The exhausting work of acclimating to chronically elevated CO₂

Carbon dioxide (CO2) is the exhaust of life. The inability to clear this metabolic waste can have serious consequences for health. Accumulating CO2 from metabolism is normally eliminated from tissue (CO2 source) by (a) increases in blood flow, washing it out to venous blood, and (b) increases in alveolar ventilation, eliminating it from venous blood to the atmosphere (CO2 sink). Respiratory chemoreflexes in response to increases in CO2/H+ are mediated by (a) peripheral (carotid body) chemoreceptors, which detect CO2/H+ in an oxygen-dependent manner and (b) central (brainstem) chemoreceptors; the latter normally dominate the CO2/H+ responsiveness in normoxic conditions. Elimination of metabolically derived CO2 is critically important to air breathing organisms. Due to its relatively high solubility in body fluids, CO2 retention represents a challenge for acid–base homeostasis, which is maintained in concert by the respiratory and renal systems (Zouboules et al. 2018). Reductions in blood CO2 can be brought about experimentally through voluntary or involuntary hyperventilation, where the elimination of CO2 is in excess of the metabolic rate (e.g. poikilocapnic hypoxic ventilatory response; HVR), and acute respiratory alkalosis results. Conversely, increases in blood CO2 can result from reduced elimination from chronic lung disease (reduction in the diffusing capacity of the lungs), or experimentally, through breath holding, rebreathing, or increases in ambient inspired CO2. In 1963, Karl Schaefer and colleagues explored acclimation to chronic CO2 by exposing 21 participants to an elevated ambient CO2 over 42 days in a submarine as a part of 'Operation Hideout' (Schaefer et al. 1963). Participants were confined in a submarine compartment where they breathed a fraction of inspired (FI) CO2 () and equivalent to atmospheric air for nine days (i.e. 0.0004 (0.04%) and 0.21 (21%)), followed by a 42-day period of exposure to an ambient of 0.015 (1.5%) in normoxia (i.e. normobaric normoxic hypercapnia). Their results demonstrated a mild but significant increase in the pressure of alveolar CO2 () and ventilation during the CO2 exposure period, which persisted throughout the subsequent 9-day recovery. Using venous pH measures, they observed full renal compensation to respiratory acidosis by 24 days, which was associated with a concomitant reduction in ventilation from the initial hypercapnic ventilatory response. Although their study was relevant in magnitude and duration to a potential occupational or environmental stressor, they did not make measurements of arterial blood gases and electrolytes (only venous CO2 and pH), representing a major limitation in understanding the integrated cardiorespiratory and renal responses to chronically elevated ambient CO2. In a recent paper in The Journal of Physiology, Nicholas Burgraff and colleagues published a study where they exposed chronically instrumented goats to an increased over 30 days (Burgraff et al. 2018). Following a control period, goats were confined to a chamber and exposed to either room air or an of 0.06 (6%) in normoxia for 30 consecutive days. Similar to Schaefer et al., but larger in magnitude, systemic hypercapnia and respiratory acidosis were imposed, with a concomitant steady-state increase in ventilation that was partly attenuated as a compensatory metabolic alkalosis resulted through renal tubular reabsorption of bicarbonate and subsequent increases in arterial bicarbonate ([HCO3−]a). Interestingly, although chronic inspired 0.015 (1.5%) resulted in full acid–base acclimatization (Schaefer et al. 1963), when the hypercapnic stimulus was higher by a factor of ∼4, full compensation was not achieved, even after 30 days, likely due to the relatively higher magnitude of the hypercapnic/acidotic stimulus (Burgraff et al. 2018). In addition, Burgraff et al. (2018) demonstrated sustained reductions in cognitive performance throughout the 30 days of hypercapnia, and a larger-than-predicted steady-state ventilation, suggesting a dissociation between steady-state ventilation and the CO2/H+ chemoreflex. From an occupational and environmental physiology perspective, much of the work around acclimation/acclimatization to chronic blood gas challenges has been focused on normobaric or hypobaric hypoxia. Aside from the large body of work on high altitude natives, trekkers and climbers, John West recently advanced the principle of oxygen conditioning in public spaces for high altitude dwellers (e.g. schools, hospitals), to stave off the risks of mountain sickness, and to reverse the cognitive decline associated with chronic hypoxia (West, 2015). The question of acclimation to chronically elevated CO2 has not been investigated systematically for decades. Understanding the responses to chronically elevated CO2 is relevant to a number of occupational, recreational and environmental stressors, including hibernating mammals, scuba divers, trapped cavers and miners, submariners and astronauts on the international space station (ISS). For example, due to limitations in CO2 scrubbing technology, astronauts on the ISS are chronically exposed to 0.005–0.008 (0.5–0.8%), ∼10–20 times higher than earth, with allowable transient (∼1 h) increases in as high as 0.02 (2%; Law et al. 2014). Although the ISS may be decommissioned soon, lessons learned there, and from longitudinal studies like Schaefer et al. (1963) and Burgraff et al. (2018), will have future utility for the Lunar Orbital Platform-Gateway, set to be built in lunar orbit in 2022, with the first crewed mission in 2024. Similar to the HVR-mediated hypocapnia and the resulting respiratory alkalosis associated with high altitude ascent (e.g. Forster et al. 1975; Zouboules et al. 2018), exposure to chronic elevated CO2 also has acid–base implications, albeit in the opposite direction (see Fig. 1). Importantly, Burgraff et al. (2018) remind us that there are more integrated responses to chronically altered CO2 than merely respiratory chemoreflexes, as renal compensations are elicited to protect acid–base balance, albeit over a slower temporal domain. After as little as 6 h, primary respiratory disturbances (i.e. changes in CO2) are countered by renal compensations. With chronically elevated CO2, respiratory acidosis results from CO2 accumulation, and a compensatory relative metabolic alkalosis results, as the renal tubules reabsorb HCO3− and eliminate H+, as illustrated in the study by Burgraff et al. (2018). Comparison of integrated responses to chronic hypo- vs. hypercapnia Left column (A, C, E, G, I), chronic hypoxia-mediated hypocapnia (open circles; dashed lines are speculative extrapolations). Right column (B, D, F, H, J), chronic inspired hypercapnia (filled circles). A, chronic hypoxia, ∼4000 m: 0.21 and 0.0004; Patm 475 mmHg; 90 Torr (circles) and 0.2 Torr (squares). B, chronic normoxic hypercapnia, sea level: 0.21 and 0.03; Patm 760 mmHg; ∼150 Torr (circles) and 21 mmHg (squares). Note that and values here are corrected for airway temperature and humidification ( × (Patm – 47 mmHg)). C and D, long-term ventilatory responses to chronic hypoxia (C; leading to chronic hypocapnia in E) and chronic inspired hypercapnia (D). E and F, chronic arterial hypocapnia (E) and hypercapnia (F), representing primary respiratory acid–base disturbances (i.e. changes in ). G and H, primary respiratory disturbances (alkalosis or acidosis) are countered by secondary renal compensations (relative acidosis or alkalosis, respectively), through renal excretion of HCO3− (G) or renal reabsorption of HCO3− (H), affecting arterial [HCO3−] accordingly. I and J, renal compensations bring arterial pH back toward normal values. Note that with respect to stimulus–response relationships, hypocapnia (left column) results from hypoxic ventilatory response-mediated hyperventilation, which is itself attenuated as a new hypocapnic steady-state is achieved. Conversely, elevated ambient CO2 (hypercapnia; right column) causes an increase in ventilation (respiratory CO2 chemoreflex). Renal compensations (reflected as alterations in arterial [HCO3−]) follow respiratory disturbances (alterations in ), bringing arterial pH levels back toward baseline values. Surprisingly, the literature on arterial blood gases and acid–base in response to chronic and prolonged hypo- and hypercapnia in humans is scant (e.g. Forster et al. 1975). Thus, our integrative illustrations of idealized responses to chronic CO2 perturbations (see Fig. 1), guided by data from Forster et al. (1975) and Zouboules et al. (2018) (for hypoxic hypocapnia) and Schaefer et al. (1963) and Burgraff et al. (2018) (for relative hypercapnia), are largely speculative. However, the stimuli and responses illustrated are instructive toward an integrative understanding of chronic acid–base perturbations. Although the recent study by Burgraff et al. (2018) appears to be the most comprehensive to date on longitudinal and integrative responses to chronic elevated CO2, their model system (goats) and magnitude of stressor ( 0.06) may not be directly applicable to human occupational and environmental stressors. However, this excellent study illuminates a comprehensive integrative perspective and opens new avenues for research regarding chronic respiratory and acid–base disturbances. None declared. Both authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. This work is supported by a Natural Sciences and Engineering Research Council of Canada Discovery grant (Grant no. RGPIN-2016-04915). We wish to thank the editors and staff at the Journal of Physiology for allowing us to write this Perspective.

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