Reproducibility of the Hypercapnic Ventilatory Response Using Fixed Inspired Carbon Dioxide Levels in Healthy Men and Women

Background: The hypercapnic ventilatory response (HCVR), a measure of respiratory chemosensitivity, varies markedly between individuals and can be assessed using rebreathing, end-tidal forcing, or fixed inspired CO 2 methods. Data establishing the reproducibility of the HCVR using fixed inspired CO 2 levels remain scarce. Purpose: To evaluate the reproducibility of the HCVR and ventilatory responses to fixed inspired CO 2 in healthy men and women. We hypothesized that the HCVR determined using fixed inspired CO 2 levels would be highly reproducible between two study visits. Methods: Twenty-two healthy adults (10M/12F; age: 28 ± 7 yrs; height: 169 ± 9 cm; body mass: 71 ± 11 kg) completed a graded CO 2 exposure protocol on two separate days. Trials were scheduled based on volunteer availability, without controlling for the female volunteers’ menstrual phase. During each trial, subjects breathed increasing levels of inspired CO 2 in a stepwise manner (0%, 2%, 4%, 6%, and 8% CO 2 ; all with 21% oxygen) during successive 12-min stages. Expired air was collected via a metabolic cart and analyzed for minute ventilation (V E ). End-tidal CO 2 (PETCO 2 ) was continually measured using an infrared CO 2 analyzer. Data were averaged over the last 5 min of each stage. Four subjects (1M/3F) were unable to complete the 8% stage due to lightheadedness or breathing discomfort. HCVR was therefore calculated as the slope of V E vs PETCO 2 from 0 to 6% inspired CO 2 . Reproducibility was assessed using coefficient of variation (CV) and intraclass correlation coefficients (ICC) presented with 95% confidence intervals. Results: HCVR was highly reproducible between study visits (CV: 13.5% [10.3-19.9%]; ICC: 0.89 [0.75-0.95]). Notably, reproducibility of HCVR was similar in men (CV: 14.7% [9.9-28.4%]; ICC: 0.86 [0.50-0.97]) and women (CV: 12.1% [8.5-21.5%]; ICC: 0.88 [0.63-0.97]), despite lack of control for menstrual phase. Across inspired CO 2 concentrations, PETCO 2 exhibited CVs between 0.8% [0.6-1.2%] and 3.6% [2.8-5.2%] and ICCs between 0.65 [0.26-0.86] and 0.90 [0.76-0.96] while V E exhibited CVs between 6.9% [5.3-10.0%] and 9.7% [7.2-14.8%] and ICCs between 0.59 [0.23-0.81] and 0.89 [0.75-0.95]. Notably, at 8% inspired CO 2 , the range (64-68 mmHg) and CV (0.8% [0.6-1.2%]) for PETCO 2 were very low, despite a much larger range (35-97 L min -1 ) and CV (9.7% [7.2-14.8%]) for V E . Conclusion: These data indicate that the assessment of respiratory chemosensitivity using fixed inspired CO 2 levels to determine HCVR is highly reproducible in healthy men and women. A fixed 8% inspired CO 2 level produces a remarkably consistent, severe systemic hypercapnia despite the wide interindividual variability in HCVR. Supported by USAMRDC; author views not official US Army or DoD policy. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.