Lung-protective ventilation attenuates mechanical injury while hypercapnia attenuates biological injury in a rat model of ventilator-associated lung injury

$\textbf {Background and Objective:}$ 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