Occasional Essays
corresponding arteriovenous difference in oxygen content.
Department of Medicine, University of Pennsylvania School of Medicine, Correspondence and requests for reprints should be addressed to Alfred P. Fishman, M.D., University of Pennsylvania School of Medicine, Office of Program Development, 1320 Blockley Hall, 423 Guardian Drive, Philadelphia, 19104-6021. E-mail:
At the start of the twentieth century, studies of pulmonary hemodynamics were
largely confined to measurements of pulmonary arterial pressures in
anesthetized, open-chest animals undergoing artificial respiration (1). By then,
pressure recording was fairly well standardized, and pressures recorded in
animals by different manometric systems were generally accurate and similar in
form (2). Outflow pressures, for the calculation of pulmonary vascular resistance
and the measurement of left arterial measures, became available at midcentury
(3). A leading figure in setting standards for pressure recording was Otto Frank
(1865–1944), a distinguished German physiologist and physician, whose name is
well known to circulatory physiologists as one of the discoverers of the Frank-
Starling law of the heart. Less familiar, but seminal for the study of
hemodynamics, was his role in setting standards for the accurate recording of
vascular pressure pulses (4). These standards featured prominently in the
subsequent design and application of cardiac catheters for human use.
Another iconic physiologist of that time was Ernest Henry Starling (1866–1927)
whose heart–lung preparations that made it possible for experimental
observations to be made under rigorously controlled conditions so that
physiologic factors and mechanisms could be isolated and analyzed in
mechanical and physiologic terms. From such preparations were derived the
Frank-Starling law of the heart and Starling's forces involved in capillary
exchange. However, observations made under such artificially controlled
conditions paid the penalty of obscuring automatic adjustments that occur
under more natural conditions (Figure 1) .
The modern era of measuring pulmonary blood flow began in 1912 with August
Krogh and Johannes Lindhard who used nitrous oxide as the test gas and
popularized the use of gas uptake methods in humans (5). The use of indirect
methods became widespread. However, the indirect methods were
handicapped by two major uncertainties: (1) early recirculation, which artificially
decreased the value for cardiac output by diminishing the uptake of gas from
the alveoli, and (2) the use of alveolar gas sampling to estimate the content of
the regulatory gases in blood returning to the heart (6).
A direct approach to measuring cardiac output was suggested by Adolph Fick in
1870 in a short commentary to his local medical society in Würzburg, Germany
(Figure 2) (7). He indicated that the cardiac output could be measured by
2007 Sociedad Venezolana de Medicina Crítica Todos los derechos reservados
catheterized by way of a peripheral vein (9). His interest was in cardiac injections
rather than in blood sampling from within the heart. To convince others about
the safety of the procedure, he catheterized himself on several different
occasions and walked about, with catheter in place, climbing the stairs en route
to the X-ray department. Forssmann made sure that others were aware of his
accomplishment and its prospects. However, instead of earning plaudits for his
pioneering effort, Forssmann was rewarded with criticism and ridicule by his
Forssmann's demonstration attracted more attention in Europe and South
America than in Germany. In the United States, the lead was taken in the 1940s
by the Cardiopulmonary Laboratory at Bellevue Hospital in New York City (Figure
4) (10). André F. Cournand was the director of the laboratory, which was
sponsored by both the Chest Service run by J. Burns Amberson, M.D., and the
Medical Division of Columbia University, headed by Dickinson W. Richards, M.D.
With the strong support of these two sponsors, André Cournand established a
world-renowned cardiopulmonary laboratory. In 1951, I rotated through the
laboratory as an Established Investigator of the American Heart Association and
subsequently rejoined it as a member of the research team on the faculty of the
College of Physicians and Surgeons of Columbia University.
Spurred on in large part by the Bellevue laboratory, the use of cardiac
catheterization for diagnostic purposes spread quickly throughout medical
centers in the United States and abroad. In 1956, Forssmann shared the Nobel
Prize with Cournand and Richards for their respective roles in introducing and
standardizing cardiac catheterization. As usage spread, modifications in
equipment and technique made it possible to move cardiac catheterization from
the fluoroscopy room to the bedside where hemodynamic monitoring could be
substituted for radiographic visualization of the catheter tip. In 1953, Michael
Lategola and Hermann Rahn showed in animals how to obtain a measure of
outflow pressures for the determination of pulmonary vascular resistance. They
used a flow-directed catheter with an inflatable balloon at its tip to measure left
atrial pressure (11). In 1950, Hellems and colleagues modified the technique to
measure pulmonary "capillary" pressure in humans (12). The next step was to
move the technique from the fluoroscopy suite to the bedside. In 1970, William
Ganz and Harold J. C. Swan introduced a multilumen, balloon-tipped catheter
that could be advanced and the tip positioned under hemodynamic monitoring.
Once in place, the multilumen catheter made it possible to record
simultaneously the pressures in the pulmonary artery and left atrium (13).
Control of the pulmonary circulation was first studied in open-chest,
anesthetized animals. Although these studies showed that stimulation of nerves
to the lungs could affect pulmonary hemodynamics, there was consensus in the
1940s that the pulmonary nerves played little, if any, role in regulating the
normal pulmonary circulation. In 1946, attention shifted from nerves to local self-
regulatory mechanisms. The shift was prompted by the demonstration of von
Euler and Liljestrand, in anesthetized cats, that acute hypoxia elicits pulmonary
vasoconstriction (Figure 5) (14, 15). Shortly thereafter, the experiments with
acute hypoxia in anesthetized cats were repeated in normal, awake humans.
Thus, in 1947, Motley and colleagues, in the Cournand-Richards Laboratory,
exposed five human subjects to 10% oxygen in nitrogen for 10 minutes and
observed an increase in pulmonary arterial pressure and in pulmonary vascular
resistance, which indicated that acute hypoxia had elicited pulmonary
2007 Sociedad Venezolana de Medicina Crítica Todos los derechos reservados
Figure 6. Geoffrey Sharman Dawes (1918–1996). Dawes spent virtually all of his
career as Director of the Nuffield Institute for Medical Research. He carried on in
the tradition of Sir Joseph Barcroft who had pioneered research in fetal
physiology using animal experiments to gain insights that were directly
transferable to the human fetus and newborn.
PULMONARY HEMODYNAMICS IN PRIMARY PULMONARY HYPERTENSION
Considerable insight into pulmonary hemodynamics has been provided by
physiologic studies on primary pulmonary hypertension. The physiologic studies
were preceded by histopathologic observations made in individuals who died of
primary pulmonary hypertension (18, 19). The first clinical–pathologic case
report was made in 1891 by Ernst von Romberg, a distinguished German
physician and clinical scientist. Unable to uncover any cause for the
abnormalities in the pulmonary blood vessels, he designated the intrinsic
pulmonary vascular disease as "pulmonary vascular sclerosis" (19). This case
report led to similar case reports by others, along with speculation and debate
about the etiology of the disease. In 1901, in an unpublished lecture in Buenos
Aires, Abel Ayerza coined the descriptive term "cardiacos negros" to describe a
syndrome that today would be categorized as pulmonary hypertension and
right ventricle failure. His colleagues in Argentina designated the syndrome
"Ayerza's disease" and proposed syphilis as its etiology. Between 1901 and 1925,
case reports from South and North America and Europe supported the view that
the pulmonary vascular sclerosis described by Romberg was due to syphilitic
pulmonary arteritis. Despite some misgivings about the syphilitic etiology of
primary pulmonary hypertension, the belief remained popular until the 1940s.
The widespread belief in syphilis as the cause of primary pulmonary
THE AMINOREX EPIDEMIC
hypertension was finally laid to rest in the 1940s by Oscar Brenner, M.D., of
Birmingham, England (20). While a Rockefeller Traveling Fellow, he reviewed 100
case reports of pulmonary hypertension in the autopsy files of the Massachusetts
General Hospital. Twenty five of these patients carried the diagnosis of Ayerza's
disease. Based largely on this personal review and his review of the literature,
Brenner concluded that Ayerza's disease was neither a clinical nor a pathological
entity and that syphilis was not the cause of the disease. He pinpointed the small
muscular arteries and arterioles as the seat of the pulmonary hypertension and
described their histopathologic features. Brenner was a histopathologist rather
than a physiologist (20). As a result, he did not recognize the role played by
vasoconstriction in the pathogenesis of primary pulmonary hypertension, nor
did he appreciate the causal relationship between the pulmonary vascular
lesions and the dilated, hypertrophied right ventricle, which he pictured as
separate consequences of a shared insult.
Clinical interest in pulmonary hypertension was heightened considerably by the
teaching and writings of Paul Wood, a superb British cardiologist, teacher, and
showman. In the 1950s, he played a pivotal role in bringing the pathophysiology
of congenital and acquired heart disease to the bedside and in determining
operability. His 1950 textbook, Diseases of the Heart and Circulation, still stands
as a landmark in the cardiovascular literature (21).
A breakthrough in uncovering the pathophysiology of primary pulmonary
hypertension began in 1951 with the demonstration by Dresdale and coworkers
2007 Sociedad Venezolana de Medicina Crítica Todos los derechos reservados
disease also suggested that inherited susceptibility may play a role in the pathogenesis of the disease. Stimulated largely by the aminorex epidemic, a meeting of the World Health Organization was convened in 1975 to gather and review the scattered clinical and physiologic data about primary pulmonary hypertension. The report of this meeting identified shortcomings in the understanding not only of primary pulmonary hypertension but also of normal pulmonary hemodynamics. In addition, it recommended that ambiguities in nomenclature be eliminated. Finally, the report called for a worldwide registry that would gather data about the prevalence and natural history of primary pulmonary hypertension, which was regarded as a rare disease. AFTER THE WORLD HEALTH REPORT
The recommendation concerning a registry was implemented in 1981. This registry, which consisted of 32 clinical centers geographically distributed throughout the United States, a Coordinating Core, and a Pathology Core, collected data for 6 years. By the time the registry closed in 1987, clinical, physiologic, and therapeutic data had been collected in standardized fashion on more than 200 patients with primary pulmonary hypertension. The registry had several favorable outcomes: (1) it sharpened clinical and pathologic diagnostic criteria, (2) provided a standardized format for data collection, (3) led to the exploration and systematic evaluation of pulmonary vasodilators, (4) promoted subsequent cooperative studies among the investigators at various centers, and (5) promoted public awareness of the disease. A second meeting of the World Health Organization was held in Evian, France, in 1998. Instead of confining itself to primary pulmonary hypertension, the Evian meeting created a clinical classification of all pulmonary hypertensive diseases that is oriented toward the prevention and treatment of pulmonary hypertensive diseases. The effectiveness of the Evian diagnostic clarification was evaluated at the third meeting of the World Health Organization in Venice, Italy, in 2003. Consensus was reached that the classification has proved to be valuable for clinical and epidemiologic purposes but less so for research. This reservation was not unexpected because the classification focuses on diagnosis and treatment, whereas research on primary pulmonary hypertension has become increasingly reductionistic in nature. 2007 Sociedad Venezolana de Medicina Crítica Todos los derechos reservados
MONITOREO HEMODINÁMICO 
catheterized by way of a peripheral vein (9). His interest was in cardiac injections
rather than in blood sampling from within the heart. To convince others about
the safety of the procedure, he catheterized himself on several different
occasions and walked about, with catheter in place, climbing the stairs en route
to the X-ray department. Forssmann made sure that others were aware of his
accomplishment and its prospects. However, instead of earning plaudits for his
pioneering effort, Forssmann was rewarded with criticism and ridicule by his
Forssmann's demonstration attracted more attention in Europe and South
America than in Germany. In the United States, the lead was taken in the 1940s
by the Cardiopulmonary Laboratory at Bellevue Hospital in New York City (Figure
4) (10). André F. Cournand was the director of the laboratory, which was
sponsored by both the Chest Service run by J. Burns Amberson, M.D., and the
Medical Division of Columbia University, headed by Dickinson W. Richards, M.D.
With the strong support of these two sponsors, André Cournand established a
world-renowned cardiopulmonary laboratory. In 1951, I rotated through the
laboratory as an Established Investigator of the American Heart Association and
subsequently rejoined it as a member of the research team on the faculty of the
College of Physicians and Surgeons of Columbia University.
Spurred on in large part by the Bellevue laboratory, the use of cardiac
catheterization for diagnostic purposes spread quickly throughout medical
centers in the United States and abroad. In 1956, Forssmann shared the Nobel
Prize with Cournand and Richards for their respective roles in introducing and
standardizing cardiac catheterization. As usage spread, modifications in
equipment and technique made it possible to move cardiac catheterization from
the fluoroscopy room to the bedside where hemodynamic monitoring could be
substituted for radiographic visualization of the catheter tip. In 1953, Michael
Lategola and Hermann Rahn showed in animals how to obtain a measure of
outflow pressures for the determination of pulmonary vascular resistance. They
used a flow-directed catheter with an inflatable balloon at its tip to measure left
atrial pressure (11). In 1950, Hellems and colleagues modified the technique to
measure pulmonary "capillary" pressure in humans (12). The next step was to
move the technique from the fluoroscopy suite to the bedside. In 1970, William
Ganz and Harold J. C. Swan introduced a multilumen, balloon-tipped catheter
that could be advanced and the tip positioned under hemodynamic monitoring.
Once in place, the multilumen catheter made it possible to record
simultaneously the pressures in the pulmonary artery and left atrium (13).
Control of the pulmonary circulation was first studied in open-chest,
anesthetized animals. Although these studies showed that stimulation of nerves
to the lungs could affect pulmonary hemodynamics, there was consensus in the
1940s that the pulmonary nerves played little, if any, role in regulating the
normal pulmonary circulation. In 1946, attention shifted from nerves to local self-
regulatory mechanisms. The shift was prompted by the demonstration of von
Euler and Liljestrand, in anesthetized cats, that acute hypoxia elicits pulmonary
vasoconstriction (Figure 5) (14, 15). Shortly thereafter, the experiments with
acute hypoxia in anesthetized cats were repeated in normal, awake humans.
Thus, in 1947, Motley and colleagues, in the Cournand-Richards Laboratory,
exposed five human subjects to 10% oxygen in nitrogen for 10 minutes and
observed an increase in pulmonary arterial pressure and in pulmonary vascular
resistance, which indicated that acute hypoxia had elicited pulmonary
2007 Sociedad Venezolana de Medicina Crítica
Figure 6. Geoffrey Sharman Dawes (1918–1996). Dawes spent virtually all of his
career as Director of the Nuffield Institute for Medical Research. He carried on in
the tradition of Sir Joseph Barcroft who had pioneered research in fetal
physiology using animal experiments to gain insights that were directly
transferable to the human fetus and newborn.
PULMONARY HEMODYNAMICS IN PRIMARY PULMONARY HYPERTENSION 
disease also suggested that inherited susceptibility may play a role in the