Linking Ventilator Injury-Induced Leak across the Blood-Gas Barrier to Derangements in Murine Lung Function

Abstract

Mechanical ventilation is vital to the management of acute respiratory distress syndrome, but it frequently leads to ventilator-induced lung injury (VILI). Understanding the pathophysiological processes involved in the development of VILI is an essential prerequisite for improving lung-protective ventilation strategies. The goal of this study was to relate the amount and nature of material accumulated in the airspaces to biomarkers of injury and the derecruitment behavior of the lung in VILI. Forty-nine BALB/c mice were mechanically ventilated with combinations of tidal volume and end-expiratory pressures to produce varying degrees of overdistension and atelectasis while lung function was periodically assessed. Total protein, serum protein, and E-Cadherin levels were measured in bronchoalveolar lavage fluid (BALF). Tissue injury was assessed by histological scoring. We found that both high tidal volume and zero positive end-expiratory pressure were necessary to produce significant VILI. Increased BALF protein content was correlated with increased lung derecruitability, elevated peak pressures, and histological evidence of tissue injury. Blood derived molecules were present in the BALF in proportion to histological injury scores and epithelial injury, reflected by E-Cadherin levels in BALF. We conclude that repetitive recruitment is an important factor in the pathogenesis of VILI that exacerbates injury associated with tidal overdistension. Furthermore, the dynamic mechanical behavior of the injured lung provides a means to assess both the degree of tissue injury and the nature and amount of blood-derived fluid and proteins that accumulate in the airspaces.

Alveolar leak develops by a rich-get-richer process in ventilator-induced lung injury

“…The ZEEP/2xH group was ventilated with zero PEEP until H had risen to twice its baseline value. The PEEP group was ventilated with PEEP = 3 cmH 2 O for approximately 120 min as this duration was approximately equal to that of the ZEEP/2xH group and, based on our previous investigations [ 5 , 10 ], does not lead to the development of obvious VILI in initially healthy mice. This experimentally applied PEEP = 3 cmH 2 O is approximately equal to the mean PEEP = 2.5 cmH 2 O reported in a recent meta-analysis [ 14 ] for standard ventilation of the non-injured lung in perioperative and intensive care unit patients.…”

“…Unfortunately, mechanical ventilation comes with its own risks because of the potentially injurious stresses and strains it can inflict on an already damaged lung [ 2 ]. Such stresses and strains can cause or exacerbate the leakage of plasma-derived fluid and proteins into the airspaces of the lung where they interfere with the functioning of pulmonary surfactant [ 3 – 5 ], which increases surface tension at the air-liquid interface. This greatly increases the tissue stresses wrought by mechanical ventilation and thus predisposes the lung to ventilator-induced lung injury (VILI).…”

Neferine Protects Endothelial Glycocalyx via Mitochondrial ROS in Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome

“…Acute respiratory distress syndrome (ARDS), a significant source of morbidity and mortality in critically ill patients, is characterized by the abrupt onset of clinically significant hypoxemia with the presence of diffuse pulmonary infiltrates. An increase in pulmonary vascular permeability is the basic pathological feature of ARDS, which can further lead to the efflux of protein-rich edema fluid into the pulmonary alveolus, impairing gas exchange across the alveolar membrane and ultimately causing respiratory failure (Ware and Matthay, 2000 ; Wheeler and Bernard, 2007 ; Laffey and Kavanagh, 2017 ; Smith et al, 2017 ).…”

Quantifying Regional Lung Deformation Using Four-Dimensional Computed Tomography: A Comparison of Conventional and Oscillatory Ventilation

“…Finally, while our study focused on regional distributions of aeration, strain, and strain rate as the primary indicators of ventilation and VILI, the exact relationship between these mechanical variables and VILI is difficult to ascertain. VILI is a complicated process associated with a diverse range of mechanical stimuli (Hussein et al, 2013;Carrasco Loza et al, 2015;Güldner et al, 2016;Smith et al, 2017;Tonetti et al, 2017). So-called "mechanical power" (i.e., the rate of energy dissipation across parenchymal tissues) may provide a better prediction of VILI compared to either strain or strain rate alone (Gattinoni et al, 2016b;Serpa Neto et al, 2018).…”

“…However, measurement of regional mechanical power is not practical, given the requirement of regional gas pressure within the lung for its estimation. Alternatively, VILI may also be assessed using fluoro-deoxyglucose (FDG) uptake (Wellman et al, 2014), serum or alveolar inflammatory cytokines (Liu et al, 2013), protein content in bronchoalveolar lavage fluid (Smith et al, 2017), and histopathology. All of these quantitative measurements of lung injury require extensive durations of mechanical ventilation prior to measurement, some of which may only be obtained post mortem.…”