End-tidal CO2 changes during short breath-hold maneuvers: Variability, paradigm effects, and spirometric correlates

Breath-hold functional MRI (bh-fMRI) is a widely used method for mapping cerebrovascular reactivity (CVR). Normalization of BOLD signal changes to end-tidal CO₂ changes (Δp et CO₂) is suggested to improve between-subject comparability. The aim was to characterize magnitude and variability of Δp et CO₂ during short breath-hold maneuvers. Twenty healthy volunteers participated in this study. Ten of these participants performed five breathing paradigms: baseline breathing, and end-expiratory breath-holds of 6, 9, and 12 s, as well as a deep breathing maneuver, each repeated seven times. p et CO₂ was recorded continuously via nasal cannula. Within- and between-subject variability were quantified using the coefficient of variation (CV). Differences in Δp et CO₂ between paradigms were assessed using repeated-measures ANOVA. Ten additional participants underwent the 9 s breath-hold paradigm and spirometry; associations between Δp et CO₂ and pulmonary volumes, age, and baseline p et CO₂ were assessed using Pearson correlation. Within-subject within-paradigm CVs were low (3.4-4.7%), indicating high reproducibility. Between-subject CVs were substantially higher (19.7-35.3%). Δp et CO₂ differed significantly between the 6 and 9 s paradigms (p = 0.014, p FDR = 0.017) but not between the 9 and 12 s paradigms (p = 0.209, p FDR = 0.209). The deep breathing induced a reproducible p et CO₂ decrease. A very strong inverse correlation was observed between Δp et CO₂ and inspiratory vital capacity (IVC) (r = -0.797 (95%CI: -0.950–-0.336), p = 0.006, p FDR = 0.030). Short breath-hold maneuvers induce reproducible, yet variable CO₂ responses within individuals. Pulmonary anatomy is a key determinant of Δp et CO₂. Inadvertent deep breathing prior to breath-holding may induce p et CO₂ decreases of non-negligible magnitude, with potential implications for bh-fMRI interpretation.