Exercise Gas Exchange, Breath-by-Breath

KARLMAN WASSERMAN

Respiratory Critical Care, Physiology and Medicine, Harbor-UCLA Medical Center, Torrance, California

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Although my initial research was on capillary permeability to macromolecules, I was inadvertently and permanently diverted to the study of exercise physiology in November of 1960 because of a question posed to me by my then mentor, Julius Comroe. I shall relate how this came about shortly, but what followed was the start of a comprehensive research study in exercise physiology, leading to my springboard paper, "Interaction of Physiological Mechanisms during Exercise" by Karlman Wasserman, Antonius L. VanKessel and George G. Burton (J Appl Physiol 1967;22:71-85). This paper describes the coupling of the ventilatory and circulatory responses to cellular respiration during exercise. In addition, it provides insights into gas exchange efficiency and the regulation of acid- base balance as it relates to duration and intensity of exercise.

As a graduate student in physiology at Tulane Medical School in the late 1940s, I developed an interest in the Starling hypothesis of fluid balance across the capillary bed, the permeability of plasma proteins, and the relationship between lymph proteins and plasma proteins. It had obvious importance for the maintenance of intravascular plasma volume. Then the Korean conflict started, and the need to develop plasma volume expanders for treatment of hypovolemic shock made these studies more significant. My then mentor, Hyman S. Mayerson, Ph.D., Chairman of Physiology at Tulane Medical School, was awarded funds from the U.S. Army to study the optimal molecular size of dextran to use as a plasma volume expander. It became my job to do the studies. This led to a number of papers on capillary permeability, a significant bibliography, and my appointment to the Faculty in Physiology after receiving my Ph.D. degree in 1951. I continued my faculty position while enrolled as a medical student at Tulane.

After my graduation from Medical School, I started my Internship on the Osler Service in Internal Medicine at Johns Hopkins. While performing service on the Medical Ward, I received a telephone call from one of the staff at the NIH, offering me a Special Fellowship to work under Dr. Julius Comroe, at the new Cardiovascular Research Institute at the University of California, San Francisco (UCSF). I saw this as an exciting opportunity. Thus, I accepted this fellowship and, after completing my internship, my wife, our three young children, and I traveled cross-country with all of our possessions in our station wagon.

Early in July of 1959, I reported to Dr. Comroe's office at UCSF Hospital to discuss my research. He described a problem to me that perplexed him and that I found interesting. This related to whether or not pulmonary capillary blood flow was pulsatile in man. A paper from his department, when he was still at the University of Pennsylvania, reported it to be pulsatile. However, a later paper from the University of Columbia, using a similar technique, reported it to be nonpulsatile. He asked me to determine which was correct, but using a different technique. I was fortunate to resolve the problem in a relatively short time, and submitted an abstract with the answer that fall for presentation at the 1960 Spring American Physiological Society (APS) meeting. These findings, and subsequent studies that show the likely reason that two groups using a similar technique, obtained different results, are quite interesting and are published in the literature of that time. Dr. Comroe thought that the issue was resolved, and this set the stage for my diversion to the study of exercise.

It was November of 1960, my second year of special fellowship at the UCSF. Dr. Comroe returned from the annual American Heart Association meeting where there was extensive discussion of an "epidemic" of heart disease in the U.S. He called me into his office and told me that a screening test was needed to detect heart disease at an earlier stage, before the patient was incapacitated. He then asked me how I would approach the problem. After some thought and recalling a debate on the definition of heart failure at a Circulation Section dinner of an earlier Spring APS meeting, I responded that the test should be done during exercise and the measurement should be the oxygen uptake at which lactic acidosis started to develop. (I was to refer to this oxygen uptake later as the "anaerobic threshold.") But since it was to be a screening test, it needed to be noninvasive and rapid. I suggested that the development of lactic acidosis could be immediately detected in the breath, because excess CO₂ should be produced as HCO₃ buffered lactic acid. I suggested that our CO₂ and N₂ analyzers of that time had good enough response times so that the respiratory exchange ratio (RER) could be calculated from these measurements, breath-by-breath. He listened, and then said "Go do it!"

I had only 7 months left at UCSF, because I was to take a faculty position in Pulmonary Medicine at Stanford Medical School the following July. But I thought that, with the help of Arnold Naimark, who had joined me as a research fellow in July 1960, and Malcolm McIlroy, a staff member, we could resolve what I thought was a relatively straightforward problem. But 7 months turned into over 40 years for two reasons: (1) some reviewers thought that, for one or another reason, my hypothesis was wrong (e.g., lactate did not increase at a threshold oxygen consumption or that lactate increase had nothing to do with anaerobiosis), and (2) I discovered more questions in investigations designed to examine the questions raised by our critics, particularly pertaining to the validity of the hypotheses of ventilatory control during exercise, extant at that time.

Note that the title of my springboard paper does not identify a specific organ system's response to exercise, but addresses physiological mechanisms interacting to provide a normal response. In this paper, we questioned how the ventilatory control mechanism senses the cardiovascular response to achieve regulation of blood gases and pH, and how the cardiovascular system senses the metabolic requirement of exercise to provide predictable responses. With respect to the muscle, we addressed aerobic and anaerobic mechanisms for high- energy phosphate regeneration during exercise, as related to work intensity and duration. To illustrate the concept of how the system had to work, I made a diagram consisting of three gears, showing the interaction of muscle, circulation and ventilationFigure 21 of the springboard paper.

The paper contains 21 figures and three tables, an unusual number for an original report. One of the reviewers was very critical of this large number of illustrations and held up publication for some time because he thought that I should focus on one organ system. That, of course, was the antithesis of my approach to research in exercise, which views exercise as a process requiring an integration of all of the homeostatic control mechanisms essential for meeting the metabolic and bioenergetic demands of exercise. This paper laid the groundwork for much of the research that subsequently came from my investigative group. Figures have often been reproduced from this springboard paper, particularly, Figure 21 (the gears).

After my move to Stanford, I met several engineers who worked in Stanford Industrial Park and who were interested in what I was doing. I told them that I needed a computer that could calculate the respiratory exchange ratio (RER), breath-by-breath. They assured me that it could be done, and engineers from Central Research of Varian Associates gave me a quote of $6,400 for the job. I then obtained a supplemental grant for this amount from the NIH for its development. However, the engineers did not find the task as easy as they thought. Thus, in 1965, the vice president of research with about 8 scientists from Varian Central Research came to my laboratory and I was asked to describe what I wanted. Then, behind me a voice asked one question and then another. This was the voice of a University of California, Berkeley graduate physicist, William L. Beaver, Ph.D. He then remarked that he would have a working breath-by-breath RER computer for me in two weeks. He did!

Varian Associates, having seen Dr. Beaver's ability to incorporate physics and engineering in physiology, gave him a sabbatical leave of one year to work with me, starting in July of 1966. During this time, we studied the breath-by-breath ventilation and gas exchange responses to perturbations in work rate in man. I think that these were the first breath-by-breath measurements of gas exchange during exercise. Two papers were published from this year of collaboration. From my perspective, it was a very important year because it led to Dr. Beaver's and my continued collaboration and valued friendship for the next 35+ years. In 1973, our methods paper on how to measure exercise gas exchange, breath-by-breath, was published (J Appl Physiol), a direct outgrowth of the springboard paper. This paper is the seminal paper used by investigators and equipment manufacturers today for programming and understanding how to measure gas exchange in response to exercise, breath-by-breath. In 1986, another landmark paper was published (again Beaver technology) on how to measure the anaerobic threshold, breath-by-breath, by what became known as the V-slope method. This is likely the most commonly used and reliable gas exchange method to measure the O₂ uptake at which lactic acidosis develops.

In closing, I must concede that the Beaver special purpose, breath-by-breath RER computer was not successfully applied. This was not due to any deficiency on the part of the computer, but due to my failure to appreciate, at the time, that the substrate for metabolism in different organs of the body was not uniform, and that muscle substrate normally had a higher respiratory quotient than the body as a whole. Thus, RER can increase during exercise as work rate increases, without a significant lactate increase.

In writing this essay for the Journal, I realize that my springboard paper laid out a roadmap for my research, but that the end of the road has not been reached. This is primarily because each new study provides side roads and extends the main route. In addition, with the advances in technology, bolder questions could be asked. But my ultimate goal was to narrow the gulf between laboratory research and patient care. To this end, I believe that we have achieved some, albeit modest, success.

	Footnotes

Correspondence and requests for reprints should be addressed to Karlman Wasserman, M.D., Ph.D, Respiratory Critical Care, Physiology and Medicine, Harbor-UCLA Medical Center, 1000 W. Carson Street, Torrance, CA 90509. E-mail: kwasserman{at}rei.edu