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

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

doi:10.3389/fphys.2022.814968

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

Front Physiol. 2022 Apr 21:13:814968. doi: 10.3389/fphys.2022.814968. eCollection 2022.

Authors

Nada Ismaiel^{1

2}, Sara Whynot³, Laurette Geldenhuys⁴, Zhaolin Xu⁴, Arthur S Slutsky⁵, Valerie Chappe⁶, Dietrich Henzler^{3

7}

Affiliations

¹ Faculty of Medicine, Dalhousie University, Halifax, NS, Canada.
² Department of Anesthesia, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
³ Department of Anesthesia, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada.
⁴ Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada.
⁵ Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
⁶ Department of Physiology and Biophysics, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada.
⁷ Department of Anesthesiology, Medical Faculty, Ruhr University Bochum, Bochum, Germany.

Abstract

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. 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) Conventional HighV _E Normocapnia (high V_T, high minute ventilation, normocapnia), 2) Conventional Normocapnia (high V_T, normocapnia), 3) Protective Normocapnia (V_T 8 ml/kg, high RR), 4) Conventional iCO ₂ Hypercapnia (high V_T, low RR, inhaled CO₂), 5) Protective iCO ₂ Hypercapnia (V_T 8 ml/kg, high RR, added CO₂), 6) 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. Results: Mild ALI was achieved in all groups characterized by a decreased mean PaO₂/FiO₂ ratio from 428 to 242 mmHg (p < 0.05), and an increased mean elastance from 2.46 to 4.32 cmH₂O/L (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 CO₂ 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 CO₂ or decreasing minute ventilation, although permissive hypercapnia decreased the pH significantly and decreased liver histologic injury. 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.

Keywords: acute lung injury; hypercapnia; lung-protective mechanical ventilation; mechanical ventilalion; ventilator associated lung injury.