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; P < 0.001) in end-tidal CO2 across the spectrum from normocapnia to severe hypercapnia. Headache increased (P < 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 (n = 23). Caffeine increased ventilation and lowered end-tidal CO2 at inspired CO2 levels between 0% and 6% (P < 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; P < 0.05). Our novel findings establish prophylactic caffeine supplementation as a translational countermeasure to mitigate systemic hypercapnia and headache during CO2 exposure.NEW & NOTEWORTHY 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.