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

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