H. Thomas Robertson

Physiological Implications of the Fractal Distribution of Ventilation and Perfusion in the Lung

AbstractBoth regional ventilation and regional perfusion demonstrate progressive increases in heterogeneity as the resolution of measurement is improved. Because the efficiency of pulmonary gas exchange is dependent on the match between local ventilation and local perfusion, the correlation between these two parameters was examined over a range of scale. We marked regional ventilation and perfusion in three anesthetized pigs with aerosolized 1 μm fluorescent microspheres (FMS) and injected 15 μm FMS. The lungs were dried inflated, cut into ∼2 cm3 cubes, and regional ventilation and blood flow were calculated from measurements of the fluorescence signals extracted from each piece. Adjacent pieces were clustered into successively larger aggregate volumes, and the averages of ventilation and of perfusion were calculated for each cluster size. While the coefficient of variation for both ventilation and perfusion increased predictably as the cluster size decreased, the correlation between ventilation and perfusion within clusters remained high, averaging between 0.82 and 0.92 among animals. Thus, while both ventilation and perfusion heterogeneity increase as the resolution of measurement improves, the strong correlation between these two parameters in a normal prone lung is nearly sample size invariant. This finding explains the observed efficiency of normal gas exchange in the face of the substantial degree of ventilation and perfusion heterogeneity observed in the normal lung with high-resolution measurement.

The spatial and temporal heterogeneity of regional ventilation: comparison of measurements by two high-resolution methods.

High-resolution estimates of ventilation distribution in normal animals utilizing deposition of fluorescent microsphere aerosol (FMS technique) demonstrate substantial ventilation heterogeneity, but this finding has not been confirmed by an independent method. Five supine anesthetized sheep were used to compare the spatial and temporal heterogeneity of regional ventilation measured by both the FMS technique and by a ventilation model utilizing the data from computed tomography images of xenon gas washin (CT/Xe technique). An aerosol containing 1 microm fluorescent microspheres (FMS) was administered via a mechanical ventilator delivering a 2-s end-inspiration hold during each breath. Following the aerosol administration, sequential CT images of a transverse lung slice were acquired during each end-inspiration hold during washin of a 65% Xenon/35% oxygen gas mixture (CT/Xe technique). Four paired FMS and CT/Xe measurements were done at 30 min intervals, after which the animals were sacrificed. The lungs were extracted, air-dried and sliced in 1cm transverse sections. The lung section corresponding to the CT image was cut into 1 cm3 cubes, with notation of spatial coordinates. The individual cubes were soaked in solvent and the four fluorescent signals were measured with a fluorescence spectrophotometer. The color signals were normalized by the mean signal for all pieces and taken as the FMS estimate of ventilation heterogeneity. The CT images were clustered into 1 cm3 voxels and the rate of increase in voxel density was used to calculate voxel ventilation utilizing the model of . The regional ventilation voxel measurements were normalized by the mean value to give a CT/Xe estimate of ventilation heterogeneity comparable to the normalized FMS measurements. The overall of heterogeneity of ventilation at the 1 cm3 level of resolution was comparable by both techniques, with substantial differences among animals (coefficient of variation ranging from 37% to 74%). The repeated within-animal measurements by both techniques gave consistent values. Both techniques showed comparable large-scale distribution of regional ventilation in the caudal lobes of the supine animals. There were appreciable differences in the temporal variability of ventilation among animals. This study provides an independent confirmation of the scale-dependent heterogeneity of ventilation described by previous FMS aerosol studies of ventilation heterogeneity.

Pulmonary Blood flow does not redistribute in dogs with reposition from supine to left lateral position

Background Recent studies have questioned the classical gravitational model of pulmonary perfusion. Because the lateral position is commonly used during surgery, the authors studied the redistribution of pulmonary blood flow in the left lateral decubitus position using a high spatial resolution technique. Methods Distributions of pulmonary blood flow were measured using intravenously injected 15‐[micro sign]m diameter radioactive‐labeled microspheres in eight halothane‐anesthetized dogs, which were studied in the supine and left lateral decubitus positions in random order. Lungs flushed free of blood were air‐dried at total lung capacity and sectioned into 1,498–2,396 (1.7 cm3) pieces per animal. Radioactivity was measured by a gamma counter, and signals were corrected for piece weight and normalized to mean flow. Results Blood flow to the dependent left lung did not increase, and blood flow to the nondependent right lung did not decrease in the lateral position. The left lung received 39.3 +/‐ 7.0% and 39.2 +/‐ 8.8% (mean +/‐ SD) of perfusion in the supine and left lateral positions, respectively. Detailed assessment of the spatial distributions of pulmonary blood flow revealed the lack of a gravitational gradient of blood flow in the lateral position. The distributions of blood flow did not differ in the supine and left lateral decubitus positions. Conclusions Perfusion to each lung did not change with movement from the supine to the left lateral position. These findings contradict the prediction of increased dependent lung and decreased nondependent lung blood flow based on the gravitational model. It was concluded that the distribution of blood flow in the lateral position in dogs is dominated by pulmonary vascular structure.

Dead space: the physiology of wasted ventilation

An elevated physiological dead space, calculated from measurements of arterial CO2 and mixed expired CO2, has proven to be a useful clinical marker of prognosis both for patients with acute respiratory distress syndrome and for patients with severe heart failure. Although a frequently cited explanation for an elevated dead space measurement has been the development of alveolar regions receiving no perfusion, evidence for this mechanism is lacking in both of these disease settings. For the range of physiological abnormalities associated with an increased physiological dead space measurement, increased alveolar ventilation/perfusion ratio (V′A/Q′) heterogeneity has been the most important pathophysiological mechanism. Depending on the disease condition, additional mechanisms that can contribute to an elevated physiological dead space measurement include shunt, a substantial increase in overall V′A/Q′ ratio, diffusion impairment, and ventilation delivered to unperfused alveolar spaces. A review of current understanding of factors accounting for abnormal physiological dead space measurements in disease http://ow.ly/Dnyw1

Spatial distribution of ventilation and perfusion: mechanisms and regulation.

With increasing spatial resolution of regional ventilation and perfusion, it has become more apparent that ventilation and blood flow are quite heterogeneous in the lung. A number of mechanisms contribute to this regional variability, including hydrostatic gradients, pleural pressure gradients, lung compressibility, and the geometry of the airway and vascular trees. Despite this marked heterogeneity in both ventilation and perfusion, efficient gas exchange is possible through the close regional matching of the two. Passive mechanisms, such as the shared effect of gravity and the matched branching of vascular and airway trees, create efficient gas exchange through the strong correlation between ventilation and perfusion. Active mechanisms that match local ventilation and perfusion play little if no role in the normal healthy lung but are important under pathologic conditions.

Gas Exchange Consequences of Left Heart Failure

This review explores the pathophysiology of gas exchange abnormalities arising consequent to either acute or chronic elevation of pulmonary venous pressures. The initial experimental studies of acute pulmonary edema outlined the sequence of events from lymphatic congestion with edema fluid to frank alveolar flooding and its resultant hypoxemia. Clinical studies of acute heart failure (HF) suggested that hypoxemia was associated only with the final stage of alveolar flooding. However, in patients with chronic heart failure and normal oxygenation, hypoxemia could be produced by the administration of potent pulmonary vasodilators, suggesting that hypoxic pulmonary vasoconstriction is an important reflex for these patients. Patients with chronic left HF commonly manifest a reduced diffusing capacity, an abnormality that appears to be a consequence of chronic elevation of left atrial pressure. That reduction in diffusing capacity does not appear to be primarily attributable to increases in lung water but is improved by any sustained treatment that improves overall cardiac function. Patients with heart failure may also manifest an abnormally elevated VE/VCO2 during exercise, and that exercise ventilation abnormality arises as a consequence of both alveolar hyperventilation and elevated physiologic dead space. That elevated exercise VE/VCO2 in an HF patient has proven to be a powerful predictor of an adverse outcome and hence it has received sustained attention in the HF literature. At least three of the classes of drugs used to treat HF will normalize the exercise VE/VCO2, suggesting that the excessive ventilation response may be linked to elevated sympathetic activity.

Imaging for lung physiology: What do we wish we could measure?

The role of imaging as a tool for investigating lung physiology is growing at an accelerating pace. Looking forward, we wished to identify unresolved issues in lung physiology that might realistically be addressed by imaging methods in development or imaging approaches that could be considered. The role of imaging is framed in terms of the importance of good spatial and temporal resolution and the types of questions that could be addressed as these technical capabilities improve. Recognizing that physiology is fundamentally a quantitative science, a recurring emphasis is on the need for imaging methods that provide reliable measurements of specific physiological parameters. The topics included necessarily reflect our perspective on what are interesting questions and are not meant to be a comprehensive review. Nevertheless, we hope that this essay will be a spur to physiologists to think about how imaging could usefully be applied in their research and to physical scientists developing new imaging methods to attack challenging questions imaging could potentially answer.

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.

Determinants of Pulmonary Blood Flow Distribution

The primary function of the pulmonary circulation is to deliver blood to the alveolar capillaries to exchange gases. Distributing blood over a vast surface area facilitates gas exchange, yet the pulmonary vascular tree must be constrained to fit within the thoracic cavity. In addition, pressures must remain low within the circulatory system to protect the thin alveolar capillary membranes that allow efficient gas exchange. The pulmonary circulation is engineered for these unique requirements and in turn these special attributes affect the spatial distribution of blood flow. As the largest organ in the body, the physical characteristics of the lung vary regionally, influencing the spatial distribution on large-, moderate-, and small-scale levels.

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.