The Contribution of Surface Tension-Dependent Alveolar Septal Stress Concentrations to Ventilation-Induced Lung Injury in the Acute Respiratory Distress Syndrome

Abstract

In the acute respiratory distress syndrome (ARDS), surface tension, T, is likely elevated. And mechanical ventilation of ARDS patients causes ventilation-induced lung injury (VILI), which is believed to be proportional to T. However, the mechanisms through which elevated T may contribute to VILI have been under-studied. This conceptual analysis considers experimental and theoretical evidence for static and dynamic mechanical mechanisms, at the alveolar scale, through which elevated T exacerbates VILI; potential causes of elevated T in ARDS; and T-dependent means of reducing VILI. In the last section, possible means of reducing T and improving the efficacy of recruitment maneuvers during mechanical ventilation of ARDS patients are discussed.

Keywords: acute respiratory distress syndrome (ARDS); mechanical ventilation; recruitment maneuvers; stress concentrations; surface tension; ventilation-induced lung injury (VILI).

FIGURE 1

Single alveolar edema model. (A) Inflation and flooding effects on alveolar geometry. Optical sections of two surface alveoli in isolated, perfused rat lungs. Epithelium labeled with calcein red-orange. Transpulmonary pressure, P_L, as indicated. In bottom images, right alveolus flooded with fluorescein-labeled 5% albumin solution. Air appears black. Sections are 2-μm thick and at 20-μm sub-pleural depth. Flooding right alveolus causes bowing of central “intervening” septum that separates aerated and flooded alveoli (arrows). Scale bars from baseline image are superimposed on all other images. Right alveolus that becomes flooded and left alveolus that remains aerated have areas A_Edem and A_Adj, respectively. (B) Meniscus in flooded alveolus. Image is y–z section, constructed from confocal z-stack, of an alveolus flooded with fluorescein-labeled 5% albumin solution. Pleural surface is at top of image. Epithelium is unlabeled and, along with air, appears black. Dashed line shows meniscus at mouth of flooded alveolus. (C) Schematics of alveolus before (left) and after (right) liquid flooding. Intervening septa separate aerated from flooded alveoli. Radiating septa are directed outward from flooded alveolus and have aerated alveoli to each side. P_ALV is alveolar air pressure. P_LIQ is flooding liquid pressure. Air–liquid interface in flooded alveolus forms a meniscus. ΔP_M = P_ALV – P_LIQ is pressure drop across meniscus. ΔP_S = P_ALV – P_LIQ is pressure drop across intervening septa. Axial distending force F_A acts at ends of sectioned septa and is greater in radiating septa around flooded alveolus on the right than in normally-stressed septa around aerated alveolus on the left. Ratio of summed F_A over alveolar surface is an effective distending pressure P_D applied to central alveolus. (D) Alveolar compliance. Alveolar areas plotted vs. P_L for pairs of adjacent alveoli, one of which becomes flooded as in (A). Slope of lines is a two-dimensional analog of compliance. Statistics: ^∗Area greater at P_L of 15 than 5 cm H₂O (p < 0.01), for state before or after one alveolus is flooded. ^#Area different after than before one alveolus is flooded, at constant P_L (p < 0.01). ^##Same as “#” but p < 0.02. ^‡Slope less after than before one alveolus is flooded (p < 0.01). (A,B,D) Modified, with permission, from Perlman et al. (2011).

FIGURE 2

Stress concentrations in injured regions. Schematic representations showing stressed intervening and radiating septa in (A) homogeneously and (B) heterogeneously flooded regions. While only single layers of radiating septa are shown, computational modeling indicates radiating septa, especially those around a larger injured area, penetrate further into surrounding, aerated parenchyma (see text).

FIGURE 3

Forces acting on septa. (A) Normal planar septum between two aerated alveoli. Distending force F_A applies axial tension. Interfacial surface tension, T, and tissue stress, σ_T, counter F_A. (B) Intervening septum separating flooded (top) from aerated (bottom) alveolus. Due to ΔP_S, which is ∼T, septum bows into flooded alveolus. Inflation-induced increases in F_A and σ_T tend to reduce bowing. Inflation-induced increase in T acting along septum tends to reduce bowing, but inflation-induced increase in T also increases ΔP_S, which tends to increase bowing. Net result is that inflation sometimes increases bowing (Figure 1A).

FIGURE 4

Ventilation-induced lung injury (VILI) assays. (A) Local VILI assay of ventilation-induced injury to alveolar–capillary barrier in the presence of heterogeneous alveolar flooding. Top schematic: Isolated lung is perfused with fluorescein-labeled blood/5% albumin mixture. A glass micropipette is used to puncture a surface alveolus and infuse non-fluorescent 3% albumin solution, which causes heterogeneous alveolar flooding in a local region. Menisci are present in flooded alveoli. Middle images: With P_L held at 5 cm H₂O, the region is imaged by confocal microscopy over 5-min baseline period. “L” labels alveoli flooded with non-fluorescent liquid. Then, five ventilation cycles are administered with an end-expiratory P_L equivalent to an in vivo positive end-expiratory pressure (PEEP) of 10 cm H₂O and a tidal volume, V_T, of 12 ml/kg. Following ventilation, P_L is returned to 5 cm H₂O, and the region is imaged for 10 additional minutes. Bottom graph: plot of increase above baseline of normalized fluorescence in alveolar liquid vs. time. Gray: experimental, heterogeneously flooded regions in lungs subjected to five ventilation breaths with 10 cm H₂O PEEP and V_T as specified (fluorescein intensity quantified in alveolar flooding liquid). Black: control, aerated regions in lungs subjected to five ventilation breaths with 10 cm H₂O PEEP and 6 or 12 ml/kg V_T (data for two V_T groups combined; fluorescein intensity quantified in liquid lining layer). Statistics: ^∗p < 0.01 vs. baseline; #p < 0.01 vs. both other groups at the same time point; °p < 0.01 vs. control group at the same time point. Figure modified, with permission, from Wu et al. (2014). (B) Global VILI assay of ventilation-induced increase in T in the presence of heterogeneous alveolar flooding. Table: summary of experimental protocol and T-values, all determined at P_L of 15 cm H₂O, at different time points. Statistics: ^∗p < 0.05 vs. T-values at two earlier time points. Image: representative view of alveolar flooding pattern on surface of lungs at final time point after induction of VILI and elevation of T. Alveolar edema liquid labeled by fluorescein administered to the perfusate. Figure modified, with permission, from Wu et al. (2017).

FIGURE 5

Pressure barrier, ΔP_B, traps liquid in flooded alveoli. According to the Laplace relation, pressure in liquid below meniscus is P_LIQ = P_ALV – 2T/R < P_ALV, where R is the meniscus radius. At the border between two adjacent alveoli, shared septum terminates at alveolar duct or sac, and liquid phases of alveoli are presumably continuous. Thus, in the plane of the figure, the interface has a small convex radius R_B at the border of the flooded alveolus. In the plane perpendicular to the figure, the end of the septum and the interface should have larger concave radius R_D of duct or sac, indicated by dashed gray curve. Again, according to the Laplace relation, the liquid phase pressure at the border of the alveolus is P_LIQ._BORD = P_ALV + T(1/R_B – 1/R_D) > P_ALV. Thus, pressure barrier ΔP_B = P_LIQ._BORD – P_LIQ = T(1/R_B – 1/R_D + 2/R) > 0 traps liquid in the flooded alveolus. As ΔP_B ∼ T, lowering T lowers ΔP_B and increases the likelihood of liquid escape from the flooded alveolus, i.e., the likelihood of re-aeration. Figure modified, with permission, from Kharge et al. (2015) and Wu et al. (2017).