Pediatric Pulmonology 30:1–2 (2000)
Editorial
Classical Respiratory Physiology—Gone the
Way of the Dinosaurs? Do We Need a
Jurassic Park?
With more and more emphasis on molecular biology,
there are an increasing number of young pediatric pul-
monologists who do not understand what classic respi-
ratory physiology has taught us and how it forms the
rational basis of how we treat our patients. Perhaps this is
progress, but when it comes to a decision whether a
patient needs a lung transplant for advanced cystic fibro-
sis (CF) or other lung diseases, classic spirometry plays
a far greater role than the data in a Northern blot. Fur-
thermore, while we now genotype most of our CF pa-
tients, it is the FEV1 that guides our day-to-day manage-
ment. Most of our current trainees are far more familiar
with the use of molecular techniques for the diagnosis of
disease than with the role that static elastic recoil forces
play in the determination of forced expiratory flow. In
fact, I would guess that most have never even measured
lung elastic recoil in a person, be it a patient or one of
their colleagues. With this in mind, I suspect that many
had difficulties in understanding the very informative
article by Van Muylem and Baran1 that appears in this
issue of the Journal.
In 1951, Comroe and Fowler2 reported that monitoring
the expired concentration of nitrogen N2 after a single
deep breath of oxygen could detect inhomogeneity of
ventilation. Kjellmer et al.3 modified the test, and it be-
gan to enjoy increasing popularity by 1959. In 1969,
Anthonisen et al.4 used the test to quantify the slope of
the linear portion of the alveolar plateau (phase III), and
the concept of closing volume began to appear in the
literature. A few years later, Buist and Ross5 published
normal values for the slope of phase III and closing vol-
umes, as a fraction of total lung capacity, and the single
breath nitrogen (N2) washout test became a widely used
measure of ventilatory inhomogeneity and early airway
disease, especially in smoking-related lung disease.
With the increasing awareness of the concept that both
convection and gas diffusion are important in gas trans-
port, it was inevitable that investigators would evaluate
the consequences of inspiring gases with different diffu-
sivities.6,7 In the current issue of the Journal, Van Muy-
lem and Baran1 used this technique to give us a better
understanding of the early pathophysiology of CF. Based
on the concept that the low molecular weight helium (He)
© 2000 Wiley-Liss, Inc.
will diffuse more readily and faster than the much denser
gas sulfur hexafluoride (SF6), they attempted to charac-
terize the site of airway pathology early and late in the
course of CF. As they pointed out, increases in the slope
of phase III in a single breath N2 washout test do corre-
late with inhomogeneity of ventilation, but it is not spe-
cific as a marker of a particular abnormality of patho-
logical process. It must be noted that resident gases such
as N2 are diluted by the inhaled oxygen (O2). O2 will
show up in relatively high concentrations in the first
expired gas, whereas it will progressively decrease as
expiration proceeds in the face of inhomogeneous distri-
bution of ventilation and late appearance of resident N2.
This will increase the N2 slope of phase III and the clos-
ing volume. When the negative slope for the inhaled
heavy nonresident gas SF6 is treated as positive, it can be
compared to the positive slope of the N2 washout. In
normal subjects, the slope of phase III for SF6 will be
greater than that for N2, since the lesser diffusivity of the
SF6 will accentuate any inhomogeneity that might be
normally present. In contrast, for a single breath test that
contains He, the slope will be the same or will be less
than the slope of phase III for N2 because the greater
diffusivity of the lighter gas will improve homogeneity
of ventilation. Because convection is the predominant
mechanism of gas transport in the central regions of the
lung and diffusion in the peripheral regions, Van Muy-
lem and Baran1 argue that a difference in slopes of phase
III between He and SF6 would point to sites of anatomi-
cal abnormalities in patients with CF and in smokers.
This is exactly what they found, with the differences in
the slopes of phase III between SF6 and He being slightly
negative in CF, suggesting a peripheral location of the
pathology. Of interest, the slope of the N2 washout dif-
fered between both the CF group and the smokers com-
pared to the normal subjects, but only the (SF6-He)
slopes distinguished the CF group from the other two.
Furthermore, it was the younger CF patients who had the
negative (SF6-He) slope, suggesting that the older CF
patients had more advanced central disease. Although not
unique in their suggestion that the early airway abnor-
malities in CF occur in the terminal and respiratory bron-
chioles, this demonstration is truly an elegant application
of classical respiratory physiologic principles. In a pre-
vious article, Van Muylem et al.8 suggested that this test
may have application in monitoring early signs of rejec-
tion in patients with lung transplants. In other words, this
2 Coates
noninvasive test lends itself to repeated measurements
that can monitor disease progression and the response to
treatment in diseases other than CF. The only drawback
is that a mass spectrometer is required, which limits ap-
plicability to specialized laboratories.
Traditionally, much of the concept of laboratory assis-
tance to medical care stemmed from physical findings in
the patient and the search for reproducible and objective
means of quantifying these findings. The observation that
patients with obstructive lung disease had limitations of
ventilation and specifically forced expiration was behind
the development of both spirometry and the maximal
expiratory flow volume curve. Both these tests have
gained widespread prominence, and much of the physi-
ology is understood. This stands in sharp contrast to the
CF gene. Here, using ingenious mapping techniques,
groups led by Lap-Chee Tsui and Francis Collins discov-
ered the defective gene in 1989, before the defective
protein (CFTR) was known.9 The defective protein turns
out to be a chloride channel and membrane regulator but,
more than 10 years later and with our ability to actually
synthesize CFTR,10 we still do not understand how ab-
normal CFTR causes the disease. Indeed, we are still
debating the electrolyte and water composition of the
airway lining liquid in CF.11 Many of the delays in capi-
talizing on our new molecular understanding in CF are
due to our deficiencies in really understanding its patho-
physiology. The usual course of discovery of a molecular
defect is that the physiologist tells the molecular biolo-
gist what the physiological abnormality is, and then the
molecular biologist searches for the specific mutations
that would explain the physiological behavior. For ex-
ample, hematologists knew that red cells sickled in a
hypoxic environment long before the protein chemists
identified the point mutation leading to sickle-cell dis-
ease. The challenge in CF is to go the other way around:
we know the molecular defect, but are still to understand
the exact pathophysiological mechanism. In other words,
if we lose sight of our physiological roots, we will lose
much of our understanding of the disease process occur-
ring within the patient and hence be less able to take
advantage of the benefits offered by new technologies.
We should be grateful to Van Muylem and Baran1 for
using tools that so elegantly take us back to these physi-
ological roots.
—ALLAN L. COATES, MD, CM, B Eng (Elect)
Division of Respiratory Medicine
Hospital for Sick Children
Department of Paediatrics
Faculty of Medicine
University of Toronto
Toronto, Ontario, Canada
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