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Nada Ismaiel, Sara Whynot, Laurette Geldenhuys, Zhaolin Xu, Arthur S. Slutsky, Valerie Chappe, Dietrich Henzler

• \(\textbf {Background and Objective:}\) Lung-protective mechanical ventilation is known to attenuate ventilator-associated lung injury (VALI), but often at the expense of hypoventilation and hypercapnia. It remains unclear whether the main mechanism by which VALI is attenuated is a product of limiting mechanical forces to the lung during ventilation, or a direct biological effect of hypercapnia. \(\bf Methods:\) Acute lung injury (ALI) was induced in 60 anesthetized rats by the instillation of 1.25 M HCl into the lungs via tracheostomy. Ten rats each were randomly assigned to one of six experimental groups and ventilated for 4 h with: 1) \(\textbf {Conventional \(HighV_{E}\) Normocapnia}\) (high \(V_{T}\), high minute ventilation, normocapnia), 2) \(\textbf {Conventional Normocapnia}\) (high \(V_{T}\), normocapnia), 3) \(\textbf {Protective Normocapnia}\) (\(V_{T}\) 8 ml/kg, high RR), 4) \(\textbf {Conventional \(iCO_{2}\) Hypercapnia}\) (high \(V_{T}\), low RR, inhaled \(CO_{2}\)), 5) \(\textbf {Protective \(iCO_{2}\) Hypercapnia}\) (\(V_{T}\) 8 ml/kg, high RR, added \(CO_{2}\)), 6) \(\textbf {Protective endogenous Hypercapnia}\) (\(V_{T}\) 8 ml/kg, low RR). Blood gasses, broncho-alveolar lavage fluid (BALF), and tissue specimens were collected and analyzed for histologic and biologic lung injury assessment. \(\bf Results:\) Mild ALI was achieved in all groups characterized by a decreased mean \(PaO_{2}/FiO_{2}\) ratio from 428 to 242 mmHg (\(\it p\) < 0.05), and an increased mean elastance from 2.46 to 4.32 \(cmH_{2}O\)/L (\(\it p\) < 0.0001). There were no differences in gas exchange among groups. Wet-to-dry ratios and formation of hyaline membranes were significantly lower in low \(V_{T}\) groups compared to conventional tidal volumes. Hypercapnia reduced diffuse alveolar damage and IL-6 levels in the BALF, which was also true when \(CO_{2}\) was added to conventional \(V_{T}\). In low \(V_{T}\) groups, hypercapnia did not induce any further protective effect except increasing pulmonary IL-10 in the BALF. No differences in lung injury were observed when hypercapnia was induced by adding \(CO_{2}\) or decreasing minute ventilation, although permissive hypercapnia decreased the pH significantly and decreased liver histologic injury. \(\bf Conclusion:\) Our findings suggest that low tidal volume ventilation likely attenuates VALI by limiting mechanical damage to the lung, while hypercapnia attenuates VALI by limiting pro-inflammatory and biochemical mechanisms of injury. When combined, both lung-protective ventilation and hypercapnia have the potential to exert an synergistic effect for the prevention of VALI.