The Fick Principle and the Steady State

ALFRED P. FISHMAN

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In 1952, an unheralded paper in the Journal of Clinical Investigation marked a turning point in my career (Fishman, A. P., J. McClement, A. Himmelstein and A. Cournand, Effects of acute anoxia on the circulation and respiration in patients with chronic pulmonary disease studied during the "steady state". J. Clin. Invest. 1952;31:770-781). The paper had a forked message: one branch showed that in patients with chronic obstructive pulmonary disease (COPD), as in normal individuals, acute hypoxia elicits an increase in pulmonary arterial pressure and blood flow (cardiac output); this increase in pressure and flow could be clinically meaningful in patients with COPD in whom bouts of acute hypoxia are likely to occur spontaneously during exercise, sleep, or upper respiratory infection; the other limb showed that to obtain accurate measurements of cardiac output during acute hypoxia, precautions have to be taken to ensure a steady state of the respiration and circulation.

I arrived at the Bellevue Hospital on foot. A homeless person showed me the way to get in. Following instructions, I climbed the steps to the first floor, reached the landing a little breathless from exertion, somewhat flushed with anticipation and moderately tachycardic from both. Before opening the fire door, I paused to catch my breath. My mind raced.

Although I was officially there as an "Established Investigator of the American Heart Association," in reality I was not yet established. I had been awarded the five-year Established Investigatorship based largely on success in introducing the Kolff artificial kidney into the United States and in demonstrating its effectiveness in treating acute renal failure; this experience with acute renal failure subsequently pointed the way for using renal dialysis in treating chronic renal failure (Fishman, A. P., et al. Am. J. Med. 1949;7:15). In reality, my credentials were those of a research fellow. The period in the Cournand-Richards Cardiopulmonary Laboratory at Bellevue Hospital was primarily intended to provide proper mentoring for a career in clinical investigation. It also afforded the opportunity to learn the technique of right heart catheterization.

I pulled open the fire door. It opened onto a dimly lit corridor, poorly illuminated by light let in through unwashed windows. Opposite the windows, a series of closed doors, beyond which (I was to learn later) were the individual laboratories and offices. The doors were windowless, unmarked, and invited no entry. But far down the empty corridor, I could see a beam of light. Possibly an open door. I headed for it and soon found myself in the doorway of an officeCournand's office. I recognized him immediately from the physiology meetings. He sat beneath the window, hunched over a large wooden desk, totally immersed in writing. I panicked. I was unexpected, unannounced and intruding. I had to back out. I began to step back. Too late. He had sensed my presence.

"Who are you? What do you want? What are you doing here?"

Then, without pause, he answered his own questions. "You are in the wrong place. You probably belong uptown with Stan Bradley" (uptown, at the Columbia-Presbyterian Medical Center). I desperately wanted to get away. But, a restraining hand from behind held me in place. Ruth Fabian, his long-time administrative assistant (and future wife) spoke over my shoulder. "He belongs here. You and Dr. Richards accepted him months ago. I have room for him in my office." The crisis was over. She had saved the day. Cournand had nothing more to say. He swiveled back to his work. We were dismissed.

During the next few weeks, I wandered from room to room, introducing myself, observing tests, and witnessing procedures. There was much new for me to see: cardiac catheterization, bronchospirometry, pulmonary function tests, and exercise tests; all executed by practiced teams with full compliments. But I was not enrolled in any project or assigned a mentor. I was destined to observe and, occasionally, to lend a helping hand.

Between procedures, I took refuge in the analytic laboratory, presided over by Mrs. Lester, a gentle supervisor with many years of experience and loyalty to Cournand. There, between samples of blood and gas, the skilled technicians took time to show me how to use the Haldane and Van Slyke apparatuses. When they were busy, I turned to the old data books and practiced the calculations. The data books were destined to be the turning point in my Cournand-Richards experience.

In one of the books, I came across the data which were the basis for a recent publication from the Laboratory on the effects of acute hypoxia on the pulmonary circulation in normal subjects (Motley, H. L., A. Cournand, et al. Am. J. Physiol. 1947;150:315). The report indicated that acute hypoxia elicited pulmonary vasoconstriction as reflected in an increase in pulmonary arterial pressure accompanied by a decrease in cardiac output. Although, the increase in pulmonary arterial pressures was no surprise, the decrease in cardiac output was unexpected.

In the study by Motley and colleagues, cardiac output was determined by the general Fick equation, usually written:

where O₂ is oxygen consumption and C(a  v)_O2 is arteriovenous difference in O₂ content.

The principle underlying this equation had been enunciated by Fick at the July 9, 1870 meeting of the Würzburg Physikalische-Medizinische Gesellschaft but he had no data to show because he lacked the equipment for gas analysis.

For Cournand and Richards, the obstacle to the application of the Fick principle in humans was the need for mixed venous blood. The way to overcome this hurdle was shown by Forssman who catheterized his own right heart without physical harm (Klinische Wochenschrift, Nov. 5, 1929). In this demonstration, Cournand and Richards saw the answer to their prayer. They proceeded at Bellevue Hospital to validate the safety of the procedure (Proc. Soc. Exp. Biol. 1941;46:462) and then to standardize and apply the Fick equation.

Neither Fick nor Cournand and Richards took cognizance of the need for a steady state of the respiration and circulation for valid measurement of oxygen consumption. Nor did they have reason for concern in experiments involving ambient air breathing conducted in a tranquil and reassuring environment. Experiments involving a switch from ambient air to breathing a hypoxic gas mixture proved to be a different matter.

As I plowed through the data upon which the paper by Motley and colleague was based, I was struck by the low values for oxygen consumption and the high values for the respiratory exchange ratios (R) during acute hypoxia. In my outside reading, I had come across similar values for R in reports by Hermann Rahn and Arthur Otis from the Laboratory of Wallace O. Fenn on acclimatization to altitudes. In the Rahn and Otis experiments, R values were high early in the exposure to simulated high altitudes but gradually returned to normal, reflecting a transition from an unsteady to a steady state of the respiration and circulation and reequilibration of oxygen stores throughout the body at the lower oxygen tensions.

Could it be that the high values for R that entered into the calculation of oxygen consumption, indicated that the exposures to acute hypoxia in the Cournand-Richard's Laboratory had been too brief for a return to a steady state? Was 10% O₂ too hypoxic a mixture and 10 min of exposure too short a time for reequilibration? If so, values calculated for oxygen consumption would be underestimates, causing the values for cardiac output to be too low. I recalculated the data, using normal R values. The results showed this to be the case: cardiac output measured under steady-state conditions would increase during acute hypoxia. Although an increase, rather than the decrease in cardiac output reported by Motley and coworkers, would not invalidate the conclusion of their paper about the pressor effect of acute hypoxia, it would avoid misconceptions about the effect of acute hypoxia on the heart.

I summoned the courage to arrange a return engagement with Cournand. We met in his office. He heard me out. Although clearly upset, he said little. He reviewed my calculations and assumptions one by one. He found no errors. He sat back in his chair. Finally, "It is better that we found the mistake than for others to do so." Off he went with the sheets of paper to notify Richards.

During the next few days, I had several meetings with Richards and Cournand. Finally, I was asked to present my findings to the assembled members of the Laboratory. All recognized the problem: what to do about it? The consensus was that a follow-up study should be done on patients with chronic pulmonary disease, using lesser degrees of hypoxia for longer periods. I was to be incorporated into one to the catheterization teams for purposes of the study. The results of the study were reported in the JCI paper of 1952: allowing return to a steady state by administering less hypoxic mixtures for longer periods of time than in the study by Motley and colleagues, elicited an increase, rather than a decrease, in cardiac output.

Before leaving the Laboratory, I was able to take further advantage of the Fick principle by modifying it to measure blood flow through each lung separately. And, a few years later, as a real established investigator in my own laboratory, uptown at the Columbia-Presbyterian Medical Center, I took another turn at the Fick principle, using it to measure collateral (bronchial artery) blood flow.

The reader who has kept up with me this far should bear in mind that this tale of a research experience is only an anecdote. In my seven years of research training, I was exposed to seven different mentors; each approached science and training with a different personality, personal philosophy, and distinct manner. Each made a mark on my evolution into a clinical scientist. But no period of training shaped my career as much as the experience with Cournand and Richards. In time, we became close colleagues. I was with them when they shared the Nobel Prize in physiology and medicine with Werner Forssmann. And, long after I moved uptown (to the Columbia-Presbyterian Medical Center), Cournand continued to keep a watchful eye on me from downtown (Bellevue Hospital) while Richards, whom I had first met during my trying introduction to the Bellevue Laboratory, became a lifelong mentor, friend, and colleague with whom I spent many hours exploring vistas beyond the bounds of cardiopulmonary medicine (Fishman, A. P., D. W. Richards. Circulation of the BloodMen and Ideas. New York, Oxford University Press, 1964).

	Footnotes

Correspondence and requests for reprints should be addressed to Alfred P. Fishman, M.D., University of Pennsylvania, School of Medicine, 423 Guardian Drive, 1320 Blockley Hall, Philadelphia, PA 19104