The normal distribution of the hypoxic ventilatory response and methodological impacts: a meta-analysis and computational investigation.

The hypoxic ventilatory response (HVR) is the increase in breathing in response to reduced arterial oxygen pressure. Over several decades, studies have revealed substantial population-level differences in the magnitude of the HVR as well as significant inter-individual variation. In particular, low HVRs occur frequently in Andean high-altitude native populations. However, our group conducted hundreds of HVR measures over several years and commonly observed low responses in sea-level populations as well. As a result, we aimed to determine the normal HVR distribution, whether low responses were common, and to what extent variation in study protocols influence these findings. We conducted a comprehensive search of the literature and examined the distributions of HVR values across 78 studies that utilized step-down/steady-state or progressive hypoxia methods in untreated, healthy human subjects. Several studies included multiple datasets across different populations or experimental conditions. In the final analysis, 72 datasets reported mean HVR values and 60 datasets provided raw HVR datasets. Of the 60 datasets reporting raw HVR values, 35 (58.3%) were at least moderately positively skewed (skew > 0.5), and 21 (35%) were significantly positively skewed (skew > 1), indicating that lower HVR values are common. The skewness of HVR distributions does not appear to be an artifact of methodology or the unit with which the HVR is reported. Further analysis demonstrated that the use of step-down hypoxia versus progressive hypoxia methods did not have a significant impact on average HVR values, but that isocapnic protocols produced higher HVRs than poikilocapnic protocols. This work provides a reference for expected HVR values and illustrates substantial inter-individual variation in this key reflex. Finally, the prevalence of low HVRs in the general population provides insight into our understanding of blunted HVRs in high-altitude adapted groups. KEY POINTS: The hypoxic ventilatory response (HVR) plays a crucial role in determining an individual's predisposition to hypoxia-related pathologies. There is notable variability in HVR sensitivity across individuals as well as significant population-level differences. We report that the normal distribution of the HVR is positively skewed, with a significant prevalence of low HVR values amongst the general healthy population. We also find no significant impact of the experimental protocol used to induce hypoxia, although HVR is greater with isocapnic versus poikilocapnic methods. These results provide insight into the normal distribution of the HVR, which could be useful in clinical decisions of diseases related to hypoxaemia. Additionally, the low HVR values found within the general population provide insight into the genetic adaptations found in populations residing in high altitudes.

Inflammatory gene expression during acute high-altitude exposure.

The molecular signalling pathways that regulate inflammation and the response to hypoxia share significant crosstalk and appear to play major roles in high-altitude acclimatization and adaptation. Several studies demonstrate increases in circulating candidate inflammatory markers during acute high-altitude exposure, but significant gaps remain in our understanding of how inflammation and immune function change at high altitude and whether these responses contribute to high-altitude pathologies, such as acute mountain sickness. To address this, we took an unbiased transcriptomic approach, including RNA sequencing and direct digital mRNA detection with NanoString, to identify changes in the inflammatory profile of peripheral blood throughout 3 days of high-altitude acclimatization in healthy sea-level residents (n = 15; five women). Several inflammation-related genes were upregulated on the first day of high-altitude exposure, including a large increase in HMGB1 (high mobility group box 1), a damage-associated molecular pattern (DAMP) molecule that amplifies immune responses during tissue injury. Differentially expressed genes on the first and third days of acclimatization were enriched for several inflammatory pathways, including nuclear factor-κB and Toll-like receptor (TLR) signalling. Indeed, both TLR4 and LY96, which encodes the lipopolysaccharide binding protein (MD-2), were upregulated at high altitude. Finally, FASLG and SMAD7 were associated with acute mountain sickness scores and peripheral oxygen saturation levels on the first day at high altitude, suggesting a potential role of immune regulation in response to high-altitude hypoxia. These results indicate that acute high-altitude exposure upregulates inflammatory signalling pathways and might sensitize the TLR4 signalling pathway to subsequent inflammatory stimuli. KEY POINTS: Inflammation plays a crucial role in the physiological response to hypoxia. High-altitude hypoxia exposure causes alterations in the inflammatory profile that might play an adaptive or maladaptive role in acclimatization. In this study, we characterized changes in the inflammatory profile following acute high-altitude exposure. We report upregulation of novel inflammation-related genes in the first 3 days of high-altitude exposure, which might play a role in immune system sensitization. These results provide insight into how hypoxia-induced inflammation might contribute to high-altitude pathologies and exacerbate inflammatory responses in critical illnesses associated with hypoxaemia.

Changes in hypoxic and hypercapnic ventilatory responses at high altitude measured using rebreathing methods.

Ventilatory responses to hypoxia and hypercapnia play a vital role in maintaining gas exchange homeostasis, and in adaptation to high-altitude environments. This study investigates the mechanisms underlying sensitization of hypoxic and hypercapnic ventilatory responses (HVR and HCVR, respectively) in individuals acclimatized to moderate high altitude (3800 m). Thirty-one participants underwent chemoreflex testing using the Duffin modified rebreathing technique. Measures were taken at sea level and after 2 days of acclimatization to high altitude. Ventilatory recruitment thresholds (VRT), HCVR, and HVR were quantified. Acclimatization to high altitude resulted in increased HVR (p<0.001) and HCVR (p<0.001), as expected. We also observed that the decrease in VRT under hypoxic test conditions significantly contributed to the elevated HVR at high altitude since the change in VRT across hyperoxic and hypoxic test conditions was greater at high altitude compared to baseline sea level tests (p=0.043). Pre-VRT ventilation also increased at high altitude (p<0.001), but the change did not differ between oxygen conditions. Taken together, this data suggests that the increase in HVR at high altitude is at least partially driven by a larger decrease in the VRT in hypoxia versus hyperoxia at high altitude compared to sea level. This study highlights the intricacies of respiratory adaptations during acclimatization to moderate high altitude, shedding light on the roles of the VRT, baseline respiratory drive, and two-slope HCVR in this process. These findings contribute to our understanding of how the human respiratory control responds to hypoxic and hypercapnic challenges at high altitude.

Improvements in sleep-disordered breathing during acclimatization to 3800 m and the impact on cognitive function.

Sojourners to high altitude often experience poor sleep quality due to sleep-disordered breathing. Additionally, multiple aspects of cognitive function are impaired at high altitude. However, the impact of acclimatization on sleep-disordered breathing and whether poor sleep is a major contributor to cognitive impairments at high altitude remains uncertain. We conducted nocturnal actigraphy and polygraphy, as well as daytime cognitive function tests, in 15 participants (33% women) at sea level and over 3 days of partial acclimatization to high altitude (3800 m). Our goal was to determine if sleep-disordered breathing improved over time and if sleep-disordered breathing was associated with cognitive function. The apnea-hypopnea index and oxygen desaturation index increased on night 1 (adj. p = 0.026 and adj. p = 0.026, respectively), but both improved over the subsequent 2 nights. These measures were matched by poorer self-reported sleep quality on the Stanford Sleepiness Scale and PROMIS questionnaires following 1 night at high altitude (adj. p = 0.027 and adj. p = 0.022, respectively). The reaction time on the psychomotor vigilance task was slower at high altitude and did not improve (SL: 199 ± 27, ALT1: 224 ± 33, ALT2: 216 ± 41, ALT3: 212 ± 27 ms). The reaction times on the balloon analog risk task decreased at high altitude (SL: 474 ± 235, ALT1: 375 ± 159, ALT2: 291 ± 102, ALT3: 267 ± 90 ms), perhaps indicating increased risk-taking behavior. Finally, multiple cognitive function measures were associated with sleep-disordered breathing and measures of subjective sleep quality, rather than low daytime arterial oxygen saturation. These data indicate that sleep-disordered breathing at moderately high altitude improves with partial acclimatization and that some aspects of cognitive performance in unacclimatized sojourners may be impacted by poor sleep rather than hypoxemia alone.