Prophylactic caffeine mitigates systemic hypercapnia and headache during graded carbon dioxide exposure in healthy males and females: a randomized crossover trial

Exposure to elevated inspired carbon dioxide (CO₂) levels, an environmental threat in several occupational settings, is known to induce systemic hypercapnia and provoke headache. However, the impact of CO₂ exposure dose on headache severity has not been determined, and countermeasures to mitigate systemic hypercapnia and headache during CO₂ exposure are lacking. In this study, we first characterized respiratory responses and headache with graded CO₂ exposure (sequential 12-min stages of 0%, 2%, 4%, 6%, and 8% inspired CO₂, all with 21% oxygen) during seated rest in 24 healthy males and females. As expected, graded CO₂ exposure resulted in stepwise increases (41 ± 3, 43 ± 2, 46 ± 2, 53 ± 2, 65 ± 1 mmHg; <i>P</i> < 0.001) in end-tidal CO₂ across the spectrum from normocapnia to severe hypercapnia. Headache increased (<i>P</i> < 0.05) beginning at 4% inspired CO₂ (1 ± 2, 2 ± 3, 8 ± 8, 16 ± 13, 32 ± 20 mm on a 100-mm visual analog scale). Participants then completed the same graded CO₂ exposure 1 h following either caffeine (400 mg) or placebo supplementation in a randomized, double-blind, crossover manner (<i>n</i> = 23). Caffeine increased ventilation and lowered end-tidal CO₂ at inspired CO₂ levels between 0% and 6% (<i>P</i> < 0.05), corresponding with a leftward shift in the end-tidal CO₂-ventilation response curve with unchanged slope. Caffeine substantially reduced headache during graded CO₂ exposure, an effect that was most pronounced at 8% inspired CO₂ (placebo: 25 ± 15 mm, caffeine: 13 ± 12 mm; <i>P</i> < 0.05). Our novel findings establish prophylactic caffeine supplementation as a translational countermeasure to mitigate systemic hypercapnia and headache during CO₂ exposure.<b>NEW & NOTEWORTHY</b> In this study, we first characterized systemic hypercapnia and headache severity during graded CO₂ exposures (sequential 12-min stages of 0%, 2%, 4%, 6%, and 8% inspired CO₂). Using a randomized, double-blind, crossover trial, we then showed that prophylactic treatment with 400 mg caffeine mitigates systemic hypercapnia and headache during graded CO₂ exposure. Overall, these novel findings establish caffeine as the first evidence-based countermeasure to mitigate adverse effects associated with CO₂ exposure.