Oxygen and Carbon Dioxide Transport
Oxygen and Carbon Dioxide Transport
Oxygen and Carbon Dioxide Transport
T
he respiratory and circulatory systems function capacity of the lung (DL) is its conductance (AD/T) when
together to transport oxygen (O2) from the lungs to considered for the entire lung; thus, with Ficks equation,
the tissues to sustain normal cellular activity and to DL can be calculated as follows:
transport carbon dioxide (CO2) from the tissues to the lungs Equation 24.1
for expiration. CO2, a product of active cellular metabolism,
is transported from the tissues via systemic veins to the gas = A D (P1 P2 )
V
lungs, where it is expired (Fig. 24.1). To enhance uptake T
and transport of these gases between the lungs and tissues,
V = DL (P1 P2 )
specialized mechanisms (e.g., binding of O2 and hemoglo- V
bin and HCO3 transport of CO2) have evolved that enable DL =
(P1 P2 )
O2 uptake and CO2 expiration to occur simultaneously.
Moreover, these specialized mechanisms facilitate uptake of where V gas = gas diffusion.
O2 and expiration of CO2. To understand the mechanisms Ficks law of diffusion could be used to assess the diffu-
involved in the transport of these gases, gas diffusion prop- sion properties of O2 in the lungs, except that the capillary
erties, as well as transport and delivery mechanisms, must partial pressure of oxygen cannot be measured. This limita-
be considered. tion can be overcome with the use of carbon monoxide
(CO) rather than O2. Because CO has low solubility in the
Gas Diffusion capillary membrane, the rate of CO equilibrium across the
capillary is slow, and the partial pressure of CO in capillary
Gas movement throughout the respiratory system occurs blood remains close to 0. In contrast, the solubility of CO
predominantly via diffusion. The respiratory and circulatory in blood is high. Thus the only limitation for diffusion of
systems contain several unique anatomical and physiological CO is the alveolar-capillary membrane, and thus CO is a
480
CHAPTER 24 Oxygen and Carbon Dioxide Transport 481
CO2 O2 useful gas for calculating DL. The capillary partial pressure
elimination uptake
Lung (P2 in Eq. 24.1) is essentially 0 for CO, and therefore DL
can be measured from the diffusion of carbon monoxide
Systemic Systemic (V CO) and the average partial pressure of CO in the
veins arteries alveolus; that is,
Equation 24.2
= DL (P1 P2 )
V
Alveoli
V V CO
DL CO = =
Pulmonary P1 P2 PACO
capillaries
where DLCO = diffusion capacity of the lung for carbon
monoxide.
Assessment of DLCO has become a classic measurement
Metabolic Metabolic of the diffusion barrier of the alveolar-capillary membrane.
CO2 O2 It is useful in the differential diagnosis of certain obstructive
40 mL/L 50 mL/L
lung diseases, such as emphysema.
IN THE CLINIC
A patient with interstitial pulmonary fibrosis (a restrictive lung
Systemic disease) inhales a single breath of 0.3% CO from residual
capillaries volume to total lung capacity. He holds his breath for 10
seconds and then exhales. After discarding the exhaled gas
from the dead space, a representative sample of alveolar gas
from late in exhalation is collected. The average alveolar CO
pressure is 0.1mm Hg, and 0.25mL of CO has been taken
up. The diffusion capacity for CO in this patient is
CO2 production O2 use
by cells Tissue by cells V CO
DL =
Fig. 24.1 Oxygen (O2) and Carbon Dioxide (CO2) Transport in
PACO
Arterial and Venous Blood. Oxygen in arterial blood is transferred 60 seconds/minute
= 0.25 mL/10 seconds
from arterial capillaries to tissues. The flow rates for O2 and CO2 are 0.1mm Hg
shown for 1L of blood. = 15 mL/minute/mm Hg
gas and is limited only by the amount of blood perfusing Diffusion limitation for O2 and CO2 would occur if red
the alveolus. In contrast, a gas that is diffusion limited, blood cells spent less than 0.25 seconds in the capillary
such as CO, has low solubility in the alveolar-capillary bed. This is occasionally the case in very fit athletes during
membrane but high solubility in blood because of its high vigorous exercise and in healthy subjects who exercise at
affinity for hemoglobin (Hgb). These features prevent the high altitude.
equilibration of CO between alveolar gas and blood during
the red blood cell transit time. Oxygen Transport
The high affinity of CO for Hgb enables large amounts
of CO to be taken up in blood with little or no appreciable Oxygen is carried in blood in two forms: dissolved O2 and
increase in its partial pressure. Gases that are chemically O2 bound to Hgb. The dissolved form is measured clinically
bound to Hgb do not exert a partial pressure in blood. in an arterial blood gas sample as the partial pressure of
Like CO, both CO2 and O2 have relatively low solubility arterial oxygen (PaO2). Only a small percentage of O2 in
in the alveolar-capillary membrane but high solubility in blood is in the dissolved form, and its contribution to
blood because of their ability to bind to Hgb. However, O2 transport under normal conditions is almost negligible.
their rate of equilibration is sufficiently rapid for complete However, dissolved O2 can become a significant factor in
equilibration to occur during the transit time of the red conditions of severe hypoxemia. Binding of O2 to Hgb
blood cell within the capillary. Equilibration for O2 and to form oxyhemoglobin within red blood cells is the
CO2 usually occurs within 0.25 seconds. Thus O2 and CO2 primary transport mechanism of O2. Hgb not bound to
transfer is normally perfusion limited. The partial pressure O2 is referred to as deoxyhemoglobin or reduced Hgb. The
of a gas that is diffusion limited (i.e., CO) does not reach O2-carrying capacity of blood is enhanced about 65 times
equilibrium with the alveolar pressure over the time that by its ability to bind to Hgb.
it spends in the capillary (Fig. 24.3). Although CO2 has
a greater rate of diffusion in blood than O2 does, it has a Hemoglobin
lower membrane-blood solubility ratio and consequently
takes approximately the same amount of time to reach Hgb is the major transport molecule for O2. The Hgb
equilibration in blood. molecule is a protein with two major components: four
nonprotein heme groups, each containing iron in the
reduced ferric (Fe+++) form, which is the site of O2 binding,
and a globin portion consisting of four polypeptide chains.
Start of End of Normal adults have two -globin chains and two -globin
capillary capillary chains (HgbA), whereas children younger than 6 months of
Alveolar age have predominantly fetal Hgb (HgbF), which consists
of two chains and two chains. This difference in the
Normal structure of HgbF increases its affinity for O2 and aids
N2O
in the transport of O2 across the placenta. In addition,
HgbF is not inhibited by 2,3-diphosphoglycerate (2,3-
O2 (normal)
DPG), a product of glycolysis; thus O2 uptake is further
enhanced.
Partial pressure
IN THE CLINIC
In the inherited homozygous condition known as sickle cell
iron molecule in the heme group and change it from the disease, affected individuals have an amino acid substitution
reduced ferrous state (Fe++) to the ferric state (Fe+++), which (valine for glutamic acid) on the chain of the Hgb molecule.
reduces the ability of O2 to bind to Hgb. This creates a sickle cell Hgb (HgbS), which, when not
bound to oxygen (deoxyhemoglobin or desaturated Hgb),
can transform into a stiff gelatinous material that distorts the
Oxyhemoglobin Dissociation Curve normal biconcave shape of the red blood cell to a crescent,
or sickle-shaped, form. This change in appearance from
In the alveoli, the majority of O2 in plasma quickly diffuses spherical to a sickle shape increases the tendency of the
into red blood cells and chemically binds to Hgb. This red blood cell to form thrombi or clots that obstruct small
process is reversible, so that Hgb quickly gives up its O2 to vessels and creates a clinical condition known as acute
tissue through passive diffusion (the concentration of O2 sickle cell episode. The symptoms of such an episode vary,
depending on the site of the obstruction (e.g., in the brain,
in Hgb decreases). The oxyhemoglobin dissociation curve stroke; in the lungs, pulmonary infarction) and are commonly
illustrates the relationship between PO2 in blood and the associated with intense pain. The spleen is a common site
number of O2 molecules bound to Hgb (Fig. 24.4). The of obstruction/infarction, and the ensuing tissue damage
S shape of the curve demonstrates the dependence of Hgb compromises the immune capabilities of affected individuals
saturation on PO2, especially at partial pressures lower than and renders them susceptible to recurrent infections. In the
homozygous form, this condition is life-shortening; however,
60mm Hg. The clinical significance of the flat portion of individuals with the heterozygous form are resistant to
the oxyhemoglobin dissociation curve (>60mm Hg) is that malaria. Thus an individual with heterozygous alleles has a
a drop in PO2 over a wide range of partial pressures (100 survival advantage in regions of the world where malaria is
to 60mm Hg) has a minimal effect on Hgb saturation, prevalent, which may explain why the sickle cell mutation has
which remains at 90% to 100%, a level sufficient for normal been preserved through evolution. The increased affinity of
HgbF for O2 confers advantages to individuals with sickle cell
O2 transport and delivery. The clinical significance of the disease in that the cells do not desaturate as much when
steep portion (<60mm Hg) of the curve is that a large O2 is released from Hgb to the tissue and thus are less likely
amount of O2 is released from Hgb with only a small change to become deformed in the sickle shape. Sickle cell disease
in PO2, which facilitates the release and diffusion of O2 is most prevalent among individuals of African American
into tissue. The point on the curve at which Hgb is 50% descent, but it is also observed in Hispanic, Turkish, Asian,
and other ethnic groups.
saturated with O2 is called the P50, and it is 27mm Hg in
normal adults.
484 S E C T I O N 5 Berne & Levy Physiology
methemoglobin. Under normal conditions, about 1% to 2% Tissue hypoxia is a condition in which O2 available
of Hgb is bound to CO and nitric oxide. to cells is insufficient for maintaining adequate aerobic
metabolism. Thus anaerobic metabolism is stimulated and
Oxygen Saturation, Content, and Delivery results in the increases in levels of lactate and H+ and the
subsequent formation of lactic acid. The net result can lead
Each Hgb molecule can bind up to four O2 atoms, and to a significant decrease in blood pH. In cases of severe
each gram of Hgb can bind up to 1.34mL of O2. The term hypoxia, the extremities, toes, and fingertips may appear
O2 saturation (SO2) refers to the amount of O2 bound to blue-gray (cyanotic) because of lack of O2 and increased
Hgb in relation to the maximal amount of O2 (100% O2 deoxyhemoglobin levels. There are four major types of
capacity) that can bind Hgb. At 100% O2 capacity, the tissue hypoxia (hypoxic hypoxia, circulatory hypoxia,
heme groups of the Hgb molecules are fully saturated with anemic hypoxia, histotoxic hypoxia), discussed in detail in
O2, and at 75% O2 capacity, three of the four heme groups Chapter 23.
are occupied. Binding of O2 to each heme group increases
the affinity of the Hgb molecule to bind additional O2. The Erythropoiesis
O2 content in blood is the sum of the O2 bound to Hgb
and the dissolved O2. Oxygen content is decreased in the Tissue oxygenation depends on the concentration of Hgb
presence of increased CO2 and CO and in individuals with and thus on the number of red blood cells available in the
anemia (Fig. 24.7). circulation. Red blood cell production (erythropoiesis) in
Oxygen delivery from the lungs to tissues is dependent the bone marrow is controlled by the hormone erythro-
on several factors, including cardiac output, the Hgb poietin, which is synthesized in the kidneys by cortical
content of blood, and the ability of the lung to oxygenate interstitial cells. Although Hgb levels are normally very
the blood. Not all of the O2 carried in blood is unloaded stable, decreased O2 delivery, low Hgb concentration, and
at the tissue level. The actual O2 extracted from blood by low PaO2 stimulate the secretion of erythropoietin. This
the tissue is the difference between the arterial O2 content increases the production of red blood cells. Chronic renal
and the venous O2 content, multiplied by cardiac output. disease damages the cortical interstitial cells and thereby
Under normal conditions, Hgb leaves the tissue 75% suppresses their ability to synthesize erythropoietin. This
saturated with O2, and only about 25% is actually used by causes anemia, along with decreased Hgb because of the
tissues. Hypothermia, relaxation of skeletal muscles, and an lack of erythropoietin. Erythropoietin replacement therapy
increase in cardiac output reduce O2 extraction. Conversely, using epoetin alfa (Epogen, Procrit) or darbepoetin alfa
a decrease in cardiac output, anemia, hyperthermia, and (Aranesp) effectively increases red blood cell production.
exercise increase O2 extraction.
200
Carbon Dioxide Transport
a
Glucose Metabolism and Carbon
Normal
160
Dioxide Production
v
CO2 is produced at a rate of approximately 200mL/minute
under healthy conditions, and typically, 80 molecules of
O2 content (mL/L)
120 50% HgbCO a CO2 are expired by the lung for every 100 molecules of
50% Hgb a O2 that enter the capillary bed. The ratio of expired CO2
to O2 uptake is referred to as the respiratory exchange
80 ratio and, under normal conditions, is 0.8 (80 molecules
of CO2 to 100 molecules of O2). This ratio is similar at the
v
v tissue to blood compartment, where it is referred to as the
40 respiratory quotient.
The body has enhanced storage capabilities for CO2,
in comparison with O2, and hence PaO2 is much more
20 40 60 80 100
sensitive to changes in ventilation than is PaCO2. Whereas
PaO2 is dependent on several factors, in addition to alveolar
PO2 (mm Hg)
ventilation, arterial PaCO2 is solely dependent on alveolar
Fig. 24.7 A comparison of O2 content curves under three conditions ventilation and CO2 production. There is an inverse rela-
shows why carboxyhemoglobin (HgbCO) dramatically reduces the O2 tionship between alveolar ventilation and PaCO2.
transport system. Fifty percent HgbCO represents the binding of half
the circulating Hgb with carbon monoxide (CO). The 50% hemoglobin
and 50% HgbCO curves show the same decreased O2 content in Bicarbonate and Carbon Dioxide Transport
arterial blood. However, CO has a profound effect in lowering venous
partial pressure of oxygen. The arterial (a) and mixed venous (v) points In blood, CO2 is transported in red blood cells primarily
of constant cardiac output are indicated. as bicarbonate (HCO3) but also as dissolved CO2 and as
486 S E C T I O N 5 Berne & Levy Physiology
Cell
O2
Plasma capillary
CO2
Plasma
5%
H2O
21% CO2 dissolved O2 + Hgb
CO2 O2
HgbO2
CO2 + HgbO2 HgbCO2 Cl
RBC
Carbonic anhydrase transport
63% CO2 + H2O H2CO3 H+ + HCO3
Rapid hydration of CO2
RBC Cl
Na+
1%
CO2 plasma protein carbamino
Plasma 5%
transport Slow
CO2 + H2O H2CO3 H+ + HCO3 NaHCO3 20
5% hydration
of CO2
CO2 dissolved in plasma H2CO3 1
Fig. 24.8 Mechanisms of CO2 Transport in Blood. v . The predominant mechanism by which CO2
is transported from tissue cells to the lung is in the form of bicarbonate anion (HCO3). H2CO3, carbonic
acid; HgbO, oxyhemoglobin; NaHCO3, sodium bicarbonate; RBC, red blood cell.
carbamino protein complexes (i.e., CO2 binds to plasma synthesis of HCO3; high levels of free H+ (low pH) cause
proteins and to Hgb; Fig. 24.8). Once CO2 diffuses through the reaction to shift to the left.
the tissue and enters plasma, it quickly dissolves. The reac-
tion of CO2 with H2O to form carbonic acid (H2CO3) is Regulation of Hydrogen Ion Concentration
the major mechanism for the generation of HCO3 in red and Acid-Base Balance
blood cells:
Equation 24.3 The H+ concentration (pH) has a dramatic effect on many
metabolic processes within cells, and regulation of pH is
CO2 + H2O H2CO3 H+ + HCO3 essential for normal homeostasis. In the clinical setting,
The reaction normally proceeds quite slowly; however, it is blood pH is measured to assess the concentration of H+.
catalyzed within red blood cells by the enzyme carbonic The normal pH range for adults is 7.35 to 7.45 and is
anhydrase. The HCO3 diffuses out of the red blood cell in maintained by the lungs, kidneys, and chemical buffer
exchange for Cl, in a process known as the chloride shift, systems. In the respiratory system, conversion of CO2 to
which helps the cell maintain its osmotic equilibrium. This HCO3, illustrated as follows, is a major mechanism of
chemical reaction (see Fig. 24.8) is reversible and can be buffering and regulating the H+ concentration (pH):
shifted to the right to generate more HCO3 in response
to more CO2 entering the blood from tissues, or it can be Equation 24.4
shifted to the left as CO2 is exhaled in the lungs, which CO2 + H2O H2CO3 H+ + HCO3
reduces HCO3 levels. The free H+ is quickly buffered
within the red blood cell by binding to Hgb. Buffering of (with hydrogen yielding)
H+ is critical for keeping the reaction moving toward the H+ + Hgb H Hgb
CHAPTER 24 Oxygen and Carbon Dioxide Transport 487
at 37C, has a value of 0.03. Also, pK is the negative Blood. Venous blood can transport more CO2 than arterial blood can
logarithm of the overall dissociation constant for the reac- at any given PCO2. In comparison with the HgbO2 equilibrium curve,
the CO2 curves are essentially straight lines between a PCO2 of 20 and
tion and has a logarithmic value of 6.1 for plasma at 37C. a PCO2 of 80mm Hg. Long dashes represent the arterial equilibrium
Acute hyperventilation secondary to exercise or anxiety curve; short dashes represent the venous equilibrium curve.
reduces PCO2 and thereby causes an increase in pH (respira-
tory alkalosis). Conversely, if PCO2 increases because of
hypoventilation secondary to an overdose of a respiratory
depressant, the pH decreases (respiratory acidosis). Acid- at different sites, deoxygenated Hgb has greater affinity
base imbalances are also caused by metabolic disorders such for CO2 than oxygenated Hgb. Thus deoxygenated blood
as metabolic acidosis (e.g., lactic acidosis, ketoacidosis, and (venous blood) freely takes up and transports more CO2
renal failure) and metabolic alkalosis (e.g., hypokalemia, than oxygenated arterial blood does. The deoxygenated
hypochloremia, vomiting, high doses of steroids). Hgb more readily forms carbamino compounds and also
more readily binds free H+ released during the formation of
Carbon Dioxide Dissociation Curve HCO3. The effect of changes in oxyhemoglobin saturation
on the relationship of CO2 content to PCO2 is referred to as
In contrast to O2, the dissociation curve for CO2 in blood the Haldane effect and is reversed in the lungs when O2 is
is linear and directly related to PCO2 (Fig. 24.9). The degree transported from the alveoli to red blood cells. This effect
of Hgb saturation with O2 has a major effect on the CO2 is illustrated by a shift to the left in the CO2 dissociation
dissociation curve. Although O2 and CO2 bind to Hgb curve in venous blood in comparison with arterial blood.
Key Points
1. Gases (nitrous oxide, ether, helium) that have a rapid to 90%. This ensures adequate Hgb saturation over a
rate of air-to-blood equilibration are perfusion limited. large range of PO2 values.
Gases (CO) that have a slow air-to-blood equilibration 5. The CO2 dissociation curve is linear and directly
rate are diffusion limited. Under normal conditions, related to PCO2. PCO2 is solely dependent on alveolar
O2 and CO2 exchange are perfusion limited but can be ventilation and CO2 production.
diffusion limited in some situations. 6. The CO2 to HCO3 pathway plays a critical role in
2. The major transport mechanism of O2 in blood is the regulation of H+ ions and in maintaining acid-base
within the red blood cell bound to Hgb, and for CO2, balance in the body.
it is within red blood cells in the form of HCO3. 7. Tissue oxygenation is dependent on Hgb within
3. The reversible reaction of CO2 with H2O to form red blood cells and subsequently the number (and
H2CO3, with its subsequent dissociation to HCO3 production) of red blood cells, which is controlled by
and H+, is catalyzed by the enzyme carbonic anhydrase the hormone erythropoietin. Low O2 delivery, low Hgb
within red blood cells and is the major mechanism for concentration, and low PaO2 stimulate the secretion of
generation of HCO3. erythropoietin in the kidneys.
4. The O2 dissociation curve is S shaped. In the plateau 8. Tissue hypoxia occurs when insufficient amounts of O2
area (>60mm Hg), increasing or decreasing PO2 has are supplied to the tissue to conduct normal levels of
only a minimal effect on Hgb saturation from 100% aerobic metabolism.
488 S E C T I O N 5 Berne & Levy Physiology
Additional Readings Hughes JM. Assessing gas exchange. Chron Respir Dis. 2007;4:205-214.
Petersson J, Glenny RW. Gas exchange and ventilation-perfusion
Butler JP, Tsuda A. Transport of gases between the environment relationships in the lung. Eur Respir J. 2014;44:1023-1041.
and alveolitheoretical foundations. Compr Physiol. 2011;1: Sheel AW, Romer LM. Ventilation and respiratory mechanics. Compr
1301-1316. Physiol. 2012;2:1093-1142.
Calverley PMA, Koulouris NG. Flow limitation and dynamic Stickland MK, Lindinger MI, Olfert IM, etal. Pulmonary gas
hyperinflation: key concepts in modern respiratory physiology. exchange and acid-base balance during exercise. Compr Physiol.
Eur Respir J. 2005;25:186-199. 2013;3:693-739.
Hillman SS, Hancock TV, Hedrick MS. A comparative meta-analysis Whipp BJ. Physiological mechanisms dissociating pulmonary CO2
of maximal aerobic metabolism of vertebrates: implications for and O2 exchange dynamics during exercise in humans. Exp Physiol.
respiratory and cardiovascular limits to gas exchange. J Comp 2007;92:347-355.
Physiol [B]. 2013;183:167-179.