Thirty-eight years ago, a paper entitled “Regional pulmonary function studied with xenon133” was published in the Journal of Clinical Investigation (Ball WC Jr., Stewart PB, Newsham LGS, Bates DV: J Clin Invest 1962;41:519–531). This originated from the Royal Victoria Hospital and McGill University in Montreal. It became one of the top 100 cited papers in clinical research between 1961 and 1978; this is the story of how it came about. Our work was triggered by two papers in the German scientific literature by Knipping and Venrath and their colleagues that had been published in 1957. They described the use of xenon133 detected externally over the chest in the study of lung disease, a method they christened “IsotopenThorakographie.” They showed variations in ventilation distribution, but the measurements were not precisely quantitative. Professor Ronald Christie moved from St. Bartholomew's Hospital in London to McGill and the Royal Victoria Hospital in Montreal in 1955, and I had been working with him in London since returning from my Army service in 1947, and had accepted an associate professorship of medicine at McGill, being charged to set up an investigative group in cardiac and respiratory research. When I arrived in Montreal in 1956, Ronald drew my attention to Knipping's work, which had been sent to him by the authors.
Our research group in London had been pursuing a major interest in emphysema. The introduction of the study of tomograms of the lung by George Simon had shown us, more clearly than one could appreciate from plain films, that emphysema was not often uniform in distribution. John West and Philip Hugh-Jones at Hammersmith had pioneered the use of lobar gas sampling together with a mass spectrometer to give lobar information, and we knew that they were preparing to study regional lung perfusion using radioactive CO2 made in a cyclotron at the hospital. Ronald and I discussed these options in considerable detail, and I realized that one might get a quantitative estimate of ventilation distribution if the radioactive count rate over the lung after a single inspiration containing Xe133 were to be compared to the count rates obtained after the lung had equilibrated with the gas. This would be possible because xenon was relatively insoluble (only about 2% would be taken up during a ten-second breathhold).
Our first problem was that we were going to have to record a lot of data simultaneously. I knew that a multi-channel tape recorder had been developed for the United States space program, and I found out that I could buy a 30-channel tape deck. We wanted to record FM channels on this, and the expert on this method was Ted Radford, who had earlier worked on lung mechanics at the Harvard School of Public Health, but was now in the DuPont Laboratories in Wilmington, Delaware. I went down to see him there and learned everything I could about the methodology. Our final setup recorded from six counters behind the chest, another in the closed circuit, and another at the mouth; volume was recorded by a potentiometer that replaced the axle on the wheel of a spirometer; and we also had a voice channel to log the progress of the study. We built the counters from copper tubing, with a 3 5/8th inch lead collimator, the crystal, a photomultiplier tube, a special miniature preamplifier (about which more later), and a circuit card that discriminated the impulse energy level. This would have the effect of “focusing” the counter. All of this fitted into the tube. This development work was done by David Pengelly, newly graduated in engineering from the University of Toronto, who had joined the group in 1956, and Lionel Bartlett who had come from St. Bartholomew's Hospital to join us in 1957.
Our second problem was to get an assured supply of Xe133. This was only available from Radiochemicals in Amersham in England. I visited there and they agreed to ship a phial of 300 millicuries of highly purified Xe133 in a 10 ml glass ampoule every three weeks on a flight from London to Montreal, and they signed an undertaking to do this for two years. We were joined by Wil Ball from Johns Hopkins, who had both an engineering and a medical degree, and Brian Stewart from the UK who had been working with isotopes in the study of pleural fluid in the Department of Physiology at McGill. Lloyd Stevens Newsham, the Physicist to the Royal Victoria, kept a close and helpful eye on our activities. We were all set to go.
I have said nothing about funding. I had put in an Equipment Grant Request to the Medical Research Council of Canada, but when this was turned down, I was gently informed that it exceeded, by a factor of about ten, any equipment grant they had ever made. Fortunately, a new Medical Wing was being built at the Royal Victoria, and Ronald Christie found out that there was a generous allotment for original equipment from the Federal government if research laboratories were included; this paid for everything. After we had assembled the equipment, but before we had published any papers, I received a call from the Royal Canadian Mounted Police in Ottawa (internal security division) asking me to receive a visit from a senior officer. He arrived, and after we had shut the door of my small office in the Royal Victoria, he said he had come because I had purchased ten very small amplifiers from a company in Los Angeles, and as far as the RCMP knew, these were only useful in espionage work; and they wondered why a physician in the Royal Victoria would need them. We walked downstairs to the xenon lab and showed him how they were being used. After a cup of tea, he departed satisfied.
Wil Ball had the idea of dissolving xenon133 in saline and injecting it into an arm vein; the counters could then measure it over the lung and we could calculate perfusion delivery as well as ventilation. In this way we could measure the regional distribution of ventilation in the six zones of the lung; and then measure as well the distribution of the pulmonary blood flow as seen by the same counters. The basic work on normal subjects at rest was quickly extended, particularly after we were joined by Lamberto Bentivoglio, Charlie Bryan, and Heather MacLeish who studied the effect of exercise on ventilation and perfusion distribution; and by Joseph Milic-Emili who came from Jere Mead's laboratory in the Harvard School of Public Health. He had an outstanding command of current understanding of lung mechanics, and immediately applied this knowledge to sorting out the impact of gravity and of the shape of the normal pressure–volume curve of the lung on ventilation distribution. Assisted by his fellows, he studied the effect of different body positions on blood and gas distribution and has recently revisited the 1966 paper (Can Respir J 2000; 7:71–76) which was another of the 100 most cited papers in clinical research between 1961 and 1978. This analysis was undoubtedly a stellar achievement.
We then designed a new collimation system dividing the back of the lung into six tightly collimated regions. Rudy Dollfuss and Milic-Emili studied what happened when a bolus of Xe133 was inserted into different parts of a full inspiration, and the resultant regional distribution was measured (Respir Physiol 1967;2:234–246). This work built on studies using a bolus of helium and a mass spectrometer in Julius Comroe's laboratory in Philadelphia initiated by Ward Fowler in which I had participated in 1952. Our observations were highly reproducible, but we could not interpret them in any meaningful way, so our abstract at the 1952 Federation Meetings never resulted in a published paper. When the first xenon bolus experiments were to hand, I wrote to Ward because the xenon results fully explained our earlier observations. The bolus experiments led us to suggest that under certain conditions, airway closure could occur, and we invented the term “closing volume” to describe what we thought was happening. These observations were important because they revealed for the first time the earliest effect of cigarette smoking on lung function in young adults, before the FEV1 had fallen. We surmised that airway closure occurred in normal subjects under some conditions, but many of our friends and colleagues did not believe this; it was not until 1975 (J Appl Physiol 38:1117–1125) that the late Ludwig Engel, Alex Grassino, and Nick Anthonisen, in extremely elegant experiments involving nitrous oxide and xenon133, showed beyond doubt that airway closure was actually occurring.
At this time at McGill, a number of the younger faculty, including myself, were pressing for curriculum reforms. As part of these, we instituted a scheme whereby second year medical students spent a whole week with single faculty members, and then reported on their experience. One spent a week with the professor of Pediatrics, and reported that during that week he did not see the professor do anything that a public health nurse could not have done better. We enjoyed that. My student studied the ongoing xenon research, and then reported that: “Dr. Bates is busy measuring the distribution of ventilation and perfusion in the lung which he thinks is very important; but I can't see much sense in it.” Oh well!
So a technique that was originally devised to measure variations in regional function in the lungs of cases of emphysema (which incidentally turned out to be considerable), ended up explaining the effect of gravity on the distribution of ventilation in the normal lung, and on the effect of altered lung recoil as a result of normal aging. It used to be a favorite question of mine to ask the new fellows to explain why, in normal aging of the lung, the arterial PaO2 fell but the PaCO2 did not. It also opened up investigations of the zone of small airways in the lung, and this had important consequences. New technologies in respiratory research have always had the effect of opening up our understanding of unexpected areas—as Julius Comroe liked to emphasize. How the xenon story came about was a consequence of originality (5%); ingenuity (10%); good fortune (20%); persistence and determination (15%); and wonderful fellows, technicians and colleagues (50%), many of whom still look back on this era of their lives as particularly blessed.
