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

Abstract

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-minute 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 hour 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.