Frontiers in physiology · 2026
End-tidal CO2 responses and ventilatory correlates during voluntary hyperventilation: a repeated-measures pilot study.
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Wang Liping, Xue Lihao, Jia Fenglin, Zhang Huibian, Yu Lihua, Wang GuiYou, Gu Zhao
Аннотация
BACKGROUND: Controlled voluntary hyperventilation is widely used to study the ventilatory control of end-tidal CO2 (PetCO2), but the breath-by-breath determinants of PetCO2 during an externally paced maneuver remain incompletely characterized. This repeated-measures pilot study aimed to describe PetCO2 changes and to quantify associations with ventilatory timing and expired gas output during paced voluntary hyperventilation.
METHODS: Thirty healthy males (age range 19.2-39.8) performed a metronome-paced voluntary hyperventilation maneuver at 30 breaths/min intended to last up to 3 min. Breath-by-breath data were recorded with a COSMED K5 (COSMED, Rome, Italy). After excluding breaths with implausible respiratory frequency, 2,298 breaths from 30 participants were analyzed with a linear mixed model (LMM) using a cubic B-spline for elapsed time, participant-specific random intercepts and random slopes, and fixed effects of minute ventilation (VE), expired CO2 output (VCO2), and expiratory time (Te). A generalized estimating equation (GEE) with AR(1) working correlation was a sensitivity analysis, and participant-level cluster-bootstrap CIs provided the primary inferential intervals.
RESULTS: Participant-level mean PetCO2 during the maneuver was 17.1 ± 1.8 mmHg (range 13.3-21.2 mmHg) and declined over time. In the primary LMM, VE β = -0.144, VCO2 β = 0.009, and Te β = 4.18. Because residual diagnostics showed non-normality, heteroscedasticity, and strong serial autocorrelation (GEE AR(1) alpha approximately 0.79 for the spline model and 0.86 for the linear-time model), cluster-bootstrap CIs are reported as the primary inferential intervals: VE -0.174 to -0.110, VCO2 0.005 to 0.012, Te 2.330 to 6.164, and a predicted PetCO2 change from 0 to 180 s of -8.58 mmHg (95% CI -10.30 to -6.92 mmHg). Marginal R2 = 0.775 and conditional R2 = 0.828; leave-one-participant-out cross-validation yielded R2 = 0.737 and RMSE = 2.52 mmHg.
CONCLUSIONS: PetCO2 during paced hyperventilation was associated with elapsed time, VE, VCO2, and Te. Because VE and VCO2 are algebraically coupled, and VCO2 and PetCO2 also share information from the expired-CO2 signal, they should not be interpreted as independent physiological determinants; the principal contribution is the within-participant expiratory-time association. The findings are exploratory and require confirmation in clinical populations.
METHODS: Thirty healthy males (age range 19.2-39.8) performed a metronome-paced voluntary hyperventilation maneuver at 30 breaths/min intended to last up to 3 min. Breath-by-breath data were recorded with a COSMED K5 (COSMED, Rome, Italy). After excluding breaths with implausible respiratory frequency, 2,298 breaths from 30 participants were analyzed with a linear mixed model (LMM) using a cubic B-spline for elapsed time, participant-specific random intercepts and random slopes, and fixed effects of minute ventilation (VE), expired CO2 output (VCO2), and expiratory time (Te). A generalized estimating equation (GEE) with AR(1) working correlation was a sensitivity analysis, and participant-level cluster-bootstrap CIs provided the primary inferential intervals.
RESULTS: Participant-level mean PetCO2 during the maneuver was 17.1 ± 1.8 mmHg (range 13.3-21.2 mmHg) and declined over time. In the primary LMM, VE β = -0.144, VCO2 β = 0.009, and Te β = 4.18. Because residual diagnostics showed non-normality, heteroscedasticity, and strong serial autocorrelation (GEE AR(1) alpha approximately 0.79 for the spline model and 0.86 for the linear-time model), cluster-bootstrap CIs are reported as the primary inferential intervals: VE -0.174 to -0.110, VCO2 0.005 to 0.012, Te 2.330 to 6.164, and a predicted PetCO2 change from 0 to 180 s of -8.58 mmHg (95% CI -10.30 to -6.92 mmHg). Marginal R2 = 0.775 and conditional R2 = 0.828; leave-one-participant-out cross-validation yielded R2 = 0.737 and RMSE = 2.52 mmHg.
CONCLUSIONS: PetCO2 during paced hyperventilation was associated with elapsed time, VE, VCO2, and Te. Because VE and VCO2 are algebraically coupled, and VCO2 and PetCO2 also share information from the expired-CO2 signal, they should not be interpreted as independent physiological determinants; the principal contribution is the within-participant expiratory-time association. The findings are exploratory and require confirmation in clinical populations.