Background: Acute lyypercapnic acidosis protects against lung injury caused by nonseptic insults and after both pulmonary and systemic sepsis. The authors wished to dissect the contribution of the acidosis versus hypercapnia per se to the effects of hypercapnic acidosis on the hemodynamic profile and severity of lung injury induced by systemic sepsis.Methods: In the hypercapnic acidosis series, adult male Sprague-Dawley rats were randomized to normocapnia or hypercapnic acidosis-produced by adding 5% carbon dioxide to the inspired gas-and cecal ligation and puncture performed. in the buffered hypercapnia series, animals were first randomized to housing under conditions of environmental normocapnia or hypercapnia-produced by exposure to 8% carbon dioxide-to allow renal buffering. After 96 h, cecal ligation and puncture was performed. In both series, the animals were ventilated for 6 h, and the severity of the lung injury and hemodynamic deterioration were assessed.Results: Both hypercapnic acidosis and buffered hypercapnia attenuated the development and severity of hypotension and reduced lactate accumulation compared to normocapnia. Hypercapnic acidosis reduced lung injury and inflammation, decreased mean (+/- SD) bronchoalveolar lavage protein concentration (232 +/- 50 versus 279 +/- 27 mu g . ml(-1)) and median neutrophil counts (3,370 versus 9,120 cells . ml(-1)), and reduced histologic lung injury. hi contrast, buffered hypercapnia did not reduce the severity of systemic sepsis Induced lung injury.Conclusions: Both hypercapnic acidosis and buffered hypercapnia attenuate the hemodynamic consequences of systemic sepsis. In contrast, hypercapnic acidosis, but not buffered hypercapnia, reduced the severity of sepsis-induced lung injury.