316 PERIPHERAL GAS EXCHANGE
commonly in infants with acute viral bronchiolitis
where they are thought to arise due to the ‘popping
open’ of fluid menisci in bronchioles. The lack of
effective collateral ventilation between adjacent lung
units in the first year of life is thought to contribute
to crackles in this age group. Crackles are also heard
with interstitial lung diseases in both children and
adults, pulmonary fibrosis in adults, and in inflammatory diseases involving small peripheral airways,
such as exacerbations of cystic fibrosis lung disease.
Animal Models
Animal models have been used to investigate a
number of pediatric pulmonary diseases. Lung
growth and development, in particular the adverse
effects of drugs such as corticosteroids, has been
studied using rats, mice, rabbits, lambs, and primates. Rodents are born without alveoli and develop
them while breathing air, a situation very different
from that occurring in humans. Recent studies using
primates have provided fascinating insights into the
effects of air quality and allergen exposure on lung
development; however, these studies are expensive
and have been limited in scope.
Animal models have also been used to study the
mechanisms underlying complex diseases such as
asthma. However, here the vast majority of studies
have been undertaken in adult animals with mature
immune systems – a situation that does not mimic the
human counterpart. Studies on the effects of early life
respiratory infections on subsequent respiratory diseases are attracting considerable interest. However,
most of these have been conducted in small animals
with relatively crude measurements of lung function.
See also: Allergy: Overview. Asthma: Overview; Acute
Exacerbations. Breathing: Breathing in the Newborn;
Fetal Lung Liquid. Bronchiolitis. Bronchopulmonary
Dysplasia. Chest Wall Abnormalities. Corticosteroids: Therapy. Croup. Cystic Fibrosis: Cystic Fibrosis
Transmembrane Conductance Regulator (CFTR) Gene.
Environmental Pollutants: Overview; Diesel Exhaust
Particles. Epithelial Cells: Type II Cells. Infant Respiratory Distress Syndrome. Laryngitis and Pharyngitis. Lung Development: Overview; Congenital
Parenchymal Disorders. Pneumonia: Overview and
Epidemiology; Atypical; Community Acquired Pneumonia,
Bacterial and Other Common Pathogens; Fungal (Including Pathogens); Nosocomial; Parasitic; Mycobacterial;
Viral; The Immunocompromised Host. Signs of Respiratory Disease: Breathing Patterns; General Examination;
Lung Sounds. Symptoms of Respiratory Disease:
Cough and Other Symptoms. Sleep Apnea: Children.
Surfactant: Overview.
Further Reading
Jobe AH, et al. (1998) Fetal versus maternal and gestational age
effects of repetitive antenatal glucocorticoids. Pediatrics 102(5):
1116–1125.
Jobe AH, et al. (2000) Effects of antenatal endotoxin and
glucocorticoids on the lungs of preterm lambs [see comment].
American Journal of Obstetrics and Gynecology 182(2): 401–408.
Martinez FD (1997) Definition of pediatric asthma and associated
risk factors. Pediatric Pulmonology 15(supplement): 9–12.
Martinez FD, et al. (1995) Asthma and wheezing in the first six
years of life. New England Journal of Medicine 332(3): 133–138.
Robinson MJ and Roberton DM (eds.) (2003) Practical Paediatrics, 5th edn., Edinburgh: Churchill.
Silverman M (ed.) (2002) Childhood Asthma and Other Wheezing
Disorders, 2nd edn., London: Arnold.
Sly PD, Turner DJ, and Hantos Z (2004) Measuring lung function
in murine models of pulmonary disease. Drug Discovery Today:
Disease Models 1(3): 337–343.
Stein RT, et al. (1999) Respiratory syncytial virus in early life and
risk of wheeze and allergy by age 13 years [see comment]. Lancet 354(9178): 541–545.
Taussig LM and Landau LI (eds.) (1999) Pediatric Respiratory
Medicine. St Louis: Mosby.
Tyler WS, Tyler N, Magliano DJ, et al. (1991) Effects of ozone
inhalation on lungs of juvenile monkeys: morphometry after a
12-month exposure and following a 6-month post exposure period. In: Berglund R, Lawson D, and Mckee D (eds.) Tropospheric Ozone and the Environment, pp. 151–160. Pittsburgh
PA: Air and Waste Management Association.
PERIPHERAL GAS EXCHANGE
P D Wagner, University of California – San Diego, La
Jolla, CA, USA
& 2006 Elsevier Ltd. All rights reserved.
Abstract
Gas exchange in any tissue or organ requires O2 delivery (and
CO2 removal) along a transport pathway involving, sequentially, the lungs, heart, blood, circulation, and tissues. Convective
factors governed mostly by the lungs, heart, blood, and circulation determine how much O2 reaches each tissue, while
diffusion underlies tissue O2 unloading and transport to mitochondria. O2 consumption may be limited by these transport
processes, or alternatively may be set by tissue metabolic demand. The maximal amount of O2 available to mitochondria is
not determined uniquely by any one step in the transport pathway, but by all in an integrated manner. Because the pathway
steps are arranged in series, poor function of any single step
significantly reduces maximal O2 transport, while greater than
PERIPHERAL GAS EXCHANGE 317
normal function of any such step increases overall transport
only slightly. When considering central and peripheral limitations to O2 transport, it is evident that convective O2 delivery to
tissues depends in part on peripheral factors (regional vascular
conductances), while diffusive unloading in the periphery depends in part on central factors (especially blood flow). In both
health and disease, central and peripheral factors contribute to
limitations on O2 transport, at least in the area of muscle function during exercise, where the O2 transport system is often
stretched to its limits.
In fact, the serial linkage among these transport
processes is such that the performance of any one
step affects the function of the others. In turn, this
means that no single step in the O2 transport chain
uniquely determines O2 transport capacity; each step
will affect O2 transport. Since identical processes
govern the elimination of CO2 produced in the tissues, and the exchange of other gases as well, this
article will focus only on O2.
The O2 Transport Pathway
This encyclopedia focuses on the lungs, but for O2 to
reach the mitochondria of the many tissue cells
throughout the body, it must be transported not only
from the air to the pulmonary capillary blood, but
also from there through the circulation to the various
tissue vascular beds. In these beds, O2 must then
leave the circulation and diffuse to the mitochondria.
The O2 transport pathway therefore involves several
organs and tissues and a variety of associated transport processes.
Figure 1 illustrates the entire pathway in diagrammatic form. O2 uptake by the lungs begins with ventilation, a largely convective process (see Ventilation:
Overview). This delivers O2 from the air to the alveoli in the lungs. Next, diffusion across the pulmonary blood–gas barrier moves O2 from the alveoli
into the capillary blood, where O2 rapidly combines
with hemoglobin (see Diffusion of Gases. Hemoglobin). The heart and circulation are then responsible
for convective movement of O2 in the blood around
the body to the microvascular beds of the many tissues and organs where it is to be used. Finally, for it
to support metabolism, O2 must diffuse out of the
microvasculature into the mitochondria.
O2 transport to tissues therefore requires the integrated effort of the lungs, heart, and blood vessels, blood and tissues together acting like a bucket
brigade – a serially linked set of transport functions.
Structures
Functions
Ventilation
Lungs
Diffusion
Capillaries
Heart, blood,
circulation
Perfusion
Capillaries
Diffusion
Tissues
Figure 1 A model of the entire O2 transport pathway from the
air down to the tissues, encompassing the lungs, blood, heart,
circulation, and tissues in a serially linked system. The major
structure, function, and process at each step are indicated.
O2 Transport to the Tissue/Organ
Vasculature: Convection
Pulmonary gas exchange has been considered extensively in the article Ventilation, Perfusion Matching.
The end result of this process is arterial blood with a
particular level of O2, expressed as PO2 (PaO2 ), O2
saturation (SaO2 ), and O2 concentration (CaO2 ). The
rate at which this O2 is delivered to the tissue vascular beds is the product of CaO2 and the rate of
blood flow (Q̇) to the tissue(s) in question. This is
’ O ) and is a convective
called systemic O2 delivery (Q
2
process. It is expressed as follows:
’ CaO
’O ¼Q
Q
2
2
½1
’ O is the rate of
If cardiac output is used for Q̇, Q
2
O2 delivery to all tissues of the body; if Q̇ were blood
’ O would define O2
flow to an exercising muscle, Q
2
delivered to that muscle.
If the normally negligible contribution of physically dissolved O2 to CaO2 is ignored, and since 1 g
hemoglobin (Hb) can bind 1.39 ml O2, we can restate eqn [1] as follows:
’ 1:39 ½Hb SaO
’O ¼Q
Q
2
2
½2
’ O is the
It is very important to realize that while Q
2
amount of O2 delivered to the tissue vascular bed(s),
not all of this O2 can be extracted from the blood and
find its way to the mitochondria. Thus, eqn [2] does
not define how much O2 is actually available to the
cells. Equation [2] is however helpful in laying out the
factors that determine O2 delivered to the tissues. It
can be seen that cardiovascular factors that determine
’ hematological factors that determine [Hb], and
Q,
(mostly pulmonary) factors that determine SaO2 all
’ O in a linked, multiplicative fashion. Clearly,
affect Q
2
no single component of the O2 transport system sets
’ O ; there is no single limiting factor to its value. A
Q
2
fall in any of the three components will reduce max’ O , defining the classic causes of insufficient
imal Q
2
tissue oxygenation: ‘stagnant’, ‘anemic’, and ‘hypoxic’
forms of ‘hypoxia’, respectively. The importance of
’ O is that there are many circumstances
considering Q
2
in which O2 delivery is thought to be limiting tissue
318 PERIPHERAL GAS EXCHANGE
O2 Transport from the Tissue/Organ
Vasculature to the Mitochondria:
Diffusion
The process by which O2 moves from Hb (in the red
cells flowing through tissue vascular beds) to tissue
cell mitochondria has long been known to be one of
simple diffusion. Microvascular PO2 is higher than
that in tissue cells due to ongoing cellular metabolic
use of O2, creating a PO2 gradient that drives movement of O2 from Hb to mitochondria. The factors
that determine how much O2 can move to the cells
(V’ O2 ) are in principle the same as in the lungs (see
Diffusion of Gases. Ventilation, Perfusion Matching).
Diffusive flux for O2 will be greater: (1) the greater
the capillary–tissue cell interfacial area (A); (2) the
shorter the distance from red cells to mitochondria
(d); and (3) the larger the PO2 difference between
capillaries (PCAPO2) and mitochondria (PMITOO2).
Thus:
V’ O2 ¼ k A ðPCAP O2 PMITO O2 Þ=d
¼ D ðPCAP O2 PMITO O2 Þ
½3
Here k is the diffusion coefficient per unit area and
distance; D ¼ kA/d and represents the total O2 conductance, or ‘diffusing capacity’. For many years,
focus was on diffusion distance as the key element
regulating O2 availability, but more recent research
suggests that the capillary–tissue contact area is more
important, at least in skeletal muscle, where myoglobin probably mitigates the issue of distance by facilitating O2 diffusion within myocytes.
The size of the PO2 gradient is limited. Thus, upstream microvascular PO2 is limited by arterial PO2
and downstream mitochondrial PO2 is limited by
the minimal value required to support oxidative
5
O2 consumption (l min−1)
O2 availability and thus tissue function. Well-known
examples include exercise, ascent to altitude (which
affects many tissues and organs, not just the muscle
during exercise), hypoxemia from pulmonary disease,
reduced perfusion in heart failure, various anemias,
and, possibly, multiple organ failure syndromes.
While in eqn [2], [Hb] and SaO2 will be the same
for blood reaching all tissues and organs, two complex issues that affect regional tissue perfusion and
’ O are: (1) how cardiac output is regulated;
thus Q
2
and (2) how cardiac output is distributed among the
many body tissues and organs. These processes must
optimize not only O2 transport but also maintain
blood pressure and vital organ perfusion in the face
of competing demands for blood flow and O2. These
topics are well beyond the scope of this chapter, but
suggestions for reading are included in the ‘Further
reading’ section.
4
3
2
1
Mean capillary P O2
Muscle venous P O2
0
0
10
20
30
P O2 (mmHg)
40
Figure 2 Variation in leg V’ O2 MAX in trained normal subjects as
inspired O2 levels (F IO2 ) are acutely altered. V’ O2 MAX changes
with F IO2 in proportion to the PO2 gradient between the muscle
capillaries and mitochondria, compatible with a limitation on
V’ O2 MAX set by O2 tissue diffusion. The gradient may be represented by either muscle venous or mean capillary PO2 . Reproduced from Roca J, Hogan MC, Story D, et al. (1989) Evidence for
tissue diffusion limitation of V’ O2 max in normal humans. Journal of
Applied Physiology 67: 291–299, with permission from American
Physical Society.
phosphorylation, thought to be about 1–3 mmHg. It
is worth noting that the right shift of the O2Hb curve
(that occurs as CO2 is loaded from the tissues to the
blood) assists O2 unloading by helping to maintain the
PO2 gradient even as O2 continues to leave the blood.
In the lungs of normal subjects (other than exceptional athletes), there is evidence for complete diffusive
equilibration between alveolar and endcapillary PO2 as
O2 is taken up, even during heavy exercise. However,
in these same subjects (perhaps except for the very
sedentary), the unloading of O2 in the tissues is often
limited by the diffusive process. Put simply, under such
conditions, tissue capillary blood cannot have all its
O2 unloaded because this would eliminate the red cell
to mitochondrion PO2 gradient necessary to drive O2
flux in the first place. Therefore, at high rates of O2
utilization, some O2 must remain behind in the blood
draining the tissues to provide the driving gradient for
diffusion. A good example is in skeletal muscles during
exercise. Figure 2 shows how maximal exercise capacity is linearly and proportionally related to the O2
diffusion gradient as arterial PO2 is varied by changing
inspired O2 levels in normal athletic subjects.
Limits to Tissue O2 Transport and
Utilization
Limitation of O2 Utilization: O2 Supply Versus O2
Demand
In any tissue or organ, there are physiological limits
to O2 transport. They are described by eqns [2] and
PERIPHERAL GAS EXCHANGE 319
40
35
30
VO2 (µmol min−1)
2 mmHg, mitochondrial O2 consumption is reduced
as PO2 falls (supply limitation). However, when PO2
is higher than about 2 mmHg, O2 consumption fails
to increase further, implying that demand has been
more than met by supply (demand limitation).
Graphical Analysis of O2 Supply and Demand
Limitation
Resting human metabolic O2 consumption (V’ O2 ) is
about 300 ml min 1. By far the greatest stress on the
O2 transport system comes during heavy exercise
when V’ O2 rises to about 3 l min 1 in sedentary normal subjects and to as much as 5 l min 1 in elite
athletes. During maximal exercise, the convective
and diffusive transport processes, and especially their
integration, can be conveniently depicted on a diagram, as shown in Figure 4. This figure depicts tissue
O2 consumption on the ordinate and tissue venous
PO2 on the abscissa. It can be shown that average
PO2 along the tissue capillary is proportional to
that in the exiting tissue venous blood, so that the
average O2 diffusion gradient can be represented by
tissue venous PO2 in this diagram. In addition,
mitochondrial PO2 is low enough, compared to mean
capillary values, so that it can be neglected. As a
result, eqn [3], describing V’ O2 as a function of the
diffusive process, can be plotted as a straight line
through the origin having a slope proportional to D.
Convection: VO2 = Q × [CaO2− C vO2]
Diffusion:
O2 consumption (ml min–1)
[3] applied to that tissue/organ, and reflect capacity
for both the convective and diffusive transport components of the O2 transport pathway. There are also
limits on how much O2 can be used by the tissue/
organ (set by biochemical limits to oxidative phosphorylation). To understand tissue oxygenation,
one must therefore know, for a particular tissue/organ and under the desired study conditions, whether
maximal ATP production is being limited by O2
transport (‘supply’) or by O2 utilization (‘demand’).
This is not always easy to establish, especially in
intact humans. Most simply, if an experimental
increase in O2 transport leads to an increase in O2
used, one would infer that ‘supply’ limitation is operating. Failure to increase O2 used as supply is augmented points to ‘demand’ limitation. Unfortunately,
some methods for increasing O2 supply have the potential to increase demand at the same time. Sympathomimetic drugs used in critically ill patients in
intensive care units are a typical example of this
problem. This is unfortunate, because if in an ill
patient, metabolism were shown to be O2 supply
limited, it would make sense to search for therapeutic
maneuvers to increase O2 availability, unless the
therapy also increased O2 demand. However, if metabolism were demand-limited, increasing O2 supply
may not be beneficial, and may even aggravate cell
tissue damage. In recent years, this conundrum has
been a topic of interest in critically ill patients.
The classical relationship between mitochondrial
PO2 (reflecting supply) and O2 consumption (reflecting demand) shown in Figure 3 illustrates the supply–
demand issue well. When PO2 is less than about
25
20
VO2 = D × k × P vO2
(a)
4000
VO max (a)
2
3000
VO2max (b)
2000
1000
Diffusion
(b)
Convection
0
15
0
10
5
0
0.0
0.5
1.0
1.5
2.0
PO2 (mmHg)
2.5
3.0
Figure 3 Relationship between O2 consumption (ordinate) and
PO2 (abscissa) in an isolated mitochondrial preparation. Below
about 2 mmHg PO2 , O2 consumption is O2 supply limited, while at
higher PO2 values, V’ O2 is independent of PO2 , and thus not limited
by O2 supply. Reproduced from Wilson DF, Erecinska M, Drown
C, and Silver IA (1977) Effect of oxygen tension on cellular energetics. American Journal of Physiology 233: C135–C140, with
permission from American Physical Society.
10 20 30 40 50 60 70 80 90 100
Muscle venous PO2 (mmHg)
Figure 4 Diagram bringing together the diffusive and convective components of peripheral O2 transport. V’ O2 is on the ordinate, tissue venous PO2 on the abscissa. The straight line of
positive slope reflects the laws of diffusion, indicating that V’ O2 is
proportional to the diffusion gradient for O2 (related to venous
PO2 ). The curved line of negative slope reflects mass balance,
plotting the Fick principle equation relating V’ O2 to blood flow and
arteriovenous O2 concentration difference. Their point of crossing
indicates the maximal possible value of V’ O2 that the O2 transport
chain as a system can support. (a) Maximal mitochondrial V’ O2
exceeds O2 supply; the latter limits V’ O2 MAX . (b) Maximal mitochondrial V’ O2 is less than O2 supply; V’ O2 MAX is set by maximal
mitochondrial V’ O2 .
320 PERIPHERAL GAS EXCHANGE
Then, using principles of mass balance, V’ O2 can also
be expressed by the well-known Fick principle:
’ ½CaO CvO V’ O2 ¼ Q
2
2
½4
where CvO2 is tissue venous O2 concentration. CvO2
is uniquely related to venous PO2 by the known
O2Hb dissociation curve (see Hemoglobin). Thus,
eqn [4] can also be plotted in Figure 4, and appears
as an inverted O2Hb dissociation curve decreasing in
value as venous PO2 rises. Both relationships describe
O2 flux, and the only point on the diagram where
both are simultaneously satisfied is their point of intersection. This point thus indicates both, maximal
O2 available to mitochondria (ordinate) and the necessarily unique value of PvO2 that enables that maximal V’ O2 (abscissa). Most importantly, this diagram
shows the integration among all parts of the O2
transport system: eqn [3] depends on tissue diffusional conductance; eqn [4] on heart, blood, and
lungs as described above in eqn [2]. If any of these
transport factors were to change, the crossing point
of the two lines would also change, shifting maximal V’ O2 .
This analysis presumes that mitochondrial V’ O2 is
indeed limited by O2 supply, not demand. In other
words, maximal possible demand exceeds the V’ O2 at
the crossing point, as for example, dashed line (a)
in the figure. If maximal V’ O2 was not limited by O2
supply, but rather by demand, it would be lower than
indicated by the crossing point in Figure 4 (e.g., as in
dashed line (b)). The tissue venous PO2 would be the
PO2 where the curved Fick principle line and line (b)
intersect. This venous PO2 represents the only point
on the figure where eqn [4] (i.e., mass conservation)
is satisfied under these conditions.
Mathematical Analysis of O2 Supply Limitation
Another way to analyze the interaction between the
convective and diffusive elements of O2 unloading in
peripheral capillaries is to use calculus to determine
the equation describing the time course of O2 unloading along the capillary. This can be done in elegant algebraic form if one is willing to approximate
the O2Hb dissociation curve by a straight line of
slope b. When this is done, one finds that under the
presumption of supply, not demand, limitation, maximal O2 consumption can be expressed as
’ f1 exp ½D=ðb QÞg
’
V’ O2 ¼ PaO2 b Q
½5
’ is in fact the same
In this equation, PaO2 b Q
’ O in eqn [1]. This is because CaO ¼ PaO b.
as Q
2
2
2
The exponential term in curly brackets gives the
fraction of O2 delivered to the tissue vasculature that
can be extracted and transported by diffusion to
the mitochondria. D is the diffusional conductance
for O2.
This equation provides great insights into the interplay between convective and diffusive factors in
tissue O2 unloading. Most importantly, extraction
depends on the ratio D/(b Q̇), not just on D itself.
An increase in either b or Q̇ without a similar increase in D would reduce the fractional extraction of
O2 from the blood. Also of importance, both b and
Q̇ appear in the numerator in front of the curly
brackets as well. Hence, an increase in either b or Q̇
would have two opposing effects: increasing convective O2 delivery but decreasing diffusive O2 extraction. These offsetting effects mean that changes in
V’ O2 will always be relatively less than changes in
either b or Q̇ alone.
Examination of eqn [5] also leads to the conclusion that when Q̇ (or b) is very low, V’ O2 becomes
very dependent on Q̇ or (b). However, as Q̇ increases, the offsetting effects mentioned above
balance each other to a greater extent. Ultimately,
further increases in Q̇ will not increase O2 availability as offsetting effects become essentially equal. This
behavior is typical of that seen in a linked ‘bucket
brigade’ system such as the O2 transport chain, and
turns out to be true in principle for any link in the
chain: the weakest link (if substantially weaker than
all others) dictates maximal function of the entire
pathway.
This also means that for an increase in function of
the whole O2 pathway, it is more effective to have
modest, matched, increments in every step of the
pathway than a large increase in just one. It is thus
no surprise that exercise training, as one example of
an adaptable O2 transport system, is accompanied by
increases in function of most steps in the transport
pathway.
Other Factors Affecting O2 Transport in Tissues
The above discussion highlights the two principal
determinants of tissue O2 availability – overall tissue
perfusion and the extent of diffusion from red cells to
mitochondria. There are additional factors that may
interfere with cellular O2 delivery, but how important they are varies from tissue to tissue and is difficult to quantify.
One such factor is direct arteriovenous diffusion of
O2 between thin-walled arterioles and venules that
lie in close proximity to one another. This is however
not felt to be a very important limitation to O2
transport. Another is tissue vascular shunting, the
diversion of blood through vascular channels that
directly connect arterioles and venules, bypassing the
tissue cells. This may be important in certain tissues
PERIPHERAL GAS EXCHANGE 321
such as the skin, but appears less important in, for
example, exercising skeletal muscle. However, possibly more important is perfusion/metabolism inequality. This may occur both between organs and
within organs, and acts much like ventilation/perfusion inequality in the lungs (see Ventilation, Perfusion Matching), impairing the transport of O2
between the tissue vasculature and the mitochondria.
It remains very hard to assess experimentally, and
therefore its role remains uncertain in both health
and disease. When such inequality exists, tissue regions that are underperfused in relation to their metabolic O2 needs cannot get the O2 they require while
those that are overperfused, receive more O2 than
they can use. Tissue dysfunction may then occur in
the underperfused regions, even if overall O2 delivery
to the tissue appears normal. Early data from initial
methods to examine such inequality has revealed
modest levels of heterogeneity that would be predicted to have only minor effects on tissue function,
at least in exercising skeletal muscles.
Limits to O2 Transport/Utilization in
Health and Disease
Central and Peripheral Limitations
It has become popular to ask whether maximal O2
utilization, for example during exercise, is limited by
‘central’ or ‘peripheral’ factors. Most workers define
central factors as those pertaining to the lungs, blood,
and cardiovascular system, while peripheral factors
are thought of as those affecting muscle tissue O2 extraction. This has a certain logic and appeal, since O2
’ O in eqn [2]) and O2 extraction can be
delivery (Q
2
separately measured. However, there are several problems with this concept, both in theory and experimentally. The first is that while systemic O2 delivery
(eqn [2]) at first sight seems to separate central and
peripheral factors since Q̇, Hb, and SaO2 are supposedly centrally determined by the heart, blood, and
lungs, this is an oversimplification. Most importantly,
when interested in specific tissues, it is blood flow to
those tissues that is important. Peripheral vascular
factors that affect between-organ blood flow distribution thus are included implicitly in the supposedly
central component. Regarding the ‘peripheral’ component, as eqn [5] shows, extraction is as dependent
on blood flow (Q̇) as on the diffusion conductance
(D). Since Q̇ is in part determined by cardiac function,
extraction cannot be taken as a simple index of peripheral function. Thus, the so-called ‘central’ factors
affect the so-called ‘peripheral’ factors, and vice versa.
To separate central from peripheral factors, one
needs to determine D (eqn [5]) per se, not just
extraction. This can be done using the graphical
analysis shown in Figure 4. Proper assessment of
central function really requires not just tissue/organ
blood flow measurements but also cardiac output as
well. Proper assessment of peripheral function requires measuring not just extraction, but also diffusional conductance, D, as well.
The most closely studied system examining limits
to O2 transport and utilization in humans is the skeletal muscle during exercise. While there is interest
in other organs and tissues, the muscles collectively
have, by far, the highest ability to consume O2 than
any organ system. This makes exercise an attractive
model for studying O2 transport limitations. Moreover, maximal muscle O2 utilization varies greatly
among individuals, posing many interesting questions, and impaired muscle function is a hallmark of
many chronic diseases, lending clinical significance.
O2 Transport/Utilization Limitation in
Sedentary Normal Subjects
When sedentary normal subjects exercise maximally,
achieving peak V’ O2 values of about 3 l min 1, evidence suggests that they are not limited in their exercise capacity by limits to O2 supply. When given
high concentrations of O2 to breathe, exercise capacity is not increased. Similarly, modest reduction in
inspired O2 levels does not cause a fall in exercise
capacity. This implies that because O2 availability
does not affect exercise, peak V’ O2 is limited by metabolic capacity to consume O2.
O2 Transport/Utilization Limitation in
Athletic Normal Subjects
When sedentary subjects undergo several weeks of
intense exercise training, they become sensitive to
inspired O2 levels. Thus, exercise capacity increases
with hyperoxia and falls with hypoxia. This is also
observed in competitive athletes. In contrast to the
untrained state, this suggests that in trained subjects,
functional limits to the O2 transport system determine maximal exercise capacity. The implication is
that adaptation to exercise training augments cellular
metabolic potential more than O2 transport.
O2 Transport/Utilization Limitation in Patients with
Chronic Cardiopulmonary Diseases
It has long been held that in severe chronic lung disease, the ability to ventilate is the factor limiting exercise intensity. Similarly, in patients with severe
chronic heart failure, exercise has been considered
limited by poor cardiac function alone; in patients
with chronic renal failure, the low Hb concentration
is blamed for reduced exercise capacity. In support of
322 PERIPHERAL GAS EXCHANGE
this idea, acute administration of O2 often improves
exercise capacity (that is, while the extra O2 is being
given), suggesting that the muscles could perform
better even in the face of continuing primary organ
failure if more O2 was available.
In fact, skeletal muscle may function at normal or
near-normal levels if the limiting effect of the failed
central organ can be removed. Experimentally, this
can be achieved by studying the exercise capacity of
small muscle groups. The concept is simply that a
small muscle group can be supported by even a failing
heart, lung, or kidney, even while more conventional
exercise by large muscle groups cannot. Treadmill and
cycle exercise involve large groups of muscles, and
usually take the failed heart or lungs to their limits
of performance before maximal muscle function is
reached. Thus, a small muscle group, such as the
knee-extensors of one leg, may be able to perform at
(near) normal levels when exercised alone. However,
when treadmill or cycle exercise is undertaken on the
same day, the same patient with cardiopulmonary
disease will show clear exercise impairment.
Such results show that it is undoubtedly true that
the lungs (via limited ventilation and gas exchange
impairment), heart (via limited blood flow), and kidneys (via low Hb levels) play major roles in exercise
limitation in diseases of those organs, and that this is,
at least in part, due to impaired systemic O2 availability. But it is now accepted that additional factors
may contribute.
There is evidence that not all patients with advanced cardiopulmonary or renal disease have normal
skeletal muscles. They certainly exhibit the manifestations of detraining (low peak V’ O2 , early blood
lactate appearance, and reduced oxidative enzyme
capacity), as might be expected of very sedentary individuals. Exercise training applied to small muscle
groups can improve O2 transport and treadmill or
cycle exercise capacity even when the original cardiopulmonary failure remains. Training of larger muscle
groups can produce effects such as delayed blood lactate appearance, also improving exercise performance.
Possibly, there are myopathic changes in some patients that contribute to exercise limitation over and
above those of detraining, even in those patients with
normal skeletal muscle mass. However, this is still a
subject of considerable debate among the research
community. Severe loss of muscle mass is sometimes
seen in advanced diseases of the heart and lungs, and
while we do not fully understand the reasons for this,
it has been proposed that this may be a systemic
manifestation of cardiopulmonary disease resulting from increased levels of circulating inflammatory cytokines such as tumor necrosis factor alpha
(TNF-a) and interleukins. Clearly this is a myopathic
manifestation of these diseases and must contribute
to exercise limitation.
In spite of such possibilities, improving O2 availability through muscle training does lead to improved
exercise capacity even while the primary cardiopulmonary disease is present. Even small improvements
have clinical significance in patients whose exercise
ability is severely impaired to begin with.
Heart and/or lung transplantation form a natural
model to study the consequences of cardiopulmonary
disease on O2 transport and exercise. Surprisingly,
well after recovery from the surgery itself, lung
transplant patients show incomplete restoration of
exercise capacity despite normalization of ventilation
and pulmonary gas exchange. Typically, patients
are capable of no more than 50% of what an agematched normal subject can achieve. This commonly
found result suggests that severe heart or lung disease
has systemic effects on O2 transport and utilization
that give rise to a longstanding peripheral component
to exercise limitation that persists even after transplantation. While not fully understood, it is known
that immunosuppressive drugs required to control
organ rejection after transplant are myopathic and
may be more likely responsible for this outcome. In
summary (in the absence of muscle wasting), it remains unclear whether severe cardiopulmonary diseases per se affect muscles beyond the effects of
detraining. Even if they do, regular exercise will improve exercise capacity to some extent and usually
will improve quality of life.
See also: Diffusion of Gases. Hemoglobin. Ventilation, Perfusion Matching. Ventilation: Overview.
Further Reading
Hogan MC, Bebout DE, and Wagner PD (1991) Effect of increased
Hb–O2 affinity on VO2max at constant O2 delivery in dog muscle
in situ. Journal of Applied Physiology 70: 2656–2662.
Krogh A (1919) The number and distribution of capillaries in
muscle with calculations of the pressure head necessary for supplying the tissue. Journal of Physiology (London) 52: 409–415.
Maltais F, Jobin J, Sullivan MJ, et al. (1998) Metabolic and hemodynamic responses of lower limb during exercise in patients with
COPD. Journal of Applied Physiology 84: 1573–1580.
Maltais F and LeBlanc P (2000) Peripheral muscle dysfunction in
chronic obstructive pulmonary disease. Clinical Chest Medicine
21: 665–677.
Maltais F, LeBlanc P, Simard C, et al. (1996) Skeletal muscle adaptation to endurance training in patients with chronic obstructive pulmonary disease. American Journal of Respiratory and
Critical Care Medicine 154: 442–447.
Maltais F, LeBlanc P, Whittom F, et al. (2000) Oxidative enzyme
activities of the vastus lateralis muscle and the functional status
in patients with COPD. Thorax 55: 848–853.
Maltais F, Simard AA, Simard C, Jobin J, Desgagnes P,
and LeBlanc P (1996) Oxidative capacity of the skeletal
muscle and lactic acid kinetics during exercise in normal
PERMEABILITY OF THE BLOOD–GAS BARRIER
subjects and in patients with COPD. American Journal of Respiratory and Critical Care Medicine 153: 288–293.
Piiper J, Meyer M, and Scheid P (1984) Dual role of diffusion in
tissue gas exchange: blood–tissue equilibration and diffusion
shunt. Respiratory Physiology 56: 131–144.
Piiper J and Scheid P (1981) Model for capillary–alveolar equilibration with special reference to O2 uptake in hypoxia. Respiratory Physiology 46: 193–208.
Piiper J and Scheid P (1983) Comparison of diffusion and perfusion limitations in alveolar gas exchange. Respiratory Physiology 51: 287–290.
Richardson RS, Noyszewski EA, Kendrick KF, Leigh JS, and Wagner PD (1995) Myoglobin O2 desaturation during exercise: evidence of limited O2 transport. Journal of Clinical Investigation
96: 1916–1926.
Richardson RS, Tagore K, Haseler L, Jordan M, and Wagner PD
(1998) Increased VO2max with a right shifted Hb–O2 dissociation curve at a constant O2 delivery in dog muscle in situ. Journal of Applied Physiology 84: 995–1002.
323
Roca J, Hogan MC, Story D, et al. (1989) Evidence for tissue
diffusion limitation of V’ O2 max in normal humans. Journal of
Applied Physiology 67: 291–299.
Rowell LB (1993) Human Cardiovascular Control. New York:
Oxford University Press.
Scheid P, Hlastala MP, and Piiper J (1981) Inert gas elimination
from lungs with stratified inhomogeneity: theory. Respiratory
Physiology 44: 299–309.
Wagner PD (1996) Determinants of maximal oxygen transport
and utilization. Annual Review of Physiology 58: 21–50.
Weibel ER (1984) The Pathway for Oxygen. Structure and Function in the Mammalian Respiratory System. Cambridge, MA:
Harvard University Press.
Williams TJ, Patterson GA, McClean PA, Zamel N, and Maurer JR
(1992) Maximal exercise testing in single and double lung transplant
recipients. American Review of Respiratory Diseases 145: 101–105.
Wilson DF, Erecinska M, Drown C, and Silver IA (1977) Effect of
oxygen tension on cellular energetics. American Journal of
Physiology 233: C135–C140.
PERMEABILITY OF THE BLOOD–GAS BARRIER
R M Effros, Harbor–UCLA Medical Center, Torrance,
CA, USA
& 2006 Elsevier Ltd. All rights reserved.
Abstract
Two continuous membranes separate the blood and gas phases
of alveoli: the endothelium and the epithelium. Gases readily
dissolve in cellular membranes of both layers and rapidly exchange between blood and air. Carbon monoxide is generally
used to monitor gaseous diffusion. Electrolytes and water can
cross intercellular junctions, but water molecules can also
traverse a variety of specific water channels (aquaporins) in cell
membranes. The endothelium restrains the movement of proteins but is relatively permeable to electrolytes. Transcapillary
edema formation is governed by hydrostatic and protein osmotic gradients (Starling forces). The epithelium resists passive
movement of both electrolytes and proteins, and airspace edema
formation is primarily restrained by osmotic buffering of electrolytes. Capillary injuries, including elevations in capillary
pressures, can result in leakage of proteins and red cells into the
interstitium, from where they can make their way into the airspaces if the epithelium is ruptured by increases in interstitial
pressure. Edema fluid is normally reabsorbed from the airspaces
by active sodium transport. Uncertainty persists regarding the
osmolality of airway fluid, and methods of collecting respiratory
fluid (bronchoalveolar lavage and exhaled breath condensates)
have been complicated by uncertainty regarding dilution. Increased epithelial permeability to solutes can be detected by
accelerated clearance of radioaerosols from the lungs.
Description
Gases
Since most gas exchange occurs in the alveoli, this
discussion of gas exchange is primarily limited to the
permeability of the alveoli. The tissue barriers that
separate blood from air in the alveoli (Figure 1) are
arranged to maximize gas exchange and minimize
fluid movement into the airspaces. Exchange of O2
and CO2 is enhanced by the arrangement of capillaries and epithelial cells, with extremely attenuated
endothelial and epithelial membranes facing the alveolar gas. The movement of gases across this barrier
is accomplished by passive diffusion – that is, random movement of gas molecules from compartments
in which they are more numerous to those in which
they are less numerous. The rate of diffusion is limited by the resistance of the membranes to gas movement, the molecular weight of the gaseous molecules,
the solubility of the gases in the barrier, and the area
and thickness of the barrier. The high solubility of
most gases in the cell membrane lipids is responsible
for the remarkable efficiency of gas exchange in the
lungs. Similarly, lipophilic solutes instilled into the
lungs (e.g., the alcohols, nicotine, and acetone) also
diffuse rapidly between the airspace and blood compartments. Equilibration of inert gases between the
airspaces and capillaries is virtually complete well
before the blood has traversed the pulmonary microcirculation. However, equilibration of oxygen between the airways may not be complete, particularly
in the presence of disease, because of the large binding capacity of hemoglobin for oxygen, which provides a large ‘sink’ for this gas. As described
elsewhere, the higher affinity of hemoglobin for CO
makes it easier to use this indicator for evaluating
gaseous diffusion because it can be assumed that
PCO in the capillary remains negligible. Diffusion of