Objective: Deliberate induction of hypercapnic acidosis protects against lung injury after ischemia-reperfusion, endotoxin-induced, and ventilation-induced lung injury. The efficacy of hypercapnic acidosis in bacterial lung infection, a common cause of acute respiratory distress syndrome, is not known. Furthermore, its effect may differ depending on the presence or absence of antibiotic therapy. We investigated whether hypercapnic acidosis-induced by adding CO2 to inspired gas-would protect against acute lung injury induced by pulmonary Escherichia coli instillation in an in vivo model in the presence and absence of effective antibiotic therapy.Design: Prospective randomized animal study.Setting: University research laboratory.Subjects: Adult male Wistar-Kyoto rats.Interventions: The animals were anesthetized and ventilated. In series 1, rats were administered intravenous ceftriaxone (100 mg.kg(-1)) and randomized to normocapnia (Normocapnia-ABx; FICO2 0.00, n=10) or hypercapnia (Hypercapnia-ABx; FICO2 0.05, n=10) groups. E, coli (8.4x10(8) colony forming units) was instilled intratracheally. Series 2 animals did not receive antibiotics. They were randomized to normocapnia (Normocapnia, n=10) or hypercapnia (Hypercapnia, n=10) groups, and intratracheal E, coli was administered. All animals were ventilated for 6 hrs.Measurements and Main Results: In series 1, there were no differences between Hypercapnia-ABx and Normocapnia-ABx groups with regard to: (A-a)o(2) gradient (mean +/- SEM; 215 +/- 13 vs. 252 +/- 22 mm Hg), Pao(2), bronchoalveolar lavage neutrophil count, static lung compliance, or histologic injury. Lung bacterial yield was not different between the groups. In series 2, in the absence of antibiotic therapy, there were no differences between Hypercapnia and Normocapnia groups in: (A-a)o(2) gradient (mean SEM, 345 25 vs. 332 23 mm Hg), systemic Pao(2), bronchoalveolar lavage neutrophil count, or static lung compliance. Lung bacterial yield was not altered by hypercapnia in either series 1 or 2.Conclusions: We conclude that hypercapnic acidosis did not alter the magnitude of the lung injury induced by intratracheal E. coli instillation in the presence or absence of antibiotics.