Steady-state chemoreflex drive captures ventilatory acclimatization during incremental ascent to high altitude: Effect of acetazolamide

Abstract

Ventilatory acclimatization (VA) is important to maintain adequate oxygenation with ascent to high altitude (HA). Transient hypoxic ventilatory response tests lack feasibility and fail to capture the integrated steady-state responses to chronic hypoxic exposure in HA fieldwork. We recently characterized a novel index of steady-state respiratory chemoreflex drive (SSCD), accounting for integrated contributions from central and peripheral respiratory chemoreceptors during steady-state breathing at prevailing chemostimuli. Acetazolamide is often utilized during ascent for prevention or treatment of altitude-related illnesses, eliciting metabolic acidosis and stimulating respiratory chemoreceptors. To determine if SSCD reflects VA during ascent to HA, we characterized SSCD in 25 lowlanders during incremental ascent to 4240 m over 7 days. We subsequently compared two separate subgroups: no acetazolamide (NAz; n = 14) and those taking an oral prophylactic dose of acetazolamide (Az; 125 mg BID; n = 11). At 1130/1400 m (day zero) and 4240 m (day seven), steady-state measurements of resting ventilation (V̇_I ; L/min), pressure of end-tidal (P_ET )CO₂ (Torr), and peripheral oxygen saturation (SpO₂ ; %) were measured. A stimulus index (SI; P_ET CO₂ /SpO₂ ) was calculated, and SSCD was calculated by indexing V̇_I against SI. We found that (a) both V̇_I and SSCD increased with ascent to 4240 m (day seven; V̇_I : +39%, p < 0.0001, Hedges' g = 1.52; SSCD: +56.%, p < 0.0001, Hedges' g = 1.65), (b) and these responses were larger in the Az versus NAz subgroup (V̇_I : p = 0.02, Hedges' g = 1.04; SSCD: p = 0.02, Hedges' g = 1.05). The SSCD metric may have utility in assessing VA during prolonged stays at altitude, providing a feasible alternative to transient chemoreflex tests.

Keywords: acetazolamide; acid-base; carbonic anhydrase inhibitor; high altitude; hypoxic ventilatory response; novel methodology; renal compensation; respiratory chemoreflexes; steady-state chemoreflex drive; ventilatory acclimatization.

FIGURE 1

Ventilatory acclimatization with ascent to 4240 m over 7 days in the combined participant group (n = 25). (a) Minute ventilation (V̇_I) prior to (1130/1400 m and following ascent to 4240 m. (b) Steady‐state chemoreflex drive (SSCD) prior to and following ascent to 4240 m. Individual participants (gray circles) are connected for within‐individual comparisons. Gray dash and error bars represent mean (values reported on graph) and standard deviation. Individual p‐values are reported on each graph, where p < 0.05 denotes statistical difference from baseline (1130/1400 m). ES, effect size calculated via Hedges' g.

FIGURE 2

Ventilatory acclimatization before and after ascent to 4240 m over 7 days without and with prophylactic oral acetazolamide. (a) Minute ventilation (V̇_I) prior to (1130/1400 m) and following ascent to 4240 m in the no acetazolamide (NAz) group (n = 14). (b) Steady‐state chemoreflex drive (SSCD) prior to and following ascent to 4240 m in the NAz group (n = 14). (c) Minute ventilation (V̇_I) prior to and following ascent to 4240 m in the acetazolamide (Az) group (n = 11). (d) SSCD prior to and following ascent to 4240 m in the Az group (n = 11). White circles, individual participants in the NAz group (panels a and b). Black circles, individual participants in the Az group (panels c and d). Individual participants are connected for within‐individual comparisons.

FIGURE 3

Comparison of participants with and without oral acetazolamide in metrics of ventilatory acclimatization following ascent to 4240 m over 7 days. (a) Comparison of delta V̇_I (4240–1400 m) between no acetazolamide (NAz; n = 14) and acetazolamide (Az; n = 11) subgroups with ascent. (b) Comparison of delta SSCD between NAz and Az subgroups with ascent. (c) Comparison of absolute minute ventilation (V̇_I) following ascent to 4240 m in the NAz; versus Az subgroups. (d) Comparison of absolute steady‐state chemoreflex drive (SSCD) following ascent to 4240 m in the versus Az subgroups. These participants in a–c are from those that were compared with 1130/1400 m (i.e., before and after ascent; n = 25; see Figures 1 and 2). (e) Comparison of absolute minute ventilation (V̇_I) following ascent to 4240 m in the no acetazolamide (NAz; n = 22) versus acetazolamide (Az; n = 12) groups. (d) Comparison of absolute steady‐state chemoreflex drive (SSCD) following ascent to 4240 m in the no acetazolamide (NAz; n = 22) versus acetazolamide (Az; n = 12) groups. In (e and f), these values are from every available participant measurement made at 4240 m (n = 34). White circles, individual participants in the NAz group. Black circles, individual participants in the Az group. Dash and error bars represent mean and standard deviation (values reported on graph). Individual p‐values and effect sizes (ES) are reported on each graph, where p < 0.05 denotes a statistical difference between NAz and Az groups. ES, effect size calculated via Hedges' g.