Distribution of Pulmonary Blood Flow

JOHN B. WEST

Department of Medicine, University of California San Diego, La Jolla, California

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The prosaic accounts of the first description of the topographical inequality of blood flow in the lung (West, J. B., and C. T. Dollery. Distribution of blood flow and ventilation-perfusion ratio in the lung, measured with radioactive CO₂. J. Appl. Physiol. 1960;15:405-410) and the ensuing three-zone model (West, J. B., C. T. Dollery, and A. Naimark. Distribution of blood flow in isolated lung; relation to vascular and alveolar pressures. J. Appl. Physiol. 1964;19:713-724) are highly artificial reports of the studies, and give very little information about how it really happened. Research is much more unpredictable (and fun) than these stolid accounts suggest.

A preliminary paragraph is necessary to set the scene. I had graduated in medicine at Adelaide University, Australia and moved to London in 1953 with few plans except to see the world. However, I was fortunate in being accepted as a resident at Hammersmith Hospital because this was by far the best London teaching hospital that catered to foreign graduates. I had little idea about what direction to pursue except that, being interested in physical phenomena such as pressures and flows, I was drawn to cardiology or pulmonology. It happened that the Post-Graduate Medical School at Hammersmith was about to embark on a new program in clinical respiratory physiology, and Dr. Charles Fletcher suggested that I learn some respiratory physiology at the Medical Research Council Pneumoconiosis Research Unit in South Wales and then come back to Hammersmith to work with Dr. Philip Hugh-Jones.

I returned to Hammersmith in the fall of 1956 to find two extraordinary research opportunities. The first was that Kemp Fowler, another Australian, had developed the first mass spectrometer specifically designed for respiratory physiology. We used this to analyze expired gas, and this was my introduction to the arcane world of ventilation-perfusion inequality. I still think this is one of the most elegant and satisfying topics in respiratory physiology. Another avenue opened up by the new mass spectrometer was the ability to sample gas in various lobes of the lungs at bronchoscopy to measure lobar function (Thorax 1960;15:154). Although this was a stimulating journey at the time, it turned out to be a dead end.

But by far the most extraordinarily serendipitous event occurred when the Medical Research Council cyclotron at Hammersmith Hospital started to produce radioactive oxygen-15, and we were asked whether we could think of anything to do with it! It is a remarkable coincidence that the three primary respiratory elements: oxygen, carbon, and nitrogen, each have a very short-lived cyclotron-produced isotope (¹⁵O, ¹¹C, ¹³N). The half-life of ¹⁵O is only two minutes so that very large amounts of radioactivity can be introduced into a subject with only a small radiation dose. This was an opportunity that comes along only once or so in a lifetime.

Initially we inhaled ¹⁵O-labeled molecular oxygen and, with counters placed over the chest, measured the initial increase in radioactivity as a measure of regional ventilation, and the rate of removal of radioactivity by the blood flow as a measure of regional perfusion. However the "clearance rate," as we called it, of radioactive molecular oxygen was slow, and we soon found that ¹⁵O-labeled CO₂ enabled us to obtain a more accurate measurement of regional blood flow. At this time, the thought was that by looking at regional ventilation and blood flow, we could provide the thoracic surgeon with useful information about the function of diseased lobes, to complement the measurements we were making at bronchoscopy with the mass spectrometer.

I still remember our astonishment when measurements made in seated normal volunteers showed a striking increase in the clearance rate from the top to the bottom of the lung. Indeed, in some subjects the clearance at the extreme apex of the lung was almost nonexistent. This dramatic topographical inequality of blood flow came as a complete surprise to us and this finding was absolutely serendipitous. Regrettably, any hypothesesso cherished by modern NIH Study Sectionswere completely missing! It is true that in retrospect there had been one or two previous studies suggesting that blood flow increased down the lung. These had mainly come from bronchospirometry, particularly when small catheters were passed into different lobes. However the significance of these studies had been largely overlooked. To us, the gradient of blood flow down the lung came as a complete surprise. We quickly found that the pattern of blood flow depended on posture, implying that gravity was the culprit.

These early studies with ¹⁵O produced other surprises as well. One was when we prepared ¹⁵O-labeled water vapor and inhaled this with counters confidently situated over the chest. Nothing happened; the detectors showed no increase in counting rate in spite of the fact that a millicurie or so of radioactivity had been inhaled! The answer was quickly found when we moved the counters to the nasopharynx and trachea areas. All the inhaled water vapor had exchanged with that lining the upper respiratory tract (Nature 1961;189:588).

We spent two very productive years studying the distribution of blood flow in normal subjects under various conditions, and in patients with lung and heart disease. I then temporarily moved away from this topic for two years because of attractive opportunities elsewhere. One of these years was spent in the Himalayas doing high-altitude physiology with the 1960-1961 Silver Hut Expedition led by Sir Edmund Hillary, and the other was a year in Hermann Rahn's department of physiology in Buffalo, NY where I thought more about ventilation- perfusion inequality. When I returned to Hammersmith at the end of 1962, we decided to embark on a systematic study of the mechanisms responsible for the uneven distribution of blood flow in the lung.

A critical step in this study was setting up an isolated perfused dog-lung preparation which allowed us to measure the topographical inequality of blood flow in the lung. We were fortunate that there was an ample supply of greyhound dogs in London because of the popularity of greyhound racing, and the dealers were only too happy to let us have the animals that came last. These lungs were some 25 cm high when supported with the apex at the top and so were ideally suited to making topographical studies. However, maintaining the isolated perfused lungs in good condition without developing pulmonary edema was a challenge and something of an art rather than a science. Fortunately, the experimental surgeons at Hammersmith were working on perfusion of isolated organs and they gave us many tips. We concentrated on systematically varying the pulmonary arterial and venous pressures because it had become clear that hydrostatic pressures played a major role. Eventually we were able to show that with normal pulmonary vascular pressures, we could exactly reproduce the pattern of topographical inequality of blood flow that occurred in upright normal subjects, and we soon had good data on the results of changing the vascular pressures.

Perhaps the most important concept in the resulting three-zone model of the distribution of blood flow was the Starling resistor, sluice, or waterfall phenomenon. Simply stated, this describes how flow through a collapsible tube surrounded by a pressure chamber is determined by the upstream pressure minus the pressure chamber, rather than the downstream pressure, when chamber pressure exceeds downstream pressure. Exactly how we came by this seminal notion is unclear but we were certainly not the originators.

One of the major players in the development of this idea was Solbert Permutt. At the Fifth Annual Aspen Conference in June of 1962, he suggested that the lung can be modeled as "an infinite number of Starling resistors, one above the other" and that this could explain the pressure-flow relations in the whole lung (Med. Thorac. 1962;19:239). That presentation certainly influenced our ideas. However, interest in the characteristics of flow through collapsible tubes had been around for much longer than this in physiology. For example, Banister and Torrance, in 1960, had shown how tracheal pressure could determine blood flow through the lungs when the pressure was raised. They compared the behavior with that of a sluice where the flow of water over the sluice gate is independent of the height of the gate. Previous to that Guyton and his colleagues, in 1957, had clearly recognized that blood flow could be limited by collapse of veins, as had Holt even earlier, in 1944. Thus the concept is old and trying to pinpoint its origin is like trying to pick up mercury. We simply exploited the idea to explain the increase in blood flow down zone 2, and have never claimed originality for describing the basic physical phenomenon.

The original three-zone model was modified in several ways and one of these will be mentioned here. When we systematically investigated the effects of changing lung volume on the distribution of blood flow in humans, we found that there was an additional zone of reduced blood flow (zone 4) in the most dependent region of the human lung, and that this extended further up the lung as lung volume was decreased (Respir. Physiol. 1968;4:58). We attributed this region of reduced blood flow to increased resistance in the extra-alveolar vessels because these have their narrowest caliber in the most dependent regions of the lung where alveolar expansion is least, and their caliber will depend on overall lung volume.

Most of the studies described above were carried out in the 1950s and 1960s and many of the present generation of pulmonary postdoctoral fellows and junior faculty are blissfully unaware of them. More recently there has been much interest in the inequality of blood flow at a particular level in the lung, emphasizing that additional factors cause substantial perfusion inhomogeneity (J. Appl. Physiol. 1991;71:620). For the record, we have never claimed that gravity is responsible for all the uneven blood flow in the human lung, and indeed we have made several studies of inequality at the alveolar level. However, it is clear that gravity has a dominant role in the upright human lung.

Are there any lessons to be learned from all this? Perhaps one is that major advances in technology, such as the availability of cyclotron-produced short-lived radioisotopes, can make an enormous impact. Happily, we were in the right place at the right time. Another factor was the research environment at Hammersmith, where we had complete freedom to follow our nose, and there was none of the proposal writing that is so frustrating and time consuming today. There were fewer investigators in those days, and the competition for funds was presumably much less. I wonder if our children will have so much fun.

	Footnotes

Correspondence and requests for reprints should be addressed to John B. West, M.D., Ph.D., University of California San Diego, Department of Medicine 0623A, 9500 Gilman Drive, La Jolla, CA 92093-0623. E-mail: jwest{at}ucsd.edu