Robb W. Glenny

Determinants of regional ventilation and blood flow in the lung

The principles of ventilation and perfusion distribution in the lung form the foundation of pulmonary physiology and remain cornerstones in caring for critically ill patients. Due to improved imaging technologies with greater spatial resolution, our understanding of the determinants of local ventilation and blood flow have evolved over the past five decades. This review provides a brief history of how the concepts governing regional ventilation and perfusion have developed and presents the most recent studies that are shaping new perspectives on the determinants of ventilation and perfusion. How these new principles apply to acute lung injury and gas exchange in the intensive care unit (ICU) are reviewed.

Quantifying the genetic influence on mammalian vascular tree structure.

The ubiquity of fractal vascular trees throughout the plant and animal kingdoms is postulated to be due to evolutionary advantages conferred through efficient distribution of nutrients to multicellular organisms. The implicit, and untested, assertion in this theory is that the geometry of vascular trees is heritable. Because vascular trees are constructed through the iterative use of signaling pathways modified by local factors at each step of the branching process, we sought to investigate how genetic and nongenetic influences are balanced to create vascular trees and the regional distribution of nutrients through them. We studied the spatial distribution of organ blood flow in armadillos because they have genetically identical littermates, allowing us to quantify the genetic influence. We determined that the regional distribution of blood flow is strongly correlated between littermates (r2 = 0.56) and less correlated between unrelated animals (r2 = 0.36). Using an ANOVA model, we estimate that 67% of the regional variability in organ blood flow is genetically controlled. We also used fractal analysis to characterize the distribution of organ blood flow and found shared patterns within the lungs and hearts of related animals, suggesting common control over the vascular development of these two organs. We conclude that the geometries of fractal vascular trees are heritable and could be selected through evolutionary pressures. Furthermore, considerable postgenetic modifications may allow vascular trees to adapt to local factors and provide a flexibility that would not be possible in a rigid system.

High-resolution spatial measurements of ventilation-perfusion heterogeneity in rats

This study was designed to validate a high-resolution method to measure regional ventilation (VA) in small laboratory animals, and to compare regional Va and perfusion (Q) before and after methacholine-induced bronchoconstriction. A mixture of two different colors of 0.04-microm fluorescent microspheres (FMS) was aerosolized and administered to five anesthetized, mechanically ventilated rats. Those rats also received an intravenous injection of a mixture of two different colors of 15-microm FMS to measure regional blood flow (Q). Five additional rats were labeled with aerosol and intravenous FMS, injected with intravenous methacholine, and then relabeled with a second pair of aerosol and intravenous FMS colors. After death, the lungs were reinflated, frozen, and sequentially sliced in 16-microm intervals on an imaging cryomicrotome set to acquire signal for each of the FMS colors. The reconstructed lung images were sampled using randomly placed 3-mm radius spheres. Va within each sphere was estimated from the aerosol fluorescence signal, and Q was estimated from the number of 15-microm FMS within each sphere. Method error ranged from 6 to 8% for Q and 0.5 to 4.0% for Va. The mean coefficient of variation for Q was 17%, and for Va was 34%. The administration of methacholine altered the distribution of both VA and Q within lung regions, with a change in Va distribution nearly twice as large as that seen for Q. The methacholine-induced changes in Va were not associated with compensatory shifts in Q. Cryomicrotome images of FMS markers provide a high-resolution, anatomically specific means of measuring regional VA/Q responses in the rat.

Sporadic coordinated shifts of regional ventilation and perfusion in juvenile pigs with normal gas exchange

Repeated high‐resolution measurements of both regional pulmonary ventilation and regional blood flow (r) have revealed that ∼6 to 10% of the summed spatial and temporal heterogeneity can be attributed to spontaneous temporal variability. To test the hypothesis that the spontaneous temporal shifts of r and r are coordinated, 12 anaesthetized juvenile pigs had pairs of colours of aerosol and intravenous fluorescent microspheres (FMS) administered simultaneously at 20 min intervals to mark r and r. The animals were killed, the lungs inflated, air‐dried and cut into ∼2 cm3 cubes. The concentrations of FMS colours from each cube, representing r and r at every 20 min interval, were measured with a fluorescence spectrophotometer. The correlation between per‐piece temporal shifts in r and r, calculated as the mean within‐piece covariance, was positive (P < 0.001) for every temporally adjacent pair of measurements in every animal, although there were large differences in the magnitude of the mean temporal covariance among animals. The individual cubes with the most positive temporal covariance across all measurement periods usually demonstrated a large single‐interval coordinated shift of r and r, with average temporal covariance observed at the other intervals. The largest between‐interval shifts in r and r included equal proportions of coordinated increases and coordinated decreases. High‐resolution measurements of r and r acquired over 20 min intervals reveal that the overall positive correlation between temporal changes in r and r is driven by relatively infrequent large‐magnitude changes within small regions of the lung.