J Appl Physiol 97: 1603–1604, 2004.

First published August 23, 2004; doi:10.1152/classicessays.00024.2004. Editorial Focus

ESSAYS ON APS CLASSIC PAPERS

Understanding pulmonary gas exchange: ventilation-perfusion relationships

This essay looks at the historical significance of four APS classic papers that are
freely available online:
Fenn WO, Rahn H, and Otis AB. A theoretical study of the composition of the
alveolar air at altitude. Am J Physiol 146: 637– 653, 1946 ([Link]
[Link]/cgi/reprint/146/5/637).
Rahn H. A concept of mean alveolar air and the ventilation-bloodflow relation-
ships during pulmonary gas exchange. Am J Physiol 158: 21–30, 1949 (http://
[Link]/cgi/reprint/158/1/21).
Riley RL and Cournand A. “Ideal” alveolar air and the analysis of ventilation-
perfusion relationships in the lungs. J Appl Physiol 1: 825– 847, 1949 (http://
[Link]/cgi/reprint/1/12/825).
Riley RL and Cournand A. Analysis of factors affecting partial pressures of
oxygen and carbon dioxide in gas and blood of lungs: theory. J Appl Physiol 4:
77–101, 1951 ([Link]

ONE OF THE FEW GOOD THINGS to come out of World War II was ing” in the hope of improving the performance of pilots at high
a dramatic increase in our understanding of respiratory physi- altitude. Although none of the protagonists had apparently had
ology and, in particular, pulmonary gas exchange. In some any previous training in human physiology and, it is said, were
instances the circumstances were peculiar. As has been pointed vague about the subdivisions of lung volume, this group laid
out elsewhere (2), one of the major centers for this work at the the foundations of the modern understanding of pulmonary gas
University of Rochester, New York, had inauspicious begin- exchange and mechanics.
nings. Wallace Fenn was working on muscle contraction and The other thread in the story came from an equally unlikely
potassium movement across cell membranes, Hermann Rahn source. Joseph Lilienthal at the U.S. Naval School of Aviation
(Fig. 1) was developing a bioassay method in frogs for pitu- Medicine in Pensacola, Florida, was asked to investigate car-
itary hormones, and Arthur Otis was studying the activation of bon monoxide levels in the blood of pilots because this was
the enzyme tyrosinase in grasshopper eggs. Yet because of the thought to be a possible contributor to the large number of fatal
exigencies of war these three were asked by the U.S. Air Force crashes during training. He was using the microsyringe ana-
(USAF) to study the “physiological effects of pressure breath- lyzer recently developed by Scholander and Roughton (10),
and Richard Riley (Fig. 2), whose office was across the hall,
had the idea that it might be possible to measure the PO2 and
Address for correspondence: J. B. West, UCSD Dept. of Medicine 0623A, PCO2 of arterial blood by equilibrating a small bubble of gas
9500 Gilman Drive, La Jolla, CA 92093-0623 (E-mail: jwest@[Link]).

Fig. 1. Hermann Rahn. Fig. 2. Richard L. Riley.

[Link] 8750-7587/04 $5.00 Copyright © 2004 the American Physiological Society 1603
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Editorial Focus
1604 ESSAYS ON APS CLASSIC PAPERS

with blood and analyzing this in the syringe (9). This sparked Indeed the basic ventilation-perfusion ratio equation is decep-
Riley’s interest in the mechanisms of hypoxemia in lung tively simple:
disease and led to a study of the role of ventilation-perfusion V̇ A 8.63 ⫻ R ⫻ 共CaO2 ⫺ Cv៮ O2兲
inequality. A related anecdote is that Riley developed pulmo- ⫽
nary tuberculosis in 1948 and, while resting at home, reflected Q̇ PACO2
on the mysteries of ventilation-perfusion inequality, corre- where V̇A is alveolar ventilation, Q̇ is blood flow (both in
sponded with the Rochester group, and developed his influen- l/min), R is respiratory exchange ratio, CaO2 and Cv៮ O2 are the
tial four-quadrant diagram. As he said, “Never was enforced oxygen concentrations in effluent and mixed-venous blood (in
confinement given more profitable psychotherapy” (6). ml/dl), and PACO2 is the alveolar PCO2 (Torr).
As a result of the discoveries of these two groups of The problem comes in implementing this equation because
investigators, the American Journal of Physiology and the the solution depends on the oxygen and carbon dioxide disso-
Journal of Applied Physiology have the distinction of publish- ciation curves, which are not only nonlinear but interdepen-
ing the seminal papers on ventilation-perfusion relationships dent. This is the reason why the study of ventilation-perfusion
(1, 4, 7, 8). Unhappily, V̇A/Q̇ inequality (to use the argot of the relationships relied heavily on graphical analysis (5) until
initiated) is not fashionable at the present time, but to me it is numerical solutions became possible with the advent of the
one of the most elegant and satisfying areas in the whole of computer (12).
pulmonary gas exchange. I fell in love with the topic, as did The four papers on which this short essay is based will
many others, and my car license plate still says VAQ. remain classics because an understanding of ventilation-perfu-
As implied above, the two groups and their disciples, Fenn, sion relationships will always be important in analyzing pul-
Otis, and Rahn in Rochester and then Buffalo on the one hand, monary gas exchange in normal lungs under unusual condi-
and Riley and his colleagues in Pensacola and subsequently at tions, such as at high altitude, and is the cornerstone for dealing
Johns Hopkins on the other, came at the problem from different with abnormal gas exchange in patients with lung disease. The
directions. The Rochester group under contract with the USAF American Physiological Society can rightly be proud of its role
started with attempts to better understand pulmonary gas ex- in developing this fundamental area of knowledge.
change at high altitude, and indeed their emphasis continued to REFERENCES
be on the gas side of the pulmonary blood-gas barrier and in
1. Fenn WO, Rahn H, and Otis AB. A theoretical study of the composition
particular the development of the enormously powerful oxy- of the alveolar air at altitude. Am J Physiol 146: 637– 653, 1946.
gen-carbon dioxide diagram (5). By contrast, Riley and his 2. Otis AB and Rahn H. Development of concepts in Rochester, New York,
colleagues began with the factors determining the arterial PO2, in the 1940s. In: Pulmonary Gas Exchange. Ventilation, Blood Flow, and
Diffusion, edited by West JB. New York: Academic, 1980, vol. 1.
and the four-quadrant diagram, for example, emphasized the 3. Pappenheimer JR. Standardization of definitions and symbols in respi-
roles of the oxygen and carbon dioxide dissociation curves. ratory physiology. Fed Proc 9: 602– 605, 1950.
They went on to develop a three-compartment model of pul- 4. Rahn H. A concept of mean alveolar air and the ventilation-bloodflow
monary gas exchange where one compartment was “ideal” in relationships during pulmonary gas exchange. Am J Physiol 158: 21–30,
1949.
the sense that gas exchange was optimal, another compartment 5. Rahn H and Fenn WO. A Graphical Analysis of the Respiratory Gas
had unperfused alveoli, and a third had unventilated alveoli. Exchange: the O2-CO2 Diagram. Washington, DC: American Physiolog-
This model was the gold standard for assessing ventilation- ical Society, 1955.
perfusion inequality in patients with lung disease until the 6. Riley RL. Development of the three-compartment model for dealing with
uneven distribution. In: Pulmonary Gas Exchange. Ventilation, Blood
introduction of the multiple inert gas elimination technique Flow, and Diffusion, edited by West JB. New York: Academic, 1980, vol.
allowed V̇A/Q̇ distributions to be described (11). 1, p. 67– 85.
An intriguing feature of these two groups is that their work 7. Riley RL and Cournand A. “Ideal” alveolar air and the analysis of
was largely independent and followed different courses, al- ventilation-perfusion relationships in the lungs. J Appl Physiol 1: 825–
847, 1949.
though apparently the two groups kept in touch. A feature of 8. Riley RL and Cournand A. Analysis of factors affecting partial pressures
some of the early papers from both groups is that they are now of oxygen and carbon dioxide in gas and blood of lungs: theory. J Appl
difficult to read because of the awkward nomenclature. It was Physiol 4: 77–101, 1951.
a major advance in 1950 when a committee chaired by John 9. Riley RL, Proemmel DD, and Franke RE. A direct method for deter-
mination of oxygen and carbon dioxide tensions in blood. J Biol Chem
Pappenheimer agreed on the symbols that we still use to- 161: 621– 633, 1945.
day (3). 10. Scholander PF and Roughton FJW. Micro gasometric estimation of the
These papers show that the key to understanding pulmonary blood gases. II. Carbon monoxide. J Biol Chem 148: 551–563, 1943.
gas exchange in individual lung units is that the composition of 11. Wagner PD, Saltzman HA, and West JB. Measurement of continuous
distributions of ventilation-perfusion ratios: theory. J Appl Physiol 36:
the alveolar gas (and therefore the effluent blood) depends on 533–537, 1974.
only four primary factors: ventilation, blood flow, composition 12. West JB. Ventilation-perfusion inequality and overall gas exchange in
of inspired gas, and composition of mixed venous blood. computer models of the lung. Respir Physiol 7: 88 –110, 1969.

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