The syndromic definition of Acute Respiratory Distress Syndrome (ARDS) encapsulates a spectrum of pulmonary physiological abnormalities and chest radiographic findings. Furthermore, it involves variations in biological pathways of injury, supported by evidence from plasma protein biomarkers and gene expression profiles (Force et al., 2012). In the low-altitude Intensive Care Unit (ICU) settings (ranging from 0 to 1,500 m), the clinical outcomes of ARDS patients requiring invasive mechanical ventilation primarily rely on the effectiveness of ventilatory support (Rubenfeld et al., 2005; Bellani et al., 2016). Inadequate respiratory variables, associated to partial arterial oxygen pressure (PaO₂) to fraction of inspired oxygen (Fio2) ratio often correlates with elevated mortality rates in such cases (Rubenfeld et al., 2005; Bellani et al., 2016). Various indicators predictive of progression towards a fatal outcome include parameters such as the Partial Pressure of Arterial Oxygen to Fraction of Inspired Oxygen ratio (PAFI), the Saturation of Arterial Oxygen to Fraction of Inspired Oxygen ratio (SAFI), as well as scores derived from the Sequential Organ Failure Assessment (SOFA) and Acute Physiology and Chronic Health Evaluation (APACHE) systems, all of which serve as respiratory indices. Additionally, markers of inflammation, including cytokine levels and C-reactive protein (CRP) levels, are integral in discerning the clinical trajectory of ARDS patients (Calfee et al., 2015; Ortiz et al., 2022).

At elevations exceeding 2,500 m (high altitude), a reduction in barometric pressure (BP) results in approximately one-third reduction in PaO₂. Despite this, more than 150 million people worldwide reside above high altitude (Arias-Reyes et al., 2021a; Zubieta-DeUrioste et al., 2023). Furthermore, prominent urban centers in Latin America, like La Paz (Bolivia), Quito (Ecuador), Bogotá (Colombia), and Mexico City (Ciudad de México, Mexico), are situated at high altitudes and collectively house more than 38,181,350 people (Zubieta-DeUrioste et al., 2023).

To counteract the reduced PaO₂ levels to which permanent high-altitude residents are exposed, physiological, cellular, and molecular adaptations occur to maintain the balance between oxygen supply and demand (Arias-Reyes et al., 2021a). These adjustments primarily involve increased ventilation (regulated by the respiratory control system and carotid bodies), erythropoiesis-mediated rise in red blood cell count (Soliz et al., 2005; Zubieta-Calleja et al., 2007), generalized vasodilation, and angiogenesis (regulated by vascular endothelium angiogenetic factors) (Scheinfeldt and Tishkoff, 2010). These significant physiological differences between residents at sea-level and those at high-altitudes raise concerns about the appropriateness and safety of applying guidelines that do not consider high-altitude ICU settings. In fact, given that PaO₂ levels of 50–67 mmHg and peripheral oxygen saturation (SatpO₂) of 89%–95% are considered normoxemic values in permanent high-altitude residents (Viruez-Soto et al., 2022; Viruez-Soto et al., 2020), current high-altitude medical guidelines lack specific markers conducive to reducing the high mortality rate, approximately 50% of ARDS patients in the ICU (Arias Ramos et al., 2022). Hence, in this study, we analyzed respiratory, hematological, inflammatory, and comorbidity clinical data of ICU patients diagnosed with ARDS from Bogotá, Colombia, and El Alto, Bolivia, located 2,640 and 4,150 m above sea level, respectively. The aim was to identify clinical markers that could facilitate a more effective therapeutic approach and improve survival outcomes. Our findings strongly suggest that in high-altitude settings, ICU survival among ARDS patients primarily depends on monitoring inflammatory parameters rather than respiratory failure. By prioritizing monitoring of inflammatory markers, there is potential to significantly improve survival rates in these settings. These results emphasize the necessity of redefining high-altitude pathophysiology, especially in ICUs, where a comprehensive understanding is vital for patient survival.

An ambispective cohort study was carried out in patients admitted to the ICU with a diagnosis of ARDS in two third-level hospitals located in Colombia and Bolivia: University Hospital San José de Bogotá (Altitude: 2,640 m above sea level) and University Hospital Agramont from El Alto city in Bolivia (Altitude: 4,150 m above sea level). Data collection spanned retrospectively from April 2022 to April 2023 and prospectively from April to June 2023, extracted from electronic medical records covering the hospitalization period. The study was conducted using data collected from the initial day of ICU admission until the patient’s death or discharge from the ICU, with a maximum follow-up period of 28 days after admission. Obtaining post-discharge records was not considered due to difficulty in maintaining contact with discharged patients. The protocol for this study, numbered 691–2023, was approved by the Ethical Committee of Hospital San Jose and the Hospital Agramont.

In this research, we performed a comparative analysis aimed at identifying clinical characteristics that impact the survival rates of intensive care unit (ICU) patients residing in two high-altitude regions: Bogotá, Colombia, located at an elevation of 2,640 m above sea level, and El Alto, Bolivia, located at an altitude of 4,150 m above sea level. The main findings of our study can be summarized as follows: first, C-reactive protein (CRP) emerges as the most reliable prognostic indicator for survival outcomes or mortality rates among ARDS ICU patients at high altitudes, with leukocytes, lymphocytes, basophils, neutrophils, and APACHE II score ranking second in relevance as significant indicators; second, respiratory and oxygenation parameters, such as PaO2/FiO2 or SaO2/FiO2 do not show an association with increased mortality in our study; third, no significant differences were found in this study depending on the altitude tested (2,640 and 4,150 m); fourth, no significant differences were found in this study depending on sex. Together, these results underscore the critical importance of revisiting existing guidelines for high-altitude ICUs, as they have been derived from settings that have not considered individuals who are adapted to permanent exposure to barometric hypoxia above 2,500 m.

Despite the compelling clinical significance uncovered by this study, which reveals the greater resilience of high-altitude permanent residents who are ICU patients with ARDS to hypoxic conditions, the findings are not surprising (Guo et al., 2023; Molano-Franco et al., 2023). Indeed, it is widely described in the scientific literature that chronic exposure to altitude hypoxia shapes intricate physiological, cellular, and molecular adaptations that allow gas exchange balance to be maintained (Horscroft et al., 2017; Mallet et al., 2023; Moore, 2017; Storz, 2021; Arias-Reyes et al., 2021b; Jochmans-Lemoine et al., 2018). In fact, it is these alterations that have facilitated successful human colonization of high-altitude regions (Zubieta-DeUrioste et al., 2023). However, these findings propel us into an area of opportunity, poised to revolutionize clinical care practices not only in high-altitude environments but also in sea-level hospitals. Indeed, the recalibration of guidelines designed specifically for high-altitude hospitals, with a special focus on improving inflammatory parameters, promises to substantially mitigate the persistently high mortality rates observed in ICU patients with ARDS. In parallel, investigating deeper into the intricate cellular and molecular mechanisms that underpin the greater resistance to hypoxia of high-altitude residents reveals an opportunity for possible new therapeutic strategies that may also be useful for sea-level ICU patients. In this context, erythropoietin deserves to be mentioned, a drug highly used in the clinic due to its safety and effectiveness (Ehrenreich et al., 2020; Jelkmann and Jelkmann, 2013). Indeed, erythropoietin, in addition to its erythropoietic property, is known to promote increased ventilation in hypoxic environments through direct interaction with brainstem centers that regulate ventilation (Soliz et al., 2005; Ballot et al., 2015; Soliz et al., 2009). Furthermore, we also know now that erythropoietin has anti-inflammatory, antioxidant, and angiogenic properties (Arcasoy, 2008; Nekoui and Blaise, 2017). In line, recent studies from our research group have shown a direct correlation between decreased serum erythropoietin levels and increased risk of mortality among high-altitude ICU patients with COVID-19 (Viruez-Soto et al., 2021). On the other hand, it is imperative to point out that scant attention is still being paid to unraveling the intricate mitochondrial adaptations generated by permanent residence at high altitudes. Adaptation to hypobaric hypoxia orchestrates the regulation of mechanisms that range from the modulation of oxidative stress, the regulation of inflammation, metabolic recalibration, and cellular differentiation to intercellular communication (Lee et al., 2020). Indeed, our previous investigations showed a striking contrast in mitochondrial efficiency between the liver and brain of mice (mammals adapted to high altitude) versus rats (mammals nonexistent above 2,500 m) (Arias-Reyes et al., 2021b; Arias-Reyes et al., 2023). Ultimately, a comprehensive investigation into the intricate cellular and molecular mechanisms, including the activation of hypoxia-inducible factors, enhancement of inflammatory responses, and reversal of mitochondrial dysfunction, which underpin the heightened resistance to hypoxia, is imperative (Rybnikova and Lukyanova, 2023).

A fascinating aspect of our research is the striking similarity of patient outcomes between altitudes of 2,650 m (Bogotá) and 4,150 m (El Alto). Surprisingly, despite the different altitudes, the physiological, cellular, and molecular adaptations induced by hypobaric hypoxia at these elevations appear to confer comparable benefits in terms of resistance to the complications of respiratory distress in ICU settings. Indeed, our data reveal that ICU patients with ARDS, regardless of altitude, exhibited elevated levels of C-reactive protein (CRP) and significant alterations in the levels of leukocytes, lymphocytes, basophils, and neutrophils among those who died from the condition. Based on these findings, it is tempting to speculate that individuals living at altitudes, whether healthy or sick, might be more susceptible to inflammation-induced injuries compared to those living at sea level. In fact, it has been suggested that acute mountain sickness, the etiology of which is still poorly understood, may be due to underlying inflammatory processes that are difficult to detect (Julian et al., 1985). In line with this, prescriptions of aspirin and ibuprofen have proven effective in preventing this condition (Burtscher et al., 1998; Xiong et al., 2017). Similarly, it has been suggested that chronic mountain sickness (a disease unique to high-altitude populations characterized by excessive erythrocytosis) may have its roots in inflammatory dysregulations that are challenging to identify (Villafuerte and Corante, 2016). Indeed, it is known that acetazolamide, used to prevent the progression of chronic mountain sickness, also has anti-inflammatory properties (Li et al., 2018; Shukralla et al., 2022).

This study had the inherent limitations of an observational cohort study, along with the conditions mentioned below. Although several respiratory parameters were assessed during the critical first 24 h of ICU admission, more detailed data on ventilatory mechanics are necessary to integrate both inflammatory and granular ventilatory variables. Such integration would provide a more comprehensive understanding of ARDS pathophysiology and its impact on patient outcomes. Additionally, the size of high-altitude hospitals presents challenges in recruiting large cohorts of patients. Despite this obstacle, our study successfully enrolled 52 patients in Bogotá and 18 patients in El Alto. Additionally, these pioneering efforts are expected to raise awareness among physicians and patients about the need to establish altitude-specific pathophysiological guidelines. We also anticipate that this work will promote greater participation in scientific studies from other hospital centers in the near future, improving the richness and integrity of our findings. It is also worth mentioning that the consistency of our study’s results in two hospital centers in different countries and altitudes supports the robustness of our conclusions.

Our study focused only on patients with ARDS and did not cover other potential etiologies. However, we anticipate that future research will delve deeper into these associated pathologies, increasing our understanding of the pathophysiology of high-altitude ICU patients.

Additional parameters, such as PEEP, lung mechanics, and duration of mechanical ventilation, were not thoroughly investigated in this study. Consequently, the mechanical ventilation strategy adopted in the two hospitals must account for altitude variances and the patient’s initial condition, including pulmonary hypertension and right ventricular function. This strategy should encompass low tidal volume, limitation of plateau pressure, and appropriate PEEP levels to minimize pulmonary stress, enhance PaO₂ to counteract hypoxic pulmonary vasoconstriction, and mitigate hypercapnia. Hence, further exploration of these parameters is essential to discern their significance in high-altitude ICU settings and refine our approach to patient care within such environments.

In conclusion, the upcoming update of ARDS diagnostic and treatment criteria promises greater relevance and usefulness in the clinical setting. Indeed, this study shows that alterations in specific inflammatory markers are strongly associated with increased mortality, while oxygenation variables, including PaO2/FiO2 and SaO2/FiO2, do not show a significant correlation with mortality risk. These findings highlight the importance of focusing on inflammatory parameters when assessing prognosis in ARDS, particularly in high-altitude settings. This study is significant as it represents a pioneering initiative among high-altitude clinicians to identify critical clinical parameters that predict mortality or survival in patients with ARDS in high-altitude ICU settings. Looking ahead, with ongoing advancements in medical research, our findings underscore the necessity for more comprehensive studies to validate the direct impact of monitoring inflammatory parameters on patient survival. These findings will undoubtedly contribute to improving and refining existing medical protocols within high-altitude ICU facilities, addressing the unique challenges posed by the considerable resistance to hypoxia observed in the permanent inhabitants of these regions.