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470 VENTILATION, PERFUSION MATCHING
Papazian L, Thomas P, Garbe L, et al. (1995) Bronchoscopic or blind
sampling techniques for the diagnosis of ventilator-associated
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National Nosocomial Infections Surveillance System. Critical
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Torres A, Carlet J, Bouza E, et al. (2001) Ventilator-associated
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VENTILATION, PERFUSION MATCHING
P D Wagner, University of California – San Diego,
La Jolla, CA, USA
& 2006 Elsevier Ltd. All rights reserved.
Abstract
The lungs exist primarily to exchange gases between the environment and the blood. This is accomplished by three linked
processes: convective transport of air to the alveoli (ventilation),
diffusion of gas molecules between alveolar gas and pulmonary
capillary blood, and convective transport in blood by cardiac
pumping (perfusion). The lung is unique because these processes
are accurately described by simple mass balance considerations,
which show that the ventilation/perfusion ratio (V̇A/Q̇) is the
key determinant of alveolar gas exchange. When the V̇A/Q̇ is not
the same everywhere throughout the lungs, V̇A/Q̇ inequality is
said to exist, causing hypoxemia, hypercapnia, and reduced O2
uptake and CO2 elimination. This compromises tissue metabolism, and may cause tissue hypoxia and acidosis. Clinical
assessment of V̇A/Q̇ inequality is thus important, and uses three
measures: alveolar–arterial PO2 difference, physiological deadspace, and physiological shunt. The body has three principal
ways of compensating for continuing V̇A/Q̇ inequality. First,
mixed venous PO2 falls and PCO2 rises, usually restoring V̇O2 and
V̇CO2, but causing further hypoxemia and hypercapnia. Second,
ventilation increases, stimulated partly by hypoxemia and
hypercapnia. While usually effective in normalizing arterial
PCO2 , PO2 often remains low. Third, cardiac output may rise,
increasing mixed venous, and thus arterial, PO2 .
Description
Basic Principles
The principal function of the lungs is the uptake of
O2 from the atmosphere into the circulating blood,
and the elimination of CO2 produced by metabolism.
This requires three major gas transport processes:
ventilation (see Ventilation: Overview) to bring inspired air to the alveoli, and alveolar gas to the
atmosphere; diffusion (see Diffusion of Gases) to
transfer gases across the alveolar–capillary blood–gas
barrier; and blood flow (see Pulmonary Circulation)
to transport gases in blood between the lungs and
body tissues. Other gases, including inhaled pollutants and anesthetics, are exchanged similarly. The
same principles of gas exchange apply to all gases,
whether they form chemical species in blood or are
carried simply in physical solution, and for both uptake and elimination. Except for a few situations, the
process of diffusion reaches equilibration. That is,
alveolar and endcapillary partial pressures of gases
are not significantly different. Here it will be considered that diffusion equilibration exists.
Ventilation is tidal, and tidal volume is usually small
(B500 ml) compared to alveolar volume (B3000 ml).
Because anatomical deadspace (the volume of the conducting airways) is B150 ml, the amount of fresh air
reaching alveoli with each breath is only 500–150 or
B350 ml. Each breath thus ‘‘tops up’’ the alveolar
volume by only about 10%. Respiratory frequency
is B15 breaths min 1. This pattern of small but frequent breaths causes alveolar gas concentrations to
vary minimally within each breath. They are therefore
taken to be constant (under steady-state conditions).
Despite pulsatile pulmonary blood flow, endcapillary
and arterial blood gas concentrations are also taken to
be constant in time.
Because the amounts of inhaled gases depend
on ventilation, and the amounts transported in the
blood depend on blood flow, it is apparent that ventilation and blood flow critically affect the amounts
of gas exchanged, and also the alveolar and blood
concentrations and partial pressures. These concepts
can be considered more concretely by describing gas
exchange using the laws of mass balance. These laws
acknowledge that all molecules of a gas removed
from alveolar gas during gas uptake appear in the
blood, while during gas elimination, all molecules
removed from the blood appear in the alveolar gas.
Ventilation, Perfusion, and Gas Exchange
Using O2 as the example, the laws of mass balance
are now applied to steady-state gas exchange to
VENTILATION, PERFUSION MATCHING 471
quantify the relationships between ventilation, blood
flow, and alveolar (and endcapillary) concentrations
(and partial pressures).
The volume of O2 inhaled per minute is the product of the total inspired alveolar ventilation (V̇I) and
the fractional concentration of O2 in inspired gas
(FIO2 ):
½1
Volume inhaled ¼V’ I FIO2
law of partial pressures. V’ I and V’ A are almost identical, differing only when the amount of O2 taken
up does not equal the amount of CO2 eliminated.
Normally, V’ O2 is B300 ml min 1, V’ CO2 is B240 ml
min 1. The difference, 60 ml min 1, is small in
comparison to normal alveolar ventilation, which is
usually 5–6 l min 1. While taking V’ I ¼ V’ A will introduce a small error, for ease of presentation, equality will be assumed so that
The volume of O2 exhaled per minute is the product
of the total expired alveolar ventilation (V̇A) and the
fractional concentration of O2 in alveolar gas (FAO2 ):
’ ¼ k ½Cc0 CVO =½PIO PAO V’ A=Q
2
2
2
O2
Volume exhaled ¼V’ A FAO2
½2
The difference between these must be the amount of
O2 transferred from the atmosphere to the pulmonary capillary blood, that is, the V’ O2 :
V’ O2 ¼ V’ I FIO2 V’ A FAO2
½3
We can apply identical considerations to the pulmonary circulation. The volume of O2 that leaves the
capillaries en route to the left atrium per minute is
’ and the
the product of pulmonary blood flow (Q)
concentration of O2 in that blood (Cc0O2 ):
’ Cc0
Volume leaving ¼ Q
O2
½4
However, the blood entering the pulmonary circulation carries O2 , and the volume of O2 in this venous
’ and
blood entering per minute is the product of Q
concentration of O2 in the venous blood:
’ CVO
Volume entering ¼ Q
2
½5
The difference between the volumes of O2 leaving
and entering the pulmonary circulation/min is the
amount of O2 taken up from the alveolar gas (V’ O2 ):
’ Cc0 Q
’ CVO
V’ O2 ¼ Q
2
O2
½6
Equations [3] and [6] both describe the amount/min
of O2 taken up by the lungs (which in a steadystate equals tissue metabolic rate), and may thus be
combined:
’ Cc0 Q
’ CVO
V I FIO2 V’ A FAO2 ¼ Q
2
O2
Which may be rearranged to
’ ¼ ½Cc0 CVO =½ðV’ I=V’ AÞ FIO FAO ½7
V’ A=Q
2
2
2
O2
or
’ ¼ k ½Cc0 CVO =½ðV’ I=V’ AÞ
V’ A=Q
2
O2
PIO2 PAO2 ½8
where k allows fractional concentrations (F) to be
replaced by partial pressures (P) based on Dalton’s
½9
Now because alveolar and endcapillary PO2 values
are taken to be the same (see above and Diffusion
of Gases), Cc0O2 is the O2 concentration corresponding to the alveolar PO2, PAO2 . This equation therefore
states: for a given composition of the venous blood
(CVO2 ) and inspired gas (PIO2 ), the alveolar PO2
(PAO2 ) is uniquely determined by the ratio of venti’
lation to blood flow (V’ A=Q).
In a region of lung having a low value of V̇A/Q̇
(e.g., partial airway obstruction), PAO2 must be low.
If airway obstruction is complete, V̇A is zero, and
local PO2 equals that of venous blood. If the local
V̇A/Q̇ ratio is high (e.g., partial vascular obstruction),
PAO2 will be high. If vascular obstruction is complete,
Q̇ is zero, and PAO2 must equal that of inspired gas.
Identical principles may be applied to all other
gases, and similar relationships will be obtained. For
CO2 this becomes
’ ¼ k ½CVCO Cc0 =½PACO PICO V’ A=Q
2
2
2
O2
½10
The unique relationship between V̇A/Q̇ and PAO2
(and between V̇A/Q̇ and PACO2 ) is shown in Figure 1.
Normal total alveolar ventilation and pulmonary
blood flow are each about 5–6 l min 1. Therefore,
the overall lung V̇A/Q̇ ratio is B1.0. Figure 1 shows
that PAO2 is B100 mmHg and PACO2 is B40 mmHg
at that V̇A/Q̇ ratio. Hence, these values are those
expected in a perfectly homogeneous lung with a
normal V̇A/Q̇ ratio. They are very close to what is
seen in young normal subjects, suggesting close
matching of ventilation to blood flow throughout
the many alveoli in their lungs.
Ventilation/Perfusion Inequality and
Gas Exchange
All normal subjects have what is called ventilation/
perfusion (V̇A/Q̇) inequality. This is defined as the
situation where the V̇A/Q̇ ratio is not the same everywhere throughout the lungs. It results from both
gravitational and nongravitational influences on
how both ventilation and blood flow are distributed
(see Pulmonary Circulation. Ventilation: Overview).
472 VENTILATION, PERFUSION MATCHING
50
Alveolar P CO2 (mmHg)
Alveolar PO2 (mmHg)
140
120
100
O2
80
60
40
20
0
0.001
(a)
0.01
0.1
1
10
100
40
30
CO2
20
10
0
0.001
1000
(b)
Ventilation/perfusion ratio
0.01
0.1
1
10
100
Ventilation/perfusion ratio
1000
(c)
140
Alveolar PCO2 (mmHg)
Alveolar PO2 & P CO2 (mmHg)
The O2–CO2 diagram
50
O2
120
100
80
60
40
CO2
20
0
0.001
40
30
20
10
0
0.01
0.1
1
10
100
Ventilation/perfusion ratio
0
1000
(d)
20
40 60 80 100 120 140 160
Alveolar PO2 (mmHg)
Figure 1 (a) Alveolar PO2 (P AO2 ) depends on the ventilation/perfusion (V̇A/Q̇) ratio, based on eqn [8]. When the V̇A/Q̇ ratio is normal
(B1), P AO2 ¼ 100 mmHg. When V̇A/Q̇ is both very low and very high, P AO2 is insensitive to V̇A/Q̇. Part (b) shows the corresponding
relationship for P AO2 , and part (c) superimposes the two for comparison. Part (d) plots P ACO2 against P AO2 , creating the O2–CO2
diagram, where each point on the line corresponds to a unique value of V̇A/Q̇. The left end of the line represents a V̇A/Q̇ of 0, reflecting
mixed venous blood composition; the right end similarly reflects inspired gas and an infinitely high V̇A/Q̇.
When V̇A/Q̇ inequality exists, gas exchange becomes
inefficient. Specifically, arterial PO2 falls, arterial
PCO2 rises, and pulmonary V’ O2 and V’ CO2 both fall,
failing to meet the body’s metabolic needs to supply
O2 and eliminate CO2. Unless V’ O2 and V’ CO2 are restored, either by removing the cause of inequality or
by the compensatory mechanisms discussed below,
tissue damage will ensue.
How V̇A/Q̇ inequality causes these changes is conveniently illustrated in a simple model of inequality in
a ‘two alveolus’ lung. Figure 2(a) depicts a perfect
lung for reference, and two examples of inequality. In
Figure 2(b) an inhaled foreign object has reduced
ventilation in one alveolus by 90%; in Figure 2(c) a
blood clot has reduced blood flow in one alveolus
similarly by 90%. In both cases, this is the only
perturbation. Thus, total alveolar ventilation and
pulmonary blood flow remain normal, and the distribution of blood flow in Figure 2(b) and of ventilation in Figure 2(c) are unchanged from control.
Moreover, venous blood composition is the same in
all three cases. Therefore, these examples illustrate
pure effects of inequality prior to any compensatory
changes (described below) that would normally occur.
PAO2 and PACO2 in each alveolus in Figure 2 were
obtained from the relationships in Figure 1. In
Figure 2(a), each alveolus has the same V̇A/Q̇ ratio
of 1.0, and thus has the same PAO2 and PACO2 . As the
expired gas streams from the two alveoli mix, overall
exhaled PO2 must be the same as PAO2 in each
alveolus, that is, 100 mmHg. So too, mixed exhaled
PACO2 must be 40 mmHg. Turning to the vascular
side, each ‘pulmonary vein’ carries blood at the
same PO2 of 100 mmHg and PCO2 of 40 mmHg.
Thus, mixed arterial blood must also have these
values. Consequently, there is no difference between
mixed alveolar and mixed arterial PO2 (or PCO2 )
in this perfect lung. V’ O2 is 300 ml min 1 and V’ CO2
240 ml min 1, numbers determined by inserting
PAO2 ¼ 100 into eqn [3], and PACO2 ¼ 40 into the
corresponding equation for CO2.
In Figure 2(b), exemplifying partial airway obstruction, the same analysis is now applied, using
Figure 1 to determine the alveolar PO2 and PCO2 for
the two alveoli. With 90% reduction in ventilation of
the left alveolus, its V̇A/Q̇ ratio becomes 0.1, while
redistribution of ventilation to the right alveolus
makes its V̇A/Q̇ ratio 1.6. PAO2 and PACO2 (Figure 1)
VENTILATION, PERFUSION MATCHING 473
VA (total) = 5.2
VA (total) = 5.2
100 (mixed exhaled PO )
2
40 (mixed exhaled PCO )
Q (total) = 6.0
VO = 300
2
VCO = 240
115 (mixed exhaled PO )
2
36 (mixed exhaled PCO )
Q (total) = 6.0
VO = 199
2
VCO = 213
2
2
2
2
VA :
VA : 2.6
PAO :
2
PACO :
2
Q:
VA /Q :
2.6
PAO :
2
PACO :
100
40
100
40
3
0.9
0.3
47
46
2
Q:
3
0.9
100 (mixed arterial PO2)
40 (mixed arterial PCO2)
(a)
VA/Q :
4.9
119
35
3
3
0.1
1.6
58 (mixed arterial PO )
2
40 (mixed arterial PCO )
2
(b)
V A (total) = 5.2
108 (mixed exhaled PO )
2
31 (mixed exhaled PCO )
Q (total) = 6.0
VO
2
= 263
2
VCO = 182
2
VA :
3
PAO :
2
PACO :
141
17
2
Q:
VA/Q:
3
75
44
0.3
5.7
10
0.53
75 (mixed arterial PO )
2
42 (mixed arterial PCO )
2
(c)
Figure 2 (a) This shows a lung divided into two hypothetical alveoli, each receiving 50% of the total alveolar ventilation and perfusion.
Each therefore has the same V̇A/Q̇ ratio, making the lung homogeneous. This lung exchanges normal amounts of O2 and CO2; arterial
PO2 and PCO2 are 100 and 40 mmHg, respectively. (b) Severe airway obstruction in one airway, reducing alveolar V̇A/Q̇ tenfold. The
result is arterial hypoxemia and hypercapnia, and reduced O2 uptake and CO2 elimination. (c) Severe pulmonary vascular obstruction,
also causing hypoxemia, hypercapnia, and reduced gas exchange. P AO2 and P ACO2 for each alveolus in all three models are derived
from eqns [8] and [10].
are shown. As the two alveoli exhale and their gas
streams mix, the mixed exhaled PO2 (PEO2 ) must be
the average of the PAO2 values from each, weighted by
the amounts of exhaled gas coming from each. This is
simply applying principles of mass conservation:
PEO2 ¼ ½PAO2 ðleftÞ V’ AðleftÞ þ PAO2 ðrightÞ
V’ AðrightÞ=V’ AðtotalÞ
¼ 115 mmHg
½11
Similar mixing of the endcapillary blood from the
two alveoli produces a mixed arterial PO2 of 58
mmHg. Here, the mixing computation is done using
endcapillary O2 concentrations, not partial pressures.
The PO2 corresponding to this mixed arterial O2 concentration is then read from the oxygen–hemoglobin
dissociation curve (see Oxygen–Hemoglobin Dissociation Curve).
When eqn [3] is used with the mixed expired PO2
above, V’ O2 for the entire lung is seen to be only
199 ml min 1. V’ CO2 is also reduced, to 213 ml min 1.
Thus, this model of V̇A/Q̇ inequality shows substantial arterial hypoxemia and slight hypercapnia
(compared to A), and reduced ability to exchange
both O2 (34% reduction in V’ O2 ) and CO2 (11%
reduction in V’ CO2 ).
In Figure 2(c), the model of pulmonary vascular
obstruction, an identical analysis shows that mixed
exhaled PO2 and PCO2 will be 108 and 31 mmHg respectively; mixed arterial PO2 and PCO2 will be 75 and
42 mmHg, respectively, and V’ O2 and V’ CO2 for the
entire lung are both reduced, to 263 (12% reduction)
and 182 (24% reduction) mmHg, respectively.
The important result is that it does not matter
whether the cause of the V̇A/Q̇ inequality resides in
the airways or the vasculature, hypoxemia and hypercapnia will occur, as will a reduction in the amount
474 VENTILATION, PERFUSION MATCHING
of both O2 and CO2 that the lungs can exchange.
The absolute effects differ with the nature of the inequality, and in particular the model in Figure 2(b)
affects O2 more than CO2 while the model in Figure
2(c) affects CO2 more than O2.
Compensation for Ventilation/Perfusion
Inequality
The reductions in V’ O2 and V’ CO2 described above
prevent the lungs from meeting the tissue metabolic
requirements. If the V̇A/Q̇ inequality is not corrected,
compensatory mechanisms must be brought into play
to restore V’ O2 and V’ CO2 .
Three principal mechanisms exist. The first is a fall
in venous PO2 (and rise in venous PCO2 ). This happens immediately and requires no conscious effort or
energy expenditure. It is effective because prior
to developing V̇A/Q̇ inequality, venous PO2 is high
enough (B40 mmHg) to provide enough room for
such a fall. This can usually restore the arterio
venous O2 concentration difference and therefore
V’ O2 (and V’ CO2 ). However, it causes a further fall in
arterial PO2 (and rise in arterial PCO2 ). In the model
in Figure 2(b), this mechanism can restore the V’ O2
and V’ CO2 of the entire lung. Venous PO2 would have
to fall by about 10 mmHg and venous PCO2 would
have to increase by about 5 mmHg. Arterial PO2 and
PCO2 would now be 48 and 45 mmHg respectively,
showing more hypoxemia and hypercapnia than before compensation occurred. In Figure 2(c), corresponding changes restore V’ O2 and V’ CO2 , resulting in
venous PO2 and PCO2 values lower by about 2 and
higher by about 16 mmHg, respectively. Arterial PO2
falls to 63 and PCO2 rises to 57 mmHg, respectively.
While this primary, rapid, automatic process
achieves the major objective of restoring both V’ O2
and V’ CO2 , the fall in arterial PO2 and rise in arterial
PCO2 put the patient at greater risk of tissue hypoxia
and acidosis than even the initial disturbance of
V̇A/Q̇ relationships caused.
The second compensatory mechanism is an increase in ventilation. This mitigates arterial hypoxemia and hypercapnia, reducing tissue hypoxia and
acidosis. The stimuli to increasing ventilation in the
face of V̇A/Q̇ inequality (arterial hypoxemia, acidosis, and especially hypercapnia) are discussed in the
article Ventilation: Control. Depending on the cause
of V̇A/Q̇ inequality, increased ventilation may not be
possible, as for example when severe chest trauma is
responsible. But when in the models of Figure 2 ventilation is progressively increased, arterial PO2 and
PCO2 gradually improve. Since V’ O2 and V’ CO2 have
already been restored by the first compensatory
mechanism, they remain normal as ventilation is
raised. Figure 3 shows the effects of ventilatory compensation in the two models of Figure 2. Note that
arterial PCO2 is much easier to normalize than is arterial PO2 , especially in the model of airway obstruction with very low V̇A/Q̇ ratios. This directly reflects
the differences in the shapes and slopes of the O2
and CO2 dissociation curves in blood (see Carbon
Dioxide. Oxygen–Hemoglobin Dissociation Curve).
Because the curve for CO2 is nearly linear while that
for O2 is quite nonlinear, arterial PCO2 is easier to
normalize than is arterial PO2 .
This difference in ability to restore arterial PO2 and
PCO2 by increased ventilation often leads to a large
increase in ventilation, sufficient to cause hypocapnia, while still not normalizing arterial PO2 (as the
model suggests in Figure 3(b)). Figure 3 shows the
progression of expected arterial blood gas values that
would be anticipated stage by stage as these compensation processes occurred for the two models in
Figure 2. It should be realized that while these stages
are presented sequentially, in real life they would be
occurring essentially together over a short time frame
and would probably all be in place by the time a
physician saw the patient.
An important conclusion from analyzing this sequence of events is that just because a patient with
V̇A/Q̇ inequality may present with hypoxemia but
not hypercapnia, it should not be thought that inequality affects only O2 and not CO2. In fact, some
patterns of inequality, especially those in which areas
of very high V̇A/Q̇ ratio develop, can affect CO2
more than O2 (Figure 2(c)).
The third way in which the body can compensate
for V̇A/Q̇ inequality is by increasing cardiac output.
This is not infrequently seen in young asthmatic patients, and in the intensive care unit in patients who
have high cardiac outputs from sepsis and other pathologies. What an increase in cardiac output allows is
an increase in the venous PO2 . This can be deduced
from eqn [6], otherwise known as the Fick principle.
This equation shows that for a given metabolic rate
’ results in a
(V’ O2 ), and increase in cardiac output (Q)
reduction in the arteriovenous O2 concentration difference, and in turn a rise in venous PO2 . When low
V̇A/Q̇ ratio regions exist, an increase in venous PO2
will result in an increase in arterial PO2 . For example,
in model B, increasing cardiac output from 6 to
10 l min 1 permits an increase in arterial PO2 from 48
to 55 mmHg. While this seems modest, arterial O2
saturation would rise from about 83% to almost 90%,
significantly enhancing the arterial O2 concentration.
While increases in either or both ventilation and
cardiac output allow both arterial PO2 and PCO2
to move towards normalization, two points need
VENTILATION, PERFUSION MATCHING 475
50
110
Arterial PCO 2 (mmHg)
Arterial PO2 (mmHg)
100
90
80
70
60
50
40
30
Obstruction :
Venous PO2 :
Ventilation :
O2 uptake :
45
40
35
30
25
Pre Post
41.6 41.6 32.5 32.3 32.2 32.1 32.0 31.9 31.8
5.2
5.2
300 199
Obstruction :
Venous PCO2 :
7.5
Ventilation :
300 300 300 300 300 300 300
CO2 elimination :
5.2
5.8
6.0
6.3
6.5
7.0
5.2
5.2
5.2
5.8
6.0
6.3
240 213 240 240 240 240
6.5
7.0
7.5
240 240 240
(b)
110
60
100
55
Arterial PCO2 (mmHg)
Arterial PO2 (mmHg)
(a)
Pre Post
45.8 45.8 50.2 45.4 44.1 42.4 41.2 38.7 36.6
90
80
70
60
50
Ventilation :
O2 uptake :
40
35
30
25
40
Obstruction :
Venous PO2 :
50
45
Pre Post
41.6 41.6 39.8 41.3 41.2 40.8 40.4 39.5 38.7
5.2
5.2
5.2
300
263
300 300
6.0
7.0
7.5
8.0
Obstruction :
Venous PCO2 :
Ventilation :
9.0 10.0
300 300 300 300
300
(c)
CO2 elimination :
Pre Post
45.8 45.8 62.4 54.7 47.9 45.1 42.6 38.4 35.0
5.2
5.2
240 182
5.2
6.0
7.0
7.5
240 240 240 240
8.0
9.0 10.0
240 240 240
(d)
Figure 3 Compensation for V̇A/Q̇ inequality in the models of Figure 2, showing how arterial PO2 (a, c) and PCO2 (b, d) respond. Parts
(a) and (b) reflect airway obstruction; parts (c) and (d) vascular obstruction. In each case, the second bar shows effects of inequality prior
to compensation. The third bar shows restoration of V’ O2 and V’ CO2 by changes in mixed venous PO2 and PCO2 alone. The remaining bars
show responses to increasing alveolar ventilation. See text for more details.
further consideration. First, increasing ventilation
and cardiac output are both energy requiring, and
patients with already compromised ventilatory or
cardiac pumps may not be able to respond well. Second, in those patients who do respond with brisk
increases in ventilation and/or cardiac output, the
improvement in their arterial blood gases may lead
the physician to underestimate the extent of the underlying V̇A/Q̇ inequality. In other words, patients
who show substantial increases in either ventilation
or cardiac output and have nearly normal arterial
blood gases may still have considerable V̇A/Q̇ inequality, and should be managed with this in mind.
Assessment of Ventilation/Perfusion
Inequality
The detailed assessment of V̇A/Q̇ inequality is difficult, especially in clinical settings. Most often, the
lung is modeled as consisting of three virtual alveoli.
One of these is unventilated, but perfused, and is
labeled as a ‘shunt’. Another is ventilated but not
perfused, and is labeled as a ‘deadspace’. The third is
labeled the ‘ideal’ alveolus, and is both perfused and
ventilated. The objective in assessing V̇A/Q̇ inequality
in this framework is to (1) apportion total ventilation
between the ideal and deadspace alveoli on the one
hand, and (2) apportion total cardiac output between
the ideal and shunt alveoli on the other. This is a
gross oversimplification of reality in almost all patients, but does provide a quantitative index of V̇A/Q̇
inequality that can be useful in guiding therapy.
To apportion ventilation between the ideal and
deadspace alveoli, one must measure both arterial
PCO2 (PaCO2 ) and the PCO2 of mixed expired gas
(PECO2 ). On the presumption that the deadspace alveolus contains no CO2 (because it is unperfused and
therefore cannot get CO2 from the blood), while the
476 VENTILATION, PERFUSION MATCHING
PCO2 of the ideal alveolus equals that of the measured
arterial blood, a conservation of mass analysis (much
like that in eqn [11]) shows that the fraction of the
total ventilation received by the deadspace alveolus
(commonly referred to as VD/VT) comes to
V D=V T ¼½PaCO2 PECO2 =PaCO2
½12
This is called the ‘physiological’ deadspace because it
is measured using functional variables, and because it
includes all causes of deadspace in a single outcome
measure. Specifically, the normal contribution to
deadspace from the conducting airways is a part of
VD/VT, as are additional components caused by the
presence of any regions of high V̇A/Q̇ ratio, if any. In
other words, VD/VT would be around 0.3 in a normal
subject because the conducting airway volume is
about 150 ml while the tidal volume is about 500 ml
(150/500 ¼ 0.3). Any value of VD/VT higher than this
would suggest the presence of alveolar regions of
high V̇A/Q̇ ratio. This conclusion must be accepted
with caution however, since changes in tidal volume
can have an obvious, significant effect on VD/VT since
the numerator, conducting airway volume, is relatively constant as tidal volume changes. To overcome
this limitation, multiplying VD/VT by measured tidal
volume will yield an absolute value for VD per breath.
This should be about 150 ml in a normal person irrespective of tidal volume, and so an increase above
such a value is a better indication of the presence of
areas of high V̇A/Q̇ ratio. In reality, conducting airway volume varies with body size, and a commonly
used estimate is about 1 ml per pound of body mass,
correcting mass for obesity when significant.
To estimate perfusion in the ‘shunt’ alveolus, a
similar mass conservation approach is taken, but in
this case one uses measures of O2 exchange. One
must measure both arterial and venous (pulmonary
arterial) O2 concentrations (CaO2 and CvO2 , respectively). The endcapillary O2 concentration in the
ideal alveolus (Cc0O2 ) cannot be measured but is
needed and is thus calculated from an estimate of its
alveolar PO2. The equation that describes the perfusion of the shunt alveolus as a fraction of the total
cardiac output (QS/Q̇T) is
’ T ¼ ½Cc0 CaO =½Cc0 CvO QS=Q
2
2
O2
O2
½13
Unlike the case for VD/VT, QS/Q̇T in normal subjects
is essentially zero. Thus, any elevation (perhaps allowing 0.01–0.02 to encompass the range of normal
responses) is abnormal. An important consideration
in applying this equation arises when CvO2 is not in
fact measured, but is assumed. As the equation
shows, an error in CvO2 will give rise to an incorrect
value for QS/Q̇T. The second major consideration
when using this equation relates to the meaning of
the value obtained as QS/Q̇T. In the case where there
is truly a pure shunt in the patient’s lung (e.g., in
lobar consolidation, in atelectasis, or in the event of a
right to left intracardiac communication), the value
obtained accurately estimates the fraction of the cardiac output that is perfusing the abnormal pathway.
However, in the relatively more common setting
where areas of low V̇A/Q̇ ratio are present rather
than true shunts, the value of QS/Q̇T must be thought
of as the fraction of the cardiac output that would
flow through a hypothetical shunt pathway and lead
to the same arterial PO2 as measured in the patient.
Because alveolar (and thus endcapillary) PO2 in low
V̇A/Q̇ regions is higher than in venous blood flowing
through a pure shunt pathway, the actual perfusion
rate in low V̇A/Q̇ areas will always exceed that
obtained from eqn [13].
A special consideration relates to use of eqn [13]
when FIO2 is raised, as is often the case in the ICU.
The higher the FIO2 , the less will regions of low V̇A/Q̇
ratio interfere with O2 exchange. In particular, when
FIO2 is 1.0, each ventilated alveolus, no matter what
its V̇A/Q̇ ratio is, contains only O2, CO2, and water
vapor as the resident N2 is eliminated. This means
that even in regions of very low V̇A/Q̇ ratio, alveolar
PO2 will be several hundred mmHg, and allow full
saturation of endcapillary blood. In practice, this
means that QS/Q̇T breathing pure O2 will be zero
even if V̇A/Q̇ inequality is present, unless there is also
a shunt. It also means that when both V̇A/Q̇ inequality and shunt coexist in the same lungs, QS/Q̇T measured while breathing air will exceed that measured
while breathing pure O2. Measuring QS/Q̇T under
both conditions therefore affords a way to separately
assess the magnitude of V̇A/Q̇ inequality and shunt.
This well-established technique should be used with
some caution, however. This is because by giving
pure O2 to a patient, some alveoli that were ventilated, albeit poorly, on room air, may cease to be
ventilated and collapse, thereby increasing the size of
the shunt. Furthermore, increasing FIO2 may release
hypoxic vasoconstriction in these hypoxic areas,
raising their perfusion levels, and increasing the
measured shunt fraction even more.
A third method for characterizing V̇A/Q̇ inequality
is to determine the alveolar–arterial PO2 difference
(AaPO2 ). As Figure 2 shows, the difference between
mixed alveolar and arterial PO2 is normally close
to zero. However, V̇A/Q̇ inequality increases alveolar and reduces arterial PO2 , causing AaPO2 to increase. While arterial PO2 is easily measured from
a blood sample, mixed alveolar PO2 is difficult to
measure, and is thus calculated from the alveolar gas
equation. This equation uses eqn [3] above and the
VENTILATION, PERFUSION MATCHING 477
corresponding equation for CO2 to estimate alveolar
PO2 (PAO2 ) as
PAO2 ¼ PIO2 PACO2 =R þ PACO2
FIO2 ½ð1 RÞ=R
½14
A simpler version ignores the third term because it
generally is only 1–2 mmHg:
PAO2 ¼ PIO2 PACO2 =R
½15
where R is the ratio of V’ CO2 to V’ O2 (the respiratory
exchange ratio). Then
AaPO2 ¼ PAO2 PaO2
½16
Most often, one uses the measured arterial PCO2
(PaCO2 ) in place of the alveolar value, because they
are generally quite similar. This means that the
AaPO2 can be calculated from just the arterial PO2
and PCO2 , provided one knows PIO2 (inspired PO2 )
and R. PIO2 is usually easy to determine, but R is
often assumed. It should be recognized that small
errors in R can cause substantial errors in AaPO2 .
The final expression is
AaPO2 ¼ PIO2 PaCO2 =R PaO2
The Multiple Inert Gas Elimination
Technique
Another approach to assessing the amount of V̇A/Q̇
inequality is to use what is known as the multiple
inert gas elimination technique (MIGET) to measure
directly the frequency distribution of ventilation/perfusion ratios throughout the lungs. This method
makes use of the fact that the degree to which any
particular inert gas is eliminated by the lungs from
the body (after being introduced by either inhalation
or intravenous infusion) depends on the distribution
of ventilation and blood flow throughout the lungs.
The degree of elimination also depends on the blood
solubility of the gas, and it turns out that it is necessary to have about six or so gases of widely differing solubilities to obtain sufficient information
from which to compute the distribution.
The physiological basis of this method is the same
mass balance principle discussed extensively above
Asymptomatic asthma,
.PaO2 = 79; FEV1 = normal
Normal subject
1.8
1.8
Normal VA /Q
1.2
0.9
0.6
0.0
No
shunt
No
low VA /Q
No
high VA /Q
1.2
0.9
0.6
0.3
(a)
0.01
0.1
1
10
Ventilation/perfusion ratio
0
100
(b)
Severe, chronic asthma,
.PaO2 = 53; FEV1 = 35% predicted
1.8
0.01
0.1
1
10
Ventilation/perfusion ratio
100
COPD: predominant emphysema
Normal VA /Q
Normal VA /Q
1.5
Low VA /Q
1.2
0.9
0.6
No
shunt
No
high VA /Q
Ventilation ( ),
Blood flow ( )
Ventilation ( ),
Blood flow ( )
No
high VA /Q
1.8
1.5
1.2
0.6
0.0
0
0.01
0.1
1
10
Ventilation/perfusion ratio
100
High VA /Q
0.9
0.3
0.0
(c)
Low VA /Q
No
shunt
0.0
0
0.3
Normal VA /Q
1.5
Ventilation ( ),
Blood flow ( )
Ventilation ( ),
Blood flow ( )
1.5
0.3
½17
No
shunt
0
(d)
Low VA /Q
0.01
0.1
1
10
Ventilation/perfusion ratio
100
Figure 4 V̇A/Q̇ distribution showing how ventilation and blood flow are distributed with respect to V̇A/Q̇ ratio throughout the lungs. The
normal distribution (a) is narrow and symmetrical; that in mild asthma (b) and severe asthma (c) contains normal areas and also areas of
very low V̇A/Q̇ ratio, the latter due to partial airway obstruction; that in emphysema (d) has, in addition to normal regions, areas of very
high V̇A/Q̇ probably caused by continued ventilation through poorly perfused ‘holes’ in the lung.
478 VESICULAR TRAFFICKING
for O2 and CO2, and shown in eqns [9] and [10].
From the measured pattern of elimination of the several gases, mathematical procedures are used to calculate the distribution of V̇A/Q̇ ratios that best fit the
elimination pattern over all six gases. The results are
expressed as two separate but linked frequency distributions – one for ventilation and one for blood
flow as in Figure 4. These distributions show how
ventilation and blood flow are distributed along the
V̇A/Q̇ ratio axis from essentially zero to essentially
infinity. Figure 4(a) shows the distribution in a young
normal subject; Figure 4(b) exemplifies mild asthma,
Figure 4(c) severe asthma, and Figure 4(d) emphysema. The normal subject shows a narrow distribution around a mean V̇A/Q̇ of about 1, devoid of areas
of very low or high V̇A/Q̇ ratio. The asthmatic lung
contains substantial regions of very low V̇A/Q̇ ratio,
but does not have areas of abnormally high ratio. The
low V̇A/Q̇ areas in asthma presumably reflect partially
obstructed airways, and may be seen even when
forced expiratory volume in 1 s (FEV1) is normal or
only slightly reduced. In contrast, the lung with
emphysema shows abnormalities in the high V̇A/Q̇
domain, likely the result of continued ventilation of
poorly perfused ‘holes’ in the lung parenchyma.
The MIGET provides the most complete picture
of V̇A/Q̇ inequality currently available that is usable
in intact humans. It is a complex technique that
demands considerable expertise and attention to
detail, and remains a useful research tool in areas
such as understanding the pathophysiology of, and
therapeutic responses to, new treatments for lung
diseases.
See also: Carbon Dioxide. Diffusion of Gases. Oxygen–Hemoglobin Dissociation Curve. Pulmonary
Circulation. Ventilation: Overview; Control.
Further Reading
Kelman GR (1968) Computer programs for the production of O2–
CO2 diagrams. Respiration Physiology 4: 260–269.
Rahn H and Fenn WO (1955) A Graphical Analysis of the Respiratory Gas Exchange. Washington, DC: American Physiological Society.
Riley RL and Cournand A (1949) ‘‘Ideal’’ alveolar air and the
analysis of ventilation/perfusion relationships in the lung. Journal of Applied Physiology 1: 825–847.
Riley RL and Cournand A (1951) Analysis of factors affecting
partial pressures of oxygen and carbon dioxide in gas and blood
of lungs: theory. Journal of Applied Physiology 4: 77–101.
Wagner PD (1978) Measurement of the distribution of ventilation/
perfusion ratios. In: Davies DG and Barnes CD (eds.) Regulation
of Ventilation and Gas Exchange, pp. 217–260. New York:
Academic Press.
Wagner PD and West JB (1980) Ventilation–perfusion relationships. In: West JB (ed.) Ventilation, Blood Flow and Diffusion,
pp. 219–262. New York: Academic Press.
West JB (1969) Ventilation/perfusion inequality and overall gas
exchange in computer models of the lung. Respiration Physiology 7: 88–110.
West JB (1990) Ventilation/Blood Flow and Gas Exchange. Oxford
and Philadelphia: Blackwell Scientific Publications and Lippincott.
West JB and Wagner PD (2000) Ventilation, blood flow and gas
exchange. In: Murray JF and Nadel JA (eds.) Textbook of Respiratory Medicine, pp. 55–89. Philadelphia, PA: Saunders.
VESICULAR TRAFFICKING
N E Vlahakis, Mayo Clinic Rochester, Rochester, MN,
USA
& 2006 Elsevier Ltd. All rights reserved.
Abstract
Vesicular trafficking is a continuous and dynamic process in all
cells of the body, in which lipid vesicles move from the cell
surface to intracellular lipid endosomes (endocytosis) or from
organelles and endosomes to the cell surface (exocytosis). It
functions as both a homeostatic process for maintenance of quiescent cell function and a stress response to ensure rapid protein
synthesis, targeted intracellular transport, and expression of
proteins on the cell surface or their release to the extracellular
environment. Vesicles are primarily composed of lipid molecules
that serve not only as a mechanical barrier to the perivesicular
environment but also a physical support for their protein cargo
during transport within the cell. Membrane lipids also provide a
physical structure to prime vesicles for budding or fusion or to
modulate protein function and resultant transduction of cellular
signaling. Respiratory epithelium is polarized and the apical and
basolateral membranes are maintained by tightly controlled and
membrane-specific vesicular trafficking pathways to maintain
this polarized phenotype. Any defect in this transport machinery
can result in inadequate responses to cellular stressors or respiratory disease, such as cystic fibrosis and interstitial lung disease.
The vesicular trafficking process in type II alveolar pneumocytes
has many unique features and is essential for surfactant secretion
and reuptake. In addition, a rapid and targeted trafficking response is required for alveolar cells to add lipids to the cell
surface to prevent cell rupture or to ‘patch’ cell breaks.
Description
General Mechanisms of Vesicular Trafficking
Lipid vesicles originate in the endoplasmic reticulum
(ER), budding from the ER as a means to distribute