Prophylactic Caffeine Mitigates Systemic Hypercapnia and Headache During Graded Carbon Dioxide Exposure

Background: Exposure to increased inspired carbon dioxide (CO 2 ) levels can occur in several occupational and recreational settings and leads to the development of systemic hypercapnia and headache. Importantly, effective countermeasures to mitigate hypercapnia and headache during CO 2 exposures are currently lacking. Purpose: To examine whether caffeine ingestion mitigates systemic hypercapnia and headache during CO 2 exposure. We hypothesized that caffeine would increase ventilation, decrease end-tidal CO 2 (P ET CO 2 ), and reduce headache severity. Methods: Healthy participants (12M/12F) first completed a control trial in which they progressed through increasing levels of inspired CO 2 in a stepwise manner (0%, 2%, 4%, 6%, 8%; all with 21% oxygen) in successive 12-minute stages. During each stage, headache severity was assessed at minute eight using a 100 mm visual analog scale. Ventilation and P ET CO 2 were measured using a pneumotachometer and infrared capnometer, respectively, and averaged over the final 5 minutes of each stage. Participants (11M/12F) then repeated the trial on two separate days in which they ingested a capsule with either placebo or 400 mg of caffeine one hour before the trial began in a double-blind, randomized, counterbalanced, crossover design. Data were analyzed in SPSS with linear mixed models and Bonferroni post-hoc tests. The hypercapnic ventilatory response (HCVR, the slope of ventilation versus P ET CO 2 ) was analyzed via paired t-test. Results: During the control trial, graded CO 2 exposure resulted in stepwise increases (p<0.001) in P ET CO 2 across the spectrum from normocapnia to severe hypercapnia (41±3, 43±2, 46±2, 53±2, 65±1 mmHg). Increases in headache (p<0.05) were observed beginning at 4% inspired CO 2 (1±2, 2±3, 8±8, 16±13, 32±20 mm). Compared to the placebo trial, caffeine increased ventilation and decreased P ET CO 2 at 0% through 6% inspired CO 2 (p<0.05); this marked ventilatory stimulation occurred with unchanged HCVR (p=0.55). Caffeine substantially reduced headache severity during graded CO 2 exposure, an effect that was most pronounced at 8% inspired CO 2 (placebo: 25±15 mm, caffeine: 13±12 mm; p<0.05), despite the lack of effect of caffeine on ventilation and P ET CO 2 at 8% inspired CO 2 . Conclusion: Caffeine effectively increased ventilation and mitigated systemic hypercapnia and headache during graded CO 2 exposure. We conclude that prophylactic caffeine can be an effective countermeasure during elevated inspired CO 2 . 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.