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CO2 accumulation may limit crew survival in a disabled submarine. Reversible sedation using diazepam and flumazenil was proposed to reduce CO2 production.Two groups of three resting subjects were studied during a 48-h placebo phase with diazepam and flumazenil placebos, followed by a 48-h drug phase with oral diazepam to induce sedation and intranasal flumazenil to reverse it. CO2 exchange was measured every 2.5 h; twice a day, cognitive testing and meals were preceded by placebo or flumazenil. Return to sedated state was produced with either placebo or diazepam. In the drug phase, initial diazepam doses (10 to 40 mg) were followed by maintenance doses to achieve sedation corresponding to Alertness Scores of 3 or 4.In the drug phase, subjects received a total of 360-495 mg of diazepam (with doses of 5-40 mg), average alertness score was 3.75, and mean Vco2 was 14% less than in the placebo phase (0.212 vs. 0.248 L x min(-)). Subjects were 21-36% less active when sedated with diazepam. The mean flumazenil dose to restore full alertness was 0.36 mg, with subjects being conversant and oriented within 5 min, performing cognitive tasks at 86-97% of their baseline. Subjects could follow instructions and ambulate independently, though unsteadily 6 h after final flumazenil dose; at 72 h they exhibited normal cognitive and physical functions.Reversible sedation to lower crew metabolism in a disabled submarine may be effective, safe, and practical.