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

TITLE=Lung-Protective Ventilation Attenuates Mechanical Injury While Hypercapnia Attenuates Biological Injury in a Rat Model of Ventilator-Associated Lung Injury

JOURNAL=Frontiers in Physiology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2022.814968

DOI=10.3389/fphys.2022.814968

ISSN=1664-042X

ABSTRACT=<p><bold>Background and Objective:</bold> 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.</p><p><bold>Methods:</bold> 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) <bold>Conventional HighV</bold><sub><bold>E</bold></sub><bold>Normocapnia</bold> (high V<sub>T</sub>, high minute ventilation, normocapnia), 2) <bold>Conventional Normocapnia</bold> (high V<sub>T</sub>, normocapnia), 3) <bold>Protective Normocapnia</bold> (V<sub>T</sub> 8 ml/kg, high RR), 4) <bold>Conventional iCO</bold><sub><bold>2</bold></sub><bold>Hypercapnia</bold> (high V<sub>T</sub>, low RR, inhaled CO<sub>2</sub>), 5) <bold>Protective iCO</bold><sub><bold>2</bold></sub><bold>Hypercapnia</bold> (V<sub>T</sub> 8 ml/kg, high RR, added CO<sub>2</sub>), 6) <bold>Protective endogenous Hypercapnia</bold> (V<sub>T</sub> 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.</p><p><bold>Results:</bold> Mild ALI was achieved in all groups characterized by a decreased mean PaO<sub>2</sub>/FiO<sub>2</sub> ratio from 428 to 242 mmHg (<italic>p</italic> &lt; 0.05), and an increased mean elastance from 2.46 to 4.32 cmH<sub>2</sub>O/L (<italic>p</italic> &lt; 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<sub>T</sub> groups compared to conventional tidal volumes. Hypercapnia reduced diffuse alveolar damage and IL-6 levels in the BALF, which was also true when CO<sub>2</sub> was added to conventional V<sub>T</sub>. In low V<sub>T</sub> 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<sub>2</sub> or decreasing minute ventilation, although permissive hypercapnia decreased the pH significantly and decreased liver histologic injury.</p><p><bold>Conclusion:</bold> 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.</p>