Inhomogeneous Computed Tomographic Densities in Lungs in Acute Respiratory Distress Syndrome: Stress Multipliers Leading to Ventilator-induced Injury?
Authors: Stephen H. Loring, Daniel Talmor
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

In this issue of the Journal, Cressoni and colleagues (pp. 149–158) extend their investigations into the mechanisms of ventilator-induced lung injury (VILI) in patients with acute respiratory distress syndrome (ARDS) (1). In approaching the question of how relatively small tidal volumes in ARDS can cause lung injury, they first acknowledge the concepts of “the second hit” and “baby lung.” They then go on to ask if stress amplification at the boundary between regions of lung of differing density might further contribute to the development of VILI. They base their hypothesis on the theoretical analysis of Mead and colleagues (2). Mead reasoned that the stress needed to expand a region of homogeneous lung would be the transpulmonary pressure, and that if a small region of the lung were to decrease in volume, or become atelectatic, it would be subjected to a greater expanding stress, thus amplifying the inflating pressure needed to restore its original volume.

To explore this question, Cressoni and colleagues used computed tomographic (CT) scans from 148 patients with ARDS and 100 control subjects to estimate normal and pathological levels of lung inhomogeneity that could lead to stress amplification and localized lung injury. Because the relative expansion of different parts of the lung could not be directly measured, they used the spatial inhomogeneity of lung CT density as a measure of underinflation in the denser regions. Inhomogeneous density was assessed over the entire lung by comparing the density of each individual voxel with the average density of a surrounding spherical shell with a diameter of 2.4 to 3.6 mm. Because the density of 95% of these voxels in normal lungs differed from that of their surrounding shells by a factor of less than 1.61, this value was chosen as the normal limit for inhomogeneity, and higher ratios were defined as abnormal inhomogeneity. In normal lungs, inhomogeneous regions accounted for about 5% of the voxels and occurred principally at the periphery of the lung and near the large vessels and hilar structures. In patients with ARDS, inhomogeneous voxels were 18% of the total and occurred largely at the interface between “healthy” and “diseased” regions (i.e., at the border between regions with high and normal CT density).

Patients were categorized according to the severity of ARDS, which was significantly related to the proportion of abnormally inhomogeneous voxels, being 14% in mild ARDS and 23% in severe ARDS. As would be expected from this, the proportion of abnormally inhomogeneous voxels was also significantly correlated with PaO2/FiO2, physiological shunt fraction, plateau pressure, and dead-space fraction. Finally, the lung inhomogeneity was significantly greater in patients who died than in survivors. The extent of lung inhomogeneity appears to be an important indicator of ARDS severity and predicts outcome, and the authors are to be congratulated for this novel finding.

However, whether inhomogeneity in CT density implies stress amplification of the type Mead and colleagues described remains an open question. Their analysis predicted that a transpulmonary pressure of 30 cm H2O throughout a homogeneous lung would increase to approximately 140 cm H2O at the surface of a spherical region that had decreased to one-tenth of its original volume. This assumes that the constant tensile force on alveolar walls would be applied to a smaller spherical surface of the contracted region. Their analysis, which was illustrated with a lung model constructed from condoms, required that the shape of the lung region undergoing contraction be preserved as its volume decreased, so that a spherical region would contract to a smaller sphere, etc. To the extent that alveolar contraction occurs principally in one dimension, as in plate-like atelectasis, stress amplification could be far less than suggested by Mead and colleagues.

More importantly, as acknowledged by Cressoni and colleagues, there is uncertainty concerning the interpretation of CT density, specifically, whether it can actually be interpreted as indicating alveolar collapse in diseased lungs. As articulated by Hubmayr (3), the dorsoventral gradient of CT density seen in ARDS may be due largely to differences in the amount of alveolar fluid content, and may not simply reflect a gradient of alveolar size. Hubmayr suggests that the denser regions of diseased lungs could have alveolar size similar to surrounding regions, whose alveoli are not flooded. If this were true, it would preclude increases in stress associated with alveolar size heterogeneity.

If this alternative hypothesis is correct and stress amplification is not important, how would we explain the correlations of extent of inhomogeneity with assessments of disease severity, physiological indices of disease, and mortality? To the extent that more severely diseased lungs are likely to have more regions with either flooding or consolidation, it would not be surprising that the extent of inhomogeneity reflects the extent of pathology and correlates with respiratory dysfunction.

A recent imaging study may bear on the question of whether stress amplification occurs at the margins of collapsed regions in ARDS lungs. Bellani and colleagues (4) used positron emission tomography and CT scans in 13 patients with ARDS to colocalize the site of increased CT density and areas of increased metabolic activity due to neutrophils, which are implicated in the inflammation of VILI. They found that throughout the ventilated lung, there was a significant positive correlation between the end-inspiratory plateau pressure, a known risk factor for stress-induced VILI, and the degree of metabolic activity. They also found no difference in the metabolic activity in regions that were normally aerated and those that were undergoing cyclic recruitment and derecruitment. They concluded that these findings did not support the importance of “atelectrauma” caused by cyclic recruitment and derecruitment of alveoli (5). Implicit in their observations is the absence of any indication that there is greater inflammatory activity at the borders of aerated and nonaerated lung. Although resolution of positron emission tomography is too limited to test the stress amplification hypothesis at present, this line of evidence seems not to support stress-induced lung inflammation bordering regions high CT density. We await further studies in this area.

The study by Cressoni and colleagues makes a significant contribution to the literature by quantifying inhomogeneity in the lungs of patients with ARDS and by associating the degree of this inhomogeneity with disease severity and outcomes. The debate over the interpretation of CT density in ARDS, whether this represents areas of atelectasis subject to stress amplification or not, will need to be resolved by further studies.