Respiratory Physiology: Ventilation, Blood Flow, and Gas Exchange

SECTION B
RESPIRATORY PHYSIOLOGY
10 VENTILATION, BLOOD FLOW,

AND GAS EXCHANGE
MEREDITH C. MCCORMACK, md, mhs • JOHN B. WEST, md, phd, dsc
INTRODUCTION Distribution of Pulmonary Oxygen

VENTILATION Blood Flow Carbon Dioxide
Total and Alveolar Ventilation Active Control of the Pulmonary GAS EXCHANGE
Inequality of Ventilation Circulation Causes of Hypoxemia
BLOOD FLOW Damage to Pulmonary Capillaries by Oxygen Sensing
High Wall Stresses
Pressures of the Pulmonary Circulation KEY POINTS
BLOOD-GAS TRANSPORT
Pulmonary Vascular Resistance
INTRODUCTION without alveoli. All these bronchi make up the conduct-

ing airways. Their function is to channel inspired gas to
This first chapter in the section on respiratory physiology is the gas-exchanging regions of the lung. Because the con-
devoted to the primary function of the lung: gas exchange. ducting airways contain no alveoli and therefore take no
Herein, the principles of ventilation and blood flow that part in gas exchange, they constitute the anatomic dead
underlie gas exchange are reviewed. Although the lung has space.
other functions, such as metabolizing some compounds, fil- Each terminal bronchiole conducts air to a respiratory
tering unwanted materials from the circulation, and acting unit, or acinus. The acinus is where alveolization, and
as a reservoir for blood, gas exchange is its chief function. therefore gas exchange, begins. The acinus can also be
Respiratory diseases frequently interfere with ventilation, termed the terminal respiratory unit, indicating its chief
blood flow, and gas exchange and may ultimately lead to role in gas exchange. The terminal bronchioles divide into
respiratory failure and death. respiratory bronchioles that have occasional alveoli bud-
ding from their wall, which then transition to the alveolar
ducts, structures that are completely lined with alveoli. This
VENTILATION alveolated region of the lung where gas exchange takes
place is known as the respiratory zone. The distance from
The anatomy of the airways and the alveolar region of the terminal bronchiole to the most distal alveolus is only
the lung is discussed in Chapter 1. There we saw that the approximately 5 mm, but the respiratory zone makes up
airways consist of a series of branching tubes that become most of the lung in terms of gas volume (some 2–3 L).
narrower, shorter, and more numerous as they penetrate The morphologic characteristics of the human airways
deeper into the lung. This process continues down to the were greatly clarified by Weibel.1 He measured the number,
terminal bronchioles, which are the smallest airways length, width, and branching angles of the airways, and he
116
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10 • Ventilation, Blood Flow, and Gas Exchange 117
Z 500
Trachea
0
Conducting zone
400
Total cross-sectional area (cm2)

BR 2
3
300
BL 4
TBL 200
Conducting Resp.
17 zone zone
respiratory zones
18
Transitional and
RBL 19 100
20 Terminal
AD 21 bronchioles
22
0
AS 23
0 5 10 15 20 23
Figure 10.1 Idealization of the human airways according to Weibel’s Airway generation
model A. The first 16 generations of airways constitute the conducting
zone, the next three generations are the respiratory bronchioles constitut- Figure 10.2 Cross- sectional area of the different zones. Diagram
ing the transitional zone, and the final three generations are the alveolar showing the extremely rapid increase in total cross-sectional area of the
ducts and alveolar sacs constituting the respiratory zone. Note that the airways in the respiratory (Resp.) zone as predicted from the Weibel model
RBL, AD, and AS make up the transitional and respiratory zones. AD, alve- in Fig. 10.1. (Modified from West JB. Respiratory Physiology: The Essentials. 9th
olar duct; AS, alveolar sac; BL, bronchiole; BR, bronchus; RBL, respiratory ed. Baltimore: Lippincott Williams & Wilkins; 2012.)
bronchiole; TBL, terminal bronchiole; Z, airway generation. (Modified from
Weibel ER. Morphometry of the Human Lung. Berlin: Springer-Verlag; 1963.)
sudden increase in cross-sectional area. As a consequence,
diffusion begins to take over as the dominant mode of gas
proposed models that, although they are idealized, make transport. Naturally, there is no sharp transition; flow
pressure flow and other analyses much more tractable. changes gradually from primarily convective to primarily
The most commonly used Weibel model is the so-called diffusive in the general vicinity of generation 16.
model A, shown in Figure 10.1. Note that the first 16 gen- One implication of this change in mode of flow is that
erations (Z) make up the conducting airways ending in the many aerosol particles penetrate to the region of the ter-
terminal bronchioles. The next three generations constitute minal bronchioles by convective flow, but they do not
the respiratory bronchioles, in which the degree of alveola- penetrate further because of their large mass and resulting
tion steadily increases. This is called the transitional zone low diffusion rate. Thus, sedimentation of these particles is
because the nonalveolated regions of the respiratory bron- heavy in the region of the terminal respiratory bronchioles.
chioles do not have a respiratory function. Finally, there This is one reason why this region of the lung is particularly
are three generations of alveolar ducts and one generation vulnerable to the effects of particulate air pollutants (see
of alveolar sacs. These last four generations constitute the Chapters 72 and 102).
true respiratory zone. Another implication of this dichotomously branching air-
Other models of the airways have been proposed.2 way tree is that the greater the number of branch points, the
However, the Weibel model has been of great value to respi- greater the potential for nonuniform distribution of airflow
ratory physiology, and an example of its use is shown in among the distal airways and alveoli. In addition, repeated,
Figure 10.2. Here the model clarifies the nature of gas flow possibly minor, differences in flow distribution at each branch
in all generations of the airways in the lung. Figure 10.2 point will give rise to spatial correlation of flow; in other words,
shows that, if the total cross-sectional area of the airways neighboring regions will tend to have more similar flows than
of each generation is calculated, there is relatively little regions located far apart, other factors being equal.
change in area until we approach generation 16, that is, Figure 10.3 shows the major divisions of lung volume.
the terminal bronchioles. Near this level, the cross-sectional Total lung capacity is the volume of gas contained in the
area increases very rapidly. This has led some physiologists lungs at maximal inspiration. The vital capacity is the vol-
to suggest that the shape of the combined airways is similar ume of gas that can be exhaled by a maximal expiration
to a trumpet or even a thumbtack. from total lung capacity. The volume remaining in the lung
The result of this rapid change in area is that the mode of after maximal expiration is the residual volume (RV). Tidal
gas flow changes in the region of the terminal bronchioles. volume refers to the normal respiratory volume excursion.
Proximal to this point, flow is convective, or “bulk,” that is, The lung volume at the end of a normal expiration is the
similar to the sort of flow that results when beer is poured functional residual capacity (FRC). Figure 10.3 also indicates
out of a pitcher. However, when the gas reaches the region the inspiratory reserve volume and the expiratory reserve
approximating the level of the terminal bronchioles, its for- volume. These volumes change in characteristic directions
ward velocity decreases dramatically because of the very with different respiratory diseases, such as COPD and lung
118 PART 1 • Scientific Principles of Respiratory Medicine
Liters Another way of measuring alveolar ventilation in normal

subjects is to use the alveolar ventilation equation, which
Total expresses mass conservation of carbon dioxide by defining
6 lung carbon dioxide production (V̇CO2), which in a steady state is
capacity
equal to the amount of CO2 exhaled in a given time, as the
IRV
Vital product of alveolar ventilation (V̇A) and fractional alveolar con-
capacity centration of carbon dioxide (Faco2). Because concentration
is proportional to partial pressure, the relationship can be
4 written as:
Tidal V̇CO2 = V̇A × FACO2 = V̇A × PACO2/K Eq. 4
volume
This can then be rearranged as follows:
2 ERV V̇CO2
V̇A = × K Eq. 5
PACO2
Functional
residual Residual where V̇CO2 is the volume of carbon dioxide exhaled per unit
capacity volume time, Paco2 is the alveolar Pco2, and K is a constant (0.863
when V̇A is expressed in L/min, V̇CO2 in mL/min, and Paco2
0
in mm Hg). In patients with normal lungs, the Pco2 of
Figure 10.3 Major divisions of lung volumes. Values are illustrative only; alveolar gas and that of arterial blood are virtually identi-
there is considerable normal variation. ERV, expiratory reserve volume; IRV,
inspiratory reserve volume. (Modified from West JB. Respiratory Physiology:
cal. Therefore, the arterial Pco2 can be used to determine
The Essentials. 9th ed. Baltimore: Lippincott Williams & Wilkins; 2012.) alveolar ventilation from Eq. 5. The equation then becomes
V̇CO2
V̇A =× K Eq. 6
fibrosis, so their measurement becomes important (see PaCO2
Chapters 31 and 32). This equation is often used in patients with lung disease, but
the value then obtained is the effective alveolar ventilation.
TOTAL AND ALVEOLAR VENTILATION This is not the same as the alveolar ventilation as defined
in Eq. 3. Because patients with lung disease must increase
Total Ventilation their total ventilation to overcome the inefficiency of gas
Total ventilation, also called minute ventilation, is the exchange caused by ventilation-perfusion inequality just to
total volume of gas exhaled per minute. It is equal to the keep arterial Pco2 normal, V̇A from Eq. 6 will be less than
tidal volume times the respiratory frequency. (The volume that from Eq. 3.
of inhaled air is slightly greater than the exhaled volume
because more oxygen is inhaled than carbon dioxide is Anatomic Dead Space
exhaled, but the difference is usually less than 1%.) Alveolar The anatomic dead space is the gas volume contained
ventilation is the amount of fresh inspired air (non–dead- within the conducting airways. The normal value is in the
space gas) that enters the alveoli per minute and is therefore range of 130 to 180 mL and depends on the size and posture
available for gas exchange. of the subject. It can be estimated, as described earlier, as
1 mL per pound of ideal body weight. The value increases
Alveolar Ventilation slightly with large inspirations because the radial traction
Because the tidal volume (Vt) is made up of the dead-space exerted on the bronchi by the surrounding lung paren-
volume (Vd) and the volume of gas entering (or coming from) chyma increases their size. Anatomic dead space can be
the alveoli (Va), the alveolar ventilation can be measured measured by Fowler’s method,3 in which a single breath of
from the following equations: oxygen is inhaled and the concentration of nitrogen in the
VT = VD + VA Eq. 1 subsequent expiration is analyzed, as shown in Figure 10.4.
Multiplying by respiratory frequency gives Physiologic Dead Space

V̇E = V̇D + V̇A Eq. 2 Unlike anatomic dead space, which is determined by the
anatomy of the airways, physiologic dead space is a func-
where V̇A is the alveolar ventilation, and V̇E and V̇D are tional measurement based on the ability of the lungs to
the expired total ventilation and dead-space ventilation, eliminate carbon dioxide. It is defined by the Bohr equation:
respectively. VD PACO2 − PECO2
Therefore, = Eq. 7
VT PACO2
V̇A = V̇E − V̇D Eq. 3
where A and E refer to alveolar and mixed expired gas,
A difficulty with this method is that the anatomic dead respectively. In subjects with normal lungs, the Pco2 of
space is not easy to measure, although a value for it can be alveolar gas and that of arterial blood are virtually the
assumed with little error. One milliliter per pound of body same, so that the equation is often written as
weight is a common assumption. This approximation will
overestimate dead space in obese subjects and so should be VD PaCO2 − PECO2
= Eq. 8
applied using ideal body weight for height. VT PaCO2
INEQUALITY OF VENTILATION and more recent studies have used ventilation single-
photon emission computed tomography and positron emis-
Not all the alveoli are equally ventilated, even in the nor- sion tomography scanning techniques.6–8
mal lung. There are several reasons for this, related both Measurements in upright normal subjects show that the
to gravitational and to nongravitational influences on gas ventilation per unit volume of the lung is greatest near the
distribution. base of the lung and becomes progressively smaller toward
Gravitational Influences on Inequality the apex. When the subject lies supine, this difference
becomes much less, but the ventilation of the dependent
Hyperpolarized helium and xenon magnetic resonance (posterior) lung exceeds that of the uppermost (anterior). In
imaging have been used to measure regional ventilation,4,5 the lateral decubitus position, again, the dependent lung is
better ventilated. (These results refer to an inspiration from
FRC.)
Start of inspiration
with 100% O2 An explanation of this gravitational inequality of ven-
tilation is shown in Figure 10.5A, which depicts condi-
80 tions at FRC.9 The intrapleural pressure is less negative at
the bottom than at the top of the lung. This pattern can
End of O2
N2 concentration %
be attributed to the weight of the lung, which requires a

expiration
Start of larger pressure below the lung than above it to balance
40 expiration Recorder the downward-acting weight forces.10 There are two con-
Sampling sequences of this lower expanding pressure on the base of
Alveolar tube
the lung. First, the resting volume of the basal alveoli is
plateau
N2 meter smaller, as shown by the pressure-volume curve. Second,
the change in volume for a given change in intrapleural
0 pressure is greater because the alveoli are operating on a
0 5 10 steeper part of the pressure-volume curve. Thus, the venti-
A Time (sec) lation (change in volume per unit resting volume) is greater
at the base than the apex. However, if a normal subject
makes a small inspiration from RV (rather than from FRC),
an interesting change in the distribution of ventilation is
40
N2 concentration %
seen. The major share of the ventilation now goes to the

B Alveolar apex of the upright lung, whereas the base becomes very
plateau poorly ventilated. Figure 10.5B shows why a different pat-
tern is seen in this case. Now the intrapleural pressures are
A less negative, and the intrapleural pressure at the base of
0 the lung actually exceeds atmospheric pressure. For a small
0 0.2 0.4 0.6 0.8 fall in intrapleural pressure, no gas will enter the extreme
B Expired volume (liters) base of the lung, and only the apex will be ventilated. Thus,
Figure 10.4 Fowler’s method of measuring the anatomic dead space
the normal pattern of ventilation is reversed in this early
with a rapid N2 analyzer. (A) After a test inspiration of 100% O2, the N2 phase of inhalation.
concentration rises during expiration to an almost level plateau repre- In this way, obesity may change the distribution of
senting pure alveolar gas. (B) N2 concentration is plotted against expired ventilation; for example, obesity-associated factors may
volume, and the dead space is the volume at the vertical dashed line that alter the gravitational distribution of inhaled methacho-
makes the areas to the left and to the right of the dashed vertical lines (A
and B) equal. In this example, the dead space is ≈150 mL (or 0.15 L). (Modi- line, and thus methacholine- induced bronchoconstric-
fied from West JB. Respiratory Physiology: The Essentials. 9th ed. Baltimore: Lip- tion. Findings from studies using two-dimensional and
pincott Williams & Wilkins; 2012.) three-dimensional imaging modalities suggest diversion of
–10 cm H2O –4 cm H2O

Intrapleural Intrapleural
Volume
Volume
pressure (FRC) pressure (RV)
–2.5 cm H2O +3.5 cm H2O

100% 100%
50% 50%
Figure 10.5 The inequality of ventilation down the lung due

to gravity. (A) An inspiration from functional residual capacity.
(B) The situation at very low lung volumes (see text for details). +10 0 –10 –20 –30 +10 0 –10 –20 –30
FRC, functional residual capacity; RV, residual volume. (Modified Intrapleural pressure (cm H2O) Intrapleural pressure (cm H2O)
from West JB. Respiratory Physiology: The Essentials. 9th ed. Balti-
more: Lippincott Williams & Wilkins; 2012.) A B
ventilation from the base into the upper lung zone among accomplished principally by diffusion within the airways. If
obese individuals.6 there is abnormal dilation of an airway, the diffusion pro-
cess may not be complete within the breathing cycle, and
Airway Closure the distal alveoli will be less well ventilated than the proxi-
At RV, the compressed region of the lung at the base in mal alveoli.
Figure 10.5B does not have all its gas squeezed out because Heterogeneity in ventilation can be assessed by single-
small airways, probably in the region of the respiratory breath and multibreath nitrogen washout (MBNW) methods,
bronchioles, close first and trap gas in the distal alveoli. which are described in Chapters 31 and 32. Three major
This is known as airway closure. In young normal subjects, indices are derived from the MBNW.18,19 The lung clear-
airways close only at lung volumes below FRC. However, ance index is a global measure of ventilation heterogene-
in older normal subjects, the volume at which the basal ity but does not allow any specific anatomic localization
airways close (closing volume) increases with age and may of the site of heterogeneity. The more uneven the ventila-
encroach on the FRC. The reason for this increase is that, tion, the higher the lung clearance index, and abnormali-
with aging, the lung loses some of its elastic recoil, and the ties are apparent in obstructive airways disease, such as
intrapleural pressures therefore become less negative, thus asthma, COPD, and cystic fibrosis. Two other indexes, Scond
approaching the situation shown in Figure 10.5B. Under and Sacin, describe the contribution of convection (driven
these conditions, basal regions of the lung may be ventilated by pressure gradients, which take place in the conducting
only intermittently, with resulting defective gas exchange. airways) and diffusion (driven by concentration gradients,
A similar situation frequently develops in patients with which take place in the extreme periphery of the lung, likely
COPD in whom lung elastic recoil decreases. Airway closure beginning at the entrance to the lung acinus) to overall het-
promotes air trapping and hyperinflation characteristic of erogeneity of ventilation.
poorly controlled asthma. Exaggerated airway closure may
be a feature of airway hyperresponsiveness in asthma,11
particularly among obese individuals with asthma.12,13 BLOOD FLOW
Nongravitational Influences on Inequality Blood flow is as important for gas exchange as is ventila-
In addition to the inequality of ventilation caused by gravi- tion. This has not always been appreciated, partly because
tational factors (Fig. 10.5), nongravitational mechanisms the process of ventilation is more obvious, especially in the
also exist. This is proved by the fact that even astronauts in dyspneic patient, and is more accessible to measurement.
space, in microgravity, show uneven ventilation.14,15 This Much has been learned about the pulmonary circulation in
has been confirmed by studies in which labeled small par- the past few years, especially about its metabolic functions.
ticles in inspired gas demonstrate variability in ventilation The anatomy and function of the pulmonary circulation
at a given horizontal level at which gravitational forces are are described in Chapters 1 and 6.
equal.4 At least three factors have been proposed to explain
the uneven ventilation in the distal, smaller regions of the PRESSURES OF THE PULMONARY CIRCULATION
lung.
One of these factors is the existence of uneven time con- The pressures in the pulmonary circulation are very low
stants.16 The time constant of a region of lung is given by compared with those in the systemic circulation, and this
the product of its resistance and compliance (analogous to feature is responsible for much of its special behavior. The
the time constant in electrical circuits, which is the product normal pressures in the human pulmonary artery are typi-
of electrical resistance and capacitance). Lung units with cally approximately 25 mm Hg systolic, 8 mm Hg diastolic,
different time constants inflate and deflate at different flow and 15 mm Hg mean. Normal mean pulmonary arterial
rates. Depending on the breathing frequency, a unit with a pressure is thus six times lower than that in the systemic
large time constant does not complete its filling before expi- arterial circulation, which is approximately 100 mm Hg.
ration begins and therefore is poorly ventilated; the faster The evolutionary force keeping the pressures in the pulmo-
the frequency, the less time for ventilation. In contrast, a nary circulation low is the mechanical vulnerability of the
unit with a small time constant, which fills rapidly, may extremely thin blood-gas barrier; higher pressures in the
receive a high proportion of gas from the anatomic dead pulmonary capillaries would cause stress failure of the cap-
space, reducing its effective alveolar ventilation. illary wall.20
Another cause of uneven ventilation in small lung units
is the asymmetry of their structure, which can result in a Pressure Inside Blood Vessels
greater penetration of gas by diffusion into the smaller units Because the pulmonary arterial pressure is so low, hydro-
than into the larger.17 The resulting somewhat complex static effects due to gravity within the pulmonary circula-
behavior is known as diffusion-and convection-dependent tion become very important. The adult upright human
inhomogeneity and may play an important role in lung lung is some 30 cm high, giving a hydrostatic difference in
disease. pressure of 30 cm blood between the extreme apex and the
A third possible reason for uneven ventilation is the pres- base, which is equivalent to approximately 23 mm Hg. As a
ence of concentration gradients along the small airways. result, there are very substantial differences in flow within
This is known as series inequality. Recall that inspired gas the small pulmonary arteries and the capillaries between
reaches approximately the region of the distal terminal the top and bottom of the upright lung. This topic is dis-
or proximal respiratory bronchioles by convective flow, cussed further in the section “Distribution of Pulmonary
but gas flow over the rest of the distance to the alveoli is Blood Flow.”
Arteries Capillaries Veins Alveolus Alveolar vessels

0
Extra-alveolar
Pulmonary vascular resistance
vessels
20
40
(% total)
60
Figure 10.7 Diagram of alveolar and extra-alveolar vessels. The alveo-
lar vessels are mainly the capillaries and are exposed to alveolar pressure.
80 The extra-alveolar vessels have their lumina enlarged by the pull of radial
traction (outward-oriented arrows) of the surrounding parenchyma. (Modi-
100 fied from West JB. Respiratory Physiology: The Essentials. 9th ed. Baltimore: Lip-
pincott Williams & Wilkins; 2012.)
PA 30–50 20 10 10 20 30–50 PV
Diameters (µm) The alveolar vessels are largely capillaries that course
Figure 10.6 Pressure drop along the pulmonary circulation as deter- through the alveolar walls. The pressure to which they are
mined by direct puncture of vessels. The normal pressure drop is exposed is very nearly alveolar pressure. However, it can
greatest at the capillaries, and its mean pressure is approximately halfway be shown that, when the lung is expanded from a very low
between pulmonary artery (PA) pressure and pulmonary vein (PV) pres-
sure. (Modified from Bhattacharya J, Nanjo S, Staub NC. Factors affecting lung lung volume, this pericapillary pressure falls below alveolar
microvascular pressure. Ann N Y Acad Sci. 1982;384:107–114.) pressure because of surface tension effects in the alveolar
lining layer.24 By contrast, during deflation from high lung
volumes, surface tension effects are much reduced and the
Various techniques have been used to determine the pat- pericapillary pressure is very close to alveolar pressure.
tern of pressure drop along the pulmonary blood vessels. The extra-alveolar vessels are not exposed to alveolar
These include measurement of the transudation pressure pressure. The caliber of these vessels is determined by the
on the pleural surface of isolated lung, measurement of the radial traction of the surrounding alveolar walls and there-
pressure transient resulting from the injection of a slug of fore depends on lung volume. When the lung inflates, the
low-or high-viscosity blood into the pulmonary artery,21 caliber of these vessels increases; when the lung deflates,
and direct puncture of different-sized vessels along with their caliber decreases because of the elastic tissue in their
direct measurement of hydrostatic pressure.22 The direct walls and also because of a small amount of smooth muscle
puncture measurements indicate that much of the nor- tone. The important point is that extra-alveolar vessel resis-
mal pressure drop in the pulmonary circulation probably tance falls with lung inflation, whereas alveolar vessel (cap-
takes place in the pulmonary capillaries (alveolar vessels), illary) resistance rises with lung inflation.
and that the mean capillary pressure is approximately half- The small vessels (≈30 μm diameter) in the corners of
way between that in the pulmonary artery and that in the the alveolar walls behave in a manner that is intermediate
pulmonary vein (Fig. 10.6). The distribution of pressure between that of the alveolar capillaries and the extra-alveolar
along the pulmonary blood vessels depends on lung vol- vessels. These corner vessels can remain open when the cap-
ume. At low states of lung inflation, the resistance of the illaries are closed. Indeed, this is the normal appearance in
extra-alveolar vessels (see next section) increases and more zone 1 lung25 (see later section on the distribution of blood
pressure drop then takes place across the pulmonary arter- flow). However, the shape and attachments of the corner ves-
ies and veins instead of the capillaries. By contrast, there is sels are very different from those of the larger extra-alveolar
evidence that, at very high states of lung inflation, the resis- vessels, and it is unlikely that the pressure outside them var-
tance of the capillary bed is increased, and therefore there ies in the same way when the lung expands.
will be an additional pressure drop in the capillaries. The extra-alveolar vessels are surrounded by an interstitial
Of interest, the pressures in the pulmonary circulation perivascular space, which has an important role in the pas-
are highly pulsatile; indeed, if the normal systolic and dia- sive movement of extravascular fluid in the lung. The lymph
stolic pressures in the main pulmonary artery are 25 and vessels run in this space, although these lymph vessels do not
8 mm Hg, respectively, this is a much greater proportional open into this space or drain this fluid. One of the earliest his-
change than the systolic-diastolic difference in systemic tologic signs of interstitial pulmonary edema is “cuffing” of
arteries (120 and 80 mm Hg, respectively). There is good the interstitial perivascular space around the extra-alveolar
evidence that the pulsatility of pressure, and therefore flow, vessels (see Figs. 14.4 and 14.5).26,27 There is evidence that
extends to the pulmonary capillaries.23 the perivascular pressure is very low compared with the
hydrostatic pressure in the interstitium of the alveolar wall.
Pressures Outside Blood Vessels As a consequence, fluid that moves from the capillaries into
Some pulmonary blood vessels are exposed to alveolar pres- the interstitial space of the alveolar wall eventually flows to
sure (or very nearly), whereas others are outside the influ- the perivascular low-pressure region by virtue of the hydro-
ence of alveolar pressure but are very sensitive to the state static pressure gradient.28 The interstitial edema fluid then
of lung inflation. These two types of vessels are known as moves toward the hilum or toward the pleural space (see
alveolar and extra-alveolar, respectively (Fig. 10.7). Chapter 14).
The decreases in pulmonary vascular resistance shown

PULMONARY VASCULAR RESISTANCE
in Figure 10.8 help to limit the work of the right heart under
Pulmonary vascular resistance is given by the following conditions of high pulmonary blood flow. For example, dur-
relationship: ing exercise, both pulmonary arterial and venous pressures
rise. Although the normal pulmonary vascular resistance is
Pulmonary arterial − Pulmonary venous remarkably low (the normal 5 L/min pulmonary blood flow
pressure pressure Eq. 9 is associated with an arterial-venous pressure difference of
PVR = only approximately 10 mm Hg), the resistance falls to even
Pulmonary blood flow
lower values when the pulmonary arterial and venous pres-
Because all three variables vary between systole and dias- sures rise, as during exercise.
tole, mean values are generally used. This definition is Two mechanisms responsible for the fall in pulmonary
similar to that used for electrical resistance, which is the dif- vascular resistance are recruitment, the opening up of pre-
ference of voltage across a resistor divided by the current. viously closed blood vessels, and distention, the increase in
However, whereas the resistance of an electrical resistor is caliber of vessels. Figure 10.9A shows experimental data
independent of the voltage at both ends and the current, from rapidly frozen dog lung preparations, indicating the
this is not the case for pulmonary vascular resistance. For importance of recruitment as the pulmonary arterial pres-
example, an increase in either pulmonary arterial pressure is raised from low values.29 Note that the number of
sure or pulmonary venous pressure generally results in a open capillaries per millimeter of length of alveolar wall
decrease in pulmonary vascular resistance because, as cap- increased from approximately 25 to more than 50 as pul-
illary pressure rises, there is both capillary recruitment and monary arterial pressure was raised from zero to almost
distention (see later). Similarly, if pulmonary blood flow is
increased (e.g., by raising pulmonary arterial pressure),
pulmonary vascular resistance usually decreases.
It is important to appreciate that a single number for pul- 300
Pulmonary vascular resistance (PVR)

monary vascular resistance is an incomplete description of
the pressure-flow properties of the pulmonary circulation.
However, in practice, pulmonary vascular resistance is
often a useful measurement because, although the normal 200
(cm H2O/L/min)
PVR vs
value varies considerably, we often wish to compare the arterial pressure
value in a normal lung with the higher values in abnormal
ones.
100
Pressure-Flow Relations PVR vs
venous pressure
If pulmonary blood flow is measured in an isolated, perfused
lung, when pulmonary arterial pressure is raised (while
pulmonary venous pressure, alveolar pressure, and lung 0
volume are held constant), then flow increases relatively 10 20 30 40
more than pressure. Figure 10.8 shows that pulmonary
Pulmonary arterial or venous pressure
vascular resistance decreases both when pulmonary arte- (cm H2O)
rial pressure is raised and when pulmonary venous pres-
sure is raised (other pressures held constant). The unifying Figure 10.8 The drop in pulmonary vascular resistance seen when the
pulmonary arterial or venous pressure is raised in a canine lung prep-
explanation for reduced resistance in both cases is that the aration. When one pressure was changed, the other was held constant.
increases in intravascular pressure induce vascular recruit- (Modified from West JB. Respiratory Physiology: The Essentials. 9th ed. Baltimore:
ment and distension. Lippincott Williams & Wilkins; 2012.)
RECRUITMENT DISTENTION
60 7
Mean width of capillaries (µm)
6
Number of open capillaries
per mm alveolar septum
Figure 10.9 Mechanisms responsi-

50 ble for the fall in pulmonary vascular
5
resistance with increases in vascular
4 pressures. (A) Recruitment of pulmo-
40 nary capillaries as the pulmonary arte-
3 rial pressure, the perfusing pressure,
is raised. (B) Distention of pulmonary
2 capillaries as their pressure is increased.
30
(A, Modified from Warrell DA, Evans JW,
1 Clarke RO, et al. Pattern of filling in the
pulmonary capillary bed. J Appl Physiol.
20 0
1972;32:346–356. B, Modified from Gla-
0 10 20 0 10 20 30 40 50 zier JB, Hughes JMB, Maloney JE, West
Perfusing pressure (cm H2O) JB. Measurements of capillary dimen-
Capillary pressure (cm H2O)
sions and blood volume in rapidly frozen
A B lungs. J Appl Physiol. 1969;26:65–76.)
15 cm H2O. Figure 10.9B shows data on the importance of volume is increased from very low values, vascular resis-
distention of pulmonary capillaries.25 Note that the mean tance first decreases and then increases. The lung normally
width of the capillaries increased from approximately 3.5 operates near the minimal value of vascular resistance, that
to nearly 7 μm as the capillary pressure was increased to is, FRC coincides with a low vascular resistance.
approximately 50 cm H2O. Beyond that, there was very At very low lung volume, the increase in pulmonary
little change. vascular resistance is caused by the decrease in caliber of
The mechanism of recruitment of pulmonary capillaries is the extra-alveolar vessels. Because these vessels are nor-
not fully understood. It has been suggested that, as the pul- mally held open by the radial traction of the surrounding
monary arterial pressure is increased, the critical opening parenchyma, their caliber is least in the collapsed lung.30
pressures of various arterioles are successively overcome. Another factor that may contribute to the high pulmonary
However, it has been shown that the red blood cell concen- vascular resistance at low states of lung inflation is folding
tration, used as a measure of perfusion, varied within areas and distortion of pulmonary capillaries.31,32
supplied by single arterioles, indicating that capillaries, not At high lung volume, the increase in pulmonary vascular
arterioles, probably accounted for the heterogenous perfu- resistance is probably caused by narrowing of the pulmo-
sion.29 This suggests that vessels are recruited at the capil- nary capillaries. An analogy is a piece of thin rubber tubing
lary rather than the arterial level. that narrows considerably when it is stretched sideways,
The mechanism of distention of pulmonary capillaries is across its diameter. This distortion increases the resistance
apparently simply the bulging of the capillary wall as the to fluid moving through it. Direct measurements on rapidly
transmural pressure of the capillaries is raised. This behav- frozen dog lungs show that the mean width of the capillar-
ior is likely caused by a change in shape of the capillaries ies is greatly decreased at high states of lung inflation.25
rather than actual stretching of the capillary wall. Surface In considering the effects of lung inflation, a distinction
tension forces and also longitudinal tension in the alveolar should be made between “positive” and “negative” pressure
wall associated with lung inflation tend to flatten the capil- inflation. The results shown in Figure 10.10 were found
laries at low capillary transmural pressures; this means that with negative-pressure inflation, that is, when the lung was
their diameter can then increase when capillary pressure expanded by reducing pleural pressure and the relation-
rises. In photomicrographs of rapidly frozen lung prepara- ship between pulmonary arterial and alveolar pressures
tions, pulmonary capillaries with very high intracapillary was held constant. If positive-pressure inflation is used (i.e.,
pressures show remarkable bulging.25 alveolar pressure is increased with respect to pulmonary
Recruitment and distention also provide mechanisms for arterial pressure), pulmonary vascular resistance increases
increasing both the surface area of the lung microvascu- even more at high states of lung inflation. The reason is
lature in contact with alveolar gas and the red cell transit that lung inflation is then associated with a decrease in the
time through the microvasculature, which may facilitate transmural pressure of the capillaries and they are, in effect,
gas exchange. squashed by the increased alveolar pressure.
Effect of Lung Volume Other Factors Affecting Pulmonary Vascular
Lung volume has an important influence on pulmonary Resistance
vascular resistance. Figure 10.10 shows that, as lung Various drugs affect pulmonary vascular resistance. In
some instances, the effects depend on the species of animal.
However, in general, serotonin, histamine, and norepi-
nephrine cause contraction of pulmonary vascular smooth
120 muscle and increase vascular resistance. These drugs are
particularly effective as vasoconstrictors when the lung
resistance (cm H2O/L/min)
volume is small and the radial traction of surrounding

Pulmonary vascular
100 parenchyma on the extra-alveolar vessels is weak. Drugs

that often relax smooth muscle in the pulmonary circula-
tion include acetylcholine and isoproterenol. However, nor-
80 mal pulmonary blood vessels have little resting tone, so the
degree of potential relaxation is small.
The autonomic nervous system exercises a weak con-
trol on the pulmonary circulation. There is evidence that
60
increased sympathetic tone can cause vasoconstriction
50 100 150 200 and stiffening of the walls of the larger pulmonary arteries.
Lung volume (mL) Both α- and β-adrenergic receptors are present.33 Increased
Figure 10.10 Effect of changing lung volume on pulmonary vascular parasympathetic activity has a weak vasodilator action. As
resistance. At low lung volumes, resistance is high because the extra- already indicated, any changes of vascular smooth muscle
alveolar vessels are narrowed (central circle) and because pulmonary capil- tone are much more effective at low states of lung inflation,
laries become folded and distorted (vessels radiating from central circle). when the extra-alveolar vessels are narrowed or, in the fetal
At high lung volumes, capillaries are stretched and their caliber reduced;
this is probably the major contributor to increased vascular resistance at
state, when the amount of smooth muscle present is much
high lung volumes. (Data from a canine lung preparation.) (Modified from greater than in the adult.
West JB. Respiratory Physiology: The Essentials. 9th ed. Baltimore: Lippincott Wil- Pulmonary edema increases vascular resistance by
liams & Wilkins; 2012.) poorly understood mechanisms. It may be that mechanisms
differ depending on the type and stage of edema. Interstitial this point, no flow can be detected. These observations and
pulmonary edema causes marked cuffing of the perivas- others have led to the following model of blood flow.
cular spaces of the extra-alveolar vessels. Presumably, the
edema increases their vascular resistance34 because the Three-Zone Model for the Distribution of
edema widens the perivascular space and thereby reduces Blood Flow
the radial traction of the surrounding parenchyma that Figure 10.11 shows a simple model for understanding the
normally holds the vessels expanded. In addition, however, factors responsible for the inequality of blood flow in the
edema in the interstitium of the alveolar wall may encroach lung.38 The lung is divided into three zones according to
on the pulmonary capillaries to some extent, thus increas- the relative magnitudes of the pulmonary arterial, alveolar,
ing their vascular resistance.35 Pulmonary edema may and venous pressures.
also increase pulmonary vascular resistance by reducing Zone 1 is that region of the lung above the level at which
ventilation to the most affected regions, thereby reducing pulmonary arterial equals alveolar pressures; in other
the local alveolar Po2 and stimulating hypoxic pulmonary words, in this region, alveolar pressure exceeds arterial
vasoconstriction. pressure. Measurements in isolated lungs show that there
is no blood flow in zone 1, the explanation being that the
collapsible capillaries close because the pressure outside
DISTRIBUTION OF PULMONARY BLOOD FLOW
exceeds the pressure inside. Micrographs of rapidly frozen
Just as for ventilation, blood flow is not partitioned equally lung from zone 1 show that the capillaries have collapsed,
to all alveoli, even in the normal lung. Both gravitational although occasionally trapped red blood cells can be seen
and nongravitational factors affect the distribution of blood within them.25 The vertical level of blood flow can also
flow. be influenced by the surface tension of the alveolar lining
layer, as discussed earlier. If measurements are made on a
Normal Distribution lung immediately after it is inflated from a near-collapsed
The distribution of pulmonary blood flow can conveniently state, blood flow reaches 3 or 4 cm above the level at which
be measured using radioactive materials. In one technique, pulmonary arterial and alveolar pressures are equal.24 This
radioactive xenon is dissolved in saline and injected into a can be explained by the surface tension, which lowers the
peripheral vein. When the xenon reaches the pulmonary pericapillary hydrostatic pressure to below the alveolar
capillaries, it diffuses into the alveolar gas because of its pressure and permits flow.
low blood solubility. The resulting distribution of radio- Zone 2 is the part of the lung in which pulmonary arte-
activity within the lung can be measured using a gamma rial pressure exceeds alveolar pressure, but alveolar pres-
camera and reflects the regional distribution of blood sure exceeds venous pressure. Here the vessels behave like
flow. Subsequently, the distribution of alveolar volume Starling resistors,39 that is, as collapsible tubes surrounded
is obtained by having the subject rebreathe radioactive by a pressure chamber. Under these conditions, flow is
xenon to equilibrium. By combining the two measure- determined by the difference between arterial and alveolar
ments, the blood flow per unit alveolar volume of the lung pressures, rather than by the difference between arterial
can be obtained. In another technique, the distribution and venous pressures. One way of looking at this is that the
of blood flow can be measured with radioactive albumin thin wall of the vessel offers no resistance to the collapsing
macroaggregates and with a variety of radioactive gases, pressure, so the pressure inside the vessel at some point
such as 15O-labeled carbon dioxide and 13N. Finally, func-
tional magnetic resonance imaging of the lung can be
used to assess distribution of pulmonary blood flow.36 This
noninvasive technique does not expose subjects to radio-
activity; therefore, it can be used repetitively and shows Zone 1
great promise for the future. PA>Pa>PV
In the normal upright human lung, pulmonary blood
flow decreases approximately linearly with distance up the
lung, reaching very low values at the apex.37 However, if Alveolar Zone 2
PA Pa>PA>PV
the subject lies supine, apical and basal blood flow become
the same, and now blood flow is less in the anterior (upper- Pa PV
most) than posterior (lowermost) regions of the lung. Thus,
Arterial Venous Distance
blood flow distribution is highly dependent on gravitational
effects. During exercise in the upright position, both apical
and basal blood flow rates increase, and the relative differ-
ences are reduced.
The factors responsible for the uneven distribution of Zone 3
blood flow due to gravitational influences can be studied Pa>PV>PA
Blood flow
conveniently in isolated lung preparations. These studies
show that, in the presence of normal vascular pressures, Figure 10.11 Three-zone model designed to account for the uneven
blood flow decreases approximately linearly up the lung38 gravitational distribution of blood flow in the lung. Pa, pulmonary
arterial pressure; Pa, pulmonary alveolar pressure; Pv, pulmonary venous
as it does in intact humans. However, if the pulmonary arte- pressure. (Modified from West JB, Dollery CT, Naimark A. Distribution of blood
rial pressure is reduced, blood flows only up to the level at flow in isolated lung: relation to vascular and alveolar pressures. J Appl Physiol.
which pulmonary arterial equals alveolar pressures; above 1964;19:713–724.)
along its length becomes equal to chamber pressure, and exaggerated42 and, under these conditions, zone 4 extends
the flow is determined by arterial minus chamber pressure. further up the lung. The opposite effect is seen if a vasodila-
This behavior has been variously referred to as the water- tor drug such as isoproterenol is infused into the pulmonary
fall39 or sluice40 effect and can be demonstrated in rubber- circulation. With interstitial edema, the contribution of the
tube models on the laboratory bench. The increase in blood extra-alveolar vessels increases because the edema creates a
flow down zone 2 can be explained by the increase in hydro- cuff of fluid around the vessels and the vessels narrow. This is
static pulmonary arterial pressure down the zone, whereas thought to be the cause of the increased pulmonary vascular
the alveolar pressure remains constant. Thus, the pressure resistance seen at the base of the human lung in conditions
difference determining flow increases linearly with distance of interstitial pulmonary edema,34 in which the distribution
down the lung. of blood flow often becomes inverted (e.g., in chronic mitral
Zone 3 is that part of the lung in which venous pressure stenosis).43 Under these conditions, the blood flow to the
exceeds alveolar pressure. Radioactive gas measurements apex of the upright lung consistently exceeds the flow to the
show that blood flow also increases as one measures ver- basal regions. However, the effects of interstitial edema on
tically down this zone, although, in some preparations at blood flow distribution are still not fully understood.
least, the rate of increase appears less than found in zone
2. Because the pressure difference responsible for flow is Other Factors Affecting the Distribution of Blood
arterial minus venous pressure and because these two pres- Flow
sures increase similarly with distance down the zone, the Because the influence of gravity on the distribution of blood
increase in blood flow is not explained by changes in perfus- flow in the normal lung is so important, it is not surprising
ing pressure. Instead, blood flow increases down this zone that, during acceleration of the body in an upward direc-
because vascular resistance falls with distance down the tion, the distribution of blood flow becomes more uneven.44
zone, likely because of progressive distention (confirmed For example, during exposure to +3g acceleration, that is,
histologically25) from the increasing transmural pressure three times the normal acceleration experienced by some-
(intravascular pressure increasing down the zone while one in the upright posture, the upper half of the lung is com-
alveolar pressure is constant). However, resistance may pletely unperfused.
also be reduced by recruitment of capillaries. By contrast, in astronauts at weightlessness in space, the
distribution of blood flow becomes more uniform.45 Because
The Effect of Lung Volume on the Distribution of it is not possible to use radioactive gases in this environ-
Blood Flow—Zone 4 ment, the inequality of blood flow has been determined indi-
The three-zone model of Figure 10.11, based on the effects rectly from the size of the cardiogenic oscillations for Pco2.
of pulmonary arterial, alveolar, and venous pressures, Cardiogenic oscillations are fluctuations in the concentra-
accounts for many of the distributions seen in the normal tions of gases such as oxygen, carbon dioxide, and nitrogen
lung. However, other factors play a role; one of these is during a single expiration. They have the same frequency as
lung volume. For example, under most circumstances, a the heart rate and are considered to be caused by differential
zone of reduced blood flow, known as zone 4, is seen in the rates of emptying of different parts of the lung due to con-
lowermost region of the upright human lung.41 This zone traction and dilation of the heart exerting direct pressure
becomes smaller as lung volume is increased, but careful on nearby lung parenchyma. For oscillations to be detected,
measurements indicate that a small area of reduced blood these differentially emptying regions must also have differ-
flow is still present at the lung base at total lung capacity. ent alveolar Po2 and Pco2 values; this happens when blood
As lung volume is reduced, this region of reduced blood flow and ventilation are not uniformly distributed through-
flow extends further and further up the lung so that, at FRC, out the lung. Weightlessness almost abolishes cardiogenic
blood flow decreases in the bottom half of the lung. oscillations, implying greater uniformity in the distribu-
These patterns cannot be explained by the interactions tion of blood flow and/or ventilation. Of interest, because
of the pulmonary arterial, venous, and alveolar pressures these oscillations can still be seen, albeit to a much smaller
at the alveolar vessels as in Figure 10.11. Instead, we have extent than on Earth, some inequality remains, indicating
to take into account the contribution of the extra-alveolar an effect of nongravitational factors.
vessels. As pointed out previously (see Fig. 10.10), the cali- Several nongravitational factors may account for an
ber of these vessels is determined by the degree of lung infla- uneven distribution of blood flow. One is that there may
tion; as lung volume is reduced, the vessels narrow. In the be regional differences of vascular resistance, with some
upright human lung, the alveoli are less well expanded at regions of the pulmonary vasculature having an intrinsi-
the base than at the apex because of distortion of the elastic cally higher vascular resistance than others. This has been
lung caused by its weight (see Fig. 10.5). As a result, the shown to be the case in isolated dog lungs,46 and there is
extra-alveolar vessels are relatively narrow at the base, and some evidence for higher blood flows in the dorsal than the
their increased contribution to pulmonary vascular resis- ventral regions of the lung in both intact dogs and horses.
tance results in the presence of a zone of reduced blood flow Another possible factor is a difference in blood flow between
in that region. As lung volume is reduced, the contribution the central and peripheral regions of the lung,47 although
of the extra-alveolar vessels to the distribution of blood flow this finding is controversial. Some measurements show dif-
increases, and zone 4 extends further up the lung. ferences in blood flow along the acinus, with the more dis-
Vasoactive drugs and interstitial edema can also modify tal regions of the acinus being less well perfused than the
the contribution of extra-alveolar vessels to pulmonary vas- proximal regions.48,49 Also, as pointed out earlier, because
cular resistance. With injection of vasoconstrictor drugs of the complexity of the pulmonary circulation at the alve-
such as serotonin, the role of the extra-alveolar vessels can be olar level, including the very large number of capillary
segments, it is likely that there is inequality of blood flow circulation has a limited amount of smooth muscle in the
at this level.50 There is also work suggesting that the distri- walls of the vessels, and active control of vascular tone is
bution of pulmonary blood flow in small vessels may follow weak. However, in some conditions there is an increase in
a fractal pattern.51 The term fractal describes a branching the amount of smooth muscle. This is the case in the fetal
pattern of both structure (blood vessels) and function (blood lung, in long-term residence at high altitude, and in pro-
flow) that repeats itself with each generation. This means longed pulmonary hypertension. In these situations, the
that any subsection of the vascular tree exhibits the same tone of the vascular smooth muscle plays a more significant
branching pattern as the entire tree. Were a picture of such role. However, even in the normal lung, some active control
a subsection to be enlarged, it would overlie and match the of the circulation is seen.
pattern of the whole tree. The repeated branching of blood
vessels has implications for how blood flow is distributed Hypoxic Pulmonary Vasoconstriction
independently of gravitational influences. The greater the In a region of a lung with alveolar hypoxia, vascular
number of branch points, the greater the likely inequality smooth muscle contracts and raises local vascular resis-
of perfusion among alveoli. This implies that the finer the tance, which may reduce blood flow. The precise mecha-
spatial resolution of the method used to assess flow distri- nism of such hypoxic pulmonary vasoconstriction is still
bution, the greater the amount of inequality likely to be not known but, because it can be observed in excised iso-
detected. lated lungs, it clearly does not depend on central nervous
system connections. Studies indicate that voltage-gated
Abnormal Patterns of Blood Flow potassium channels in the vascular smooth muscle cells
The normal distribution of pulmonary blood flow is fre- are involved, leading to increased intracellular calcium
quently altered by lung and heart disease. Localized ion concentrations.57–60 Furthermore, excised segments
lung disease, such as fibrosis and cyst formation, usu- of pulmonary artery can constrict if their environment
ally causes a local reduction of flow. The same is true of is made hypoxic, so there appears to be a local action of
pulmonary embolism, in which the local reduction in hypoxia on the artery itself.55 It is also known that it is
blood flow, as determined from a perfusion scan, is usu- Po2 of the alveolar gas, not of the pulmonary arterial blood,
ally coupled with normal ventilation, and this pattern that chiefly determines the response.56 This can be proved
provides important diagnostic information. Lung can- by perfusing a lung with blood with a high Po2 while keep-
cer may reduce regional blood flow, and occasionally a ing the alveolar Po2 low; under these conditions the vaso-
small hilar lesion can cause a marked reduction of blood constrictive response is still seen. The importance of local
flow to one lung, presumably through compression of factors is supported by observations that hypoxic pulmo-
the main pulmonary artery. Generalized lung diseases, nary vasoconstriction exists in transplanted lungs, despite
such as COPD and asthma, also frequently cause patchy the absence of autonomic neural innervation.55
inequality of blood flow.52,53 For further discussion of the mechanisms of hypoxic
Heart disease frequently alters the distribution of blood pulmonary vasoconstriction, see ExpertConsult.com and
flow, as might be expected from the factors responsible Chapter 6.
for the normal distribution (see Fig. 10.11). For example, The major site of vasoconstriction is in the small pulmo-
patients with increased blood flow through left-to-right nary arteries.67 In the normal human lung, the small arter-
shunts or with pulmonary hypertension usually show a ies have a meager amount of smooth muscle, which may
more uniform distribution of blood flow because of their be uneven in its distribution. This may explain why, even
higher pulmonary artery pressure.54 Diseases in which in global alveolar hypoxia (e.g., at high altitude), vasocon-
pulmonary arterial pressure is reduced, such as tetralogy striction is uneven. For example, during alveolar hypoxia,
of Fallot with oligemic lungs, are associated with reduced the variation in transit times through the pulmonary circu-
perfusion of the lung apices. Increased pulmonary venous lation of a lobe of a dog lung nearly doubles,68 and the dis-
pressure, as in mitral stenosis, initially causes a more uni- tribution of India ink particles injected into the pulmonary
form distribution than normal. However, in advanced dis- circulation becomes more uneven.69 This uneven vasocon-
ease, an inversion of the normal distribution of blood flow striction probably plays a role in the mechanism of high-
is frequently seen, with more perfusion to the upper than altitude pulmonary edema70 (see later).
to the lower zones. The mechanism for this shift is not fully Hypoxic pulmonary vasoconstriction has the effect of
understood, but, as indicated earlier, perivascular edema directing blood flow away from hypoxic regions of lung,
causing an increased vascular resistance of the extra- a redistribution that is beneficial to gas exchange. Other
alveolar vessels is thought to be a factor. things being equal, this effect reduces the amount of
ventilation-perfusion inequality in a diseased lung and lim-
ACTIVE CONTROL OF THE PULMONARY its the depression of the arterial Po2. An example of this is
seen in patients with asthma treated with certain broncho-
CIRCULATION
dilators, which can decrease hypoxic pulmonary vasocon-
The distribution of pulmonary blood flow and the pressure- striction. These sometimes reduce arterial Po2 by increasing
flow relations of the pulmonary circulation are normally blood flow to poorly ventilated areas.71,72
dominated by the passive effects of the hydrostatic pres- Probably the most important role for hypoxic pulmo-
sure gradient described earlier. Thus, the roles of gravity, of nary vasoconstriction is in the fetal period. During fetal life,
variation in vascular lengths and diameters, and of recruit- when the lungs do not undertake gas exchange, pulmonary
ment and distention can account for much of the behavior vascular resistance is very high, partly because of hypoxic
of the normal circulation. The normal adult pulmonary vasoconstriction, and only some 15% of the cardiac output
10 • Ventilation, Blood Flow, and Gas Exchange 126.e1
Endothelium-derived vasoactive substances may play a change in vascular resistance is seen. However, when the
role in hypoxic pulmonary vasoconstriction. Nitric oxide alveolar Po2 is reduced to approximately 70 mm Hg, vaso-
(NO) is an endothelium-derived relaxing factor for blood constriction begins and, at a very low Po2 approaching that
vessels. It is formed from l-arginine and is a final common of mixed venous blood, the local blood flow may be almost
pathway for a variety of biologic processes. NO activates abolished. The data shown in eFigure 10.1 are from anes-
soluble guanylate cyclase, which leads to smooth muscle thetized open-chest cats.64 Different results may be found in
relaxation by the synthesis of cyclic guanosine mono- different species and different preparations. For example, in
phosphate. Inhibitors of NO synthesis augment hypoxic the coatimundi (a small South American mammal), there
pulmonary vasoconstriction in animal preparations, and was an almost linear reduction of blood flow found between
inhaled NO reduces hypoxic pulmonary vasoconstric- alveolar Po2 values of 150 and 40 mm Hg.65 In this study,
tion in humans.61 The required inhaled concentration of the chest was closed, and the measurements were made in
NO to see an effect is extremely low (≈20 parts per mil- a very small region of lung. These conditions probably give
lion). The effects of NO on ventilation-perfusion match- the best information on the role of the phenomenon in the
ing and arterial Po2 in patients with lung disease depends local regulation of blood flow.
on whether vasodilation increases perfusion of the well- Residence at high altitude results in hypoxic pulmonary
ventilated regions of the lung or the less well-ventilated vasoconstriction, both in newcomers and in permanent res-
regions.62 idents. The increase in pulmonary arterial pressure is espe-
Vasoconstrictor peptides, known as endothelins and cially marked during exercise. If 100% oxygen is given to
released by pulmonary vascular endothelial cells, may par- normal subjects after being exposed to hypoxia for as little
ticipate in hypoxic vasoconstriction as well.63 Their role in as 2 weeks, the pulmonary arterial pressure does not imme-
normal physiologic processes and disease is still being eval- diately return to the normal level.66 This suggests that
uated, but endothelin antagonists have become important hypoxia has already induced some structural change in the
therapeutic agents in pulmonary arterial hypertension. pulmonary vessels. There is considerable variation among
The stimulus- response curve of hypoxic pulmonary individuals in the response of pulmonary arterial pressure
vasoconstriction is very nonlinear (eFig. 10.1). When the to alveolar hypoxia, leading some investigators to divide
alveolar Po2 is altered in the region above 100 mm Hg, little people into “responders” and “nonresponders.”
flows through the lungs. The rest bypasses the lungs via A particularly interesting condition is seen in racehorses,
the ductus arteriosus. The vasoconstriction is particularly which can suffer bleeding into the lungs while galloping.
effective because of the abundance of smooth muscle in the This is a common problem caused by extremely high pul-
pulmonary arteries. At birth, when the first few breaths monary capillary pressures, which approach 100 mm Hg.
oxygenate the alveoli, the vascular resistance falls dramati- Direct evidence of stress failure of pulmonary capillaries has
cally because of relaxation of vascular smooth muscle, and been shown in these animals.79 In fact, there is evidence that
pulmonary blood flow increases enormously. In this situa- elite human athletes develop some ultrastructural changes
tion, the release of hypoxic vasoconstriction is essential for in their blood-gas barrier during extreme exercise because
the transition to air breathing. significantly higher concentrations of red blood cells, total
protein, and leukotriene B4 are seen in their bronchoalveo-
DAMAGE TO PULMONARY CAPILLARIES BY lar lavage fluid compared with sedentary controls.80 This
leakage only happens at extremely high levels of exercise81;
HIGH WALL STRESSES
a similar group of athletes who exercised at submaximal
The blood-gas barrier has a basic dilemma. On one hand, levels for 1 hour showed no changes in the bronchoalveo-
the barrier has to be extremely thin to allow efficient gas lar lavage fluid.82
exchange by passive diffusion. On the other hand, the blood- Overinflation of the lung is also known to increase the per-
gas barrier must be strong because of the large mechanical meability of pulmonary capillaries. Stress failure is appar-
stresses that develop in the capillary wall when the pres- ently the mechanism because it has been shown that, for
sure in the capillaries rises or when the wall is stretched by the same capillary transmural pressure, high lung volumes
inflating the lung to high volumes. There is evidence that greatly increase the frequency of capillary wall damage.83
the blood-gas barrier is just strong enough to withstand the This is because some of the increased tension in the alveolar
highest stresses to which it is normally subjected. Unusually wall associated with lung inflation affects the capillary wall.
high capillary pressures or lung volumes can result in ultra- Damage to the capillaries by overinflation may be an impor-
structural damage or stress failure of the capillary wall, tant mechanism in ventilator-induced lung injury.
leading to a high-permeability type of pulmonary edema, or
even pulmonary hemorrhage.
When the capillary transmural pressure is raised in ani- BLOOD-GAS TRANSPORT
mal preparations, disruption of the capillary endothelium,
alveolar epithelium, or sometimes all layers of the capillary The partial pressure of a gas is an important concept in
wall is seen. In the rabbit lung, the first changes are seen any discussion of gas exchange, as described later in the
at a transmural pressure of approximately 24 mm Hg, and section on gas exchange. The partial pressure (P) of a gas
the frequency of breaks increases as the pressure is raised.73 is found by multiplying its concentration by the total pres-
Although these capillary pressures seem very high, there is sure. For example, the Po2 in dry room air at sea level
now good evidence that the capillary pressure rises to the is 159 mm Hg (0.209 × 760 mm Hg), where oxygen is
mid-30s (mm Hg) in the normal lung during heavy exer- 20.9% of room air and barometric pressure is 760 mm Hg.
cise.74 This is largely secondary to the increase in left ven- However, the relationship between Po2 and its concentra-
tricular filling pressure.75 tion in blood is not linear and is commonly described by an
At these increased capillary transmural pressures, the oxygen dissociation curve. Similar considerations apply to
“hoop” or circumferential stresses in the capillary wall carbon dioxide in blood. The physiologic factors that deter-
become extremely high. The main reason for the very mine the oxygen and carbon dioxide dissociation curves
high stresses is the extreme thinness of the wall which, in are considered later.
the human lung, is less than 0.3 μm in some places. It is
now believed that the strength of the blood-gas barrier on OXYGEN
the thin side comes from type IV collagen in the basement
membranes. The thickness of the type IV collagen layer is Oxygen is carried in the blood in two forms. By far the most
only approximately 50 nm. The delicacy of the alveoli can important component is in combination with hemoglobin.
be appreciated by scanning electron microscopy, which In addition, a small amount of oxygen is dissolved in the
demonstrates the interface of the alveolar epithelial cells blood.
and the alveolar capillary network (see Video 3.1). Hemoglobin consists of heme, an iron-porphyrin com-
Stress failure is the likely mechanism of several clini- pound, and a protein (globin) that has four polypeptide
cal conditions characterized by high-permeability pul- chains. There are two types of chains, α and β, and differ-
monary edema or hemorrhage.76 Neurogenic pulmonary ences in their amino acid sequences give rise to different
edema is associated with very high capillary pressures, types of human hemoglobin. There are unique conditions
the edema is of the high-permeability type, and ultrastruc- in which alterations in hemoglobin have clinical conse-
tural damage to the capillaries is consistent with stress quences. Examples include the normal hemoglobin F (fetal),
failure. High- altitude pulmonary edema is apparently which has a high affinity for oxygen, and hemoglobin S
caused by uneven hypoxic pulmonary vasoconstriction (sickle), which has a reduced affinity for oxygen and, in the
(referred to earlier), which allows some of the capillaries deoxygenated form, tends to aggregate and deform the red
to be exposed to high pressure.77 Again, the edema is of cell. Methemoglobin, formed as a result of exposure to vari-
the high-permeability type, and typical ultrastructural ous drugs or chemicals, is not useful for carrying oxygen
changes in the capillaries have been demonstrated in ani- and increases the oxygen affinity of the remaining hemo-
mal preparations.78 globin, thus impairing unloading of oxygen in the tissues.
Blood is able to transport large amounts of oxygen oxygen dissociation curve means that a relatively small
because oxygen forms an easily reversible combination drop in capillary Po2 can lead to the unloading of consid-
with hemoglobin (Hb) to give oxyhemoglobin (HbO2): erable amounts of oxygen. This also maintains the blood
O2 + Hb HbO2 Po2 and assists the diffusion of O2 into the tissue. A useful
Eq. 10
measure of the position of the dissociation curve is the Po2
The relationship between the partial pressure of oxygen for 50% oxygen saturation, known as the P50. The normal
and the number of binding sites of the hemoglobin with oxy- value for human blood is approximately 27 mm Hg.
gen attached is known as the oxygen dissociation curve (Fig. Various factors affect the position of the oxygen disso-
10.12). Each gram of pure hemoglobin can combine with ciation curve (see Fig. 10.12). A rightward shift indicates
1.39 mL of oxygen and, in normal blood with 15 g Hb/100 a decrease in the affinity of hemoglobin for oxygen. The
mL, the oxygen capacity (reached when all the binding sites curve is shifted to the right by an increase of tempera-
are full) is 1.39 × 15, or approximately 20.8 mL O2/100 ture, hydrogen ion concentration, the concentration of
mL of blood. The total oxygen content of a sample of blood 2,3-diphosphoglycerate (2,3-DPG) in the red cell, and the
(expressed as mL O2/100 mL of blood), which includes the Pco2. Increased Pco2 reduces the oxygen affinity mainly
oxygen combined with hemoglobin and the dissolved oxy- by the increased H+ concentration and increases oxygen
gen, is given by unloading. The ability of carbon dioxide to reduce the affin-
% saturation ity of hemoglobin for oxygen is called the Bohr effect. One
O2 content = (1.39 × Hb) × consequence of the Bohr effect is that, as peripheral blood
100
+ (0.003 × PO2 ) Eq. 11 loads carbon dioxide, the unloading of oxygen is assisted. A
rightward shift is also caused by 2,3-DPG, an end product of
where Hb is the hemoglobin concentration and the final red cell metabolism.84,85 The concentration of 2,3-DPG can
term is the oxygen dissolved in the blood (see later). be increased in the setting of chronic hypoxia.
The characteristic shape of the oxygen dissociation curve Leftward shifts of the oxygen dissociation curve mean
has several physiologic advantages. The fact that the upper an increased affinity of hemoglobin for oxygen, as can be
portion is almost flat means that a fall of 20 to 30 mm Hg caused by a reduced concentration of 2,3-DPG or by the
in arterial Po2 in a healthy subject with an initially normal presence of carbon monoxide. The concentration of 2,
value (e.g., ≈100 mm Hg) causes only a minor reduction 3-DPG falls in stored blood, which can lead to blood with
in arterial oxygen content. However, this also means that a high affinity for oxygen but with difficulty releasing oxy-
noninvasive monitoring of oxygen saturation by pulse gen to the tissues. Small amounts of carbon monoxide in
oximetry will often fail to indicate substantial falls in arte- the blood increase the affinity of the remaining oxygen for
rial Po2 (see Chapter 44). Another consequence of the flat hemoglobin and therefore cause a leftward shift of the dis-
upper part of the curve is that the diffusive loading of oxy- sociation curve. As a result, the unloading of oxygen in
gen in the pulmonary capillary is enhanced. This results the peripheral tissue is hampered. In addition, of course,
from the large partial pressure difference between alveolar the oxygen content of the blood is reduced at the same Po2
gas and capillary blood that is maintained even when most because some of the hemoglobin is bound to carbon monox-
of the oxygen has been loaded. The steep lower part of the ide. This is particularly dangerous because arterial chemo-
receptors respond to decreases in Po2 and not to decreases
in oxygen content, so the usual physiologic responses to
100 20
hypoxemia may be absent.
Arterial Dissolved oxygen, when compared to oxygen carried
Venous PO2 = 100
80 PO2 = 40 16
by hemoglobin, plays a small role in oxygen transport
Sat = 97
Sat =75 because the solubility of oxygen is so low (0.003 mL
Hemoglobin saturation %
O2 content mL/100 mL
O2/100 mL blood/mm Hg). Thus, normal arterial blood

60 12
with a Po2 of approximately 100 mm Hg contains only
0.3 mL of dissolved oxygen per 100 mL, whereas approxi-
mately 20 mL is combined with hemoglobin. However,
40 Temp DPG PCO2 pH 8 dissolved oxygen can become important under some
conditions. The most common is when a patient is given
100% oxygen to breathe. This typically raises the alveolar
20 4 Po2 to greater than 600 mm Hg, with the result that, if the
lungs are normal, the dissolved oxygen may increase from
0.3 to approximately 2 mL/100 mL blood. This dissolved
0 oxygen then becomes a significant proportion of the nor-
0 20 40 60 80 100
mal arterial-venous oxygen content difference of approxi-
mately 5 mL O2/100 mL blood.
PO2 mm Hg
Figure 10.12 Oxygen dissociation curve showing typical values for CARBON DIOXIDE
arterial and mixed venous blood. The curve is shifted to the right by
increases of temperature, 2,3-diphosphoglycerate (DPG), Pco2, and H+ Carbon dioxide is transported in the blood in three forms:
concentration. Pco2, partial pressure of carbon dioxide; Po2, partial pres-
sure of oxygen; Sat, saturation; Temp, temperature. (Modified from West
as bicarbonate (≈90%), as dissolved CO2 (≈5% of the total),
JB. Respiratory Physiology: The Essentials. 9th ed. Baltimore: Lippincott Williams and in combination with proteins such as carbamino com-
& Wilkins; 2012.) pounds (≈5%). Because carbon dioxide is some 24 times
more soluble than oxygen in blood, dissolved carbon diox- The transport of carbon dioxide by the blood plays an
ide plays a more significant role in carbon dioxide transport important role in the acid-base status of the body. This topic
than dissolved oxygen does in oxygen transport. For exam- is discussed at length in Chapter 12.
ple, approximately 10% of the carbon dioxide that diffuses
into the alveolar gas from the mixed venous blood comes
from the dissolved form. GAS EXCHANGE
Bicarbonate is formed in blood by the following hydra-
tion reaction: The primary function of the lungs is gas exchange, that is,
CO2 + H2O
CA
H2CO3 H + HCO
+ − allowing oxygen to move from the air into the blood and
3 Eq. 12
allowing carbon dioxide to move out. It is now established
The hydration of carbon dioxide to carbonic acid (and vice that movement of gas across the blood-gas interface is by
versa) is catalyzed by the enzyme carbonic anhydrase (CA), simple passive diffusion, that is, random (brownian) motion
present in high concentrations in the red cells but absent at a rate determined by temperature. Diffusion results in
from the plasma; some CA is apparently located on the net transfer of molecules from an area of high to an area
surface of the endothelial cells of the pulmonary capillar- of low partial pressure, and active transport is not required.
ies. Because the majority of the CA is in the red cell, car- The structure of the lung is well suited to this mechanism of
bon dioxide is mostly hydrated there, and bicarbonate ion gas exchange. The blood-gas barrier is extremely thin (only
moves out of the red cell to be replaced by chloride ions to 0.3 μm over much of its extent), and its area is between 50
maintain electrical neutrality (the chloride shift). Some of and 100 m2. Because Fick’s law of diffusion states that the
the hydrogen ions formed in the red cell are bound to hemo- amount of gas that moves across a tissue sheet is propor-
globin and, because deoxygenated hemoglobin is a better tional to its area and inversely proportional to its thickness,
proton acceptor than the oxygenated form, deoxygenated the blood-gas barrier is ideal for its gas-exchanging function.
blood can carry more carbon dioxide for a given Pco2 than An important concept in any discussion of gas exchange
can oxygenated blood (Fig. 10.13). In this way, oxygen is partial pressure. As described earlier in “Blood- Gas
decreases the affinity of hemoglobin for carbon dioxide, Transport,” the partial pressure of a gas is the product
thereby increasing carbon dioxide delivery at the lung. This of its concentration and the total pressure. For example,
is known as the Haldane effect. Po2 = 0.209 × 760 mm Hg = 159 mm Hg in dry air with
The carbon dioxide dissociation curve describing the 20.9% oxygen at sea level, where the barometric pres-
relationship between Pco2 and total carbon dioxide con- sure is 760 mm Hg. When air is inhaled into the upper
centration is shown in Figure 10.13. Note that the curve airway, it is warmed and saturated with water vapor. The
is much more linear in its working range than the oxy- water vapor pressure at 37°C is 47 mm Hg. Under these
gen dissociation curve (see Fig. 10.12) and that, as we conditions, the total dry gas pressure is only 760 − 47
have seen, the lower the saturation of hemoglobin with = 713 mm Hg. The Po2 of moist inspired air is therefore
oxygen, the larger the carbon dioxide concentration for a (20.9/100) × 713 = 149 mm Hg. In general, the relation-
given Pco2. ship between the partial pressure (P) and fractional concen-
tration (F) of a gas when water vapor is present is given by
Px = Fx (Pb − PH2O), where Pb is barometric pressure and
x is the species of gas.
Figure 10.14 shows an overview of the oxygen cascade
from the air that we breathe to the tissues where it is used.
60
The line represents an ideal situation that does not actually
CO2 concentration (mL/100 mL)
% HbO2
0 75 97.5 exist but does make a useful backdrop for purposes of discus-
sion. One of the first surprises is that, by the time the oxy-
gen has reached the alveoli, its partial pressure has fallen
40 from approximately 150 to 100 mm Hg. The reason for this
55 v decline is that the Po2 in the alveolar gas is determined by
CO2 concn
a balance between two factors. On the one hand, there is

50
the essentially continuous addition of oxygen by the pro-
20 a cess of alveolar ventilation and, on the other hand, there is
45
the continuous removal of oxygen by the pulmonary blood
40 50
PCO2 flow. The net result is that the alveolar Po2 settles out at
Dissolved
approximately 100 mm Hg.
It is true that the process of ventilation is intermittent
0 20 40 60 80 with each breath and not continuous. By the same token,
pulmonary capillary blood flow is known to be pulsatile.
CO2 pressure (mm Hg)
However, the volume of gas in the lung at FRC is sufficient
Figure 10.13 Carbon dioxide dissociation curves for blood of different to dampen both of these oscillations, with the result that the
oxygen saturations (oxyhemoglobin [HbO2]). Inset, The physiologic alveolar Po2 varies by only 3 or 4 mm Hg with each breath
curve between arterial (a) and mixed venous (v) blood, shown with two and by less than that with each heartbeat. Thus, alveolar
dissociation curves representing the %HbO2 for venous blood (top) and for
arterial blood (bottom). concn, concentration; Pco2, partial pressure of car-
ventilation and capillary blood flow can be regarded as con-
bon dioxide. (Modified from West JB. Respiratory Physiology: The Essentials. 9th tinuous processes from the point of view of gas exchange.
ed. Baltimore: Lippincott Williams & Wilkins; 2012.) This greatly simplifies consideration of gas exchange.
Hypoventilation
Dead space Hypoventilation is used here to refer to conditions in which
150 alveolar ventilation is abnormally low in relation to oxy-
Alveolar gas gen uptake or carbon dioxide output (see also Chapter 45).
PO2 mm Hg
End capillary blood Alveolar ventilation is the volume of fresh inspired gas
100
going to the alveoli (i.e., non–dead-space ventilation), as
mentioned earlier. As we shall see, hypoventilation always
Tissues causes a raised arterial Pco2 and also arterial hypox-
50
microvessels emia (unless the patient is breathing an enriched oxygen
mixture). It should be noted that other conditions (e.g.,
Mitochondria ventilation-perfusion inequality) can also result in carbon
0
dioxide retention, and some use the terms hypoventilation
Atmosphere Mitochondria and carbon dioxide retention interchangeably. However, this
Figure 10.14 Scheme of the oxygen partial pressures from air to tis- can be confusing because carbon dioxide can be retained
sues. A hypothetically perfect situation. Po2, partial pressure of oxygen. even when a patient is breathing more than normal, so we
(Modified from West JB. Ventilation/Blood Flow and Gas Exchange. 5th ed. do not use the terms interchangeably.
Oxford: Blackwell Scientific; 1990.)
As previously mentioned, the Po2 of alveolar gas is
determined by a balance between the rate of addition of
oxygen by alveolar ventilation and the rate of removal by
the pulmonary blood flow to satisfy the oxygen demands
In an ideal lung (see Fig. 10.14), the effluent pulmo- of the tissues. Hypoventilation results when the alveolar
nary venous blood, which becomes the systemic arterial ventilation is reduced and the alveolar Po2 therefore set-
blood, would have the same Po2 as that of the alveolar gas, tles out at a lower level than normal. For the same reason,
namely, approximately 100 mm Hg. This is very nearly the alveolar Pco2, and therefore also arterial Pco2, are also
the case in the normal lung. However, when the arterial raised.
blood reaches the peripheral tissues, Po2 falls substantially Causes of hypoventilation include depression of the respi-
en route to the mitochondria. The movement of oxygen ratory center by drugs, such as opiates, or diseases of the
in the peripheral tissues is also essentially by passive dif- brainstem, such as encephalitis; abnormalities of the spinal
fusion, and the mitochondrial Po2 is considerably lower cord–conducting pathways, such as high cervical dislocation;
than that in either the arterial or mixed venous blood. anterior horn cell diseases, including poliomyelitis, affecting
Indeed, the Po2 in the mitochondria may vary consider- the phrenic nerves or supplying the intercostal muscles; dis-
ably throughout the body, depending on the type of tis- eases of nerves to respiratory muscles (e.g., Guillain-Barré
sue and its oxygen uptake. Nevertheless, it is useful to syndrome); diseases of the myoneural junction, such as myas-
bear in mind that the mitochondria are the targets for the thenia gravis; diseases of the respiratory muscles themselves,
oxygen transport system and that any fall in the arterial such as progressive muscular dystrophy; thoracic cage abnor-
Po2 caused, for example, by inefficient pulmonary gas malities (e.g., crushed chest); upper airway obstruction (e.g.,
exchange must be reflected in a reduced tissue Po2, other thymoma); hypoventilation associated with extreme obesity
factors being equal. (obesity hypoventilation syndrome); and other causes, such
For carbon dioxide, the process is reversed. There is as metabolic alkalosis and idiopathic states.
essentially no carbon dioxide in the inspired air, and the Note that, in all these conditions, the lungs are normal.
alveolar Pco2 is approximately 40 mm Hg. Under normal Thus, this group can be clearly distinguished from those
conditions, arterial and alveolar Pco2 values are the same, diseases in which the carbon dioxide retention is associ-
whereas the Pco2 of mixed venous blood is in the range of ated with chronic lung disease. In the latter conditions, the
45 to 47 mm Hg. The Pco2 of the tissues is probably quite lungs are abnormal, and a major factor in the raised Pco2 is
variable, depending, for example, on the state of metabo- the ventilation-perfusion inequality that causes gross inef-
lism. Nevertheless, any inefficiency of the lung for carbon ficiency of pulmonary gas exchange (see later).
dioxide removal tends to raise the Pco2 of the tissues, other The rise in alveolar Pco2 as a result of hypoventilation
factors being equal. can be calculated using the alveolar ventilation equation
(see earlier section “Total and Alveolar Ventilation” for
CAUSES OF HYPOXEMIA (See Chapter 44) derivation):
Hypoxemia refers to a reduction in arterial Po2 to below V̇CO2
V̇A = × K Eq. 5
normal values. There are five causes of hypoxemia. Four PACO2
processes from within the body can impair pulmonary gas where K is a constant. This can be rearranged as follows:
exchange and cause hypoxemia when breathing room air
at sea level: hypoventilation, diffusion limitation, shunt, V̇CO2
PACO2 = × K Eq. 13
and ventilation-perfusion inequality. There is an additional V̇A
cause from outside the body, namely from a decrease in Because, in normal lungs, the alveolar (Paco2) and arterial
inspired oxygen concentration. Such a decrease in frac- (Paco2) Pco2 are almost identical, we can write:
tional concentration of oxygen in inspired gas may be found
at high altitude or with accidents in which oxygen is con- V̇CO2
PaCO2 = × K Eq. 14
sumed or displaced in inspired air. V̇A
This very important equation indicates that the level of The term in brackets is the correction factor for the differ-
Pco2 in alveolar gas or arterial blood is inversely related to ence between inspired and expired volumes. It is gener-
the alveolar ventilation. For example, if the alveolar venti- ally small during air breathing (1 to 3 mm Hg) and can be
lation is halved, the Pco2 doubles. Note, however, that this ignored in most clinical settings if the patient is breathing
is true only after a steady state has been reestablished and air. However, if the patient is being given an enriched oxy-
the carbon dioxide production rate is the same as before. In gen mixture, the correction factor increases. In someone
practice, if the alveolar ventilation of a patient is suddenly with normal lungs breathing pure oxygen, the factor is
decreased (e.g., by changing the setting on a ventilator), the approximately 10 mm Hg.
Pco2 rises over a period of 10 to 20 minutes. The rise is rapid As an example of the use of the alveolar gas equation, sup-
at first and then is more gradual as the body stores of carbon pose that a patient with normal lungs takes an overdose of
dioxide are gradually filled.86 a barbiturate drug that depresses alveolar ventilation. The
The same principles used for carbon dioxide can be patient’s alveolar Pco2 might rise from 40 to 60 mm Hg (the
applied to oxygen to understand the effect of hypoventila- actual value is determined by the alveolar ventilation equa-
tion on alveolar, and thus arterial, Po2. The corresponding tion). Before the drug, the patient’s alveolar Po2 can be cal-
mass conservation equation for oxygen is as follows, where culated assuming R = 1.0, and the small correction factor is
V̇O2 is the oxygen uptake: neglected:
V̇O2 = ( V̇I × FIO 2) − (V̇A × FAO2 ) Eq. 15 PAO2 = PIO2 − (PACO2 /R)
Here V̇I is inspired alveolar ventilation, whereas V̇A is expired = 149 − (40/1)
alveolar ventilation. Eq. 15 expresses oxygen uptake as the = 109 mm Hg
difference between the oxygen inhaled (volume per minute
of inspired gas [V̇I] × fractional concentration of oxygen [Fio2]) After the drug, and making the same assumptions, with an
and that exhaled (volume per minute of alveolar ventilation increase of Pco2 by 20 mm Hg, the alveolar Po2 will fall by
[V̇A] × fractional concentration of oxygen in alveolar gas [Fao2]). 20 mm Hg:
Normally, because a little more oxygen is taken up per minute
than carbon dioxide exhaled, V̇I exceeds V̇A. However, this PAO2 = PIO2 − (PACO2 /R)
difference is usually no more than 1% of the ventilation, and = 149 − (60/1)
clinically it can most often be ignored. If this is done, V̇I may = 89 mm Hg
then be replaced by V̇A, and Eq. 15 simplifies to
Hence, when R = 1.0, alveolar Po2 falls by 20 mm Hg, which
VO2 = VA × (FIO2 − FAO2 ) , or is the same amount by which the Pco2 rises. If R = 0.8, which
(PIO2 − PAO2 ) is a more typical resting value, and we ignore the small cor-
VO2 = VA × Eq. 16 rection factor in Eq. 19, then, when alveolar Pco2 increases
K by 20 mm Hg, alveolar Po2 decreases by 25 mm Hg, from
where Pio2 is the partial pressure of oxygen in the inspired 99 mm Hg (the Pao2 when the CO2 is 40 mm Hg and R 0.8)
gas. Thus, as ventilation falls, Pao2 must fall as well to to 74 mm Hg.
maintain the rate of oxygen uptake necessary for metabolic Both examples emphasize that, in practical terms, the
function. hypoxemia is generally of minor importance compared
Eq. 13 (reexpressed as V̇CO2 = V̇A × PACO2 /K) and Eq. 16 with the carbon dioxide retention and consequent respi-
can be usefully combined. If Eq. 13 is divided by Eq. 16, we get ratory acidosis. This is further illustrated in Figure 10.15,
VCO2 PACO2 which shows calculated changes in gas exchange as a result
=R= Eq. 17 of hypoventilation. Note that severe hypoventilation suffi-
VO2 (PIO2 − PAO2 )
cient to double the Pco2 from 40 to 80 mm Hg decreases
Here R is the respiratory exchange ratio (volume of car- the alveolar Po2 from only, say, 100 to 50 or 60 mm Hg.
bon dioxide exhaled/oxygen taken up in the same time). Although the arterial Po2 is likely to be a few millimeters
Both K and V̇A cancel out when the division is performed. of mercury lower than the alveolar value, the arterial oxy-
Rearranging this equation yields gen saturation is still approximately 80%. However, at that
level of Pco2, there is substantial respiratory acidosis, with
PACO2 Eq. 18 an arterial pH of approximately 7.2. This fact emphasizes
PAO2 = PIO2 −
R that, in pure hypoventilation, the hypoxemia is usually not
This is called the alveolar gas equation, and it uniquely as important as the carbon dioxide retention and respira-
relates alveolar Po2 to Pco2 for given values of inspired tory acidosis.
Po2 and R. It is the basis of calculations of the alveolar-to- An important feature of alveolar hypoventilation is that,
arterial Po2 difference, a commonly used index of efficiency although the arterial Pco2 is always elevated, the arterial
of pulmonary gas exchange. Because we assumed that Po2 may be returned to normal very easily by giving supple-
V̇I = V̇A in deriving this equation, it is an approximation. It mentary oxygen. Suppose that the patient with barbiturate
is possible to account for the difference between V̇I and V̇A, intoxication just discussed is given 30% oxygen to breathe.
and, when this is done, the alveolar gas equation contains If we assume that the ventilation remains unchanged, it
an additional term: can be shown (from Eq. 19) that the alveolar Po2 increases
from 74 to approximately 140 mm Hg. Thus, a relatively
PACO2  (1 − R)  small increase in inspired Po2 is very effective in eliminating
PAO2 = P IO2 − +  PACO2 × FlO 2 × Eq. 19
R  R  the arterial hypoxemia of hypoventilation.
120 Alveolar PO2 Alveolar PO2

100
Reduced contact time

100
Alveolar PO2, PCO2 mm Hg,
O2 saturation
7.6 80
and O2 saturation %
80
Arterial pH
pH Thickened
7.4 60 blood-gas
PO2 mm Hg
barrier
60
7.2
40
40 Mixed
Normal Alveolar PCO2 venous
value P O2
20
20
Exercise Rest
2 4 6 8 10
Alveolar ventilation (L/min)
0
Figure 10.15 Gas exchange during changes in ventilation. With
0 0.25 0.5 0.75
hypoventilation, note the relatively large rise in Pco2 and consequent fall
in pH compared with the modest fall in arterial oxygen saturation. Pco2, Time in capillary (seconds)
partial pressure of carbon dioxide; Po2, partial pressure of oxygen. (Modi-
Figure 10.16 Oxygen uptake along the pulmonary capillary. Typical
fied from West JB. Respiratory Physiology: The Essentials. 9th ed. Baltimore: Lip-
time courses for the change in Po2 in the pulmonary capillary when dif-
pincott Williams & Wilkins; 2012.)
fusion is normal (green line), when the contact time is reduced as during
exercise (arrow at green line), and when the blood-gas barrier is abnormally
thick (black line). Po2, partial pressure of oxygen. (Modified from West JB.
Diffusion Limitation Respiratory Physiology: The Essentials. 9th ed. Baltimore: Lippincott Williams &
Wilkins; 2012.)
Oxygen, carbon dioxide, and all other gases cross the blood-
gas barrier by simple passive diffusion. Fick’s law of diffu-
sion states that the rate of transfer of a gas through a sheet Oxygen Uptake Along the Pulmonary Capillary.
of tissue is proportional to the tissue area (A) and the differ- Figure 10.16 shows calculated changes in the Po2 of the
ence in partial pressure (P1 − P2) between the two sides, and blood along the pulmonary capillary as oxygen is taken up
it is inversely proportional to the thickness (T): under normal conditions. The calculation is based on Fick’s
law of diffusion (see Eq. 20). One of the several assumptions is
A
V̇gas = × D × (P1 − P2 ) Eq. 20 that the diffusion characteristics of the blood-gas barrier are
T uniform along the length of the capillary. The calculation is
As we have seen already, the area of the blood-gas barrier in complicated by the fact that the change in the Po2 of the cap-
the lung is enormous (50–100 m2), and the thickness is less illary blood depends on the oxygen dissociation curve. This is
than 0.3 μm in some places, so the dimensions of the barrier not only nonlinear, but it is also influenced by the simultane-
are ideal for diffusion. ous elimination of carbon dioxide. The calculation describ-
The rate of diffusion is also proportional to a constant (D), ing this is often known as the Bohr integration because it
which depends on the properties of the tissue and the partic- was first carried out in a simplified form by Christian Bohr.87
ular gas. The constant is proportional to the solubility (Sol) Modern computations take into account reaction times of
of the gas and inversely proportional to the square root of oxygen with hemoglobin and also reaction rates associated
the molecular weight (MW): with carbon dioxide elimination (see later discussion).88
Figure 10.16 shows that the time spent by the blood in
Sol
D∝
Eq. 21 the pulmonary capillary under normal resting conditions
MW is approximately 0.75 second. This number is obtained by
This equation can be used to compare the difference of dividing the volume of blood calculated to be in the pulmo-
rate of diffusion of oxygen and carbon dioxide. For each nary capillaries (75 mL) by the cardiac output (6 L/min).89
millimeter of mercury difference between capillary and The figure shows that the Po2 of pulmonary capillary blood
alveolar partial pressures, carbon dioxide diffuses approxi- very nearly reaches that of alveolar gas after approximately
mately 20 times more rapidly than oxygen through tissue one-third of the available time in the capillary. This means
sheets because carbon dioxide has a much higher solubil- that there is normally ample time for essentially complete
ity (24:1 at 37°C), whereas the square roots of the molecu- oxygenation of the blood or, as it is sometimes said, the nor-
lar weights are not very different (1.17:1). Note that this mal lung has substantial diffusion reserves.
calculation applies only to tissue sheets and does not fully If the blood-gas barrier is thickened, the rate of transfer
account for the uptake of oxygen or output of carbon diox- of oxygen across the barrier is reduced in accordance with
ide by the lung because the chemical reactions between Fick’s law, and the rate of rise of Po2 is slower, as shown
these gases and components of blood also play a role (see in Figure 10.16. Under these circumstances, diffusion may
later discussion). not be sufficient, and a Po2 difference may develop between
alveolar gas and end-capillary blood. This means that there where Q̇s is pulmonary physiologic shunt (in mL/min), Qt
is some diffusion limitation of oxygen transfer. It is impor- is cardiac output (in mL/min), Cc′o2 is end-pulmonary cap-
tant to appreciate that, under most conditions at sea level, illary oxygen content, Cao2 is arterial oxygen content, and
oxygen transfer is perfusion limited, meaning that oxygen Cvo‾ 2 is mixed venous oxygen content.
uptake is entirely dependent on blood flow. Only under Rearranging, this gives
unusual conditions, such as severe interstitial lung disease,
Qs (Cc ′O2 − CaO2 )
is there some diffusion limitation. However, at high alti- = Eq. 27
tude, diffusion limitation during exercise is universal, even QT (Cc ′O2 − CvO2 )
in health. In well-trained athletes with very rapid transit The oxygen content of end-capillary blood is usually calcu-
time through the capillaries, diffusion may be limiting dur- lated from the alveolar Po2 and the hemoglobin concentration,
ing exercise even at sea level. assuming 100% oxyhemoglobin saturation (Eq. 11), hence
For further discussion of diffusion and perfusion limitation the assumption of normalcy of all regions not subject to shunt.
and diffusion capacity measurements, see ExpertConsult.com When the shunt is caused by blood that does not have
and Chapter 31. the same oxygen content as mixed venous blood (e.g., bron-
chial venous blood), it is generally not possible to calculate
Shunt its true magnitude. However, it is often useful to calculate
Shunt refers to the entry of blood into the systemic arte- an “as if” shunt, that is, what the shunt would be if the
rial system without going through ventilated areas of lung. observed depression of arterial oxygen content were caused
Even the normal cardiopulmonary system shows some by the addition of mixed venous blood.
depression of the arterial Po2 as a result of this factor. For An important diagnostic feature of a shunt is that the
example, in the normal lung, some of the bronchial artery arterial Po2 does not rise to the normal level, which in the-
blood is collected by the pulmonary veins after it has per- ory should be 670 mm Hg, when the patient is given 100%
fused the bronchi. Because the oxygen content of this blood oxygen to breathe. The reason for this is that the shunted
has been reduced, its addition to the normal end-capillary blood that bypasses ventilated alveoli is never exposed to
blood results in a reduction of arterial Po2. Another source the higher alveolar Po2. Its addition to end-capillary blood
of normal shunting is the small amount of coronary venous therefore continues to depress the arterial Po2. Nevertheless,
blood that drains directly into the cavity of the left ventricle the arterial Po2 is elevated somewhat because of the oxygen
through the thebesian veins. Of course, most of the coro- added to the capillary blood of the ventilated lung. Most
nary venous blood ends up in the coronary sinus, and only of this added oxygen is in the dissolved form rather than
a minute fraction reaches the left ventricle directly. Such attached to hemoglobin because the blood that is perfus-
shunts depress arterial Po2 only by approximately 1 to ing lung regions with normal ventilation-perfusion ratios is
2 mm Hg. normally nearly fully saturated.
In patients with congenital heart disease, there may be The administration of 100% oxygen to a patient with a
a direct addition of venous blood to arterial blood across shunt is a very sensitive method of detecting small amounts of
a defect between the right and left sides of the heart. In shunting. This is because when the arterial Po2 is very high, a
general, this needs an increase in pressure on the right very small reduction of arterial oxygen content (or hemoglo-
side; otherwise, the shunt would only take place from left bin saturation) caused by the addition of the shunted blood
to right. In lung disease, there may be gas-exchanging causes a relatively large fall in Po2. This is directly attribut-
units that are completely unventilated because of airway able to the almost flat slope of the oxygen dissociation curve
obstruction, atelectasis, or alveolar filling with fluid or in this region.
cells. The unoxygenated blood draining from these consti- A patient with a shunt usually does not have an increased
tutes a shunt. It could be argued that such units are simply Pco2 in the arterial blood in spite of the fact that the shunted
at the extreme end of the spectrum of ventilation-perfusion blood is rich in carbon dioxide. The reason is that the chemo-
inequality (see next section), but the gas exchange prop- receptors sense any elevation of arterial Pco2 and respond
erties of unventilated units are so different (e.g., in their by increasing the ventilation. As a consequence, the Pco2
response to supplemental oxygen) that it is convenient to of the unshunted blood is reduced by the hyperventilation
separate them. until the arterial Pco2 is back to normal. Indeed, in some
When the shunt is caused by the addition of mixed venous patients with large shunts caused, for example, by cyanotic
blood (pulmonary arterial) to blood draining from the cap- congenital heart disease, the arterial Pco2 is low because
illaries (pulmonary venous), it is possible to calculate the the arterial hypoxemia increases the respiratory drive.
amount of shunt flow. This is done using a mixing equation.
The total amount of oxygen delivered into the systemic cir- Ventilation-Perfusion Relationships
culation per minute is the total blood flow (Q̇T), that is, car- The mismatching of ventilation and blood flow is the most
diac output, multiplied by the oxygen content in the systemic common cause of hypoxemia in lung disease. Uneven ven-
arterial blood (Cao2), or Q̇T × CaO2. This must equal the sum tilation and blood flow are also a cause of carbon dioxide
of the amounts of oxygen in the shunted blood (Qs × CvO2) retention. Early intimations of the importance of the subject
and the nonshunted or end-capillary blood [(QT − Qs) × Cc ′O2 go back to Krogh and Lindhard94 and Haldane.95 However,
]. Also, it is assumed that all regions of lung not subject to in the late 1940s, our understanding advanced when Fenn
shunt are normal. Thus, and colleagues96 and Riley and Cournand97 introduced
graphic analysis of gas exchange. This was an important
QT × CaO2 = (Qs × CvO2 ) + (QT − Qs) × Cc ′O2 Eq. 26 advance because the interrelationships of ventilation, blood
It can be shown90 that whether diffusive transfer of any processes appear very different, it is possible to treat them
gas is perfusion or diffusion limited depends on the ratio mathematically in a similar way and to regard each as con-
of D, the diffusive conductance of the blood-gas barrier, to tributing its own resistance to the transfer of oxygen. Such
the product of the solubility of the gas in blood (commonly an analysis was carried out by Roughton and Forster,93
referred to as beta [β]) and the total pulmonary blood who showed that the following relationship exists:
flow rate. For oxygen, β refers to the slope of the oxygen-
hemoglobin dissociation curve. Diffusive equilibration is 1 1 1
= + Eq. 22
more likely the higher the D/Q̇β ratio. DL DM (θ × VC)
It is clear that for oxygen, the slope of the blood dissocia-
tion curve is not a constant, which makes this ratio difficult where Dl refers to the diffusing capacity of the lung, Dm
to apply. It depends on the Po2 and also to a lesser extent is the diffusing capacity of the membrane (which includes
on factors that shift the dissociation curve, such as pH, the plasma and red cell interior), θ is the rate of reaction of
Pco2, temperature, and red cell 2,3-DPG concentration. oxygen (or carbon monoxide) with hemoglobin (expressed
Under hypoxic conditions, when the lung is operating on per milliliter of blood), and Vc is the volume of blood in the
the lower, steeper part of the oxygen dissociation curve, β is pulmonary capillaries.
much greater than in normoxia, when arterial Po2 is on the In the normal lung the resistances offered by the mem-
flat portion of the curve. Thus, in hypoxia the ratio D/Q̇β is brane (1/Dm) and blood reaction components [1/(θ ×
lower, and diffusive equilibration becomes less likely. This Vc)] are approximately equal. If the capillary blood vol-
helps explain why diffusion limitation for oxygen, unusual ume is reduced by disease, the measured diffusing capac-
at sea level, is common at high altitude. eFigure 10.2 shows ity of the lung is lowered. In fact, the equation can be
the extent to which perfusion and diffusion limit the trans- used to separate the two components. To do this, the
fer of gas under various conditions.90 Although the figure is diffusing capacity is measured at both high and normal
based on a number of simplifying assumptions, it is concep- alveolar Po2 values. Increasing the alveolar Po2 reduces
tually valuable. the value of θ for carbon monoxide because the carbon
Note that physiologically inert gases, such as nitrogen and monoxide has to compete with a high pressure of oxygen
sulfur hexafluoride (right-side end of eFig. 10.2), are com- for the hemoglobin. If the resulting measurements of 1/
pletely perfusion limited in their transfer. (Physiologically Dl are plotted against 1/θ, as shown in eFigure 10.3B,
inert means that, being carried in blood only in physical the slope of the line is 1/Vc, whereas the intercept on the
solution, their blood concentration is directly proportional vertical axis is 1/Dm.
to partial pressure; that is, they obey Henry’s law of solu-
bility.) The same perfusion limitation applies to oxygen Diffusing Capacity. Carbon monoxide is usually the gas
in hyperoxia because high on the dissociation curve the of choice for measuring the diffusion properties of the lung
value of β is very low so that D/Q̇β is very high and diffusion because its transfer is almost entirely diffusion limited. It
limitation is not seen. However, as just described, oxygen is true that part of the limitation has to do with the rate of
transfer under conditions of hypoxia can be partly diffusion reaction of carbon monoxide with hemoglobin (see eFig.
limited because the lung is working low on the dissociation 10.3A), but this is conveniently included in the measure-
curve, where the slope (β) is much higher than normal. This ment of diffusion properties. Although it could be argued
is particularly the case for oxygen transfer during hypoxic that we are really more interested in oxygen and the effects
exercise and explains why diffusion is limiting in the nor- of any diffusion limitation on this gas, oxygen uptake is
mal lung during maximal exercise at extreme high altitude, typically perfusion limited under normoxic conditions and
even in well-acclimatized subjects.91,92 On the summit of partly perfusion and diffusion limited under hypoxic con-
Mount Everest, there is apparently diffusion limitation even ditions. For this reason, measurements using oxygen are
at rest. often difficult to interpret, although techniques using iso-
For discussion of diffusion capacity measurements, see topes of oxygen have been proposed.90 However, for the
also Chapter 31. measurement of diffusion properties in the pulmonary func-
tion laboratory, carbon monoxide is the best gas.
Reaction Rates With Hemoglobin. When oxygen (or As indicated earlier, Fick’s law states that the amount of
carbon monoxide) is added to blood, its combination with gas transferred across a tissue sheet is proportional to the
hemoglobin is quite fast, being close to completion in 0.2 area, a diffusion constant, and the difference in partial pres-
second. Such reaction rates can be measured using special sure, and is inversely proportional to the thickness:
equipment in which deoxygenated hemoglobin and dis-
solved oxygen are rapidly mixed and the rate of formation A
V̇gas = T × D × (P1 − P2 ) Eq. 20
of oxyhemoglobin is measured photometrically. Although
hemoglobin is oxygenated rapidly within the pulmonary The actual lung is so complex that it is not possible to deter-
capillary, even this reaction significantly delays the loading mine the area and the thickness of the blood-gas barrier
of oxygen by the red cell. during life. Instead, the equation is written to combine the
The transfer of oxygen from the alveolar gas to the red factors A, T, and D into one constant, Dl, as follows:
cell can therefore be regarded in two stages: (1) diffusion of
V̇gas = DL × (P1 − P2 ) Eq. 23
oxygen through the blood-gas barrier, including the plasma
and red cell interior, and (2) reaction of the oxygen with where Dl is the diffusing capacity of the lung and conse
hemoglobin (eFig. 10.3A). Although at first sight these two quently includes the area, thickness, and diffusion properties
133.e2 PART 1 • Scientific Principles of Respiratory Medicine
of the tissue sheet, as well as the properties of the diffusing or, in other words, the diffusing capacity of the lung for
gas. Thus, the diffusing capacity for carbon monoxide is carbon monoxide is the volume of carbon monoxide trans-
given by: ferred (in milliliters per minute) at the alveolar partial pres-
VCO sure of carbon monoxide (in millimeters of mercury).
DL =
(P1 − P2 ) Eq. 24 Some people, such as cigarette smokers, have sufficient
carboxyhemoglobin in their blood that the partial pressure
where P1 and P2 are the partial pressures of carbon mon- of carbon monoxide in the pulmonary capillaries cannot be
oxide
. in alveolar gas and capillary blood, respectively, and neglected. In this case, an estimate of the partial pressure
Vco is defined as the volume of carbon monoxide exhaled per of carbon monoxide in pulmonary capillary blood can be
unit time. Because the partial pressure of carbon monoxide made using a rebreathing technique, and Eq. 24 is used to
in capillary blood is so small, it can generally be neglected. determine diffusing capacity.
In this case the equation becomes Several techniques are available for measuring the diffus-
VCO ing capacity of the lung for carbon monoxide. For a discus-
DL =
PACO Eq. 25 sion of the principles of clinical tests, see Chapter 31.
flow, and gas exchange depend on the oxygen and carbon equation. In addition, the relationship between Pco2 and
dioxide dissociation curves, which are not only nonlinear carbon dioxide concentration in blood is nonlinear.
but interdependent, and direct solutions to the gas exchange Just as in the context of the alveolar ventilation equa-
equations that relate the ventilation-perfusion ratio to gas tion (see “Hypoventilation” earlier), it is possible to write an
exchange (see later, Eqs. 29 and 30) are not possible. equation similar to Eq. 29 for oxygen exchange based on
Later, computers were used to describe the oxygen the same principles as applied for carbon dioxide. Again, the
and carbon dioxide dissociation curves.98,99 These pro- approximation is made that V̇I = V̇A to keep the equation
cedures enabled investigators to answer questions about simple but, as for the alveolar gas equation, the fact that
gas exchange that had been impossibly difficult before that V̇i slightly exceeds V̇A can formally be taken into account.
time. The behavior of distributions of ventilation-perfusion Using this approximation, the equation for oxygen is
ratios was analyzed,100 and Wagner and colleagues101
introduced the multiple inert gas elimination technique, VA (Cc ′O2 − CvO2 )
=K× Eq. 30
which allowed, for the first time, information about the Q (PIO2 − PAO2 )
dispersion, number of modes, and shape of the distribu-
tions of ventilation, of perfusion, and of their ratio to be Just as for carbon dioxide, the alveolar and end-capillary
obtained. Po2 values are taken to be identical, implying diffusion
equilibrium across the blood-gas barrier. It is seen that the
Gas Exchange in a Single Lung Unit. The Po2, Pco2, and determinants of alveolar Po2, as for carbon dioxide, are
Pn2 in any gas-exchanging unit of the lung are uniquely threefold: (1) the ventilation-perfusion ratio, (2) inspired
determined by three major factors: (1) the ventilation- and mixed venous oxygen levels, and (3) the relationship
perfusion ratio, (2) the composition of the inspired gas and between Po2 and oxygen content in blood (i.e., the oxygen
the composition of the mixed venous blood, and (3) the dissociation curve).
slopes and positions of the relevant blood-gas dissociation Graphic analysis of these relationships is assisted by the use
curves. of the oxygen–carbon dioxide diagram, in which Po2 is on the
Formally, the key role of the ventilation-perfusion ratio horizontal axis and Pco2 is on the vertical axis. Figure 10.17
can be derived as follows. The amount of carbon dioxide is an example of the use of the oxygen–carbon dioxide dia-
exhaled into the air from alveolar gas per minute is given gram to show how the Po2 and Pco2 of a lung unit change
by Eq. 4: as the ventilation- perfusion ratio is either decreased
below or increased above the normal value. Note that for
V̇CO 2 = V̇A × PACO 2 /K a given composition of inspired gas (I) and mixed venous
blood ( v ), the possible combinations of Po2 and Pco2 are
where V̇CO2 is the carbon dioxide production, V̇A is the constrained to a single line known as the ventilation-
alveolar ventilation, K is a constant, and there is no carbon perfusion ratio line. Each point on that line uniquely cor-
dioxide in the inspired gas. responds to a value of the ventilation-perfusion ratio. Note
The amount of carbon dioxide that diffuses into alveolar also that, when the ventilation-perfusion ratio is zero, the
gas from capillary blood per minute is given by: Po2 and Pco2 of end-capillary blood are those of mixed
venous blood and, when the ventilation-perfusion ratio is
VCO2 = Q(CvCO2 − Cc ′CO2 ) Eq. 28 infinity, the Po2 and Pco2 of alveolar gas are the same as
those of inspired gas. In this diagram and in the rest of this
where Q̇ is blood flow, and CvCO2 and Cc′Co2 are the con- section, we assume that there is complete diffusion equili-
centrations of carbon dioxide in mixed venous and end- bration between the Po2 and Pco2 of alveolar gas and end-
capillary blood, respectively. Now, in a steady state, the capillary blood. This is a reasonable assumption unless
amount of carbon dioxide lost from the alveoli and from the
capillary blood must be the same. Therefore,
VA × PACO2 / K = Q(CvCO2 − Cc ′CO2 ) , or 75
VA (CvCO2 − CC′CO2)
= K×
PCO2 mm Hg
Q PACo2 Eq. 29 50
v
Thus, the alveolar Pco2 and the corresponding end- Decreasing Norma
. . l
capillary carbon dioxide concentration (assuming end- 25 VA/Q Inc
capillary and alveolar Pco2 are identical) are determined r
ea .
. A/Q
by (1) the ventilation- perfusion ratio, (2) the mixed

V
si n
,
venous carbon dioxide concentration, and (3) the carbon 0
g
dioxide dissociation curve relating Pco2 to carbon dioxide 0 50 100 150

concentration.
PO2 mm Hg
Although this equation looks simple, its appearance is
deceiving because, when the ventilation-perfusion ratio, for Figure 10.17 Oxygen–carbon dioxide diagram shows how the Po2 and
example, increases, the alveolar Po2 rises. This means that Pco2 of a lung unit change as the ventilation-perfusion ratio (V̇A / Q̇)
is changed. I, inspired gas; Pco2, partial pressure of carbon dioxide; Po2,
the oxygen saturation of the blood increases, and the rela- partial pressure of oxygen; v, mixed venous blood. (Modified from West JB.
tionship between Pco2 and carbon dioxide concentration is Respiratory Physiology: The Essentials. 9th ed. Baltimore: Lippincott Williams &
altered. Thus, the alveolar Po2 is an implicit variable in the Wilkins; 2012.)
. . . .
140 VA Q VA/Q PO2 PCO2
L/min mm Hg
120 21 .24 .07 3.3 132 28
O2 content mL/100 mL
PO2 , PCO2 mm Hg
.33 .19 1.8 121 34

100 O2 content 20
.42 .33 1.3 114 37
80 PO2 19 .52 .50 1.0 108 39
.59 .66 0.90 102 40
60 18 .67 .83 0.80 98 41
.72 .98 0.73 95 41
40 17 .78 1.15 0.68 92 42
PCO2 .82 1.29 0.63 89 42
20 16 Total 5.09 6.00
0 15 Mixed alveolar 101 39

0 .01 0.1 1.0 10 100 ∞ Mixed arterial 97 40
A–a diff. 4 1
Ventilation-perfusion ratio
Figure 10.18 Changes in Po2, Pco2, and end-capillary oxygen con-
tent in a lung unit are shown as its ventilation-perfusion ratio is Figure 10.19 Regional differences of gas exchange down the upright
altered. See text for assumptions. Pco2, partial pressure of carbon diox- normal lung. The lung is divided into nine imaginary slices. Q̇ , blood flow;
ide; Po2, partial pressure of oxygen. (Modified from West JB. State of the art: V̇A, alveolar ventilation. A–a diff, alveolar-arterial difference. (Modified from
ventilation-perfusion relationships. Am Rev Respir Dis. 1977;116:919–943.) West JB. Respiratory Physiology: The Essentials. 9th ed. Baltimore: Lippincott Wil-
liams & Wilkins; 2012.)
there is marked thickening of the blood-gas barrier or one

is considering a subject exercising in hypoxia.
Figure 10.18 shows the Po2, Pco2, and oxygen content Figure 10.19 also helps to explain why ventilation-
of end-capillary blood of a lung unit as its ventilation- perfusion inequality interferes with overall gas exchange.
perfusion ratio is increased from extremely low to extremely Note that the base of the lung has most of the blood flow,
high values. The inspired gas is assumed to be air, the Po2 but the Po2 of the end-capillary blood is lowest there. As
and Pco2 of mixed venous blood are normal (40 and 45 a result, the effluent pulmonary venous blood, which
mm Hg, respectively), and the hemoglobin concentration becomes the systemic arterial blood, is loaded with mod-
is 14.8 g/100 mL. The normal value of the ventilation- erately oxygenated blood from the base. The net result is
perfusion ratio is in the range of 0.8 to 1. Note that as the a depression of the arterial Po2 below that which would
ratio is altered either above or below that value, the Po2 be seen if ventilation and blood flow were uniformly
changes considerably. By contrast, the oxygen content distributed.
increases little as the ventilation-perfusion ratio is raised The same argument applies to carbon dioxide. In this
above the normal value because the hemoglobin is nor- case, the Pco2 of the end-capillary blood is highest at the
mally almost fully saturated. The Pco2 falls considerably base, where the blood flow is greatest. As a result, the Pco2
as the ventilation-perfusion ratio is raised but rises rela- of arterial blood is elevated above that which would be seen
tively little at lower ventilation-perfusion ratio values. The if there was ventilation-perfusion equality. In other words,
quantitative information in this figure is consistent with the a lung with mismatched ventilation and blood flow is less
graphic analysis of Figure 10.17. efficient at exchanging gas, be it oxygen or carbon diox-
ide. In fact, the inefficiency applies to any gas that is being
Pattern in the Normal Lung. Both ventilation and perfu- transferred by the lung. The extent of the impairment of
sion vary throughout the lung. It is thus instructive to look gas exchange caused by any given amount of ventilation-
at the inequality of gas exchange in different regions due to perfusion inequality depends mostly on the solubility, or
gravitational influences in the normal upright lung. As pre- slope of the blood dissociation curve, of the gas. For exam-
viously stated, both ventilation and blood flow per unit vol- ple, in a lognormal distribution of ventilation-perfusion
ume decrease from the bottom to the top of the upright lung. ratios, gases with medium solubility experience the great-
However, the changes for blood flow are more marked than est interference with pulmonary transfer.104 In the normal
those for ventilation. As a consequence, the ventilation- lung, the effect of inequality due to gravity on arterial Po2
perfusion ratio increases from low values at the base to high can be modeled, as shown in Figure 10.19. Of interest, the
values at the apex of the normal upright lung (Fig. 10.19). overall effect of the normal inherent ventilation-perfusion
Because the ventilation-perfusion ratio determines the inequality on gas exchange turns out to be very small,
gas exchange in any region (see Eqs. 29 and 30), the varia- reducing arterial Po2 by only approximately 4 mm Hg from
tion in Po2 and Pco2 in the lung can be calculated. Normal that in a homogeneous lung.
composition of mixed venous blood is assumed. Note that
the Po2 increases by some 40 mm Hg from base to apex, Traditional Assessment of Ventilation- Perfusion
whereas the Pco2 falls by 14 mm Hg. The pH is high at the Inequality. A central question that has engaged the atten-
apex because the Pco2 there is low (the base excess is the tion of physiologists and physicians for many years has
same throughout the lung). Very little of the total oxygen been how best to assess the amount of ventilation-perfusion
uptake takes place at the apex, principally because the inequality. Ideally, we would like to know the actual distribu-
blood flow there is very low. tion of ventilation-perfusion ratios (see next section), but the
procedure required for this is too complicated for many clini- is imposed on the lung? The answer is that both points
cal situations. Traditionally, we rely on measurements of Po2 diverge away from the ideal point (i) along the gas and
and Pco2 in arterial blood and expired gas. blood R lines. The more extreme the degree of ventilation-
The arterial Po2 certainly gives some information about perfusion inequality, the further the divergence. Moreover,
the degree of ventilation-perfusion inequality. In general, the type of ventilation-perfusion inequality determines how
the lower the Po2, the more marked is the mismatching of much each point will move. For example, a distribution
ventilation and blood flow. The chief merit of this measure- containing a large amount of ventilation to units with high
ment is its simplicity, but a disadvantage is that its value ventilation-perfusion ratio especially moves point A down
is sensitive to the overall ventilation and pulmonary blood and to the right, away from point i. By the same token, a
flow, to inspired Po2, and to other potential causes of hypox- distribution containing large amounts of blood flow to units
emia already discussed. with low ventilation-perfusion ratios predominantly moves
Arterial Pco2 is so sensitive to the level of ventilation that point a leftward along the blood R line.
it gives little information about the extent of the ventilation- It is clear that the horizontal distance between points A
perfusion inequality. However, the most common cause of and a (i.e., the mixed alveolar-arterial Po2 difference) would
an increased Pco2 in chronic lung disease is mismatching be a useful measure of the degree of ventilation-perfusion
of ventilation and blood flow, as explained later in the sec- inequality. Unfortunately, this index is impossible to obtain
tion on ventilation-perfusion inequality and carbon dioxide in most patients because A denotes the composition of
retention. mixed expired gas, excluding the anatomic dead-space gas.
Because of these limitations, the alveolar-arterial Po2 In most diseased lungs the alveoli empty sequentially, with
difference is frequently measured and is more informative poorly ventilated alveoli emptying last, so that a post–dead-
than the arterial Po2 alone because it is less sensitive to the space sample is not representative of all mixed expired
level of overall ventilation. To understand the significance alveolar gas. In a few patients who have essentially uniform
of this measurement, we need to look in more detail at how ventilation but uneven blood flow, this index can be used,
gas exchange is altered by the imposition of ventilation- and it is occasionally reported in patients with pulmonary
perfusion inequality. embolism. In this instance, the Po2 of end-tidal gas is taken
Figure 10.20 shows an oxygen–carbon dioxide diagram to represent mixed expired alveolar gas.
with the same ventilation-perfusion line as that in Figure Because the mixed expired alveolar Po2 is usually
10.17. Suppose initially that this lung has no ventilation- impossible to obtain, a more useful index is the Po2 differ-
perfusion inequality. The Po2 and Pco2 of the alveolar gas ence between ideal alveolar gas and arterial blood, that
and arterial blood would then be represented by point i, is, the horizontal distance between points i and a. The
known as the ideal point. This is at the intersection of the ideal alveolar Po2 is calculated from the full alveolar gas
gas and blood respiratory exchange ratio (R) lines; these lines equation:
indicate the possible compositions of alveolar gas and arte-
rial blood consistent with the overall respiratory exchange PACO2  (1 − R) 
PAO2 = PIO2 − +  PACO2 × FIO2 × Eq. 19
ratio (carbon dioxide output/oxygen uptake) of the whole R  R 
lung. In other words, a lung in which R = 0.8 would have
to have its mixed alveolar gas point (A) located somewhere To use this equation, we assume that the Pco2 of ideal
on the line joining points i and I. A similar statement can be alveolar gas is the same as the Pco2 of arterial blood. The
made for the arterial gas point (a). rationale for this is that the line along which point a moves
What happens to the composition of mixed alveolar (in Fig. 10.20) is so nearly horizontal that the value is close
gas and arterial blood as ventilation-perfusion inequality enough for clinical purposes. It is important to note that this
ideal alveolar-arterial Po2 difference is caused by units situ-
ated on the ventilation-perfusion ratio line between points
60 i and v , that is, units with abnormally low ventilation-
. . perfusion ratios. This means that a diseased lung may
Low VA/Q
V have substantial ventilation- perfusion inequality but a
i
Hi nearly normal ideal alveolar-arterial Po2 difference if most
PCO2 mm Hg
40 gh .
Blood R a VA . of the inequality is caused by units with abnormally high
line /Q ventilation-perfusion ratios.
Ga Physiologic shunt is another useful index of ventilation-
20 A sR
lin perfusion inequality. It measures that movement of the
e arterial point away from the ideal point along the blood R
0 , line (see Fig. 10.20). It is therefore caused by blood flow
40 60 80 100 120 140
to lung units with abnormally low ventilation-perfusion
ratios. To calculate physiologic shunt, we pretend that all
PO2 mm Hg of the leftward movement of the arterial point a is caused by
Figure 10.20 Effect of ventilation- perfusion inequality on gas the addition of mixed venous blood v to ideal blood i. This is
exchange. Oxygen–carbon dioxide diagram showing the ideal point (i) not so unreasonable as it might at first seem because units
and the points for arterial blood (a) and alveolar gas (A) (see text for details). with very low ventilation-perfusion ratios put out blood
I, inspired gas; Pco2, partial pressure of carbon dioxide; Po2, partial pressure
of oxygen; Q̇ , blood flow; R, respiratory exchange ratio; v, mixed venous
that has essentially the same composition as that of mixed
blood; V̇A, alveolar ventilation. (Modified from West JB. Respiratory Physiology: venous blood (see Figs. 10.17 and 10.18). The shunt equa-
The Essentials. 9th ed. Baltimore: Lippincott Williams & Wilkins; 2012.) tion is used in the following form:
QPS (CI O2 − CaO2) patterns of ventilation-perfusion distributions in normal

= Eq. 31 subjects and patients with lung disease.101
QT (CI O2 − CvO2)
For further discussion of measuring the distribution of
where Q̇ps refers to physiologic shunt, Q̇t refers to total ventilation-perfusion ratios by the multiple inert gas tech-
blood flow through the lung, and Cio2, Cao2, and CvO2 refer nique, see ExpertConsult.com.
to the oxygen content of ideal, arterial, and mixed venous Distribution in the Normal Lung. Figure 10.21A
blood, respectively. The oxygen content of ideal blood is shows the distribution of ventilation-perfusion ratios in a
calculated from the ideal Po2 and the oxygen dissociation 22-year-old normal volunteer derived from the multiple
curve. The normal value for physiologic shunt as a ratio of inert gas technique.108 The distribution shows that the plots
total blood flow is less than 0.05. of both ventilation and blood flow are narrow, spanning
The last traditional index to be discussed is physiologic only one decade of ventilation-perfusion ratios (i.e., from a
dead space (also known as wasted ventilation). Whereas ventilation-perfusion ratio of 0.3 to one 10 times higher, of
physiologic shunt reflects the amount of blood flow going 3). As expected, this range of ventilation-perfusion ratios is
to lung units with abnormally low ventilation- perfusion slightly greater than the regional differences, which mainly
ratios, physiologic dead space is a measure of the amount of depend on gravity alone (see Fig. 10.19). However, there
ventilation going to units with abnormally high ventilation- was essentially no ventilation or blood flow outside this
perfusion ratios. Thus, the two indices provide measurements range on the ventilation-perfusion ratio scale. Note also
of both ends of the spectrum of ventilation-perfusion ratios. that there was no shunt, that is, blood flow to unventilated
To calculate physiologic dead space, we pretend that all alveoli. The absence of shunt was a consistent finding in all
the movement of the alveolar point A away from the ideal the normal subjects studied and was initially surprising. It
point i (Fig. 10.20) is caused by the addition of inspired should be pointed out that this technique is very sensitive,
gas I to ideal gas. Again, this is not so unreasonable as it in that a shunt of only 0.5% of the cardiac output approxi-
may first appear because units with very high ventilation- mately doubles the arterial concentration of sulfur hexa-
perfusion ratios behave very much like point I (see Fig. fluoride. Apparently, young normal subjects are able to
10.20). Because, as indicated earlier, it is usually impossible ventilate essentially all of their alveoli. One can conclude
to obtain a pure sample of mixed expired gas, we generally that bronchial and thebesian shunts are not detected by the
collect mixed expired gas and measure its composition, E. method.
The mixed expired gas contains a component from ana- In normal subjects, the measured arterial Po2 value
tomic dead space, which therefore moves its composition is consistent with that modeled for a given ventilation-
further toward point I. The Bohr equation (see Eq. 8) is then perfusion distribution and assuming diffusion equilibrium
used in the form for oxygen. This means that ventilation-perfusion hetero-
VD phys (PaCO2 − PECO2 ) geneity explains all of the difference between ideal alveolar
= Eq. 32 Po2 and arterial Po2 in normal lungs. For example, in older
VT PaCO2 normal subjects the variation of the ventilation-perfusion
where Vdphys is physiologic dead space, Vt is tidal volume, distribution increases, which explains the gradual fall in
and Peco2 is mixed expired Pco2, and again we exploit the arterial Po2 observed with aging. Ventilation- perfusion
fact that the Pco2 of ideal gas and that of arterial blood are mismatching must take place between lung units perfused
virtually the same. The normal value for physiologic dead by vessels 150 μm in diameter or larger to have a signifi-
space as a ratio of total ventilation is less than 0.3. (For cant effect on arterial Po2.109 This means the functional
applications of these principles in pulmonary function test- unit of oxygen exchange in terms of ventilation-perfusion
ing, see Chapter 31.) matching is the acinus, or lung units distal to a terminal
bronchiole.
Distributions of Ventilation-P erfusion Ratios. The Distributions in L ung D isease . Ventilation-perfusion
analysis of ventilation- perfusion inequality briefly de- relationships vary by disease state. Figure 10.21B–C and
scribed in the last section is sometimes known as the eFigure 10.5 show typical distributions of ventilation-
three-compartment model because the lung is conceptu- perfusion ratios from patients with COPD, contrasting a
ally divided into an unventilated compartment (shunt), an patient with an emphysematous phenotype with a patient
unperfused compartment (dead space), and a compartment with a chronic bronchitis phenotype. The distribution
that is normally ventilated and perfused (ideal). This way of typical of the pattern seen in patients with predominantly
looking at the diseased lung, which was introduced by Riley emphysema shows a broad bimodal distribution, with large
and Cournand,97 has proved to be of great clinical useful- amounts of ventilation to lung units with extremely high
ness in assessing the effects of mismatching of ventilation ventilation-perfusion ratios (alveolar dead space)110 (see
and blood flow. Fig. 10.21B). Note the small shunt of 0.7%. Mild hypoxemia
However, it was recognized many years ago that real in this patient would be explained mostly by the slight dis-
lungs must contain some sort of distribution of ventilation- placement of the main mode of blood flow to the left of nor-
perfusion ratios and that a three-compartment model is mal. Presumably, the high ventilation-perfusion ratio mode
therefore remote from reality. Computer analysis facili- reflects ventilation to lung units in which many capillaries
tated considerable advances in the understanding of the have been destroyed by the emphysematous process, reduc-
behavior of distributions of ventilation-perfusion ratios.100 ing their perfusion. Patients with COPD whose predominant
This allowed the multiple inert gas elimination technique lesion is severe bronchitis generally show a different pattern
to become the standard research technique for measuring (see Fig. 10.21C). The main abnormality in the distribution
Multiple Inert Gas Elimination Technique. The princi- A graph is then constructed, as shown in eFigure 10.4.
ples governing inert gas elimination by the lung are identi- The upper panel shows the data points of inert gas retention
cal to those of oxygen and carbon dioxide and are dictated by (arterial partial pressure divided by mixed venous partial
equations corresponding to Eqs. 29 and 30. When an inert pressure), which are joined for clarity by the broken line.
gas dissolved in saline is steadily infused into the peripheral Below this are the data points for excretion (mixed expired
venous circulation, it arrives at the lungs, and some of the partial pressure divided by mixed venous partial pressure).
gas will be exhaled. The proportion of gas eliminated by Both are plotted against the partition coefficient. Again,
ventilation from the blood of a given lung unit depends only the points are joined by a broken line. For comparison, the
on the blood-gas partition coefficient of the gas (λ) and the two solid lines show the values of retention and excretion
ventilation-perfusion ratio (V̇A / Q̇).105,106 The relationship for a lung with no ventilation-perfusion inequality but with
is given by the following equation: the same overall ventilation and blood flow. Whereas the
broken and solid lines are very close together in eFigure
Pc ′ λ 10.4, the differences are more easily seen when the lung is
= Eq. 33
Pv (λ + VA/Q) diseased (eFig. 10.5) (see “Distributions in Lung Disease”
later).
where Pc′ and P v are the partial pressures of the gas in end- These plots, called the retention-solubility and excretion-
capillary blood and mixed venous blood, respectively. Eq.33 solubility curves, contain information about the distribution
looks different from Eqs. 29 and 30 only because inert gases of ventilation-perfusion ratios in the lung. The relationship
obey Henry’s law, allowing concentration to be replaced by between the distribution of ventilation- perfusion ratios
the product of solubility and partial pressure. This, in turn, and the retention-solubility and excretion-solubility curves
permits the rearrangement of terms ending up with Eq.33. can be expressed formally by a set of simultaneous linear
The ratio of end-capillary to mixed venous partial pressure equations.107 These equations, one for each inert gas, sim-
is known as the retention. This equation is derived from ply reflect the principles of mass conservation and relate
exactly the same considerations of mass balance as applied the ventilation-perfusion distribution (i.e., the paired set of
to carbon dioxide in Eq. 4. gas exchange unit blood flows and ventilations) to a mea-
In practice, a mixture of six gases (typically, sulfur hexa- sured set of inert gas retention and excretion values. The
fluoride, ethane, cyclopropane, isoflurane, ether, and ace- distribution of ventilation-perfusion ratios that is consis-
tone) is dissolved in saline and infused into a peripheral arm tent with the pattern of inert gas retention and excretion is
vein at a constant rate until a steady state of gas exchange then determined using computer programs that solve these
is achieved (10–20 minutes). Samples of mixed expired gas simultaneous equations.
and arterial blood are then taken, and the gas concentra- The potential and limitations of this transformation have
tions in each are determined by gas chromatography. At been explored in great detail.107 The recovered distribution
the same time, cardiac output is obtained (e.g., by indica- is not unique, but in most cases the range of possible dis-
tor dilution, echocardiography, or other method), and tributions compatible with the data is small. No more than
total ventilation is also measured. From these data, mixed three modes of a distribution can be recovered, and only
venous concentrations of each inert gas can be calculated smooth distributions can be obtained. In spite of these limi-
and retention determined. In patients who already have an tations, however, the technique gives much more informa-
indwelling pulmonary arterial catheter, a sample of mixed tion about patterns of distribution of ventilation-perfusion
venous blood could be taken instead to measure mixed ratios in patients with lung disease than has previously
venous inert gas levels directly. been available.
1.5 is a large amount of blood flow going to lung units with very
low ventilation-perfusion ratios, between 0.005 and 0.1. This
Ventilation or blood flow (L/min)
Ventilation
explains the more severe hypoxemia in this type of patient
and is consistent with a large physiologic shunt. Presumably,
1.0 Blood flow the low ventilation-perfusion ratios in some lung units are
the result of partially blocked airways due to retained secre-
tions and airway disease that reduces airway diameter. It
should be emphasized that the distributions found in severe
0.5 chronic bronchitis show considerable variability.
Newer techniques are being developed to image and
No shunt quantify ventilation- perfusion matching.111–113 These
have the advantage of being less invasive and may be more
0 widely available in the future, providing the ability to detect
0 0.01 0.1 1.0 10.0 100.0 pathologic changes earlier and to improve the understand-
A Ventilation-perfusion ratio ing of subgroups of patients.
0.5
Ventilation-Perfusion Inequality and Carbon Dioxide
Retention. It is important to remember that ventilation-
perfusion inequality interferes with the uptake and elimi-
Blood flow nation of all gases by the lung (oxygen, carbon dioxide,
0.4 Ventilation carbon monoxide, and anesthetic gases). In other words,

mismatching of ventilation and blood flow reduces the
0.3
overall gas exchange efficiency of the lung. There has been
considerable confusion in this area, particularly about the
role of ventilation-perfusion inequality in carbon dioxide
0.2
retention.
Imagine a lung that is uniformly ventilated and perfused
and that is transferring normal amounts of oxygen and
0.1
carbon dioxide. Suppose that the matching of ventilation
and blood flow is suddenly disturbed while everything else
0.7% shunt
remains unchanged. What happens to gas exchange? It can
0
be shown that the effect of this “pure” ventilation-perfusion
0 0.01 0.1 1.0 10.0 100.0
inequality (i.e., with all other factors held constant) is to
B Ventilation-perfusion ratio
reduce both the oxygen uptake and carbon dioxide out-
put of the lung.100 The lung becomes less efficient as a gas
exchanger for both gases, and therefore mismatching of ven-
0.8 tilation and blood flow must cause hypoxemia and hypercap-
nia (carbon dioxide retention), other things being equal.
0.7 In practice, however, as mentioned earlier for shunt,
patients with ventilation-perfusion inequality often have

0.6
a normal arterial Pco2. The reason is that whenever the
Ventilation
0.5 Blood flow
chemoreceptors sense a rising Pco2, there is an increase in
ventilatory drive. The consequent increase in ventilation
0.4 to the alveoli usually returns the arterial Pco2 to normal.
However, such patients can only maintain a normal Pco2
0.3 at the expense of this increased ventilation to their alveoli.
The ventilation in excess of what they would normally
0.2 require is sometimes referred to as wasted ventilation and
No shunt
is necessary because the lung units with abnormally high
0.1
ventilation-perfusion ratios contribute little to eliminating
0 carbon dioxide. Such units are part of the alveolar (physi-
0 0.01 0.1 1.0 10.0 100.0 ologic) dead space. Patients with ventilation-perfusion ratio
C Ventilation-perfusion ratio inequality causing carbon dioxide retention are sometimes
said to be “hypoventilating,” but in fact they may actually
Figure 10.21 Ventilation-perfusion ratios in normal and in patients
with COPD of different mechanisms. (A) In a healthy person, the dis-
be breathing more than normal.
tribution of ventilation (open circles) and perfusion (closed circles) is nar- Although patients with mismatched ventilation and
row, unimodal, and centered around a V̇A /Q̇ of 1. (B) In a person with blood flow can usually maintain a normal arterial Pco2
emphysema- type COPD, the ventilation distribution is bimodal, with by increasing the ventilation to the alveoli, this strategy is
areas of high V̇A / Q̇ ratio. (C) In a person with bronchitis-type COPD, the much less effective at increasing the arterial Po2. The rea-
perfusion distribution is bimodal, with areas of low V̇A / Q̇. (From West JB.
Causes of and compensations for hypoxemia and hypercapnia. Compr. Physiol. son for the different behavior of the two gases lies in the dif-
2011;1:1541–1553.) ferent shapes of the carbon dioxide and oxygen dissociation
curves. The carbon dioxide dissociation curve is almost

straight in the physiologic range, with the result that an
Key Points
increase in ventilation raises the carbon dioxide output of n he magnitudes of ventilation and perfusion, as well
T
lung units with both high and low ventilation-perfusion as their distribution, are key factors determining pul-
ratios. By contrast, the nonlinearity of the oxygen disso- monary gas exchange.
ciation curve means that not all lung units benefit from n Distribution of ventilation and perfusion is predomi-
increased ventilation by increasing oxygen content in their nantly affected by gravity in the normal lung, but
effluent blood. Those units with high ventilation-perfusion intrinsic lung structure also plays a role.
ratios, which operate high on the flat portion of the disso- n Distribution of ventilation-perfusion (V̇A / Q̇) ratios is
ciation curve, increase the oxygen content in blood very nonuniform, with the V̇A / Q̇ ratio being generally
little despite large increases in Po2. In units with a low higher in nondependent lung regions and lower in
ventilation-perfusion ratio, Po2 in blood will increase more dependent lung regions.
but some hypoxemia always remains. n Regional alveolar Po and Pco are determined prin-
2 2
In summary, carbon dioxide retention can result from cipally by the V̇A / Q̇ ratio of each region. Secondary
two clearly distinct mechanisms: pure hypoventilation and factors are the Po2 and Pco2 of inspired gas and of
ventilation-perfusion inequality. The latter is a common mixed venous blood and also the shape of the oxygen
cause in clinical practice. and carbon dioxide dissociation curves.
n There are five causes of hypoxemia: decreased inspired
Effect of Changes in Cardiac Output on Gas Exchange oxygen, hypoventilation, alveolar-capillary diffusion
in the Presence of Ventilation-Perfusion Inequality. limitation, shunt, and V̇A / Q̇ inequality.
In a lung with no ventilation-perfusion inequality, the car- n There are two principal causes of hypercapnia:
diac output has no effect on arterial Po2 or Pco2. This fol- hypoventilation and V̇A / Q̇ inequality.
lows from Eqs. 4 and 16, the mass conservation equations n V̇A / Q̇ inequality is the most important cause of gas
for CO2 and O2, respectively, which do not contain cardiac exchange abnormalities in most lung diseases.
output. By contrast, these equations show that the level of
total ventilation is very important.
However, in a lung with ventilation-perfusion inequal-
ity, cardiac output can have a major effect on arterial
Key Readings
Po2 by altering the mixed venous Po2, which affects the Barer GR, Howard P, Shaw JW. Stimulus-response curves for the pul-
monary vascular bed to hypoxia and hypercapnia. J Physiol (Lond).
arterial Po2 via shunts through the lung. A reduction in 1970;211:139–155.
cardiac output reduces the Po2 of mixed venous blood; Frostell C, Fratacci M-D, Wain JC, et al. Inhaled nitric oxide: a selective
when this venous blood transits low ventilation-perfusion pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction.
regions, it exaggerates the hypoxemia. This is sometimes Circulation. 1991;83:2038–2047.
Glazier JB, Hughes JMB, Maloney JE, et al. Measurements of capillary
seen in patients with myocardial infarction, in whom the dimensions and blood volume in rapidly frozen lungs. J Appl Physiol.
reduction in arterial Po2 seems to be out of proportion to 1969;26:65–76.
the degree of ventilation-perfusion inequality. The oppo- Milic-Emili J, Henderson JAM, Dolovich MB, et al. Regional distribution of
site is sometimes seen in patients with bronchial asthma, inspired gas in the lungs. J Appl Physiol. 1966;21:749–759.
who may have unusually high cardiac outputs and a high Petousi N, Talbot NP, Pavord I, Robbins PA. Measuring lung func-
tion in airways diseases: current and emerging techniques. Thorax.
mixed venous Po2, especially when treated with some β- 2019;74(8):797–805.
agonist drugs. The result is that the arterial Po2 is higher Rahn H, Fenn WO. A Graphical Analysis of the Respiratory Gas Exchange.
than would be expected from the degree of ventilation- Washington, DC: American Physiological Society; 1955.
perfusion inequality. This important modulating effect of Riley RL, Cournand A. “Ideal” alveolar air and the analysis of ventilation/
perfusion relationships in the lung. J Appl Physiol. 1949;1:825–847.
cardiac output on gas exchange is often overlooked in the Wagner PD, Dantzker DR, Dueck R, et al. Ventilation- perfusion
clinical setting. inequality in chronic obstructive pulmonary disease. J Clin Invest.
1977;59:203–216.
Wagner PD, Dantzker DR, Iacovoni VE, et al. Ventilation-perfusion inequal-
OXYGEN SENSING ity in asymptomatic asthma. Am Rev Respir Dis. 1978;118:511–524.
Wagner PD, Laravuso RB, Uhl RR, et al. Continuous distributions of
The responses of the body to hypoxia have been greatly clar- ventilation-perfusion ratios in normal subjects breathing air and 100%
ified by the discovery of hypoxia inducible factors (HIFs). The O2. J Clin Invest. 1974;54:54–68.
initial finding was of a protein that bound to the hypoxia Wagner PD, West JB. Effects of diffusion impairment on O2 and CO2 time
response element of the erythropoietin gene under hypoxic courses in pulmonary capillaries. J Appl Physiol. 1972;33:62–71.
West JB. Ventilation/Blood Flow and Gas Exchange. 5th ed. Oxford-
conditions.114 Later it became clear that HIFs are critically Philadelphia: Blackwell Scientific Publications–Lippincott; 1990:1–120.
important in a large number of responses of cells to hypoxia. West JB. Ventilation/perfusion inequality and overall gas exchange in
More information on the physiology of hypoxia can be computer models of the lung. Respir Physiol. 1969;7:88–110.
found at ExpertConsult.com. West JB, Dollery CT. Distribution of blood flow in isolated lung: relation
to vascular and alveolar pressures. J Appl Physiol. 1964;19:713–724.
Acknowledgment West JB, Lahiri S, Gill MB, et al. Arterial oxygen saturation during exercise
at high altitude. J Appl Physiol. 1962;17:617–621.
We acknowledge the contributions of Frank L. Powell, PhD, West JB, Mathieu-Costello O. Structure, strength, failure and remodeling of
and Peter D. Wagner, MD, who authored this chapter in the pulmonary capillaries. Annu Rev Physiol. 1999;61:543–572.
previous edition of this text and contributed substantially to
the content. Complete reference list available at ExpertConsult.com.
In fact, it is now known that, in cellular hypoxia, the tran- Genes regulated by HIFs have many functions through-
scription of over a hundred messenger RNAs is increased, out the physiologic spectrum. These include mitochondrial
and the expression of an equal number of messenger RNAs genes involved with energy use, glycolytic enzyme genes
is decreased.115 influencing anaerobic metabolism, genes associated with
HIFs are heterodimeric transcription factors influenced by vascular endothelial growth factor controlling angiogen-
the amount of oxygen in the cell. A transcription factor is a esis, genes of NO metabolism and ion channels on smooth
protein that binds to specific DNA sequences in a gene and muscle cells involved with the control of pulmonary blood
thus controls the flow of genetic information from DNA to flow, erythropoietin genes affecting red cell production, and
messenger RNA. Cellular hypoxia causes an increased con- genes controlling the induction of tyrosine hydroxylase,
centration of HIF-1α, which then binds to the constitutively which plays a role in the function of the carotid body che-
expressed HIF-1β, with both binding to the hypoxia response moreceptor.117 Of particular interest is cancer, a condition
element. It is now known that most oxygen-breathing spe- that requires more energy,118 which can be supplied by a
cies express these transcriptional factors, indicating that HIFs HIF pathway. Furthermore, tumor-associated inflamma-
have been highly conserved. For example, HIF-1 is expressed tion causes the induction of glycolytic pathways119 that use
in very primitive animals, such as the worm Caenorhabditis ele- HIF signaling. The role of the HIF pathway has been iden-
gans, without specialized respiratory or circulatory systems. tified in playing a central role in the adaptive response to
This implies that HIF was most likely developed to enhance chronic hypoxia of high altitude.120,121 Thus, HIFs consti-
the survival of individual cells in low-oxygen environments. tute a master switch in the general response of the body to
After the discovery of HIF-1α, a paralog, HIF-2α, was identi- hypoxia.
fied with both overlapping and distinct functions.116
139.e2 PART 1 • Scientific Principles of Respiratory Medicine
eFIGURE IMAGE GALLERY
100 ) t)
est res
90 tr at
(a a ) a (
Pulmonary blood flow (% control)
) ia
x ia ise x ia oxi ise oxi ox
80 p o r c p o rm rc rm p er
e e
hy ex hy no ex no hy
70 O in ng in in ng in in
C 2
O u r i 2
O O u O 2 r i 2 F 6
S N O2 2
60 (d (d
Diffusion limitation (Ldiff)

1.0
50
40
0.5
30
20
10 0
0.01 0.1 1 10 100
0 .
20 40 60 80 100 120 140 160 180 200 300 400 500 D/(Qβ)
Alveolar PO2 (mm Hg) eFigure 10.2 Diffusion- limited transfer of various gases in the
lung. Diffusion limitation (Ldiff) is on a scale of 0 (no limitation) to 1 (com-
eFigure 10.1 Stimulus-response curves of hypoxic pulmonary vaso- plete limitation) (see text for details). D/Q̇β ratio, diffusive equilibrium of
constriction. Pulmonary blood flow is shown in relation to alveolar Po2 in gas in blood; SF6, sulfur hexafluoride. (From Scheid P, Piiper J: Blood gas
feline lung preparations, each represented by a separate line. Po2, partial equilibration in lungs and pulmonary diffusing capacity. In: Chang HK, Paiva M,
pressure of oxygen. (Modified from Barer GR, Howard P, Shaw JW. Stimulus- eds. Respiratory Physiology: An Analytical Approach. New York: Marcel Dekker;
response curves for the pulmonary vascular bed to hypoxia and hypercapnia. 1989:453–497.)
J Physiol [Lond]. 1970;211:139–155.)
DL
Alveolar Graphical solution of DM and VC

wall
Red cell
1
Alveolus Slope
O2 O2 + Hb HbO2 VC
DM θ×VC
1
DL
1
Intercept
DM
1 1 1
= +
DL DM θ×VC
1
A B θ
eFigure 10.3 The components of the diffusing capacity. (A) The two components of the measured diffusing capacity (Dl) of the lung: that due to the
diffusion process itself (Dm) and that attributable to the time taken for oxygen (or carbon monoxide) to react with hemoglobin (Hb) (θ × Vc). (B) 1/Dl plotted
against 1/θ can be used to derive Dm and Vc. θ is the reaction coefficient that is varied by changing the inspired oxygen to allow separation of the various
resistances. Hb, hemoglobin, HbO2, oxyhemoglobin; Vc, vital capacity.
Ethane Isoflurane Ethane Isoflurane

Cyclo- Cyclo-
Acetone
SF6 propane Ether SF6 propane Ether Acetone
1.0
1.0
Inert gas partial pressures
Arterial
Inert gas partial pressures

0.8 Venous Arterial
0.8 Venous
0.6
0.6
Expired Expired
0.4 Venous Venous
0.4
0.2
0.2
0
0
0.01 0.1 1.0 10.0 100.0
0.01 0.1 1.0 10.0 100.0
Blood-gas partition coefficient Blood-gas partition coefficient
1.5
Ventilation and blood flow (L/min)

0.6
Ventilation Blood flow Ventilation
1.0 Blood flow 0.4
0.5 0.2
3.1% shunt
No shunt
0
0
0 0.01 0.1 1.0 10.0 100.0
0 0.01 0.1 1.0 10.0 100.0
eFigure 10.5 Distribution of ventilation- perfusion ratios in a
eFigure 10.4 Use of the multiple inert gas elimination technique 60- year- old patient with COPD, predominantly emphysema. Top
to determine the distribution of ventilation-perfusion ratios in a panel, The retention and excretion solubility curves. Bottom panel,
22-year-old normal patient. Top panel, Data points for inert gas reten- The recovered distribution of ventilation- perfusion ratios. SF6, sulfur
tion (upper curve) and excretion (lower curve). Broken lines join the points. hexafluoride. (Modified from Wagner PD, Dantzker DR, Dueck R, et al.
The two solid lines show the values of retention and excretion for a lung Ventilation-perfusion inequality in chronic obstructive pulmonary disease. J
with no ventilation-perfusion inequality. Bottom panel, The recovered dis- Clin Invest. 1977;59:203–216.)
tribution of ventilation-perfusion ratios. SF6, sulfur hexafluoride. (Modified
from Wagner PD, Laravuso RB, Uhl RR, West JB. Continuous distributions of
ventilation-perfusion ratios in normal subjects breathing air and 100% O2. J
Clin Invest. 1974;54:53–68.)
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Respiratory Physiology: Ventilation, Blood Flow, and Gas Exchange

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SECTION B

10 VENTILATION, BLOOD FLOW,

INTRODUCTION Distribution of Pulmonary Oxygen

INTRODUCTION without alveoli. All these bronchi make up the conduct-

Total cross-sectional area (cm2)

Liters Another way of measuring alveolar ventilation in normal

Multiplying by respiratory frequency gives Physiologic Dead Space

be attributed to the weight of the lung, which requires a

seen. The major share of the ventilation now goes to the

–10 cm H2O –4 cm H2O

pressure (FRC) pressure (RV)

–2.5 cm H2O +3.5 cm H2O

Figure 10.5 The inequality of ventilation down the lung due

Arteries Capillaries Veins Alveolus Alveolar vessels

The decreases in pulmonary vascular resistance shown

Pulmonary vascular resistance (PVR)

Figure 10.9 Mechanisms responsi-

volume is small and the radial traction of surrounding

100 parenchyma on the extra-­alveolar vessels is weak. Drugs

O2/100 mL blood/mm Hg). Thus, normal arterial blood

a balance between two factors. On the one hand, there is

120 Alveolar PO2 Alveolar PO2

Reduced contact time

by (1) the ventilation-­ perfusion ratio, (2) the mixed

dioxide dissociation curve relating Pco2 to carbon dioxide 0 50 100 150

.33 .19 1.8 121 34

0 15 Mixed alveolar 101 39

there is marked thickening of the blood-­gas barrier or one

QPS (CI O2 − CaO2) patterns of ventilation-­perfusion distributions in normal

0.4 Ventilation carbon monoxide, and anesthetic gases). In other words,

patients with ventilation-­perfusion inequality often have

curves. The carbon dioxide dissociation curve is almost

eFIGURE IMAGE GALLERY

Diffusion limitation (Ldiff)

Alveolar Graphical solution of DM and VC

Ethane Isoflurane Ethane Isoflurane

Inert gas partial pressures

Ventilation and blood flow (L/min)

Ventilation Blood flow Ventilation

1.0 Blood flow 0.4

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100 parenchyma on the extra-alveolar vessels is weak. Drugs

by (1) the ventilation- perfusion ratio, (2) the mixed

there is marked thickening of the blood-gas barrier or one

QPS (CI O2 − CaO2) patterns of ventilation-perfusion distributions in normal

patients with ventilation-perfusion inequality often have