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CASE 19
A 23-year-old man with no medical problems is brought to the emergency center by family members who found him to be confused, nauseated, short of
breath, and complaining of a headache. The patient was found in the basement
of their home next to a furnace, where he was trying to stay warm on a cold
winter day. On examination, the patient is lethargic and confused. His lips
appear a bright pink. A urine drug screen is obtained and is negative. His
serum carboxyhemoglobin level is elevated. The patient is diagnosed with carbon monoxide poisoning and is admitted to the hospital for further treatment.
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What is the mechanism by which carbon monoxide causes hypoxia?
In which direction (right or left) would the hemoglobin–oxygen
dissociation curve shift with fetal hemoglobin compared with adult
hemoglobin?
What is the most common way in which carbon dioxide is
transported in venous blood?
154
CASE FILES: PHYSIOLOGY
ANSWERS TO CASE 19: OXYGEN-CARBON DIOXIDE
TRANSPORT
Summary: A 23-year-old man has confusion, nausea, shortness of breath, and
headache after being found near a furnace in the basement. The patient has
clinical and laboratory findings consistent with carbon monoxide poisoning.
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Hypoxia with carbon monoxide: Decreased oxygen-binding capacity
of hemoglobin.
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Fetal hemoglobin–oxygen dissociation curve: Shift to the left.
Most common way carbon dioxide is transported in the blood:
Bicarbonate (HCO3-).
CLINICAL CORRELATION
Carbon monoxide is a gas that is produced commonly by internal combustion
engines, fossil-fuel home appliances (heaters, stoves, furnaces), and incomplete combustion of nearly all natural and synthetic products. Poisoning with
carbon monoxide, if a person is exposed for a long period, can be fatal.
Symptoms include headache, shortness of breath, confusion, impaired judgment, nausea, respiratory depression, coma, and even death. It is particularly a
challenging problem because the gas is odorless and colorless; also, because
the hemoglobin molecule is saturated, the patient is “pink” but hypoxemic.
Carbon monoxide is inhaled through the lungs and binds to the oxygenbinding site of hemoglobin with a significantly higher affinity than does oxygen. The combination of carbon monoxide and hemoglobin makes
carboxyhemoglobin, which can be measured in a patient’s blood. The elevation of the carboxyhemoglobin level may give some indication of the severity
of the disease. After a person’s removal from the carbon monoxide exposure,
the carbon monoxide slowly dissociates and is excreted through the lungs.
Treatment of the poisoning includes removal from the carbon dioxide exposure and the administration of 100% oxygen (non-rebreather mask). At times
patients need intubation (coma, seizures, or cardiovascular instability) or treatment with hyperbaric oxygen (extremely elevated carboxyhemoglobin levels).
APPROACH TO OXYGEN-CARBON DIOXIDE
TRANSPORT
Objectives
1.
2.
3.
Know about the structure and function of hemoglobin.
Understand the hemoglobin–oxygen dissociation curves and the factors which may change them.
Know about carbon dioxide transport in the blood.
155
CLINICAL CASES
Definitions
Oxygen carrying capacity of blood: The sum of the amount of dissolved O2
plus the amount of O2 bound to hemoglobin in the presence of 100% O2.
Oxygen content of blood: The sum of the amount of dissolved O2 plus the
amount of O2 bound to hemoglobin at any given PO2.
Bohr effect: In the presence of CO2 hemoglobin has a lower binding affinity for O2. Because of the Bohr effect, increasing CO2 or lowering the
pH of the blood decreases the O2 affinity of hemoglobin favoring O2
release.
Haldane effect: Deoxygenation of hemoglobin increases its ability to bind
CO2.
DISCUSSION
Oxygen Transport
Metabolism consumes O2 and produces CO2. Gas exchange in the lungs
occurs when blood passing through the pulmonary capillaries releases CO2
and takes up O2. The arterial concentrations of CO2 and O2 are in equilibrium
with their concentrations in the alveolar compartment. The gas concentration
in the blood is expressed as its partial pressure, and its content is determined
by its partial pressure and its solubility in blood. The solubility of oxygen in
aqueous solution is low, and the amount of O2 that can be dissolved in normal plasma, or the O2 content, at 37∞C is 0.3 mL/100 mL at a normal arterial
partial pressure of 100 mm Hg. The O2 content of plasma is much too low to
meet a person’s metabolic demands; however, hemoglobin greatly increases
the amount of O2 the blood can carry. The O2-carrying capacity of blood is
dependent on the hemoglobin concentration. At saturating oxygen levels,
hemoglobin binds about 1.34 mL of O2 per gram of hemoglobin. Normal
blood has about 15 g of hemoglobin per 100 mL; thus, at saturation, the
amount of O2 bound to hemoglobin is
15 g Hb ¥ 1.34 mL O2/g Hb ¥ 100% saturation = 20.1 mL O2/100 mL blood
The amount of O2 bound at saturation is the O2-binding capacity of hemoglobin. The normal arterial PO2 is about 100 mm Hg. At this partial pressure,
hemoglobin is 97.5% saturated and the amount of O2 that is bound is
15 g Hb ¥ 1.34 mL O2/g Hb ¥ 97.5% saturation = 19.6 mL O2/100 mL blood
The total amount of O2 in the blood is the sum of the dissolved O2 and the
bound O2:
O2dis = 0.3 mL/100 mL blood
O2bound = 19.6 mL/100 mL blood
O2content = 19.9 mL/100 mL blood
156
CASE FILES: PHYSIOLOGY
The majority of O2 is transported in the blood bound to hemoglobin. Any
factors that influence the amount of functional hemoglobin will influence O2
transport in the blood.
Hemoglobin is the major blood protein constituent; it is contained within
the red cells of the blood and is central to gas transport and maintenance of
hydrogen ion homeostasis and acid–base balance. It is a tetrameric complex
of two a subunits and two b subunits, each of which binds an O2 molecule.
The binding of the first oxygen to hemoglobin causes a structural shift that
favors the binding of additional oxygen molecules. This cooperativity yields
a characteristic sigmoidal affinity curve for O2 binding. Several important
physiologic parameters contribute to the binding affinity of hemoglobin for O2
and affect the shape of the curve. Variables such as temperature, pH, and
CO2 alter the binding affinity for O2. The structural shift induced by O2 binding alters the ionization state of important amino acid residues, causing a shift
in their H+ dissociation constant (pKa ). O2 binding results in a decreased affinity of hemoglobin for H+ and a release of H+ from the molecule. The reaction
is readily reversible and is in equilibrium. Thus, not only does O2 binding or
release cause a change in [H+], the H+ concentration influences O2 binding by
hemoglobin. Although seemingly minor, the O2 binding affinity of hemoglobin is pH-dependent and is important to the overall physiologic function of
hemoglobin. Also, hemoglobin contributes to H+ ion homeostasis by becoming a weaker acid (higher affinity for H+) upon O2 dissociation. This shift in
the pKa is the basis of both the Haldane effect and the Bohr effect. Finally,
hemoglobin also binds CO2 with the formation of carbamino groups. The
binding is weak and readily reversible but has two important consequences:
The binding of CO2 alters O2 affinity, and hemoglobin contributes to CO2
transport in the blood.
An increase in H+ or PCO2 will shift the O2 dissociation curve to the
right with a resultant decrease in the affinity for O2. This phenomenon is
known as the Bohr effect. Another important regulator of the O2 binding affinity of hemoglobin is 2,3-diphosphoglycerate (DPG). DPG is produced by red
cells and is increased during hypoxia. An increase in DPG shifts the affinity
curve to the right, decreasing the affinity for O2 and favoring oxygen release
in the tissues (See Figure 19-1).
The effect of pH, PCO2, temperature, and 2,3-DPG on O2 binding to hemoglobin is central to gas transport by the blood. Figure 19-1 is the oxygenbinding curve of hemoglobin. Because of the steeply sigmoidal nature of the
curve through much of the physiologic range, even slight changes in the binding affinity for O2 can cause large changes in the percent of O2 saturation at a
given PO2. Thus increases in H+, CO2, temperature, or 2,3-DPG will cause O2
dissociation from hemoglobin. Conversely, a decrease in any of these factors
will increase the affinity for O2 favoring its binding to hemoglobin.
157
CLINICAL CASES
100
100
98
97
N
90
Shift to the left:
Hypothermia
Hypocapnia
Alkalosis
↓2,3 DPG
70
N
80
70
Shift to the right:
Hyperthermia
Hypercapnia
Acidosis
2,3-DPG
N
60
A
50
90
60
↓
% Hemoglobin saturation
80
91
50
40
40
30
30
20
20
10
10
0
27
0
10
20
30
40
50
60
PO2 (mm Hg)
70
80
90
0
100
Figure 19-1. Oxygen dissociation curve with shifts based on various factors.
Carbon Dioxide Transport
The transport of CO2 by the blood occurs through several different mechanisms. CO2 has a higher solubility than does O2; therefore, a larger fraction
is carried as dissolved CO2. More important, CO2 spontaneously reacts with
water to form carbonic acid:
CO2 + H2O Æ H2O CO3 Æ H+ + HCO3Carbonic acid dissociates to H+ and HCO3-. The enzyme carbonic anhydrase catalyzes this reaction and is contained in red cells. CO2 freely diffuses
into the red cell and reacts with water to form H+ and HCO3−. The HCO3− is
transported rapidly out of the red cell by the Cl−/ HCO3− exchanger in the red
cell membrane. The H+ remains in the cell and is in part buffered by the hemoglobin. Physiologically, this arrangement works to advantage because the
increase in H+ favors the dissociation of bound O2 (Bohr effect). At the same
time, dissociation of O2 causes hemoglobin to become a weaker acid (higher
affinity for H+), increasing the buffer capacity of hemoglobin. About twothirds of metabolically produced CO2 undergoes this reaction and is carried to the lungs as HCO3-.
% O2 saturation
100
Alveolus
80
CO2
60
CO2↓
40
H+↓
O2
20
0
0
20 40 60 80 100 120
PO2 (mm Hg)
Cl–
CO2 + H2O
H+ + HCO3–
H+ + HbO2
CO2
CO2 + HbO2
HHb + O2
O2
H+ + HbCO2 + O2
Pulmonary capillary
80
↓
60
CO2
40
H+
↓
% O2 saturation
100
20
0
0
20 40 60 80 100 120
PO2 (mm Hg)
CO2 + H2O
CO2
Cl
H+ + HCO3–
H+ + HbO2
CO2
CO2 + HbO2
HHb + O2
O2
H+ + HbCO2 + O2
Pulmonary capillary
Figure 19-2. Gas transport from actively metabolizing tissue and the lungs.
Tissue production of CO2 in the peripheral capillary will cause CO2 to diffuse
into the red cell. In the red cell, CO2 will react with H2O via the action of carbonic anhydrase to form H+ and HCO3−. The HCO3− is transported out of the cell
in exchange for Cl−. Both CO2 and H+ will facilitate O2 release by causing a shift
in the O2 dissociation curve of hemoglobin, lowering its O2 affinity. At the same
time, O2 dissociation will increase the affinity of Hb for H+ and CO2. As the
blood enters the pulmonary capillary, the arterial O2 will rise decreasing the
affinity for CO2. CO2 will diffuse down its concentration gradient into the alveolus resulting in HCO3− reacting with H+ to form CO2. As H+ and CO2 fall, the
O2 affinity of hemoglobin increases facilitating oxygenation.
CLINICAL CASES
159
Hemoglobin also binds CO2 directly through the formation of carbamino
groups on terminal amines. There is no cooperativity of CO2 binding, and the
dissociation curve is much flatter over the normal physiologic range. The binding affinity for CO2 is dependent on the O2 concentration. Increasing O2
causes a shift to the right with a decrease in affinity for CO2. The effect is
known as the Haldane effect.
Physiologic Relevance
Physiologically, the Bohr effect and the Haldane effect are important in the
understanding of gas transport, O2 delivery to tissues, and H+ homeostasis
(summarized in Figure 19-2). In metabolically active tissues, there is increased
production of CO2, which freely diffuses into the red cell. In the red cell, twothirds of the CO2 is converted by carbonic anhydrase to H2CO3 which dissociates to H+ and HCO3-. The HCO3- is transported into the blood in exchange for
Cl-. The elevation in CO2 and H+ will favor release of O2 from hemoglobin,
facilitating O2 delivery to the tissue. The blood leaving the tissue will have elevated H+, CO2 and HCO3-. In the lungs, O2 diffuses into the pulmonary capillary and CO2 diffuses into the alveolar compartment. In the red cell, the
increase in O2 drives the release of CO2 from the hemoglobin. The fall in CO2
reverses the reaction of HCO3- and H+ to form H2CO3 which is converted to
CO2 and H2O. The fall in both H+ and CO2 increase the affinity for O2, favoring maximal saturation of the hemoglobin.
COMPREHENSION QUESTIONS
[19.1]
A 32-year-old woman is theorizing that breathing 100% oxygen should
increase the amount of oxygen in her blood about fivefold, because
room air is composed of approximately 21% oxygen. Which of the following statements is the most accurate answer to her hypothesis?
A. The amount of oxygen carried by her hemoglobin probably will
increase markedly, but the amount soluble in her serum will remain
the same.
B. The amount of oxygen carried in her blood will not rise
appreciably.
C. The amount of oxygen in her blood will rise about fivefold.
D. The partial pressure of oxygen in her blood probably will remain
unchanged.
160
[19.2]
CASE FILES: PHYSIOLOGY
A 56-year-old man is admitted to the coronary care unit (CCU) for an
acute inferior wall myocardial infarction. The cardiologist is trying to
optimize the oxygen delivery to the myocardial tissue. Supplemental
oxygen is provided by nasal cannula at 3 L/min. Which of the following best describes the oxygen-carrying capacity of whole blood?
A. Dependent on the alveolar PO2
B. The amount of O2 dissolved in the blood
C. The sum of the dissolved O2 plus the amount bound to
hemoglobin
D. The sum of the dissolved O2 plus the amount of O2 bound to
hemoglobin under saturating conditions
E. Limited by O2 diffusion
[19.3]
In the case above, the patient had been sleeping in a small room at his
house heated with a space heater. He suffered from carbon monoxide
poisoning.
The carbon monoxide has bound to hemoglobin and reduced its
oxygen-binding capacity. Which of the following best describes the
PO2 level in the patient’s arterial blood when the paramedics were
called to evaluate him?
A. Dependent on the alveolar PO2
B. Dependent on the amount of CO bound to hemoglobin
C. Increased from normal because of displaced oxygen from
hemoglobin
D. Reduced from normal because of the CO bound to hemoglobin
[19.4]
O2 binding to hemoglobin in the pulmonary capillary is inhibited by
which of the following?
A.
B.
C.
D.
CO2 dissociation from hemoglobin
Diffusion of CO2 from pulmonary capillary to alveolus
Reaction of bicarbonate with H+
Shift to more acidic pH than is found in venous blood
Answers
[19.1]
B. Because the vast majority of oxygen content in blood is carried by
hemoglobin, breathing 100% oxygen will increase the partial pressure of oxygen but will not affect the content or oxygen-carrying
capacity.
[19.2]
D. The oxygen-carrying capacity is the total amount of oxygen that
can be carried by blood. The capacity is measured under saturating
conditions for O2. Therefore, the maximum amount of dissolved oxygen and the maximal amount of bound oxygen are obtained. It is
dependent on the amount of hemoglobin in the blood.
CLINICAL CASES
161
[19.3]
A. The O2 concentration is dependent only on the partial pressure of
O2 in the gas phase in contact with the blood, or the alveolar PO2. The
binding capacity of the blood is compromised because CO binding to
hemoglobin blocks O2 binding; therefore, the total amount of oxygen
will be reduced, but not its concentration.
[19.4]
D. In the pulmonary capillary, CO2 diffusion down its concentration
gradient into the alveolar compartment shifts the entire equilibrium to
promote O2 binding to hemoglobin. The fall in CO2 in the capillary
leads to the dissociation of CO2 from hemoglobin. The fall in CO2
also causes a shift in the equilibrium of the CO2-HCO3- buffer driving
the reaction of H+ and HCO3- toward CO2 production with an increase
in the pH. Both the fall in CO2 and the rise in pH increase the oxygenbinding affinity of hemoglobin.
PHYSIOLOGY PEARLS
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The O2 content of arterial blood is the sum of the amount of dissolved O2 plus the amount of O2 bound to hemoglobin. The O2
concentration is the partial pressure of O2 in the blood and is
determined by the partial pressure of O2 in the alveolar
compartment.
About two-thirds of the CO2 produced by metabolism is transported
by the blood in the form of HCO3-. The HCO3- is produced from
the reaction of CO2 with water and catalyzed by carbonic anhydrase in the red cells. The remaining CO2 is either dissolved or
bound to hemoglobin.
The affinity of O2 binding to hemoglobin is dependent on the pH,
[CO2], temperature, and 2,3-DPG. The combined effects of pH
and [CO2] favor O2 dissociation in the tissues and binding of O2
in the pulmonary capillary.
In conditions such as anemia and CO poisoning, the O2 concentration of arterial blood can be normal. The O2 content is lower than
normal because the amount of hemoglobin or its oxygen-binding
capacity is reduced.
REFERENCE
Powell FL. Oxygen and carbon dioxide transport in the blood. In: Johnson LR, ed.
Essential Medical Physiology. 3rd ed. San Diego, CA: Elsevier Academic Press;
2003:289-298.
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