End-tidal CO2 responses and ventilatory correlates during voluntary hyperventilation: a repeated-measures pilot study.

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.