Driving-pressure-independent protective effects of open lung approach against experimental acute respiratory distress syndrome

Abstract

Background: The open lung approach (OLA) reportedly has lung-protective effects against acute respiratory distress syndrome (ARDS). Recently, lowering of the driving pressure (ΔP), rather than improvement in lung aeration per se, has come to be considered as the primary lung-protective mechanism of OLA. However, the driving pressure-independent protective effects of OLA have never been evaluated in experimental studies. We here evaluated whether OLA shows protective effects against experimental ARDS even when the ΔP is not lowered.

Methods: Lipopolysaccharide was intratracheally administered to rats to establish experimental ARDS. After 24 h, rats were mechanically ventilated and randomly allocated to the OLA or control group. In the OLA group, 5 cmH₂O positive end-expiratory pressure (PEEP) and recruitment maneuver (RM) were applied. Neither PEEP nor RM was applied to the rats in the control group. Dynamic ΔP was kept at 15 cmH₂O in both groups. After 6 h of mechanical ventilation, rats in both groups received RM to inflate reversible atelectasis of the lungs. Arterial blood gas analysis, lung computed tomography, histological evaluation, and comprehensive biochemical analysis were performed.

Results: OLA significantly improved lung aeration, arterial oxygenation, and gas exchange. Even after RM in both groups, the differences in these parameters between the two groups persisted, indicating that the atelectasis-induced respiratory dysfunction observed in the control group is not an easily reversible functional problem. Lung histological damage was severe in the dorsal dependent area in both groups, but was attenuated by OLA. White blood cell counts, protein concentrations, and tissue injury markers in the broncho-alveolar lavage fluid (BALF) were higher in the control than in the OLA group. Furthermore, levels of CXCL-7, a platelet-derived chemokine, were higher in the BALF from the control group, indicating that OLA protects the lungs by suppressing platelet activation.

Conclusions: OLA shows protective effects against experimental ARDS, even when the ΔP is not decreased. In addition to reducing ΔP, maintaining lung aeration seems to be important for lung protection in ARDS.

Keywords: Acute respiratory distress syndrome; Atelectasis; Driving pressure; Mechanical ventilation; Open lung approach; Platelet-derived chemokine; Positive end-expiratory pressure; Recruitment maneuver.

Fig. 1

Inspiratory flow pattern, dynamic driving pressures during positive end-expiratory pressure (PEEP) titration, and the experimental scheme. a Inspiratory flow pattern of the small animal ventilator (SN-480-7, Shinano Seisakusho). b Changes in the dynamic driving pressures when decreasing PEEP from 10 to 0 cm H₂O at intervals of 2 cm H₂O. Data represent the means ± SD. c Schematic diagram of the experimental design. BGA, blood gas analysis; OLA, open lung approach; RM, recruitment maneuver

Fig. 2

Physiological and mechanical ventilation parameters. a Mean arterial blood pressure. b Dynamic driving pressure. c Tidal volume. d Respiratory rate. e Partial pressure of arterial oxygen (P_aO₂). f Partial pressure of arterial carbon dioxide (P_aCO₂). *p < 0.05 vs. control group. Data represent the means ± SD. OLA, open lung approach; RM, recruitment maneuver

Fig. 3

Computed tomography. a Representative pulmonary computed tomography images taken after 3 h of mechanical ventilation or after the final recruitment maneuver following 6 h of mechanical ventilation. b Aerated lung volumes calculated from computed tomography images. *p < 0.05 vs. control group. Data represent the means ± SD. OLA, open lung approach; RM, recruitment maneuver

Fig. 4

Histology. a Representative images of lung sections stained with hematoxylin and eosin. b Histological scores assessed in a blinded manner. Data represent the means ± SD. OLA, open lung approach

Fig. 5

Analysis of bronchoalveolar lavage fluids (BALF). a White blood cell counts (WBC). b Protein concentrations. c Comprehensive analysis of inflammatory and tissue injury markers using cytokine array analysis. d Intercellular adhesion molecule-1 (ICAM-1), e soluble receptor for advanced glycation end products (RAGE), f CXC chemokine ligand-1 (CXCL-7) concentrations in the BALF quantified by ELISA. *p < 0.05 vs. control group. Data represent the means ± SD. OLA, open lung approach