Physiological mechanism and spatial distribution of increased alveolar dead-space in early ARDS: An experimental study

Abstract

Background: We aimed to investigate the physiological mechanism and spatial distribution of increased physiological dead-space, an early marker of ARDS mortality, in the initial stages of ARDS. We hypothesized that: increased dead-space results from the spatial redistribution of pulmonary perfusion, not ventilation; such redistribution is not related to thromboembolism (ie, areas with perfusion = 0 and infinite ventilation-perfusion ratio, $\dot{V}/\dot{Q}$ ), but rather to moderate shifts of perfusion increasing $\dot{V}/\dot{Q}$ in non-dependent regions.

Methods: Five healthy anesthetized sheep received protective ventilation for 20 hours, while endotoxin was continuously infused. Maps of voxel-level lung ventilation, perfusion, $\dot{V}/\dot{Q}$ , CO₂ partial pressures, and alveolar dead-space fraction were estimated from positron emission tomography at baseline and 20 hours.

Results: Alveolar dead-space fraction increased during the 20 hours (+0.05, P = .031), mainly in non-dependent regions (+0.03, P = .031). This was mediated by perfusion redistribution away from non-dependent regions (-5.9%, P = .031), while the spatial distribution of ventilation did not change, resulting in increased $\dot{V}/\dot{Q}$ in non-dependent regions. The increased alveolar dead-space derived mostly from areas with intermediate $\dot{V}/\dot{Q}$ (0.5≤ $\dot{V}/\dot{Q}$ ≤10), not areas of nearly "complete" dead-space ( $\dot{V}/\dot{Q}$ >10).

Conclusions: In this early ARDS model, increases in alveolar dead-space occur within 20 hours due to the regional redistribution of perfusion and not ventilation. This moderate redistribution suggests changes in the interplay between active and passive perfusion redistribution mechanisms (including hypoxic vasoconstriction and gravitational effects), not the appearance of thromboembolism. Hence, the association between mortality and increased dead-space possibly arises from the former, reflecting gas-exchange inefficiency due to perfusion heterogeneity. Such heterogeneity results from the injury and exhaustion of compensatory mechanisms for perfusion redistribution.

FIGURE 1

Global and regional distributions and changes in alveolar dead-space to tidal volume fraction (VDalv/VTalv) at baseline (0 h) and 20 h of mechanical ventilation and endotoxin infusion. (A) Global VDalv/VTalv for each animal; (B,D) average distribution of VDalv/VTalv as a function of $\dot{\mathrm{V}}/\dot{\mathrm{Q}}$ and vertical position, respectively (line = mean, shadowed area = mean±SD range); (C,E) change in VDalv/VTalv between 0 h and 20 h for each animal, for each of three lung regions categorized according to their $\dot{\mathrm{V}}/\dot{\mathrm{Q}}$ ($\dot{\mathrm{V}}/\dot{\mathrm{Q}}$<0.5, 0.5<$\dot{\mathrm{V}}/\dot{\mathrm{Q}}$<10, $\dot{\mathrm{V}}/\dot{\mathrm{Q}}$ >10) or their vertical position (ventral, middle, central), “■” represents mean value (±SD). *Significant change (ie, P < .05) between 0 h and 20 h tested using paired, one-tailed, Wilcoxon sign rank tests. Overall differences between time points and regions were tested using a mixed linear model. A figure reporting also individual data for each animal is shown in the Supplemental Digital Content

FIGURE 2

Representative example, from one animal, of maps of physiological parameters derived from positron emission tomography imaging and quantification at baseline (0 h) and after 20 h of endotoxin infusion: (A) ventilation, (B) perfusion, (C) ventilation to perfusion ratio, (D) alveolar dead-space to tidal volume ratio, (E) alveolar partial pressure of CO₂ (F) removal of CO₂ achieved by ventilation. The three maps in each panel represent, from left to right, a cranial, a central, and a caudal slice, (equally spaced out of the 15 acquired by the imaging system)

FIGURE 3

Distribution and changes in physiological parameters between baseline (0 h) and after 20 h of endotoxin infusion, as a function of vertical position: (A) ventilation, (B) perfusion, (C) ventilation to perfusion ratio, (D) alveolar dead-space to tidal volume ratio, (E) alveolar partial pressure of CO₂ (F) removal of CO₂ achieved by ventilation. In the left plots, line = mean, shadowed area = mean±SD range. “■” represents mean value (±SD). *Significant change (ie, P < .05) between 0 h and 20 h tested using paired, one-tailed, Wilcoxon sign rank tests. Overall differences between time points and regions were tested using a mixed linear model (for $\dot{\mathrm{V}}/\dot{\mathrm{Q}}$ only, after log-transformation). A figure reporting also individual data for each animal is shown in the Supplemental Digital Content

FIGURE 4

Analysis of regions with inefficient CO₂ removal through ventilation (ie, removal below 50% of the average voxel), quantified as the percentage of total lung volume (ie, percentage of voxels in positron emission tomography image belonging to the lung that is classified as inefficient): (A) change in inefficient regions between baseline (0 h) and after 20 h of endotoxin infusion; (B) correlation between inefficient regions and alveolar dead-space to tidal volume fraction (VDalv/VTalv). The same analysis is repeated considering only the inefficient regions characterized by higher ventilation to perfusion fraction ($\dot{\mathrm{V}}/\dot{\mathrm{Q}}$>1), panels (C), and (D). Symbol “o” represents the value of individual animals, while “■” represents mean value (±SD). *Significant change (ie, P < .05) between 0 h and 20 h tested using paired, one-tailed, Wilcoxon sign rank tests, r², p: squared correlation coefficient and P-value of Pearson correlation tests