments should eventually be stopped. Hypoxemia should also be actively corrected, as this can prevent disease progression in some mild cases. Depending on the severity of hypoxemia, mask oxygen inhalation, HFNC oxygenation, non-invasive ventilation, invasive ventilation, and even extracorporeal membrane oxygenation (ECMO) therapy should be used in sequence. Studies [28] have shown that, for patients with mild ARDS, the success rate of non-invasive ventilation can reach 70%, and non-invasive positive-pressure ventilation can significantly improve hypoxia status and the PaO2/FiO2 ratio, reducing the rate of tracheal intubation and improving the prognosis of patients [28].


Mechanical ventilation is the most basic and effective treatment for ARDS, providing the lungs with PEEP, which is conducive to the recruitment of collapsed alveoli, reducing pulmonary interstitial and alveolar edema, and increasing body oxygenation. However, mechanical ventilation is not always beneficial, and improper application can cause significant damage to the body. Therefore, in mechanical ventilation, lung protection strategies must be emphasized.

MECHANICAL VENTILATION IN HIGH-ALTITUDE ARDS AND RIGHT HEART PROTECTION: Several factors, such as high-altitude hypoxic pulmonary vasoconstriction and increased blood viscosity, lead to a significant increase in pulmonary vascular resistance and pulmonary artery pressure in patients with ARDS in chronic hypoxic environments and increase the right ventricular afterload [14]. During mechanical ventilation, transpulmonary pressure and pulmonary inflation pressure increase, resulting in the squeezing of the alveolar capillaries; moreover, an increased pulmonary vascular resistance is observed, which increases the right ventricular afterload and subsequent acute pulmonary hypertension and right ventricular dysfunction. Meanwhile, inappropriate mechanical ventilation settings can further aggravate pulmonary hypertension, which is already physiologically elevated in patients with high-altitude ARDS. Therefore, the implemented mechanical ventilation strategy should consider the altitude difference and the baseline status of the patient’s pulmonary hypertension and right ventricular function. The ideal strategy includes 3 elements: (1) reducing lung stress; (2) improving PaO2 to reverse hypoxic pulmonary vasoconstriction; and (3) reducing hypercapnia [35], as further described below.


Prone position ventilation (PPV) is a therapeutic postural measure that assists the patient in taking a prone position during mechanical ventilation to improve the oxygenation state. Taking a prone position can change thoracic pressure, reduce lung tissue compression, reduce intrapulmonary shunt, facilitate alveolar expansion in the lower and dorsal regions of the lung, promote redistribution of gas and blood flow, improve oxygenation function, and reduce the partial pressure of carbon dioxide [41]. PPV is an important treatment for lung protection and recruitment in severe ARDS. Its efficacy in the treatment of severe ARDS has been recognized. For patients with high-altitude ARDS, PPV can also reduce both the pulmonary and systemic inflammatory response, thus improving cardiac function damaged by cytokine release. At the same time, PPV can correct right-sided heart failure by reducing driving pressure through expansion of the dorsal and dependent lung areas [42]. Pulmonary hypertension occurs in patients with high-altitude ARDS, and PPV should be implemented early and with a prolonged duration as to reduce lung injury and protect cardiac function [43]. Currently, in China and abroad, alternating prone and supine positioning is most commonly used, with a total daily PPV time of about 16 h (intermittent PPV) [43]. Owing to the hypoxic environment in high-altitude areas, the ventilation/blood flow ratio and respiratory indices of patients receiving intermittent PPV fluctuated more noticeably than those in low-altitude areas when the body position changed [44]. PPV prolongation has been reported to be more suitable for high-altitude ARDS than intermittent PPV and can improve the treatment effect [43].

We retrospectively analyzed the implementation of PPV in patients with severe ARDS in Xining, Qinghai (altitude 2261 m) [43], and compared the therapeutic effects of intermittent PPV therapy (ie, alternating prone and supine position ventilation, with a PPV time of approximately 16 h) and continuous PPV therapy (alternating lateral prone position at 20° to 30°, approximately every 4 h daily) in patients with high-altitude ARDS. We found that both PPV methods could improve the PaO2/FiO2 ratio and respiratory mechanics in patients with severe high-altitude ARDS. Still, the PaO2/FiO2 ratio in the continuous PPV group improved more significantly than that in the intermittent PPV group (mmHg, 121.8±25.3 vs 99.7±15.4, P=0.003), and continuous PPV could shorten the duration of mechanical ventilation (days: 6.0 [5.0, 7.3] vs 8.0 [7.0, 9.0], P<0.001) and the duration of stay in the ICU (days, 9.7±1.5 vs 12.1±2.2, P<0.001) [43]. In patients undergoing continuous PPV therapy, although the dorsal alveoli collapse and consolidate due to gravity, they continue to re-expand over time, showing an increase in the size of the ventilatable lung area. In one patient study, since the patient’s optimal ventilation/blood flow ratio was always maintained, the improvement in oxygenation was more apparent and stable [43].

Therefore, for patients with high-altitude ARDS, the right heart protective ventilation strategy must be combined with continuous PPV and implemented early. However, continuous PPV is more difficult and riskier and requires an experienced medical team to guide nursing care and effectively prevent complications during the treatment [45,46].


Increased pulmonary vascular permeability in patients with ARDS makes it easier for the lungs to develop edema. Fluid management in patients with ARDS has always been a difficult issue. Wiedemann et al [47] divided patients with ARDS into a restrictive group and an open fluid management group. The results showed that restrictive fluid management may be better at creating a hemodynamically stable state by controlling the rate and volume of fluid infusion, which can effectively reduce pulmonary edema, shorten the duration of mechanical ventilation in ARDS, and even reduce mortality and organ dysfunction. However, ARDS is often secondary to severe infection, trauma, shock, and other conditions, and the effective circulating blood volume is relatively insufficient. Therefore, blindly seeking to limit the amount of fluid infusion to reduce pulmonary edema can worsen the patient’s hemodynamic status and lead to insufficient perfusion of vital organs, secondary multiple organ distress syndrome, and increased mortality. The benefits and potential harms of an open fluid management strategy are the opposite of those of a restricted strategy [48]. Owing to the complex pathophysiological mechanism of high-altitude ARDS, which is often secondary to HAPE [21], great attention should be paid to fluid management to avoid the aggravation of pulmonary edema.

Healthy individuals with chronic exposure to hypoxic environments often present with physiological pulmonary artery hypertension, increased blood viscosity, decreased microcirculatory blood flow, and increased microvascular density [15]. Coupled with the cold and dry environment and the high rate of evaporation in high-altitude environments, patients with high-altitude ARDS often have insufficient capacity and volume depletion in the early stage; hence, fluid resuscitation in this stage is crucial. The increase in blood viscosity increases pulmonary blood volume. Once coupled with multiple complex factors such as tissue-cell oxygen metabolism disorder and increased capillary permeability, the window period of rehydration and the volume tolerance interval are narrowed. Some cases of ARDS in high-altitude areas develop from HAPE [15,21]. Inappropriate fluid therapy at this point increases pulmonary blood flow, induces or aggravates pulmonary edema, and leads to more severe hypoxemia and damage to the right heart function [49].

Therefore, proper fluid management must be maintained throughout the treatment process in the comprehensive treatment of high-altitude ARDS. Optimal fluid management is patient-specific, aimed at preventing increased lung fluid, maintaining oxygenation, and ensuring organ perfusion. Hemodynamic monitoring methods, such as bedside critical ultrasound and pulse index continuous cardiac output, should be used early for volume assessment and precise management. Intensivists in high-altitude areas should have a solid foundation in critical care ultrasound and hemodynamics to achieve safe volume management in high-altitude ARDS.


The timing of ECMO in the treatment of ARDS is controversial; however, ECMO has improved the treatment success and survival rates of patients with severe ARDS [1,50,51]. ECMO is therefore recommended for patients with severe ARDS who are refractory to conventional treatment. ECMO also plays a key role in treating severe ARDS caused by COVID-19 [51,52]. Although there are few reports on the use of ECMO in the treatment of high-altitude ARDS, there are no reports on the usefulness of ECMO in high-altitude ARDS related to COVID-19. Our experience shows no differences in treatment methods between patients living at high or low altitudes. However, there are differences in the indications for on-board and off-line ECMO between the patients in these 2 areas. When referring to the indications for ECMO on-board and off-line in plain areas, the patient’s PaO2/FiO2 ratio may need to be corrected according to altitude (corrected PaO2/FiO2 = measured PaO2/FiO2 × [760/barometric pressure]), while making decisions based on the pathophysiological characteristics of patients with high-altitude ARDS.

It has been reported [53] that for patients with ARDS who are still considered severe cases even after ECMO treatment, improvement as observed by lung imaging is hardly noticeable, and the effect of lung recruitment is poor. Combined with PPV treatment, the physiological function of the lungs can be maximized, making up for ECMO’s inability to improve gas redistribution. PPV for 12 h a day or longer can significantly improve patient oxygenation and facilitate ECMO weaning without compromising patient safety [54,55]. The PaO2/FiO2 ratio can increase by 20% after treatment in the prone position during ECMO, and oxygenation in the patients can still be continuously improved after changing to the supine position [55]. The continuation of PPV therapy after 7 days of ECMO therapy also results in more pronounced improvements in patient oxygenation [55,56]. However, the relevant literature does not mention the impact on the improvement of long-term oxygenation in patients with ARDS. ECMO combined with PPV therapy can shorten the stay in the ICU for patients with ARDS, improve the overall survival rate and produce better clinical results for patients [54]. These measures may remain beneficial in the treatment of ARDS in high-altitude areas.

There is currently no evidence that high-altitude hypoxia can prevent COVID-19 [57]. Higher-altitude areas show lower morbidity and mortality from COVID-19 and lower risk of severe ARDS caused by COVID-19, but this has yet to be proven [10]. However, during the 2020 pandemic, the World Health Organization’s updated clinical guidelines for COVID-19 pointed out that PPV and ECMO therapy are recommended for COVID-19 patients with ARDS when indicated [58]. Therefore, in high-altitude areas where severe ARDS complicates COVID-19, early ECMO combined with PPV therapy may improve patient outcomes.


Although research on ARDS has been conducted for decades, no effective treatment has been found yet. Supportive care measures based on respiratory support are still used in clinical practice [59]. This is also true for high-altitude ARDS.

Glucocorticoids can inhibit inflammatory reactions, reduce exudation, and inhibit fibroblast proliferation and collagen deposition. However, the use of glucocorticoids in ARDS remains controversial. Earlier studies have shown that high-dose methylprednisolone or equivalent doses of dexamethasone in the early short course of ARDS increase mortality and risk of infection [60]. In recent years, several studies [61–63] have found that for patients with early moderate-to-severe ARDS (PaO2/FiO2 <200 mmHg and within 14 days of onset), low-dose glucocorticoids can improve oxygenation, reduce mortality, and shorten ventilator time and ICU stay time, including for ARDS caused by COVID-19. The American College of Critical Care Medicine and European Society of Critical Care Medicine guidelines [64] recommend intravenous methylprednisolone 1 mg/kg/day, to be adjusted according to the patient’s condition. Although these studies were based on the results of patients with plain ARDS, they are also applicable to high-altitude ARDS.

Some drugs, including statins, vitamin C, β-agonists, neuromuscular blockers, and inhaled pulmonary vasodilators, can potentially improve short-term clinical efficacy in treating clinical ARDS but have not shown benefits in improving the survival rate of patients with ARDS [59]. More large-scale clinical studies are needed to clarify these agents’ roles in the treatment of ARDS.

Future Directions

The diagnosis and treatment standards for high-altitude ARDS remain unclear. With the wide application of HFNC in the treatment of respiratory failure and the in-depth study of oxygenation evaluation indicators, such as peripheral capillary oxygen saturation (SpO2)/FiO2 [4], the diagnosis and treatment criteria of ARDS will inevitably be updated and become more applicable to clinical practice. In the future, with further developments in medical research, more suitable criteria for diagnosing and treating high-altitude ARDS can also be anticipated. For this, a more accurate assessment of the etiology, diagnosis, and treatment and a comprehensive analysis of the factors that come into play when dealing with this disease is warranted.


People living in high-altitude areas exhibit many differences in their physiological and anatomical characteristics, owing to developmental plasticity and unique physiological adaptation mechanisms. Therefore, high-altitude ARDS also has unique pathophysiological characteristics. The diagnosis and treatment strategies for high-altitude ARDS are different from those for ARDS in lower-altitude areas. Clinicians should pay more attention to the effects of high altitude on the diagnosis and treatment of ARDS.


1. Ranieri VM, Rubenfeld GD, Thompson BTARDS Definition Task Force, Acute respiratory distress syndrome: The Berlin Definition: JAMA, 2012; 307(23); 2526-33

2. Liu X, Pan C, Si L: Front Med (Lausanne), 2022; 9; 648835

3. Bellani G, Laffey JG, Pham TLUNG SAFE Investigators; ESICM Trials Group, Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in Intensive Care Units in 50 countries: JAMA, 2016; 315(8); 788-800 [Erratum in: JAMA. 2016;316(3): 350]

4. Ortiz G, Bastidas A, Garay-Fernández M: Med Intensiva (Engl Ed), 2022; 46(9); 501-7

5. Werir HK, Reeves JT: Pulmonary hypertension, 1984; 2, New York, Future Publishing Gompang

6. Zhang SF, Lin SX, Gao W, Report of the consensus conference on diagnostic criteria of ALI/ARDS at high altitudes in Western China: Intensive Care Med, 2001; 27(9); 1539-46

7. Duan X, Li J, Chen L, Surfactant therapy for respiratory distress syndrome in high- and ultra-high-altitude settings: Front Pediatr, 2022; 10; 777360

8. Weinstein KJ, Morphological signatures of high-altitude adaptations in the Andean archaeological record: Distinguishing developmental plasticity and natural selection: Quat Int, 2017; 461; 14-24

9. O’Brien KA, Simonson TS, Murray AJ, Metabolic adaptation to high altitude: Curr Opin Endocr Metab Res, 2020; 11; 3341

10. Masuda Y, Tatsumi H, Imaizumi H, Effect of prone positioning on cannula function and impaired oxygenation during extracorporeal circulation: J Artif Organs, 2014; 17(1); 106-9

11. Arias-Reyes C, Zubieta-DeUrioste N, Poma-Machicao L, Does the pathogenesis of SARS-CoV-2 virus decrease at high-altitude?: Respir Physiol Neurobiol, 2020; 277; 103443

12. Liu L, Yang Y, Gao Z, Practice of diagnosis and management of acute respiratory distress syndrome in mainland China: A cross-sectional study: J Thorac Dis, 2018; 10(9); 5394-404

13. Shang C, Wuren T, Ga Q, The human platelet transcriptome and proteome is altered and pro-thrombotic functional responses are increased during prolonged hypoxia exposure at high altitude: Platelets, 2020; 31(1); 33-42

14. Henderson WR, Chen L, Amato MBP, Brochard LJ, Fifty years of research in ARDS. respiratory mechanics in acute respiratory distress syndrome: Am J Respir Crit Care Med, 2017; 196(7); 822-33

15. Ma SQ, Acute respiratory distress syndrome following chronic hypoxic exposure: More attention should be paid to right ventricular function at high altitude: Med J Chin PLA, 2022; 47(4); 321-25

16. West JB, High-altitude medicine: Am J Respir Crit Care Med, 2012; 186(12); 1229-37

17. Bernard GR, Artigas A, Brigham KLThe American-European Consensus Conference on ARDS, Definitions, mechanisms, relevant outcomes, and clinical trial coordination: Am J Respir Crit Care Med, 1994; 149(3 Pt 1); 818-24

18. Matthay MA, Thompson BT, Ware LB, The Berlin definition of acute respiratory distress syndrome: Should patients receiving high-flow nasal oxygen be included?: Lancet Respir Med, 2021; 9(8); 933-36

19. Meyer NJ, Gattinoni L, Calfee CS, Acute respiratory distress syndrome: Lancet, 2021; 398(10300); 622-37

20. Archer SL, Sharp WW, Weir EK, Differentiating COVID-19 pneumonia from acute respiratory distress syndrome and high altitude pulmonary edema: Therapeutic implications: Circulation, 2020; 142(2); 101-4

21. Ma SQ, Song Q, Prevention and treatment of acute high pulmonary edema: Research progress: Med J Chin PLA, 2021; 46(6); 603-8

22. Jibaja M, Ortiz-Ruiz G, García F, Garay-Fernández M: Arch Bronconeumol (Engl Ed), 2020; 56(4); 218-24

23. Ospina-Tascón GA, Calderón-Tapia LE, García AF, Zarama VHiFLo-COVID Investigators, Effect of high-flow oxygen therapy vs conventional oxygen therapy on invasive mechanical ventilation and clinical recovery in patients with severe COVID-19: a Randomized Clinical Trial: JAMA, 2021; 326(21); 2161-71 [Erratum in: JAMA. 2022;327(11):1093]

24. Alhazzani W, Evans L, Alshamsi F, Surviving sepsis campaign guidelines on the management of adults with coronavirus disease 2019 (COVID-19) in the ICU: First update: Crit Care Med, 2021; 49(3); e219-e34

25. Oczkowski S, Ergan B, Bos L, ERS clinical practice guidelines: High-flow nasal cannula in acute respiratory failure: Eur Respir J, 2022; 59(4); 2101574

26. Richalet JP, Larmignat P, Poitrine E, Physiological risk factors for severe high-altitude illness: A prospective cohort study: Am J Respir Crit Care Med, 2012; 185(2); 192-98

27. Sydykov A, Mamazhakypov A, Maripov A, Pulmonary hypertension in acute and chronic high altitude maladaptation disorders: Int J Environ Res Public Health, 2021; 18(4); 1692

28. Grieco DL, Maggiore SM, Roca O, Non-invasive ventilatory support and high-flow nasal oxygen as first-line treatment of acute hypoxemic respiratory failure and ARDS: Intensive Care Med, 2021; 47(8); 851-66

29. Brower RG, Matthay MA, Morris AAcute Respiratory Distress Syndrome Network, Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome: N Engl J Med, 2000; 342(18); 1301-8

30. Vieillard-Baron A, Matthay M, Teboul JL, Experts’ opinion on management of hemodynamics in ARDS patients: focus on the effects of mechanical ventilation: Intensive Care Med, 2016; 42(5); 739-49

31. Dzikowska-Diduch O, Kostrubiec M, Kurnicka K, The post-pulmonary syndrome – results of echocardiographic driven follow up after acute pulmonary embolism: Thromb Res, 2020; 186; 30-35

32. Suter PM, Fairley B, Isenberg MD, Optimum end-expiratory airway pressure in patients with acute pulmonary failure: N Engl J Med, 1975; 292(6); 284-89

33. Schmitt JM, Vieillard-Baron A, Augarde R, Positive end-expiratory pressure titration in acute respiratory distress syndrome patients: impact on right ventricular outflow impedance evaluated by pulmonary artery Doppler flow velocity measurements: Crit Care Med, 2001; 29(6); 1154-58

34. Bertoni M, Telias I, Urner M, A novel non-invasive method to detect excessively high respiratory effort and dynamic transpulmonary driving pressure during mechanical ventilation: Crit Care, 2019; 23(1); 346

35. Paternot A, Repessé X, Vieillard-Baron A, Rationale and description of right ventricle-protective ventilation in ARDS: Respir Care, 2016; 61(10); 1391-96

36. Jardin F, Farcot JC, Boisante L, Influence of positive end-expiratory pressure on left ventricular performance: N Engl J Med, 1981; 304(7); 387-92

37. Pettenuzzo T, Pichette M, Douflé G, Fan E, Effect of ultraprotective mechanical ventilation on right ventricular function during extracorporeal membrane oxygenation in adults with acute respiratory distress syndrome: J Cardiothorac Vasc Anesth, 2021; 35(6); 1906-8

38. Marshall BE, Hanson CW, Frasch F, Marshall C, Role of hypoxic pulmonary vasoconstriction in pulmonary gas exchange and blood flow distribution. 2. Pathophysiology: Intensive Care Med, 1994; 20(5); 379-89

39. Berg RMG, Hartmann JP, Iepsen UW, Therapeutic benefits of proning to improve pulmonary gas exchange in severe respiratory failure: Focus on fundamentals of physiology: Exp Physiol, 2022; 107(7); 759-70

40. Tabuchi A, Nickles HT, Kim M, Acute lung injury causes asynchronous alveolar ventilation that can be corrected by individual sighs: Am J Respir Crit Care Med, 2016; 193(4); 396-406

41. Lee HY, Cho J, Kwak N, Improved oxygenation after prone positioning may be a predictor of survival in patients with acute respiratory distress syndrome: Crit Care Med, 2020; 48(12); 1729-36

42. Colla J, Rodos A, Seyller H, Weingart S, Fighting COVID-19 hypoxia with one hand tied behind our back: Blanket prohibition of high-flow oxygen and noninvasive positive end-expiratory pressure in US hospitals: Ann Emerg Med, 2020; 75(6); 791-92

43. Han J, Ma S, Sun BContinuous prone position ventilation in patients with severe acute respiratory distress syndrome at high altitude: Zhonghua Wei Zhong Bing Ji Jiu Yi Xue, 2021; 33(2); 161-64 [in Chinese]

44. Du Y, Li Y, Sun RMeta analysis of observing prone position ventilation role in the oxygenation of severe pneumonia patients: Zhonghua Wei Zhong Bing Ji Jiu Yi Xue, 2018; 30(4); 327-31 [in Chinese]

45. Binda F, Galazzi A, Marelli F, Complications of prone positioning in patients with COVID-19: A cross-sectional study: Intensive Crit Care Nurs, 2021; 67; 103088

46. Dirkes S, Dickinson S, Havey R, O’brien D, Prone positioning: Is it safe and effective?: Crit Care Nurs Q, 2012; 35(1); 64-75

47. Wiedemann HP, Wheeler AP, Bernard GRNational Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Comparison of two fluid-management strategies in acute lung injury: N Engl J Med, 2006; 354(24); 2564-75

48. Mendes RS, Pelosi P, Schultz MJ, Fluids in ARDS: More pros than cons: Intensive Care Med Exp, 2020; 8(Suppl 1); 32

49. Chang WT, Hsu CH, Huang TL, MicroRNA-21 is associated with the severity of right ventricular dysfunction in patients with hypoxia-induced pulmonary hypertension: Acta Cardiol Sin, 2018; 34(6); 511-17

50. Paolone S, Extracorporeal membrane oxygenation (ECMO) for lung injury in severe acute respiratory distress syndrome (ARDS): Review of the literature: Clin Nurs Res, 2017; 26(6); 747-62

51. Guo L, Liu Y, Zhang L, Massive airway hemorrhage in severe COVID-19 and the role of endotracheal tube clamping: Infect Drug Resist, 2023; 16; 2387-93

52. Badulak J, Antonini MV, Stead CMELSO COVID-19 Working Group Members, Extracorporeal membrane oxygenation for COVID-19: Updated 2021 guidelines from the Extracorporeal Life Support Organization: ASAIO J, 2021; 67(5); 485-95

53. Chiumello D, Brioni M, Severe hypoxemia: Which strategy to choose: Crit Care, 2016; 20(1); 132

54. Culbreth RE, Goodfellow LT, Complications of prone positioning during extracorporeal membrane oxygenation for respiratory failure: a systematic review: Respir Care, 2016; 61(2); 249-54

55. Kimmoun A, Roche S, Bridey C, Prolonged prone positioning under VV-ECMO is safe and improves oxygenation and respiratory compliance: Ann Intensive Care, 2015; 5(1); 35

56. Luks AM, Grissom CK, Return to high altitude after recovery from coronavirus disease 2019: High Alt Med Biol, 2021; 22(2); 119-27

57. Millet GP, Debevec T, Brocherie F, Altitude and COVID-19: Friend or foe? A narrative review: Physiol Rep, 2021; 8(24); e14615

58. World Health Organization: Clinical management of severe acute respiratory infection when novel coronavirus (nCoV) infection is suspected Available from:WHO/nCoV/clinical/2020.2

59. Qadir N, Chang SY, Pharmacologic treatments for acute respiratory distress syndrome: Crit Care Clin, 2021; 37(4); 877-93

60. Weigelt JA, Norcross JF, Borman KR, Snyder WH, Early steroid therapy for respiratory failure: Arch Surg, 1985; 120(5); 536-40

61. Villar J, Ferrando C, Martínez Ddexamethasone in ARDS network, Dexamethasone treatment for the acute respiratory distress syndrome: A multicentre, randomised controlled trial: Lancet Respir Med, 2020; 8(3); 267-76

62. Tomazini BM, Maia IS, Cavalcanti ABCOALITION COVID-19 Brazil III Investigators, Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: The CoDEX randomized clinical trial: JAMA, 2020; 324(13); 1307-16

63. Lin P, Zhao Y, Li X, Decreased mortality in acute respiratory distress syndrome patients treated with corticosteroids: An updated meta-analysis of randomized clinical trials with trial sequential analysis: Crit Care, 2021; 25(1); 122

64. Annane D, Pastores SM, Rochwerg B, Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017: Crit Care Med, 2017; 45(12); 2078-88

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750