Increased particle flow rate from airways precedes clinical signs of ARDS in a porcine model of LPS-induced acute lung injury

Abstract

Acute respiratory distress syndrome (ARDS) is a common cause of death in the intensive care unit, with mortality rates of ~30-40%. To reduce invasive diagnostics such as bronchoalveolar lavage and time-consuming in-hospital transports for imaging diagnostics, we hypothesized that particle flow rate (PFR) pattern from the airways could be an early detection method and contribute to improving diagnostics and optimizing personalized therapies. Porcine models were ventilated mechanically. Lipopolysaccharide (LPS) was administered endotracheally and in the pulmonary artery to induce ARDS. PFR was measured using a customized particles in exhaled air (PExA 2.0) device. In contrast to control animals undergoing mechanical ventilation and receiving saline administration, animals who received LPS developed ARDS according to clinical guidelines and histologic assessment. Plasma levels of TNF-α and IL-6 increased significantly compared with baseline after 120 and 180 min, respectively. On the other hand, the PFR significantly increased and peaked 60 min after LPS administration, i.e., ~30 min before any ARDS stage was observed with other well-established outcome measurements such as hypoxemia, increased inspiratory pressure, and lower tidal volumes or plasma cytokine levels. The present results imply that PFR could be used to detect early biomarkers or as a clinical indicator for the onset of ARDS.

Keywords: ARDS; LPS-induced lung injury; mechanical ventilation; particles in exhaled air.

Conflict of interest statement

No conflicts of interest, financial or otherwise, are declared by the authors.

Figures

Fig. 1.

Results of hemodynamic parameters and blood gases during the timeline of the experiment confirming acute respiratory distress syndrome (ARDS) in our model. A: ARDS was defined according to the Berlin definition based on the partial pressure of oxygen (PaO2)-to-fraction of inspired oxygen (FIO2) ratio. Note that mild ARDS (ratio < 300 mmHg) occurred first after 90 min. B–D: hemodynamics are shown as follows: mean arterial pressure (B), cardiac output (C), pulmonary vascular resistance (D). E–H: blood gases are shown as follows: partial pressure of oxygen in arterial blood (PaO2) (E), partial pressure of carbon dioxide in arterial blood (PaCO2) (F), pH (G), lactate (H). Results are shown as means and SE and all confirm the development of ARDS in our model. All measurements were compared with baseline values. Significance was defined as P < 0.001 (***), P < 0.01 (**), P < 0.05 (*), and P > 0.05 (not significant).

Fig. 2.

A: particle flow rate (PFR) from the airways during the experimental timeline of ~6 h in the animals that received LPS and developed acute respiratory distress syndrome (ARDS; black line) and the animals that received sham treatment (blue line). Interestingly, the PFR peaked after 60 min, when no ARDS state had yet been reached. Arrows show the time for endotracheal (ET) administration and infusion in the pulmonary artery (IPA) of LPS in the animals that received LPS treatment. Note how the PFR remained unchanged compared with baseline during the whole study period in the animals that received sham treatment. B: PFR at different ARDS time points: at baseline before any administration of LPS and at different stages of ARDS. Pre-ARDS was defined as the time point between baseline and ARDS. Note the significant increase in PFR before any ARDS state was reached (pre-ARDS). The results are shown as mean and SE. Significance was defined as P < 0.001 (***), P < 0.01 (**), P < 0.05 (*), and P > 0.05 (not significant).

Fig. 3.

A: concentration of tumor necrosis factor-α (TNF-α), interleukin (IL)-10, IL-6, IL-8, , IL-12, and IL-1β in plasma measured by multiplex at baseline and at different time points after LPS administration. Significance was defined as P < 0.001 (***), P < 0.01 (**), P < 0.05 (*), and P > 0.05 (not significant, n.s.). B: hematoxylin and eosin-stained lung sections from an individual pig before (baseline) and 6 h after LPS administration (6 h post-LPS) and also after 6 h of sham treatment (6 h post-sham). Scale bars: left, 0.2 mm; right, 0.1 mm. C: lung tissue wet-to-dry weight ratio at baseline and at 6 h post LPS administration and post sham treatment.