Chapter 17 – Respiratory System: Gas
Exchange and Regulation of Breathing
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Pulmonary Circulation
The cells of the body consume an average
250 ml of oxygen per minute and produce about 200 ml of carbon dioxide
per minute. The
ratio of the carbon dioxide produced over the oxygen consumed is
called the respiratory quotient. Hence, the average
respiratory quotient is 0.8. |
The figure below illustrates the movements of
oxygen and carbon dioxide into and out of the lungs and tissue under
resting conditions. |
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The figure above illustrates how oxygen and
carbon dioxide goes between alveolar air and blood across the
respiratory membrane composed of type I epithelial cells of the
alveolar walls, endothelial cells of capillaries and the
basement
membranes sandwiched between them. |
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Diffusion of Gases
Partial Pressure of Gases
The partial pressure
of a gas is the proportion of pressure contributed by an
individual gas to the total pressure of a mixture of gases.
Partial pressure is found by multiplying:
|
1. Fractional concentration of a
gas in a mixture by, |
|
2. Total pressure exerted by a gas
mixture. |
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The total pressure of
air can be described as the sum of the major gases found in
air
| Pair |
= |
Pnitrogen |
+ |
Poxygen |
+ |
Pwater |
|
On a molar basis air
is 79% nitrogen and 21% oxygen assuming zero
humidity. Any humidity (water vapor)
subtracts from the proportions of nitrogen and oxygen. |
|
Carbon dioxide accounts for
only 0.03% of the air molecules. |
At zero humidity and at
sea
level in air:
| Pnitrogen |
= |
0.79 |
x |
760 mm Hg |
= |
600 mm Hg |
| Poxygen |
= |
0.21 |
x |
760 mm Hg |
= |
160 mm Hg |
| Pcarbon dioxide |
= |
0.0003 |
x |
760 mm Hg |
= |
0.23 mm Hg |
|
At 100% humidity the partial
pressure of H2O is 47 mm Hg. This causes partial
pressures to be:
| Pnitrogen |
= |
563 mm Hg |
| Poxygen |
= |
150 mm Hg |
| Pcarbon dioxide |
= |
0.21 mm Hg |
|
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Solubility of Gases in Liquids
Gas molecules dissolved in
water have a certain partial pressure. When a liquid and gas come
into contact, the concentration of gas molecules in the liquid is
proportional to the partial pressure of the gas. At a given partial
pressure the relative concentration of different dissolved gases
will differ based on there different solubility in the liquid. For
example carbon dioxide is 20 times more soluble in blood than
oxygen. |
Henry’s law describes
this relationship with :
|
k
|
P
|
|
Where:
| c |
= |
Molar concentration of gas |
| P |
= |
Partial pressure of gas in
atmosphere |
| k |
= |
Henry’s law constant (based on
gas and temperature) |
|
When containers of water are exposed to
100 mm Hg of pure oxygen or carbon dioxide, overtime the gas in the
air equilibrates with the gas dissolved in the liquid till they are
both at 100 mm Hg. However, because carbon dioxide dissolves more
readily in water, the concentration of the gas in the water is much
higher for carbon dioxide than for oxygen. This becomes clear
when the calculations are made: |
 |
|
Pressure at 37o C |
Concentration in Air |
Concentration in Water |
| Oxygen |
100 mm Hg |
5.2 mmole/liter |
0.15 mmole/liter |
| Carbon dioxide |
100 mm Hg |
5.2 mmole/liter |
3.0 mmole/liter |
|
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Exchange of Oxygen and Carbon Dioxide
Gases will diffuse down their partial
pressure gradients.
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Gas Exchange in the Lungs
Although partial pressures of oxygen and
carbon dioxide in the atmosphere are 160 mm Hg and 0.23 mm
Hg,
respectively, in the alveoli the pressures are 100 mm Hg for oxygen
and 40 mm Hg for carbon dioxide. This is because:
|
1. Exchanges of gas between alveoli and
capillaries. |
|
2. Mixing of atmospheric air with air of anatomic dead
spaces. |
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3. Saturation of alveoli air with water
vapor. |
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Deoxygenated blood entering the
pulmonary capillaries has a PO2 of 40 mm Hg and PCO2
of 46 mm Hg. The gases diffuse down their concentration gradients
and leave at the same partial pressures as the gases in the alveoli
(PO2 = 100 mm Hg and PCO2 = 40 mm
Hg). |
  |
Diffusion is a very rapid process taking
about 0.25 seconds or within the first 33% of the capillary length
in the alveoli. The rapidness of the rate of diffusion is due to the
relative thinness of the respiratory membrane. |
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Gas Exchange in Respiring Tissue
When oxygenated blood enters the tissue
the PO2 is 100 mm Hg and that of PCO2 is
40 mm Hg. The tissues have a lower partial pressure of oxygen because of
oxygen utilization and a higher carbon dioxide concentration because
of carbon dioxide production. |
The amount of PO2 and PCO2
in the venous blood depends on the metabolic activity of the
tissue with the greater activity resulting in lower PO2
and higher PCO2. |
The venous blood from all parts of the
body returns to the right side of the heart and mixes. The venous
blood in the right atrium is therefore called mixed
venous blood. At rest, the typical values are a PO2 of
40 mm Hg and PCO2
of 46 mm Hg.
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Determinants of Alveolar PO2 and PCO2
Alveolar PO2 and PCO2
are determined by:
|
1. PO2 and PCO2 of
inspired air. |
|
2. Minute alveolar ventilation. |
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3. Rates of oxygen consumption and carbon
dioxide production. |
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Normally PO2 and PCO2
of inspired air remains constant and the alveolar partial pressures
depend on the last two factors. This is reflected by the fact that:
|
1. When alveolar ventilation increases relative
to oxygen consumption alveolar PO2 increases and PCO2
decreases. |
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2. When alveolar ventilation decreases relative
to oxygen consumption alveolar PO2 decreases and PCO2
increases. |
|
Normal alveolar ventilation is adjusted
to meet tissue demands. This appropriate increase in ventilation is
referred to as hyperpnea. Hypoventilation occurs when
alveolar ventilation is insufficient to meet tissue demand. As a
consequence PCO2 rises and PO2 decreases. Hyperventilation
occurs when alveolar ventilation exceeds the demands of the
tissue so that PO2 increases and PCO2 decreases. |
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Transport of Gases in Blood
Oxygen Transport by
Hemoglobin
Approximately 1.5%
of
the oxygen transported in the blood is dissolved in plasma or
the cytosol of red blood cells while the remaining 98.5% is bound to
hemoglobin. The oxygen bound to hemoglobin is in
equilibrium with the oxygen dissolved in plasma which is
related to PO2. The oxygen is transported
bound to the heme portions of the hemoglobin molecule.
The binding of oxygen to hemoglobin depends upon the PO2
in the surrounding fluid. The higher the PO2 the
greater the binding. |
|
 |
Since there are four binding
sites on the hemoglobin molecule the number of oxygen molecules on a
hemoglobin molecule ranges from none to four. When four oxygen
molecules are bound to the molecule, it is said to be 100% saturated.
At 100% saturation 1 gram of hemoglobin carries 1.34 ml of
oxygen. |
The math:
|
Hemoglobin in blood 12-17gm/dL or an average of 150 gm/L |
|
Oxygen carrying capacity
1.34 ml/gram x 154
grams/liter ~ 200 ml/L |
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Cardiac output 5 liter/minute |
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Blood supplies
5 liter/minute x 200 ml O2
/L = 1000 ml O2/min. |
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|
Tissues need 250 ml O2 /min.
Therefore, under resting conditions venous blood is still
75% saturated. |
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Anemia is a decrease in O2 carrying
capacity of the blood. With anemia, tissues may not be supplied with
the oxygen they need and fatigue occurs more readily. |
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Hemoglobin Oxygen Disassociation Curve
The curve that shows percent saturation of
hemoglobin as a function of PO2 is s-shaped
(sigmoidal). The s-shaped nature of the curve can be explained in
the following way: |
At low partial pressures the affinity
of hemoglobin for O2 is low. An increase in PO2
results in only a small increase in percent saturation. |
As the PO2 increases
the hemoglobin molecule acquires at least one molecule of O2.
The binding of one molecule of O2 to hemoglobin causes a
conformational change in the hemoglobin that increases the
affinity of the remaining subunits for oxygen. This is called positive
cooperativity. The positive cooperativity causes the steep part
of the curve as the PO2 goes from 15 mm Hg to 60 mm
Hg. |
From
60 mm Hg to 80 mm Hg the slope of the curve decreases because as the
O2 binds to hemoglobin fewer binding sites become
available. Above a PO2 of 80 mm Hg the slope
of the curve becomes nearly flat. |
At the PO2 of the systemic
arteries of 100 mm Hg the hemoglobin is 98% saturated. At the PO2
of the systemic veins the hemoglobin is 75% saturated. At rest the
tissue takes only about 25% of the O2 transported in the
blood. |
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The hemoglobin oxygen disassociation
curve can shift either to the left or to the right. When the curve shifts to the right, the affinity of
oxygen for hemoglobin decreases and oxygen can be more easily
unloaded. When the curve shifts to the left, the
affinity of oxygen for hemoglobin increases and oxygen can be
more easily loaded. |
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Factors Affecting Affinity of Hemoglobin for O2
Factors that affect the
affinity of hemoglobin for oxygen include: |
|
1. Temperature
A higher temperature cause a
decrease in affinity. In more active tissue with a
higher temperature O2 unloads more easily. |
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2. pH
Hydrogen ion increases
(pH decreases) in
more active tissue. This decreases the affinity of
hemoglobin by the Bohr effect which can be
expressed in this equation
In more active tissue pH decreases and O2
is more easily unloaded. |
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 |
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3. PCO2
CO2 binds
reversibly with Hb to form carbaminohemoglobin a
molecule which has a lesser affinity for O2
. This decrease in the affinity of Hb for oxygen in the
presence of CO2 is called the carbamino
effect. |
These first three factors
work together to promote O2 unloading in
respiring tissues and O2 loading in the
lungs. |
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4. 2,3 – Diphosphoglycerate
2,3 -DPG is produced from an
intermediate compound in glycolysis and decreases
the affinity of hemoglobin for oxygen. At low oxygen levels
an enzyme catalyzes the synthesis of
2,3-DPG. Hence, 2,3-DPG concentration increases, the affinity of Hb for oxygen
decreases. This is helpful
for unloading oxygen during anemia and at high
altitudes. At high oxygen levels, oxyhemoglobin inhibits
the enzyme that synthesizes
2,3-DPG and
2,3-DPG levels decrease. |
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Carbon Dioxide Transport in Blood
The carbon dioxide in the blood exists as
| Dissolved as carbon dioxide |
: |
5-6% |
| Carbaminohemoglobin |
: |
5-8% |
| Dissolved as HCO3 – |
: |
86-90% |
|
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Role of Carbonic Anhydrase in Carbon Dioxide Transport
Carbonic anhydrase catalyzes the
reaction that converts CO2 and H2O to carbonic
acid. Carbonic acid reversibly disassociates to H+ +
bicarbonate. The equation is:
| CO2 |
+ |
H2O |
–> |
H2CO3 |
–> |
H+ |
+ |
HCO3– |
| <– |
<– |
|
Hence, an increase in PCO2 makes the blood
more acidic while a decrease in PCO2 does the
opposite. This reaction is important in the transport and
exchange of CO2 and plays an important role in
maintaining acid-base balance. |
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CO2 Exchange and Transport in Systemic
Capillaries and Veins
Respiring cells produce CO2
at the rate of 200 ml/minute. As CO2 increases in the
tissues it goes down its concentration gradient into the plasma and
into the erythrocyte. |
Most of the CO2 is converted
to bicarbonate and H+ by carbonic anhydrase in the
erythrocytes. This conversion of CO2 maintains a pressure
gradient favoring diffusion of CO2 from the tissue into
the blood. As bicarbonate levels in the erythrocyte increase,
bicarbonate ions are transported out of the erythrocyte in exchange
for Cl– . This coupled exchange of HCO3–
for Cl– is referred to as the chloride shift. The
H+ left behind in the erythrocyte is buffered by binding
to hemoglobin. |
  |
In the lungs, the pressure gradient
favors the diffusion of CO2 from the blood into the
alveoli. The decrease in CO2 causes bicarbonate in the
erythrocyte to bind with H+ to form carbonic acid which
in turn is converted into CO2 and H2O by
carbonic anhydrase. While bicarbonate in the erythrocyte decreases
more bicarbonate is brought into the erythrocyte in exchange for Cl–
. |
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Effect of Oxygen on Carbon Dioxide Transport
The PO2 affects the ability
of the blood to carry CO2. The binding of O2
to hemoglobin decreases the affinity of Hb for CO2.
Conversely, a decrease in PO2 increases the binding of CO2
to hemoglobin. This phenomenon is called the Haldane
Effect. |
 |
Study the figure below to understand the
combined effects of PO2 and PCO2 on CO2
and O2 loading and unloading. |
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Central Regulation of Ventilation
To ensure that the
rate of respiration is adequate to meet the body’s metabolic
needs it is essential to control minute alveolar respiration
to keep the partial pressures of the key gases, oxygen and
carbon dioxide, at the appropriate levels. The pattern of
ventilation is initiated and modified within the central
nervous system. |
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Neural Control of Breathing by Motor Neurons
During quiet breathing the
breathing cycle consists in the contraction of the inspiratory
muscles followed by relaxation of the same muscle during
expiration. During more active breathing the expiratory
muscles contract during the expiration phase. This is
reflected by the activity of the motor neurons innervating the
respective muscles. |
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Generation of Breathing Rhythm in the Brainstem
Respiratory control regions are present
in the medulla and pons of the brainstem. There are two general
classes of neurons located here:
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Inspiratory neurons which generate action
potentials during inspiration. |
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Expiratory neurons which generate action
potentials during expiration. |
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Respiratory Centers of the Medulla
Two respiratory centers in the medulla
include:
|
1. Dorsal Respiratory Group contains
primarily inspiratory neurons. The inspiratory neurons show a ramp
increase in activity during inspiration followed by an abrupt
termination. |
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2. Ventral Respiratory Group contains two regions of expiratory neurons and
one region of
inspiratory neurons. When the
respiratory drive increases, as during exercise, the inspiratory
neurons contribute to enhanced inspiration and the expiratory
neurons stimulate the muscles that increase the force of
expiration. |
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Respiratory Center of Pons
This center contains both inspiratory
and expiratory neurons and mixed neurons that control both
inspiratory and expiratory neurons. This center may facilitate the
transition between inspiration and expiration. |
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Central Pattern Generator
The central pattern
generator is a network of neurons
that generates a regular, repeating pattern of neural activity called the
respiratory rhythm. |
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Model of Respiratory Control During Quiet Breathing
 |
The figure above shows a
simplified model to describe how the breathing rhythm is generated
by the central pattern generator and modified by other centers of
the central nervous system. Note that the central control region
resides in the medulla but other portions of the brain including the
pons, cerebral cortex, cerebellum, limbic system, hypothalamus and
medullary cardiovascular areas provide input that can modify
this rhythm. |
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Peripheral Input to Respiratory
Centers
The central pattern
generator is reflexively controlled by various types of
receptors that include: |
|
1. Chemoreceptors – Peripheral (in
systemic arteries) and central (in brain) monitor conditions
in arterial blood and in cerebrospinal fluid. Regulate
ventilation under resting conditions. |
|
2. Pulmonary stretch receptors in smooth
muscles of airways. |
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3. Irritant receptors lining the
respiratory tract. |
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4. Proprioceptors in muscles and joints. |
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Control of Ventilation by Chemoreceptors
  |
Peripheral
chemoreceptors are located in the carotid bodies near the
carotid sinus. These are specialized cells in direct contact
with arterial blood that communicate with afferent neurons that
project to the respiratory control regions. These cells
respond to changes in arterial PO2, PCO2
or pH. The primary stimulus for chemoreceptors
is pH. The main cause of decreases in pH is an increase in PCO2.
Peripheral chemoreceptors also respond to arterial PO2
but only when arterial PO2 drops below 60 mm Hg.
This is an extreme drop that usually does not occur. |
Central
chemoreceptors are neurons in the medulla that respond
directly to changes in hydrogen ion concentration in the
cerebrospinal fluid. H ions do not cross the blood-brain
barrier but carbon dioxide does. Carbon dioxide is converted to H ion and
bicarbonate ion by carbonic anhydrase in the CSF. |
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Chemoreceptor Reflexes
Changes in PCO2 are primary
stimuli for changes in ventilation under normal conditions. Both
central and peripheral chemoreceptors are sensitive to changes in pH
but the central chemoreceptors are not exposed to H+ from
sources other than CO2 because of the blood-brain
barrier. Only the peripheral receptors are sensitive to O2
when it drops below 60 mm Hg. Activation of chemoreceptors cause an
increase in ventilation. The figure below shows this reflex operating
during hyperventilation and hypoventilation. |
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Local Regulation of Ventilation and Perfusion |
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Ventilation-Perfusion Ratio
In the normal lung, the rate of air
flow to the alveoli (ventilation, VA) is matched to
the rate of blood flow (perfusion, QA). The
relationship between these two rates is expressed by the
ventilation-perfusion ratio or, VA/QA. The
ventilation-perfusion ratio is approximately equal to 1 in
the normal lung. |
 |
In lung diseases that cause
obstruction of airways such as emphysema and bronchitis, the airflow
to certain alveoli decreases and the blood flow in the
capillaries of these alveoli will have less gas exchange. The
blood leaving these capillaries will then have a lower PO2
and a higher PCO2 and a ventilation-perfusion
ratio of less than 1. |
  |
When pulmonary capillaries are
blocked, blood flow to the alveoli decreases and the
capillaries less affected by the blockage and still flowing through
the alveoli will have a greater gas exchange. As a result the
blood and air in these alveoli will have a higher PO2
and a lower PCO2. The ventilation-perfusion ratio
will be greater than 1. |
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Local Control of Ventilation and Perfusion
In order to maintain a ventilation
perfusion ratio of 1, changes in the partial pressure of gases in
the alveoli and tissues affect contractile activity of bronchiolar
smooth muscle that adjust the diameter of the passageway, and also the
smooth muscle in the arterioles that affect the blood flow. |
 |
Oxygen acts primarily on pulmonary
arterioles with a low PO2 causing vasoconstriction with
decreased flow and carbon dioxide acts primarily on the bronchioles
with a high PCO2 causing bronchodilation and increased ventilation.
Therefore, when V/Q is high the increase in PO2 causes
vasodilation and the decrease in PCO2 causes
bronchoconstriction and the ratio returns towards 1. When V/Q is
low the decrease in PO2 causes vasoconstriction
and the increase in PCO2 causes bronchodilation.
Note that the
effect of oxygen and carbon dioxide on pulmonary arterioles is the
opposite of the effects of these gases on systemic arterioles. |
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The Respiratory System in Acid-Base Homeostasis |
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Acid-Base Disturbances in Blood
Changes in the pH of the body has
serious consequences because it changes the shape of protein
molecules. Arterial pH affects the pH of body tissues hence it is
necessary to regulate blood pH within narrow limits around the
normal of 7.4. If the pH drops below 7.35 it is said to be
in a condition of acidosis. If the pH increases to greater
than 7.45 it is said to be in a condition of alkalosis. Severe
acidosis causes depression of CNS activity and leads to coma. Severe
alkalosis causes the nervous system to become overly excitable and
causes uncontrollable muscle seizures and convulsions. |
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Role of Respiratory System in Acid-Base Balance
Hemoglobin as a Buffer
Hemoglobin can bind or
release hydrogen ions. Deoxyhemoglobin has a greater affinity
for H ions than oxyhemoglobin as described by the Bohr effect.
In the tissues:
| HbO2 |
> |
O2 |
+ |
Hb |
|
Hb |
+ |
H+ |
> |
HbH |
|
This serves as a buffer for the increase in H
ion resulting from CO2. |
In the lungs:
| HbH |
> |
H+ |
+ |
Hb |
|
Hb |
+ |
O2 |
> |
HbO2 |
|
|
|
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Bicarbonate Ions as a Buffer
When H+ increases in the
blood it combines with HCO3– to form CO2.
When CO2 increases this reaction goes in reverse to form
bicarbonate and the hydrogen ion. |
The relationship between CO2
and acidity is described by the Henderson-Hasselbach equation:
|
log
|
[HCO3] |
| [CO2] |
|
To maintain a pH of 7.4 the ratio of bicarbonate to
carbon dioxide should remain at 20:1. The lungs can regulate the
concentration of CO2. |
Respiratory disturbances that change [CO2]
can result in acid-base imbalance:
|
Respiratory acidosis is an increase in
blood acidity due to increased CO2. |
|
Respiratory alkalosis is a decrease in blood
acidity due to decreased CO2. |
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