Importance of gravity in determining the distribution of pulmonary blood flow

The following is the abstract of the article discussed in the subsequent letter:

	ABSTRACT

Chang, Hung, Stephen J. Lai-Fook, Karen B. Domino, Carmel Schimme, Jack Hildebrandt, H. Thomas Robertson, Robb W. Glenny, and Michael P. Hlastala. Spatial distribution of ventilation and perfusion in anesthetized dogs in lateral postures. J Appl Physiol 92: 745-762, 2002.We aimed to assess the influence of lateral decubitus postures and positive end-expiratory pressure (PEEP) on the regional distribution of ventilation and perfusion. We measured regional ventilation (A) and regional blood flow () in six anesthetized, mechanically ventilated dogs in the left (LLD) and right lateral decubitus (RLD) postures with and without 10 cmH₂O PEEP. was measured by use of intravenously injected 15-µm fluorescent microspheres, and A was measured by aerosolized 1-µm fluorescent microspheres. Fluorescence was analyzed in lung pieces ~1.7 cm³ in volume. Multiple linear regression analysis was used to evaluate three-dimensional spatial gradients of , A, the ratio A/, and regional PO₂ (Pr_O2) in both lungs. In the LLD posture, a gravity-dependent vertical gradient in was observed in both lungs in conjunction with a reduced blood flow and Pr_O2 to the dependent left lung. Change from the LLD to the RLD or 10 cmH₂O PEEP increased local A/ and Pr_O2 in the left lung and minimized any role of hypoxia. The greatest reduction in individual lung volume occurred to the left lung in the LLD posture. We conclude that lung distortion caused by the weight of the heart and abdomen is greater in the LLD posture and influences both and A, and ultimately gas exchange. In this respect, the smaller left lung was the most susceptible to impaired gas exchange in the LLD posture.

	LETTER

To the Editor: A recent paper (2) is the latest in a series from Hlastala, Glenny, and their colleagues in Seattle reporting their studies of the distribution of pulmonary blood flow using fluorescent microspheres. This article and others, for example, Ref. 6, raise important issues about the effects of gravity on the distribution of pulmonary blood flow.

1) The Seattle group have shown considerable heterogeneity of pulmonary blood flow at any given level in the lung, and this is an important advance. There is no controversy on this issue.

2) There is clear disagreement between the results obtained by the Seattle group and those from many other laboratories around the world on the effects of gravity on the distribution of pulmonary blood flow. As examples, early measurements with radioactive carbon dioxide showed a dramatic increase in blood flow with distance down the upright human lung with almost no flow at all at the apex (7). Measurements made with radioactive xenon showed a similar distribution with the conclusion that the apex had no perfusion at all (1). Additional extensive experiments using isolated perfused animal lungs confirmed the major influence of gravity on the distribution of blood flow and clarified that this was caused by the disparity between the hydrostatic pressure gradient in the blood vessels and the absence of a gradient in alveolar pressure (8). Other investigators have shown that exposing the human lung to increased gravitational force greatly exaggerates the topographical inequality of blood flow such that, in the upright human lung at 3 G, the upper two-thirds of the lung are unperfused (3, 5). Figure 1 shows an example from the work of Glaister (3, 4) where the measurement was made on a human volunteer on a centrifuge at an acceleration of 1, 2, and 3 G. 

View larger version (13K): [in this window] [in a new window]   Fig. 1.   Major effect of increased G on the vertical distribution of pulmonary blood flow in a normal human volunteer. The subject was seated on a centrifuge with the acceleration vector from head to foot (Gz). A: +1 Gz. B: +2 Gz. C: +3 Gz. Data from Glaister (3, 4).

3) By contrast, the Seattle group have found either a minor effect of gravity on the distribution of pulmonary blood flow or, in some cases, no effect at all. This is not surprising in some of their studies performed on small animals in the supine, prone, or lateral positions, where hydrostatic factors are small. However in a crucial experiment on anesthetized pigs where they used a parabolic flight profile to provide both increased and 0 G, they found that changing the gravitational vector from 1.8 G to 0 G resulted in no significant difference among the pulmonary blood flow distributions (6). These results are in clear disagreement with those of other investigators cited above (8) and do a disservice to our understanding of the problems encountered by fighter pilots flying high-performance aircraft.

4) What is the reason for the disagreement between the Seattle studies and those of other investigators? I believe that the answer can be found in their most recent paper (2) where on page 755, under the heading Methodological Issues, they point out that their previous studies were erroneous because they did not take into account the regional differences of lung expansion caused by its weight. In their technique, the microspheres are injected when the lung in the chest is deformed by the lung's weight, but the distribution of microspheres is measured after the lung has been removed from the chest and uniformly expanded with consequent changes in regional lung volume.

The authors clearly state this source of error on page 755 as follows: "Prior studies [by our group] have reported the vertical gradients of perfusion relative to the number of alveoli or piece weight at TLC. This paper presents perfusion gradients relative to the regional lung volume at the time of microsphere injections. The adjustment for the vertical changes in regional lung density produced vertical gradients in regional blood flow that were greater than those estimated in previous studies using TLC-measured regional volume." In other words, the earlier papers were in error because the reduced expansion in the most dependent regions of the lung (where blood flow was highest) was abolished by inflating the lung to total lung capacity (TLC), and thus the regional differences of blood flow were obscured.

5) The Seattle group should now clarify to what extent the correction for uneven lung expansion in vivo alters their previous assertions that gravity is a relatively unimportant factor in the distribution of pulmonary blood flow. Indeed they acknowledge this in their recent paper (2) on page 755 where they state "These normalization issues need further evaluation, particularly in the supine and upright body positions under both normal and increased acceleration loads with relatively large Ptp gradients." Those of us who have been puzzled by the earlier results of the group look forward to seeing the corrected distributions for the earlier studies.

	REFERENCES

1.   Anthonisen, NR, and Milic-Emili J. Distribution of pulmonary perfusion in erect man. J Appl Physiol 21: 760-766, 1966[Free Full Text].

2.   Chang, H, Lai-Fook SJ, Domino KB, Schimmel C, Hildebrandt J, Robertson HT, Glenny RW, and Hlastala MP. Spatial distribution of ventilation and perfusion in anesthetized dogs in lateral postures. J Appl Physiol 92: 745-762, 2002[Abstract/Free Full Text].

3.   Glaister, DH. The effect of positive centrifugal acceleration upon the distribution of ventilation and perfusion within the human lung, and its relation to pulmonary arterial and intraoesophageal pressures. Proc Roy Soc Lond Ser B 168: 311-334, 1967.

4.   Glaister, DH. Effect of acceleration. In: Regional Differences in the Lung, edited by West JB.. New York: Academic, 1977, p. 323-379.

5.   Glaister, DH. Effects of acceleration on the lung. In: Gravity and the Lung: Lessons From Microgravity, edited by Prisk GK, Paiva M, and West JB.. New York: Dekker, 2001, p. 39-74.

6.   Glenny, RW, Lamm WJ, Bernard SL, An D, Chornuk M, Pool SL, Wagner WW, Jr, Hlastala MP, and Robertson HT. Selected Contribution: Redistribution of pulmonary perfusion during weightlessness and increased gravity. J Appl Physiol 89: 1239-1248, 2000[Abstract/Free Full Text].

7.   West, JB, and Dollery CT. Distribution of blood flow and ventilation-perfusion ratio in the lung, measured with radioactive CO₂. J Appl Physiol 15: 405-410, 1960[Abstract/Free Full Text].

8.   West, JB, Dollery CT, and Naimark A. Distribution of blood flow in isolated lung; relation to vascular and alveolar pressures. J Appl Physiol 19: 713-724, 1964[Abstract/Free Full Text].

John B. West Department of Medicine University of California, San Diego La Jolla, California 92093-0623 E-mail: jwest{at}ucsd.edu

	REPLY

To the Editor: We appreciate the opportunity to respond to the letter submitted by Dr. John West concerning the mechanisms determining pulmonary blood flow distribution. Gravity affects both the distribution of pulmonary blood flow and compression of lung parenchyma. Our studies have focused on the effect of gravity on blood flow redistribution independent of lung compression. How regional blood flow is expressed, whether per alveolus or per lung volume, is largely dependent on the methods used to obtain the measurements and the scientific questions of interest. When microspheres are used to measure regional blood flow during different postures and physiological conditions, the volume at which the lung is fixed must be chosen arbitrarily. We have elected to fix our lungs at TLC and present our data as blood flow per alveolus. However, if one wishes to incorporate the effects of gravity on lung compression by expressing regional blood flow per lung volume, our measurements from lungs dried at TLC can be adjusted for the expected density as a function of height. Our specific responses to the five points in Dr. West's letter follow.

1) While isogravitational heterogeneity is the most important source of blood flow heterogeneity at high spatial resolution, we must note that many other investigators had made this observation long before our work was published (1, 7, 10, 13).

2) When the spatial resolution of our data is reduced to those of other laboratories, our observations do not differ as greatly as suggested by Dr. West. We clearly observe a vertical gradient in perfusion when blood flow is averaged within isogravitational planes. The strength of this relationship deteriorates when the heterogeneity of perfusion within isogravitational planes is revealed by high-resolution measurements. Dr. West presents a figure of Glaister that demonstrates a strong relationship between vertical height and regional blood flow during increased G_Z (cranial-to-caudal acceleration). The relationship was exaggerated in this study because isogravitational heterogeneity was ignored, pulmonary artery pressures were low, and the lung was compressed during imaging. Similar studies in which blood flow distribution was marked with macroaggregates during different G forces and then imaged during 1 G showed little or no change in blood flow distribution (11, 14).

3) Our study comparing pulmonary blood flow distribution in pigs during microgravity, ±1 G_x (ventral-to-dorsal acceleration), and ±1.8 G_x (6) did demonstrate changes in large-scale flow gradients when the results were expressed as an average measurement for each isogravitational plane [Fig. 1 (top), flows normalized by tissue weight, or blood flow per alveolar unit]. The gradients failed to attain statistical significance because of the variability between animals. This study investigated blood flow to the same lung regions under different gravitational conditions. It purposely ignored the effect of gravity on lung compression.

View larger version (31K): [in this window] [in a new window]   Fig. 1.   Top: vertical distribution of blood flow during 0-, +1-, and +1.8-Gx conditions (ventral-to-dorsal acceleration). Vertical gradient of perfusion was steeper at higher G levels. Bottom: blood flow adjusted for parenchymal gradients of lung density. Modified from Glenny et al. (6).

4) We agree that the gravitationally mediated compression of lung parenchyma in upright, supine, and lateral positions influences in vivo gradients of lung blood flow when expressed per regional lung volume. In the prone position, there is no appreciable in vivo gradient of lung parenchymal density. We therefore believe that the in vivo topical distribution of pulmonary blood flow in the lungs of prone horses (8), baboons (4), dogs (5), and pigs (9, 12) is appropriately measured by the distribution of intravenously injected microspheres in a TLC-inflated lung. In the prone position, the gravity-attributable gradient of perfusion is small (dogs, baboons, and pigs) and even opposite to the gravitational direction in horses (2). All of our studies previous to Chang et al. (3) expressed results as blood flow per weight of blood-free dried alveolar tissue, intentionally ignoring the effects of parenchymal compression. We do not accept that our approach is "erroneous," but we do agree that by experimental design our technique excludes the influence of in vivo gravitational compression of lung tissue that is present in all nonprone body positions. In Chang et al., we recognized that the most extreme extent of lung parenchymal compression occurs in the left lateral decubitus position, and we made adjustments to the gravitational gradients based on this recognition.

5) We stand by all of our measurements of the spatial distribution of prone blood flow as faithful representations of the in vivo flow distribution per alveolus. Dr. West now requests that we present our prior data per regional lung volume. Because there is little to no gravitational gradient in lung density when prone, all our prior studies in this posture do not need to be recalculated. In response to Dr. West's request, we used the supine pulmonary blood flow distribution data from our microgravity experiments (6) to estimate the added contribution of parenchymal compression to the gravitational gradient of flow. Figure 1 presents regional blood flow as a function of height for one animal in the supine posture during three gravitational conditions. Pulmonary blood flow is presented as both per alveoli (original data presentation; top) and per lung volume (bottom) to demonstrate differences in the results. The two plots in microgravity are identical because there is no lung compression in this environment. As expected at +1 G_x, pulmonary blood flow has a greater vertical gradient when normalized to in vivo lung volume, and this effect is magnified at +1.8 G_x. Of note, compared with the blood flow per alveolus, the slopes after correction for parenchymal compression are only 11 and 16% greater during +1 and +1.8 G_x, respectively. The relatively modest change in the slope is due to the low blood flow to the most dependent regions that are most influenced by normalization to lung volume. In vivo gravitationally directed flow gradients are apparent in all nonprone positions, but at +1 G_x these gradients are small and primarily attributable to parenchymal compression, rather than redistribution of blood flow.

	FOOTNOTES

10.1152/japplphysiol.00459.2002

	REFERENCES

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2.   Bernard, SL, Glenny RW, Erickson HH, Fedde MR, Polissar N, Basaraba RJ, and Hlastala MP. Minimal redistribution of pulmonary blood flow with exercise in racehorses. J Appl Physiol 81: 1062-1071, 1996[Abstract/Free Full Text].

3.   Chang, H, Lai-Fook SJ, Domino KB, Schimmel C, Hildebrandt J, Robertson HT, Glenny RW, and Hlastala MP. Spatial distribution of ventilation and perfusion in anesthetized dogs in lateral postures. J Appl Physiol 92: 745-762, 2002.

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5.   Glenny, RW, Lamm WJ, Albert RK, and Robertson HT. Gravity is a minor determinant of pulmonary blood flow distribution. J Appl Physiol 69: 620-629, 1991.

6.   Glenny, RW, Lamm WJ, Bernard SL, An D, Chornuk M, Pool SL, Wagner WW, Jr, Hlastala MP, and Robertson HT. Selected Contribution: Redistribution of pulmonary perfusion during weightlessness and increased gravity. J Appl Physiol 89: 1239-1248, 2000.

7.   Greenleaf, JF, Ritman EL, Sass DJ, and Wood EH. Spatial distribution of pulmonary blood flow in dogs in left decubitus position. Am J Physiol 227: 230-244, 1974[Free Full Text].

8.   Hlastala, MP, Bernard SL, Erickson HH, Fedde MR, Gaughan EM, McMurphy R, Emery MJ, Polissar N, and Glenny RW. Pulmonary blood flow distribution in standing horses is not dominated by gravity. J Appl Physiol 81: 1051-1061, 1996[Abstract/Free Full Text].

9.   Hlastala, MP, Chornuk MA, Self DA, Kallas HJ, Burns JW, Bernard S, Polissar NL, and Glenny RW. Pulmonary blood flow redistribution by increased gravitational force. J Appl Physiol 84: 1278-1288, 1998[Abstract/Free Full Text].

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12.   Mure, M, Domino KB, Lindahl SG, Hlastala MP, Altemeier WA, and Glenny RW. Regional ventilation-perfusion distribution is more uniform in the prone position. J Appl Physiol 88: 1076-1083, 2000[Abstract/Free Full Text].

13.   Reed, JH, Jr, and Wood EH. Effect of body position on vertical distribution of pulmonary blood flow. J Appl Physiol 28: 303-311, 1970[Free Full Text].

14.   Stone, HL, Warren BH, and Wagner JH. The distribution of pulmonary blood flow in human subjects during zero-G. AGARD Conf Proc 2: 129-148, 1965.

Robb W. Glenny, Michael P. Hlastala, H. Thomas Robertson Departments of Physiology and Biophysics and Medicine University of Washington Seattle, Washington 98195 E-mail: hlastala{at}u.washington.edu