VPY I

KP Paudel

Laws related to solubility of gas, physical principles of gas exchange

and exchange of gases in lungs and tissues
Basics from physical chemistry:

Gas laws
1. Boyle’s Law

For a fixed mass of gas, at a constant temperature, the product (pressure x volume) is
a constant.
Pressure x Volume = constant; p x V = constant
Or in other words:
“Temperature remaining constant, the pressure is inversely proportional to the
volume.

If P be the pressure and V be the volume of a given mass of a gas then according to
Boyle’s law:
P 1α
V

Then, P1V1=P2V2

2. Dalton’s law of Partial Pressures:

The term partial pressure means the individual pressure that each gas
would exert if it were present alone in that volume equal to that of the
mixture at the same temperature. If p1, p 2 and p3 be the partial
pressures of three components of a gaseous mixture having total
pressure P, then according to Dalton‟s law of partial pressure
P = p1+p2+p3

3. Henry‟s Law

Temperature being constant, the amount of gas dissolved in a liquid

possessing no chemical affinity for the gas varies directly with the
pressure of the gas in the surrounding medium and the solubility
coefficient of the gas.

Concentration of dissolved gas = pressure × solubility

coefficient

Physical principles of gas exchange

The exchange of gases from and to the blood takes place through the alveolar wall of
the lungs. When the alveoli are ventilated with fresh air, the next step in the
respiratory process is diffusion of oxygen from the alveoli into the pulmonary blood
and diffusion of carbon dioxide in the opposite direction. The process of diffusion is
simply random molecular motion of molecules intertwining their ways in both
directions through the respiratory membrane.

Physics of diffusion and gas pressures

All the gases that are of concern in respiration are simple molecules that are free to
move among each other, by the process of diffusion. This is also true of the gases
dissolved in fluids and tissues of the body.
For diffusion there must be source of energy and the energy as such is provided by
the kinetic motion of the molecules themselves.

Except at absolute zero temperature, all particles are in motion

Net diffusion of a gas in one direction: effect of a concentration gradient

If a gas chamber or a solution has a high concentration of a gas at one end of the
chamber and a low concentration at the other end, net diffusion of the gas will occur
from the high concentration area toward the low concentration area.

Gas pressures in a mixture of gases

Pressure is caused by the constant impact of kinetically moving molecules against a

surface.
Therefore, the pressure of gas acting on the surface of the respiratory passage and
alveoli is proportional to the summated force of impaction of all the molecules
striking the surface at any given instant. Thus, the total pressure is directly
proportional to the partial pressure or the concentration of the gas molecules. In a
mixture of gases, the pressure is exerted by each individual component, and the
pressure exerted by one component is called the partial pressure of that gas. The
total pressure of a gas in a mixture of gases, which do not react with each other, is the
sum of the partial pressure of the constituent individual gases (Dalton’s law).

Respiratory physiology: The mixture of gases, mainly involve oxygen, nitrogen, and
carbon dioxide. The rate of diffusion of each of these gases is directly proportional to
partial pressure caused by these gases.

Pressures of gases dissolved in water and tissues

Gases dissolved in water or the body tissue also exert pressure because the dissolved
gas molecules are moving randomly and have kinetic energy. When the molecules of
a dissolved gas encounter a surface like the membrane of a cell, they exert the
pressure of the gas against the surface which is directly proportional to the
concentration of the dissolved molecules, in the same way that a gas in the gaseous
phase exerts its own individual partial pressure.
Factors determining the concentration of a gas dissolved in a fluid
The pressure of a gas in a solution is determined not only by its concentration but
also by solubility coefficient of the gas.
Some types of molecules, especially, carbon dioxide are physically and chemically
attracted to water molecules while others are repelled.
When molecules are attracted, far more of them become dissolved without building
up excess pressure within the solution.
On the other hand, those that are repelled will develop excessive pressures for very
little degree of solubility, they can be dissolved without building excess pressure
within the solution.
Therefore, since both pressure and solubility coefficient determine the volume of gas
that will be dissolved in a given volume of fluid which is the concentration of the
dissolved gas-this can be expressed by the following formula, which is Henry‟s: law

Concentration of dissolved gas = pressure × solubility coefficient

Henry‟s Law

This law states that, the temperature being constant, the amount of gas dissolved in a
liquid possessing no chemical affinity for the gas varies directly with the pressure
of the gas in the surrounding medium and the solubility coefficient of the gas. If a
liquid such as water is brought into relation with a gas or a mixture of gases, they
penetrate the liquid and become dissolved in it. The amount of a gas entering the
liquid varies directly with the pressure of the gas in the surrounding medium. The
pressure of a gas in a solution is determined by its concentration and solubility
coefficient.

Pressure = (Concentration of dissolved gas) / (Solubility coefficient)

The pressure is expressed in atmospheres and concentration is expressed in volume of

gas dissolved in each volume of water. The solubility coefficients for important
respiratory gases at body temperature are following:
Oxygen 0.024
Carbon dioxide 0.57
Carbon monoxide 0.018
Nitrogen 0.012
Helium 0.008
From the above value, it is clear that carbon dioxide is more than 20 times as soluble
as oxygen, and oxygen is moderately more soluble than any of the other three gases.
These different solubilities are important because the solubility times the pressure of a
gas determines the quantity of the gas that becomes physically dissolved in the fluids
of the body and this in turn is one of the factors that determines the rate at which the
gas can diffuse through the tissues.
Diffusion of gases between the gaseous phase in the alveoli and the dissolved
phase in the pulmonary blood

The partial pressure of each gas in respiratory gas mixture tends to force molecules of
that gas into solution. On the other hand, in the pulmonary fluids, the dissolved
molecules of the same gas are randomly bounced against the interface between the
fluid and the gaseous phase, and some of these molecules escape back into the
alveoli.
The rate at which they escape is directly proportional to their partial pressure in the
solution. The direction of the net diffusion of the gas is determined by the difference
between the two partial pressures.

If partial pressure is greater in the gaseous phase, then more molecules will move into
solution than in other direction. This is the direction in which oxygen moves, thus
entering the pulmonary blood and then being carried throughout the body.
Conversely, if partial pressure is greater in the dissolved phase then net diffusion will
occur towards gaseous phase in the alveoli, as that for carbon dioxide in the lungs.

Diffusion of gases through fluids

The net diffusion of gas from the area of high pressure to the area of low pressure is
equal to the number of molecules bouncing in this direction minus the number of
molecules bouncing in the opposite direction, and this in turn is proportional to the
gas pressure difference between the two areas. There is always net diffusion from
areas of high pressure to areas of low pressure.

Quantifying the net rate of diffusion in fluids

In addition to the pressure difference, several other factors affect the rate of gas
diffusion in a fluid. These are:
a) Solubility of the gas in the fluid (S),
b) Cross-sectional area of the chamber (A),
c) Distance through which the gas must diffuse (d),
d) Molecular weight of the gas (MW), and
e) Temperature of the fluid

In the body, the temperature remains reasonably constant and need not be considered.
All the factors cited above can be expressed in a single formula, as follows:

P A S
D
d MW
Where, D is the diffusion rate
P is the pressure difference between the two ends of the diffusion pathway
The solubility and molecular weight together are called the diffusion coefficient of the
gas. Considering the diffusion coefficient for oxygen to be 1, the relative diffusion
coefficients for different gases of respiratory importance in the body fluids are as
follows:

O2 1.0
CO2 20.3
CO 0.81
N2 0.53
He 0.95

Exchange of gases in lungs and tissues

Pulmonary gas exchange

Pulmonary gas exchange means exchange of gases between the alveolar air and the
blood in the pulmonary capillaries. Gases move from one point to another because of
pressure difference between the two points. Oxygen diffuses from the alveoli into the
pulmonary capillary blood because the PO2 in the alveoli is greater than the Po 2 in
the pulmonary blood. Similarly, carbon dioxide diffuses from the pulmonary capillary
blood into the alveoli because PCO2 in pulmonary blood is greater than the PCO2 in
the alveoli.

The respiratory unit is composed of a respiratory bronchiole, alveolar ducts, atria,

and alveoli.
Alveolar walls are extremely thin and within them is solid network of capillaries. So,
the alveolar gases are in close proximity to the blood in the capillaries. Gas exchange
between the alveolar air and pulmonary blood occurs through a thin alveolo-capillary
membrane, called as respiratory membrane, also called pulmonary membrane. The
gaseous exchange between alveolar and pulmonary blood occurs through the
membrane of all the terminal portions of the lungs, called as the respiratory
membrane.

The respiratory membrane consists of following SIX layers

i. A layer of fluid lining the alveolus and containing surfactant

ii. The alveolar epithelium, composed of thin epithelial cells
iii. An epithelial basement membrane
iv. A thin interstitial space between the alveolar epithelium and capillary
membrane
v. A capillary basement membrane that in many places fuses with the epithelial
basement membrane
vi. The capillary endothelial membrane

The overall thickness of the respiratory membrane averages 0.6 micrometer (µ) and in
some places it is as little as 0.2 micrometer. Pulmonary capillary has diameter of 5
micrometer, so actually RBC squeeze through them. RBC surface membrane usually
touch the capillary wall, so that oxygen and carbon dioxide need not pass through
significant amounts of plasma as they diffuse between the alveolus and the red cell.
This too increases the rapidity
of diffusion.

Oxygen diffuses from alveoli

to pulmonary capillary blood
because the oxygen pressure in
alveoli is greater than partial
pressure of oxygen in
pulmonary blood. Conversely,
when oxygen is metabolized in
the cells, the carbon dioxide
pressure rises to a high value
which causes carbon dioxide
to diffuse into the tissue
capillaries and diffuses out of
the blood into the alveoli. The
PO2 of the gaseous oxygen at
the alveoli is 104 mm Hg,
whereas the PO2 of the
venous blood entering the
capillary averages only 40
mm Hg, it is because of the utilization of oxygen in the peripheral tissues.

The partial pressures of gases in alveoli and pulmonary venous blood are given
below:

PO2 (mm Hg) PCO2 (mm Hg)

Alveoli 104 40
Pulmonary venous blood 40 45

The difference in pressure at the alveoli and the venous capillary (104 –40 = 64
mmHg) causes
oxygen to diffuse to the capillary. During strenuous exercise, a p much as 20 times the
normal amount of oxygen. Because of the increased cardiac output, the
time that the blood remains in the capillary may be reduced to less than one half
normal times.
But also the blood is completely saturated with oxygen when it leaves the lungs; it is
because during the pulmonary blood flow, the blood is saturated with oxygen by the
time it has passed through one third of the pulmonary capillaries, and also during the
strenuous exercise the extra capillaries also open to cope with the increased demand
of the oxygen.

Factors affecting the rate of gas diffusion through the respiratory membrane

a. The pressure difference of the gases between the two sides of the
membrane.
 b. The diffusion coefficient of the gas in the substance of
the membrane, i.e., in the water of the membrane
c. The surface area of the membrane, and
d. The thickness of the membrane

The pressure difference across the respiratory membrane is the

difference between the partial pressures of the gas in the alveoli and
the pressure of the gas in the pulmonary capillary blood. The partial
pressure represents a measure of the total number of molecules of a
particular gas striking a unit area of the alveolar surface of the
membrane in unit time. When the partial pressure for a gas in the
alveoli is greater than the pressure of the gas in the blood, as is true
for oxygen, net diffusion from the alveoli into the blood occurs and
vice versa, as is true for carbon dioxide.

The diffusion coefficient for the transfer of each gas through the respiratory
membrane depends directly on its solubility in the membrane and, inversely on the
square root of its molecular weight. The rate of diffusion in the respiratory
membrane is almost exactly the same as that in water. Therefore, for a given pressure
difference, carbon dioxide diffuses 20 times as rapidly as oxygen.

The rate of diffusion through the respiratory membrane is directly proportional to

its surface area. The surface area of the alveolo-capillary membrane increases with
exercise as more capillaries open up. The surface area of the respiratory membrane is
decreased by many disease conditions. For example, in emphysema many alveoli
coalesce, with dissolution of many alveolar walls. Therefore, the new chambers are
much larger than the original alveoli, but the total surface area of the respiratory
membrane is considerably decreased because of the loss of the alveolar walls.

The rate of diffusion through the membrane is inversely proportional to the

thickness of the membrane. The thickness of the membrane occasionally increases-
for instance, as a result of edematous fluid in the interstitial space of the membrane
and in the alveoli.
Exchange of gases in tissues

Diffusion of oxygen from the capillaries to the interstitial fluid and to the cells
The pressure of oxygen in the arterial blood that reaches the tissues is about 95 mm
Hg; on the other hand, PO2 in the interstitial fluid averages only 40 mm Hg. This
difference in pressure causes oxygen to diffuse very rapidly from the blood into the
tissues, so rapidly that the capillary PO2 falls almost to equal the 40 mm Hg
pressure in the interstitium.
The PO2 of the blood entering the veins from the tissue capillaries is also about 40
mm Hg. Oxygen is always being used by the cells, so the intracellular PO2 remains
lower than the PO2 in the capillaries. The intracellular PO2 ranges from 5 mm Hg
to 40 mm Hg, averaging 23 mm Hg.

Diffusion of carbon dioxide from the cells to the tissue capillaries and from the
pulmonary capillaries to the alveoli
When the oxygen is used by the cells, most of it becomes carbon dioxide and it
increases the intracellular PCO2. Therefore, carbon dioxide diffused from the
 cells into the tissue capillaries and is then carried by the blood to the lungs,
where it diffuses from the pulmonary capillaries into the alveoli. Thus, at each
point in the gas transport chain, carbon dioxide diffuses in a direction exactly
opposite that of the diffusion of the oxygen. Also carbon dioxide diffuses about
20 times rapidly as compared to oxygen.

Pressure of the carbon dioxide at different point-

a. Intracellular PCO2 is equal to 46 mm Hg.
b. Interstitial PCO2 is equal to 45 mm Hg.
c. PCO2 of arterial blood entering tissue is equal to 40 mm Hg.
d. PCO2 of venous blood leaving tissue is equal to 45 mm Hg.
e. PCO2 of arterial blood entering alveoli is equal to 45 mm Hg.
f. PCO2 of alveolar air is equal to 40 mm Hg.

Thus, this difference of pressure at different points in the blood flow marks
the mechanism beside the exchange of carbon dioxide between air, blood
and tissues

Table: Partial pressures of Oxygen and Carbon dioxide

Inspired air Expired Alveolar air Arterial blood Venous Tissue
air blood
PO2 in mm 158 116 104 95 40 <40
Hg
PCO2 in mm 0.3 32 40 40 46 >46
Hg

TRANSPORT OF BLOOD GASES

The gases of importance are carbon dioxide and oxygen. But gases like nitrogen and
others are also present in blood. Some of the gases react with the elements of blood
but all of them remain in dissolved state in plasma. The amount of each gas
dissolved in blood depends upon the solubility coefficient of the gas in plasma and
the partial pressure of the gas governed by Henry’sla. Oxygen is utilized. in the
tissues which come from the blood in the capillaries. So, the O2 content in venous
blood is less. This venous blood now goes to lungs and there it takes up O 2 to supply
the tissues again. On the other hand CO2 is produced in the tissues and enters in
capillary blood, so there is more CO2 in venous blood. This blood then goes to the
lungs to release some of the CO2, thus in arterial blood CO2 is less and while the
blood in the capillaries picks up CO2 again from the tissues. So, CO 2 and O2 are
present both in arterial and venous blood though the transport of CO2 is loosely taken
as transport from tissue to lungs and that of O2 from lung to the tissues.

TRANSPORT OF OXYGEN

Oxygen is transported in blood in two forms:

a. Transport of oxygen in physical solution

When the blood in the pulmonary capillaries flows past the alveoli, oxygen diffuses
from the alveolus into the blood until the partial pressures equilibrate, i.e., there is no
further driving pressure difference. Because oxygen is poorly soluble in water, only a
very small amount dissolves in the plasma, and hemoglobin is necessary to deliver
sufficient oxygen to the tissues.

The amount of dissolved oxygen in plasma is small and its amount increases when the
partial pressure increases. The amount of dissolved oxygen is a linear function of
PO2. For example, 0.003 mol dissolving in each 100 ml of plasma at a PO2 of 1mm
Hg. When pulmonary capillary blood equilibrates with the alveolar PO2 of 100 mm
Hg then 0.3 ml of oxygen dissolves in each 100 ml of blood. If an animal breathes
pure oxygen so that Pao2 increases to 600 mm Hg, 1.8 ml of oxygen dissolves in each
deciliter of plasma.

In the pulmonary capillaries when PO2 of plasma increases, more O 2 is dissolved and
from this dissolved state O2 goes to Hb to form HbO 2. In the tissues, the dissolved O 2
first goes to the tissues, so PO2 of plasma decreases and then O 2 from HbO2 comes
to the plasma to maintain the PO2. In this way the dissolved O2 is responsible for the
movement of the gas. It should be noted that the PO2 is independent on the amount of
O2 present as HbO2. In case of anemia, for example; HbO2 is less but the dissolved O2
and PO2 in arterial blood is normal.

Normally at rest, in arterial blood, hemoglobin is 97% saturated and in this condition
100 ml blood contains 19.8 ml O2; out of which 19.5 ml blood is bound to Hb while
rest 0.29 ml O 2 is

bound to plasma. However, venous blood is only 75% saturated and 100 ml of this
venous blood contains 15.2 ml O2 out of which 15.1 ml O2 is bound to Hb while rest
0.12 ml O2 is dissolved in plasma. So, in rest tissue removes about 4.6 ml of O 2 from
each 100 ml of blood, out of which 4.4 ml O 2 from hemoglobin and other 0.17ml O 2
from the solution (plasma).

b. Transport of oxygen as Oxyhemoglobin

Once oxygen has diffused from the alveoli into the pulmonary blood, it is transported
principally in combination with hemoglobin to the tissue capillaries, where it is
released for use by the cells. This combination helps to transport 30-100 times as
much oxygen as transported simply in the form of dissolved oxygen in the water of the
blood. About 97 % of oxygen is transported from the lungs to the tissues in
chemical combination with hemoglobin in the red blood cells. Only a small
amount of oxygen (about 3 %) is transported in the dissolved state (i.e., in physical
solution) in the plasma and cells. Thus, under normal conditions, oxygen is carried to
the tissues almost entirely by hemoglobin. Oxyhemoglobin therefore acts as a store of
O2 in blood. From this store, O 2 is distributed to the tissues and the store is
replenished in the lungs. One gram of Hb in blood combines with 1.34 ml of O2.

Mammalian hemoglobin is a protein made up of four subunits, each of which contains

one heme moiety and its associated polypeptide chain. The polypeptides are referred
to collectively as the globin portion of the hemoglobin molecule. Heme is a
2+
protoporphyrin consisting of four pyroles with a ferrous iron (Fe ) at the center.
The ferrous iron combines with the oxygen in proportion to PO2. The hemoglobin
molecule is spheroid, an amino acid side chain being attached to each heme. The
amino acid composition of the polypeptide side chains greatly affects the affinity of
hemoglobin for oxygen and defines the different types of mammalian hemoglobin.
Adult Hb contains two and two polypeptide chains; fetal Hb contains two and two
chains. Closely related species, such as humans and anthropoid apes, have similar
amino acid sequences on the side chains, whereas more divergent species have greater
numbers of differences in amino acid sequences.
Oxygen combines loosely and reversibly with heme part of the hemoglobin. When
PO2 is high, as in pulmonary capillary it binds with hemoglobin, but when PO2 is
low, as in tissue it will be released from hemoglobin. Each of the four iron atoms in a
hemoglobin molecule combines reversibly one O2 molecule. The iron stays in the
ferrous state, so that the reaction is an oxygenation, not an oxidation and after
oxygenation the hemoglobin is called oxyhemoglobin.
Hb + O2 = HbO2

Each Hb molecule combines with 4 molecules of O2. The attachment of first molecule
is difficult but then there is conformational change in the Hb molecule and subsequent
O2 molecules can attach easily. This is called heme- heme interaction. These heme-
heme interactions are responsible for the sigmoid shape of the oxyhemoglobin
dissociation curve. The reversible combination of oxygen with hemoglobin is shown
in the oxyhemoglobin dissociation curve.

One gram of saturated hemoglobin can hold 1.36-1.39 ml of oxygen; therefore

average mammalian blood with 10-15 g of Hb per deciliter has an oxygen capacity of
13.9 -21 ml oxygen per deciliter. Anemia, a reduction in the number of circulating
erythrocytes with a consequent reduction in the amount of Hb in the blood, decreases
oxygen capacity. When the hemoglobin content of the blood increases, the oxygen
capacity of the blood increases. The latter increases during exercise; contraction of the
spleen forces more erythrocytes into the circulation and increases the oxygen capacity
of the blood. Splenic contraction is an especially rich source of erythrocytes in the
exercising horse.

Oxyhemoglobin Dissociation Curve

The Oxy-Hemoglobin Dissociation Curve underpins the relationship between PO2
and O2 saturation. Hemoglobin is over 95% saturated with oxygen when it leaves the
lungs of an animal at sea level. The curve is obtained by plotting the percentage
saturations of Hb against the respective PO2.

Table: Percentage saturation of Hb and Dissolved oxygen at different partial

prssures
PO2 (mm Hg) % Hb saturation of Hb Dissolved O2
(ml/dl) (ml/dl)
10 13.5 0.03
20 35 0.06
30 57 0.09
40 75 0.12
50 83.5 0.15
60 89 0.18
70 92.7 0.21
80 94.5 0.24
90 96.5 0.27
100 97.5 0.30

Oxygen-hemoglobin dissociation curve has a characteristic sigmoid shape. It is due to

change of configuration of the hemoglobin molecule that takes place during the
process of oxygenation. In deoxyhemoglobin, the globin units are tightly bound in a
tense (T) configuration which reduces the affinity of the molecule for O2. When the
O2 is first bound, the bonds holding the globin units are released, producing a relaxed
(R) configuration which exposes more O2 binding sites. So, the combination of the
first heme in the hemoglobin molecule with O2 increases the affinity of the second
heme for O2, and oxygenation of the second increases the affinity of the third, so that
the affinity of hemoglobin for the fourth O2 molecule is many times that for the first.
This rapid oxygenation of hemoglobin in the initial phase of its exposure to O2
explains the sharp rise in the dissociation curve in the lower range of PO2 and also
the gradual leveling off of the curve at higher range as the Hb reaches the near
saturation point.

Percentage saturation at a particular PO2 is calculated as follows:

Per cent saturation = O2 content × 100

O2 capacity
O2 content: It is the actual amount of O2 present in the sample of blood at that PO2
and it can be obtained by analysis of the blood for O2

O2 capacity: It is the maximum amount of the O 2 that the same blood can combine
with, i.e., its Hb in g × 1.34ml O2
For example, in a sample of blood there is 19 ml of O 2 at PO2 of 95 mm Hg and it
can combine with 20 ml of O2 at maximum. Then, the percentage saturation of Hb
in that sample at PO2 of 95 mm is:
O2
content
x100
O2
capacity
= 19 ml × 100
20 ml
= 95%
The oxyhemoglobin dissociation curve is actually derived from the data of a large
number of Hb solutions containing known amount of Hb and exposed to different
known partial pressures of O2. Saturation does not change proportionately with PO2.

The oxygen content of blood, i.e., the amount of oxygen combined with hemoglobin,
is determined by PO2. Above a PO2 of approximately 70 mm Hg, the oxyhemoglobin
dissociation curve is virtually flat. Further increases in PO2 add little oxygen to
hemoglobin, and the hemoglobin is said to be saturated with oxygen. This plateau in
the oxyhemoglobin disassociation curve above a PO2 of 70 mm Hg allows the
saturation of hemoglobin with oxygen, even if animals ascend to moderate altitude
where low barometric pressure results in a low oxygen tension in air (PIo2).
Diagrammatic illustration of oxygen dissociation curve

When PO2 drops to about 40 mm Hg in the capillaries the hemoglobin is about 75%
saturated, or about 14.4 ml of oxygen. This indicates that the blood normally delivers
about 5ml of oxygen per 100 ml of blood to the tissues.
Below PO2 of 60 mm Hg, the oxyhemoglobin dissociation curve has a steep slope.
This is in the range of tissue PO2 at which oxygen is unloaded from the blood. Blood
exposed to such a PO2 loses 25% of its O 2 to the tissues. In rapidly metabolizing
tissues in which tissue PO2 is lower, more O2 unloads from the blood. The oxygen
remaining in combination with hemoglobin forms a reserve that can be drawn upon
the emergences.
The middle steep part indicates that a small change in PO2 leads to a large change in
per cent saturation. This helps in easy delivery of O 2 to the tissues and also in O2
uptake in the lungs. The top portion of the curve is flat, i.e., for a large pressure
change there occurs only a slight change in saturation. This ensures a slight fall of
alveolar PO2 oxygenation of Hb in the pulmonary capillaries will not be affected very
much. In fact, it is seen that the Hb saturation remains around 90% at a height of 1000
ft in man. (Pio2= 110, AAo2= 65 mm Hg). Therefore, the curve indicates that Hb is a
very competent apparatus for picking up O2 in the lungs and delivering the same to
the tissues.

Although the all mammals have similarly shaped oxyhemoglobin dissociation curves,
the position of the curves with respect to PO2 varies which can be described by P 50.
The partial pressure of O2 at which 50% saturation of Hb occurs is called P 50. A
higher P50 is found in small mammals and allows unloading of oxygen at a high PO2
to meet their high metabolic demands.

Factors affecting the oxyhemoglobin dissociation

There are a number of factors which can displace the dissociation curve in one
direction or the other (i.e., to the right or to the left). These factors are-
 a. Hydrogen ion concentration (pH)
b. Partial pressure of Carbon dioxide (PCO2)
c. Temperature of the blood, and
d. Concentration of 2,3-diphosphoglycerate (2,3-DPG) in RBC

If the affinity of Hb towards O2 increases, more saturation will occur at a given PO2
and the curve will shift to the left. The curve will shift to the right if affinity
decreases.

A shift to right occurs when there is:

a. ↑PCO2
+
b. ↑ H
c. ↑ Temperature
d. ↑ 2,3-DPG

A shift to the left occurs when there is:

a. ↓PCO2
+
b. ↓ H
c. ↓ Temperature
d. ↓ 2,3-DPG

When the curve is shifted to the right O 2 release becomes easier. This is needed for
muscular exercise where the muscles are hot and acidic. All these shift the curve to
the right and help the muscles to get more O2.

a. Effect of pH

When the blood becomes slightly acidic with the pH decreasing from normal value of
7.4 to 7.2, the oxyhemoglobin dissociation curve shifts to the right. Conversely, an
increase in the pH from the normal 7.4 to 7.6 shifts the curve to the left.

b. Effect of PCO2

Increased Co2 content of the blood helps to release more O 2 from Hb. So, there is shift in
the oxyhemoglobin dissociation curve resulting from a change in the carbon dioxide
tension (PCO2). This is called Bohr Effect. Carbon dioxide produces the effect partly
+
due to direct combination with Hb, but mostly due to lowering the pH (by producing H
ion). Carbonic acid anhydrase is present only in the RBCs. Increased CO 2 in blood
+ + -
produces increased amount of H (CO2 + H2O); H2CO3 (H + HCO3 ) and pH
inside the RBC decreases. A change in pH alters the oxygen binding capacity of
hemoglobin by altering the structure and configuration of hemoglobin. So, this
decreases the affinity of Hb to O2 and therefore oxygen is released.

In presence of high PCO2, the curve is shifted to the right, which means that CO 2
favors dissociation of oxyhemoglobin and release of O 2. Opposite changes occur
when there is low PCO2 in the blood. The Bohr Effect is not constant among species;
in small mammals, a given change in pH produces a greater shift in the dissociation
curve than in large mammals, supposedly ensuring the delivery of oxygen during high
rates of metabolic activity, when the carbon dioxide production is greatest. The Bohr
Effect is useful during physical exercise when more CO 2 is produced and more O2
can be delivered to the tissues. In this way the active tissues get more O2.

c. Effect of temperature
An increase in tissue metabolism produces heat, which elevates body temperature and
shifts the oxyhemoglobin dissociation curve to the right (increases P50). Such a shift
facilitates dissociation of O2 from hemoglobin and releases O2 to the tissues.
Conversely, excessive cooling of the blood, as occurs in hypothermia, shifts the
dissociation curve to the left so that tissue PO2 must be lower than usual to release O 2
from hemoglobin.
d. Effect of DPG

Di-phospho glycerate (DPG) is synthesized within RBCs from glucose metabolism

via glycolytic cycle (Embden-Mayerhof Pathway). 1, 3-diphosphoglycerate
produced in the EM pathway is converted into 2, 3-diphosphoglycerate by
diphosphoglycerate mutase enzyme. This 2, 3-DPG binds with the chains of
deoxyhemoglobin. So, HbO2 releases O2 and Hb combines with 2, 3-DPG, i.e., more
O2 is released. 2, 3-DPG also acts by increasing the acidity inside the RBC as it is
acidic. Therefore, when there is increased 2, 3-DPG in the RBCs, more O 2 is
delivered to the tissues.
This is of particular help in chronic hypoxic conditions as in high altitude, lung
disease, cyanotic heart disease, etc. This is also a helpful mechanism during
prolonged exercise. But too much of 2, 3-DPG will hinder the combination of 02 with
Hb in lung and 2,3-DPG cannot be disposed of quickly like CO 2, so this mechanism
has limitations.
Fetal Hb (HbF) has no -chain and binds poorly to 2, 3-DPG, so HbF has more affinity
to O2 than adult Hb. This helps the HbF to extract O 2 from the maternal blood. This
does not cause problem in delivery of O2 as PO2 in fetal tissues is very very low. 2, 3-
DPG concentration in the RBCs increase in chronic hypoxia, and also by thyroid
hormone, androgens, etc. acidity inhibits its formation.
In hypoxic conditions that last longer than a few hours, the quantity of DPG in the
blood increases considerably, thus shifting the oxyhemoglobin dissociation curve to
the right, causing more O2 to be liberated.

Not all hemoglobins bind DPG equally. Ruminant hemoglobin in general is

unresponsive to DPG, and elephant hemoglobin binds DPG equally.

TRANSPORT OF CARBONDIOXIDE

CO2 is produced in the tissues where from it is taken up by the blood in the tissue
capillaries and then carried in venous blood. Part of the CO 2 in venous blood is given
out in lung and rest remains in arterial blood. CO2 from the tissues diffuses down the
pressure gradient as the PCO2 in the tissues is higher than in the capillaries. Transport
of carbon dioxide by the blood is not nearly so great a problem as transport of oxygen
because even in the most abnormal conditions carbondioxide can usually be
transported in far greater quantities than can oxygen.
CO2 is carried in three forms:
a.In the dissolved form (in physical solution)
-
b. In the form of bicarbonate ion (HCO3 ), and
c.In combination with hemoglobin and plasma proteins

a. In physical solution:
This is the CO2 dissolved in plasma. Its amount depends on the solubility of CO 2 in
plasma and PCO2 of plasma. CO2 is produced in the tissues; therefore tissue PCO2 is
higher (46mm Hg) than the PCO2 of the blood arriving in the capillaries (40 mm Hg).
CO2 diffuses down a concentration gradient from the tissues into the blood.

Approximately 5% of the carbon dioxide entering the blood is transported in

solution. This form is responsible for about 10% of A-V (arteriovenous) difference of
CO2.
-
b. In the form of bicarbonate ion (HCO3 ):

The majority of carbon dioxide entering the blood diffuses into the red cells, where it
undergoes one of the two chemical reactions: Most of the CO 2 combines with water
and forms carbonic acid (H2CO3), which then dissociates into bicarbonate ion and
hydrogen ion. This reaction is catalyzed by carbonic anhydrase inside the red blood
cells.

H2O + CO2 = H2CO3 = H+ + HCO3-

This reaction also occurs in plasma, but in the red cells the presence of carbonic
anhydrase accelerates the hydration of the carbon dioxide several hundredfold.
Therefore, the RBCs are responsible for transport of CO 2 in this form. H+ thus
produced is responsible for Haldane effect. Ionization of carbonic acid occurs
+ -
rapidly, and H and HCO3 accumulate within the erythrocytes. The reversible
reaction is kept moving to the right, because H+ is buffered by hemoglobin as it is a
powerful acid base buffer. In turn many bicarbonate ions produced in the erythrocytes
diffuse out along a concentration gradient into the plasma and chloride ions enter
inside the red blood cells to maintain the Gibbs-Donnan equilibrium. This is carried
- -
out by the help of HCO3 - Cl carrier protein (band-3 protein).

This transport accounts for about 70% of carbon dioxide transport from the
tissues to the lungs. This form is responsible for about 60% of the A-V difference of
CO2.

c. In combination with hemoglobin and plasma proteins:

The formation of carbamino compounds is the third form in which carbon dioxide is
transported in the blood. The terminal NH2 groups or any free NH2 group of a protein
molecule react with CO2 to produce carbamino compound.

R-NH2 + CO2 R-NHCOOH

(carbamino compound)

In addition to reacting with water, CO2 reacts directly with amine radicals of the
hemoglobin molecule to form carbaminohemoglobin. This combination of CO2 with
the hemoglobin is a reversible reaction that occurs with loose bond, so that the CO 2 is
easily released into the alveoli, where the PCO2 is lower than in the tissue capillaries.

The goblin portion of Hb contributes a lot due to its amount, which is higher than any
other blood protein. Carbamino compound is important because the reactions
involved in the formation and during release of CO2, are very rapid and require no
enzyme.

Carbamino compounds are responsible for 20-30% of the carbon dioxide exchange
occurring between the tissues and the lungs. This form is responsible for a major
part of the A-V difference of CO2.

Haldane effect:
Deoxygenation of Hb helps to carry more CO2, this is called Haldane effect.
Mechanism is as follows: Reduction of Hb is less acidic and acts as a better proton
acceptor which is produced by CO2 inside the RBCs.

H2O + CO2 = H2CO3 = H+ + HCO3-

+ +

HbO2 + H → H Hb + O2
+
As H is taken up by Hb, the reaction proceeds to right and more CO 2 is converted to
HCO3-. This is reversed in the lungs when Hb is oxygenated and releases the H +.
Now, the reaction proceeds towards left, CO2 evolves and given out to alveolar air.

H+ Hb + O2→ HbO2 + H+
 + -
H + HCO3 H2CO3 =H2O + CO2

Chloride shift:
CO2 can pass through all biological membranes and it diffuses into the capillaries
from the tissues very easily along the pressure gradient. Thereby, PCO2 in plasma
increases, so the CO2 diffuses inside the RBCs. Once inside the RBCs it must be
taken care of or the process will stop due to accumulation of CO 2 and loss of pressure
gradient. This is done by carbonic anhydrase present in the RBCs (not in plasma),
+ -
which hydrates CO2 to form H and HCO3 .

H2O + CO2 = H2CO3

+
It ensures a continuous entry of CO2 inside the RBCs. The H is taken up by the Hb,
so the HCO3- concentration in RBC increases; hence, HCO3- diffuses out of plasma
down the concentration gradient. To maintain electrical neutrality another negative
-
ion i.e., Cl enters inside the RBCs with the help of a membrane protein called band-3
- -
protein. This phenomenon of entry of Cl in exchange of HCO3 is called chloride
shift or Hamburger phenomenon. This occurs in capillaries in the tissues.
Reverse changes occur when the blood is in pulmonary capillaries. Here, Hb is
oxygenated so it releases H+. This H+ then reacts with HCO3- to form CO2 which
goes out to the alveolar air. So HCO 3- in RBC decreases, hence HCO 3- from plasma
enters the RBC to have the same fate and it continues. Chloride ions which entered in
the chloride shift now come out of RBCs and this phenomenon is called reverse
chloride shift.

CO2 dissociation curve:

In CO2 dissociation curve, volume percent of CO 2 is taken instead of percent
saturation. The curve is shifted to the right as Hb saturation increases.
Courtesy: http://cdn.lifeinthefastlane.com/wp-content/uploads/2013/01/Hb-O2-dissociation-curve.jpg
 REGULATION OF RESPIRATION
Respiration is regulated to meet the metabolic demands for delivery of oxygen and
removal of carbon dioxide. To allow the respiratory system to respond to these
different challenges, control mechanisms monitor the chemical composition of the
blood, the effort being exerted by the respiratory muscles on the lungs, and the
presence of foreign materials in the respiratory tract The nervous system normally
adjusts the rate of alveolar ventilation almost exactly to the demand of the body so
that oxygen pressure (PO2) and carbon dioxide pressure (PCO2) in the arterial blood
are hardly altered even during strenuous exercise and most other types of respiratory
stress.

Normal respiration is a rhythmic phenomenon, i.e., inspiration→ expiration, and

this occurs in a regular manner. This is affected by the respiratory centers which
receive inputs from peripheral receptors as well as from other centers and then
achieve the desired ventilation through the effectors i.e., respiratory muscles.

The central controller generates the signals that regulate the activity of the respiratory
muscles, which by contracting give rise to alveolar ventilation. Changes in alveolar
ventilation affect blood gas tensions (partial pressures) and pH, which are monitored
by the chemoreceptors, signals being returned to the central controller, so that
necessary adjustment are made to ventilation. Mechanoreceptors in various parts of
the respiratory system monitor the degree of stretch of the lungs and changes in the
airways and vasculature. Stretch receptors (proprioceptors) in respiratory muscles
monitor the effort of breathing.

THE RESPIRATORY CENTER

Respiratory rhythmicity originates in the medulla but it is tuned by higher centers in the
brain, especially the pons, which is the location of an off-switch that terminates inhalation.
Apneusis results when medullary centers are deprived of information from both the pontine
off-switch and the vagus nerve. The respiratory center is composed of several widely
dispersed groups of neurons (also called nucleus) located bilaterally in the medulla
oblongata and pons. Within the medulla, two groups of neurons fire in association
with respiration. The dorsal respiratory group is located in the ventrolateral portion of
the nucleus tractus solitarius (NTS), and the ventral respiratory group is located in the
nucleus ambiguus and retroambiguus.
 A dorsal respiratory group mainly causes inspiration.
 A ventral respiratory group causes either expiration or inspiration,
depending on which neurons in the group are stimulated.
 The pneumotaxic center, located dorsally in the superior portion of the
pons, which helps to control the rate and pattern of breathing.
Among the three, the dorsal respiratory group of neurons play the fundamental role in
control of respiration.
The Dorsal Respiratory Group of Neurons (DRG)

The dorsal respiratory group of neurons extends most of the length of the medulla.
Either all or most of its neurons are located within the nucleus of tractus solitarius,
although additional neurons in the adjacent reticular substance of the medulla also
play important roles in respiratory control. The nucleus of tractus solitarius is also
the sensory termination of both the vagal and glosso-pharyngeal nerves, which
transmit sensory signals into the respiratory center from the peripheral
chemoreceptors, the baroreceptors, and from several different receptors in the lung.
The basic rhythm of respiration is generated mainly in the dorsal respiratory group of
neurons as the SA node in heart. The axons from the dorsal respiratory group project
into the inspiratory spinal motor neurons primarily supplying those to the diaphragm.
This group of neurons emits repetitive bursts of inspiratory action potentials

It is believed to be the most important respiratory centre and is responsible for

generation of the inspiratory ramps. This is called as the ramp signal and the wave
forms the ramp fashion. Ramp means the type of electrical activity which begins very
weakly at first and increases steadily for about 2 seconds and ceases abruptly for the
next 3 seconds and then again begins the next cycle. This activity of electrical activity
of DRG is rhythmic, which is then transmitted to the respiratory motor neurons in the
anterior horn of the spinal cord and ultimately leads to the contraction of inspiratory
muscles (Diaphragm via the phrenic nerves) to cause inspiration. For normal
rhythmic respiration, it is helped by feedback information from peripheral
chemoreceptor, vagal inputs, central chemoreceptor and inputs from other centers.
Current ideas suggest that rhythmic respiration results not from the reciprocal
inhibition of inspiratory activity but by rhythmic inhibition of inspiratory activity.
Termination of inspiration can be a result of inputs from pulmonary stretch receptors
or from a central pontine “off-switch”. When inhalation is terminated, inspiratory
neurons are inhibited, so exhalation occurs passively as a result of the elastic recoil
of the lung and the chest wall.
Pneumotaxic Center

The pneumotaxic center, located dorsally in the nucleus parabrachialis of the upper
pons, transmits signals to the inspiratory area. The primary effect of this center is to
control the “switch-off”point of the inspiratory ramp, thus controlling the duration of
the filling phase of the lung cycle. When pneumotaxic signals are strong, inspiration
might last for 0.5 seconds and when weak it may last for 5 seconds.

The function of the pneumotaxic center is primarily to limit inspiration. This has a
secondary effect of increasing the rate of breathing, because limitation of inspiration
also shortens expiration and the entire period of respiration. Its absence causes
apneustic type of breathing, i.e., breathing characterized by prolonged inspiration (this
becomes prominent when the vagi are cut). It is thought that the pneumotaxic centers
relay information from higher centers. They normally cut down the activity of
inspiration, so that there is quick initiation of expiration, therefore, by the activity of
this center, the rate of respiration is increased to 30-40 beats per minute.

The Ventral Respiratory Group of Neurons (VRG)

The ventral respiratory groups of neurons are located anteriorly and laterally to the
dorsal respiratory group. Within the medulla, this group of neurons are placed in the
nucleus ambiguus cranially (supplies the accessory muscles of respiration) and the
nucleus retroambiguus caudally (supplies both the inspiratory and the expiratory
muscles i.e., external and internal costals). Axons from the ventral respiratory group
project to the spinal motor neurons of both expiratory and accessory inspiratory
muscles. Both DRG and VRG are interconnected.

The function of this neuronal group differs from that of the dorsal respiratory group
in several important ways-
a.The neurons of the ventral respiratory group remain almost totally inactive
during normal quiet respiration. Therefore, normal quiet breathing is caused
only by repetitive inspiratory signals from the dorsal respiratory group
transmitted mainly to the diaphragm, and expiration results from elastic
recoil of the lungs and thoracic cage.
b. There is no evidence that the ventral respiratory neurons participate in the
basic rhythmical oscillation that controls respiration.
c.When the respiratory drive for increased pulmonary ventilation becomes
greater than normal, respiratory signals spill over into the ventral respiratory
neurons from the basic oscillating mechanism of the dorsal respiratory area.
As a consequence, the ventral respiratory area does then contribute its share
to respiratory drive as well.
d. Electrical stimulation of some of the neurons in the ventral group causes
inspiration, whereas stimulation of others causes expiration. Therefore,
these neurons contribute to both inspiration and expiration. They are
especially important in providing the powerful expiratory signals to the
abdominal muscles during very heavy expiration. Thus, this area operates
more or les as an overdrive mechanism when high levels of pulmonary
ventilation are required, especially during exercise.

Apneustic Center

Apneustic center is located in the lower pons and it is believed to stimulate the
inspiratory centre to increase inspiratory activity. It gets feedback from vagal afferents
and also from other respiratory centers. Its function can be demonstrated only when
th
the vagus nerves (10 cranial nerve) to the medulla have been sectioned and when the
connections from the pneumotaxic center have been blocked by transecting the pons
in mid region. Then, the apneustic center of the lower pons sends signals to the dorsal
respiratory group of neurons that prevent the switch off of the inspiratory ramp signal
and block the signals from these neurons. This results in almost complete filling of
lungs with air with short expiratory gasps. The value of the apneustic center is not
well understood, but it presumably operates in association with the pneumotaxic
center to control the intensity of inspiration.

CHEMICAL CONTROL OF RESPIRATION

The ultimate goal of respiration is to maintain proper concentrations of oxygen,

carbon dioxide, and hydrogen ions in the tissues. In addition to control of respiratory
activity by the respiratory center itself, there is still another mechanism available for
controlling respiration. This is the chemoreceptor system. Chemoreceptors monitor
oxygen, carbon dioxide, and hydrogen ion concentration at several sites in the body.
There are two types of chemoreceptors on the basis of location, viz central or
medullary receptors located in the medulla and the peripheral chemoreceptors
located in carotid and aortic arches. Peripheral chemoreceptors are the only receptors
monitoring blood oxygen levels. And the ventilatory response to carbon dioxide is
mediated through the medullary chemoreceptor.

In the minute-by-minute regulation of breathing, carbon dioxide and hydrogen ion

levels are apparently more important than oxygen levels. Small changes in the arterial
carbon dioxide tension (Paco2) and hydrogen ion concentration produce major
changes in ventilation, whereas small changes in the arterial oxygen tension (Pao 2) in
physiological range have little effect on breathing.

The Central or Medullary Chemoreceptor System

Chemosensitive tissue has been localized to the ventrolateral surface of the medulla,
lateral to the pyramids, and medial to the roots of the seventh through tenth and the
twelfth cranial nerves. These areas are distinct from the dorsal respiratory group and
ventral respiratory group neurons however connected to these areas of the respiratory
centre.

These central chemoreceptors, also called medullary chemoreceptors are highly

excited by hydrogen ions. Apparently responds to changes in the pH of the interstitial
tissue fluid in which it is bathed. A decrease in pH increases ventilation, and increase
in pH decreases ventilation. Because the central chemoreceptor is bathed by brain
interstitial fluid (cerebrospinal fluid), changes in ventilation can be induced by
changes in the composition of arterial blood and by changes in the hydrogen ion
concentration of CSF.

The central chemoreceptor is separated from blood by the blood-brain barrier, which
+ -
is freely permeable to CO2 but less permeable to H and HCO3 . Though CO2 has
very little direct effect to stimulate the neurons in the chemo-sensitive area, it does
have a potent indirect effect. It does this by reacting with the water of the tissues to
form carbonic acid. This carbonic acid then dissociates into H + and HCO3-. The
interstitial fluid is poorly buffered so the pH around the chemoreceptor decreases and
this stimulates ventilation. Similarly infusing H+ into the CSF decreases the interstitial
fluid pH and increases the ventilation. The hydrogen ions then have a potent direct
stimulatory effect. Similarly decrease in hydrogen ion concentration decreases
ventilation. Hence, as the central chemoreceptor is bathed by brain interstitial fluid in
communication with cerebrospinal fluid (CSF), changes in ventilation can be induced
by changes in the composition of arterial blood and by changes in the hydrogen ion
concentration of CSF.
The Peripheral Chemoreceptor System

Special nervous chemical receptors, called peripheral chemoreceptors, are located in

carotid and aortic bodies, and their removal eliminates the respiratory response to
hypoxia. The peripheral chemoreceptors are the only receptors monitoring blood
oxygen levels, although they also respond to a lesser extent to changes in carbon
dioxide and hydrogen ion concentration. The largest numbers of the chemoreceptor
are located in the carotid bodies. However, a sizable number are in the aortic bodies
and a few are located elsewhere in association with other arteries of the thoracic and
abdominal regions of the body. The blood flow through these bodies is extreme;
twenty times the weight of the bodies themselves each minute. Blood flow per 100g
of tissue is 2000 ml/min and highest of all the organs in the body. Because of this
huge blood supply, the dissolved O 2 is sufficient for it (i.e., HbO 2 is not needed and
hence it is not stimulated in anemic hypoxia). A slight difference in PO2 can be
detected by this organ. So its removal causes loss of response to hypoxia as central
effect of hypoxia.

The carotid bodies are small projections located close to the bifurcation of the
internal and external carotid arteries. Their afferent nerve fibers pass through glosso-
th
pharyngeal nerves (9 ) cranial nerve) to the dorsal respiratory area of the medulla.
Carotid bodies contain different cell types Gomus cells (Type I cells which are mostly
responsible for the chemo-sensitivity of the carotid bodies) and Type II cells
(sustentacular cells) which support the axons and the blood vessels that ramify within
the carotid body. Type I cell is receptor cell while type II cell is neuroglial cell.
+2
Catecholamines are probably released from these Type I cells (Ca mediated) in
response to hypoxia. The catecholamines so released then stimulate the afferent nerve
endings.
When the carotid bodies are perfused with blood having a low oxygen tension, high
CO2 tension or low pH, firing rates in the carotid sinus nerve afferents increase as
PCO2 increases and pH decreases, there is an almost linear increase in ventilation.
The response to PO2 is alinear. Modest increases in firing rate and ventilation occur
as PO2 decreases from unphysiological levels of 500 mm Hg to 70 mm Hg. A fall in
PO2 particularly below 60 mm Hg, the PO2 at which hemoglobin begins to
desaturate, causes a more rapid increase in ventilation. Response of carotid bodies to
changes in PCO2 is far less in degree in comparison to the central chemoreceptor.

The aortic bodies are small masses located along the arch of the aorta. Their afferent
nerve fibers pass through the vagus nerve to the dorsal respiratory area. And these
bodies more or less behave like the carotid bodies.

Effect of Oxygen on Chemoreceptor Activity

Changes in the arterial oxygen concentration have no direct stimulatory effect on the
respiratory center itself but it in turn affects the peripheral chemoreceptors. When the
oxygen concentration in the arterial blood falls below normal, the peripheral
chemoreceptors become strongly stimulated which in turn stimulate DRG causing
increased ventilation.

Effect of Carbon Dioxide and Hydrogen Ion Concentration on Chemoreceptor

Activity

An increase in either carbon dioxide concentration or hydrogen ion concentration also

excites the chemoreceptors and in this way indirectly increases respiratory activity.
However, the direct effects of both these factors in the respiratory center itself are so
much more powerful than their effects mediated through the chemoreceptors (about
seven times as powerful) that for most practical purposes, the indirect effects of
carbon dioxide and hydrogen ions through the chemoreceptors do not need to be
considered.

Pulmonary stretch receptors

These are the receptors situated among the smooth muscles of the small airways and
are stimulated due to alteration of the shape (e.g., stretching) of these airways. These
receptors influence the centre via vagi by Hering-Breur reflexes and causes “switch-
off”the inspiratory ramp and thus stop further inspiration.

Lung irritant receptors

There are the nerve endings and are situated in between the epithelia lining the
respiratory tract. They respond to irritant materials (e.g., SO 2) in the inspired air and
reflexly cause cough or bronchospasm via vagi (myelinated fibers).

Chest wall receptors (Proprioceptors)

These are mainly the muscle spindles in the muscles of inspiration (mainly
intercostals) together with the receptors in tendons, joints and ligaments in the
thoracic cage. They are also called load detecting receptors as they sense the load of
ventilation and accordingly regulate the amount and force of muscle contraction to
achieve the desired ventilation. Therefore, this mechanism is of great help when the
needed ventilation is not achieved normally as in emphysema, asthma, fibrosis, etc.

Arterial baroreceptors
These are stretch receptors situated in different parts of the arterial tree. They are
stimulated by rise of BP and lead to reflex inhibition of respiration along with other
effects. When BP is low they are not stimulated, so respiration is not inhibited.

Other receptors:
Receptors situated in the skeletal muscles, joints, ligaments, joint capsules, etc. in
other parts of the body also have a role in respiration. These are stimulated due to
movement of joints during exercise and stimulate respiration.

ADAPTATION OF RESPIRATION DURING EXERCISE

AND
RESPIRATORY REFLEXES

Adaptation of respiration during exercise

Physical exercise leads to increase ventilation. This is needed to meet up the increased
O2 demand, to remove the CO2 produced and also to dissipate the heat produced in
the body due to exercise. The exercising muscles form tremendous amounts of carbon
dioxide and use tremendous amounts of oxygen. So, the PCO2 and PO2 change
markedly between the inspiratory and expiratory cycle of respiration. The increase in
ventilation following the onset of exercise is initially rapid, then occurs more slowly
and, provided the workload remains constant, reaches a steady state after about four
minutes. Although the ventilatory effect has been well described the reasons for the
increase ventilation are still not well understood. The probable mechanism may be as
follows:

a. Higher center:
This is the motor cortex and ventilation is definitely due to the activity of the higher
centers. Associated sympathetic stimulation may also lead to stimulation of breathing
during exercise.

b. Increased temperature of blood stimulates ventilation through the hypothalamus.

c. Movement of joints and contraction of the muscles leads to reflex stimulation of
ventilation. During exercise, the body movements especially of the limbs are believed
to increase pulmonary ventilation by exciting joint and muscle propioceptors that then
transmit excitatory impulses to the respiratory center.

d. Increased co2 load presented to the lung during exercise may also act by some
unknown way.

e. In exercise there is an increase oscillation of Paco 2 and Pao2. This is because of

high rate of CO2 production and O2 consumption. This makes a lot of differences with
one breath though the average value remains constant. This probably acts through the
peripheral chemoreceptor.
+
f. Increased plasma (K ) that occurs during exercise probably stimulates peripheral
chemoreceptor.

g. Lactic acid liberated during severe exercise:

Once the anaerobic threshold is exceeded, the production of lactic acid reduces the
blood pH. The lactic acid produced during severe exercise becomes more severe and
+
the lactic acid cannot be buffered and H concentration increases which also stimulate
respiration leading to a decrease of Paco2.
h. Increased pulmonary blood flow increases the number of active capillaries and
also distension of the capillaries leading to an increased area of the alveocapillary
membrane thus increasing pulmonary gas exchange.

Thus, the nervous factors, viz direct stimulation from cereal cortex and the reflex
proprioceptive stimulation from the muscles perhaps play more important role in
initiating and maintaining the appropriate level of ventilation during exercise so that
the muscles get an adequate supply of oxygen and the excessive carbon dioxide and
lactic acid so formed are disposed off.

Gas transport during exercise

The demands for gas transport in the blood are not constant but vary with metabolism.
Strenuous exercise represents the most extreme demand placed on the gas transport
mechanisms. In the galloping horse, oxygen consumption can increase 30-fold. The
part of the demand is provided by an increase in cardiac output, which causes the
amount of blood flowing through the lungs per minute to increase. This allows an
increased uptake of oxygen from the lungs. The cardiac output is redistributed also,
with an increased fraction of output going to the exercising muscles. The increase in
cardiac output and redistribution increases muscle blood flow by 20-fold.

The horse also meets the increased oxygen demand with an increase in the number of
circulating erythrocytes and therefore, amount of hemoglobin. Contraction of spleen
forces stored RBCs into the circulation and can increase the hematocrit from 35 up to
50%. This provides almost 50% more binding sites for oxygen. The usefulness of an
increase in hematocrit is limited, because it increases the blood viscosity, which tends
to reduce the flow of blood through the capillaries and increase the work of the heart.
The increase in muscle blood flow and hematocrit together increase the delivery of
oxygen to the muscle. Muscle also extracts a bigger percentage of the oxygen from
the blood during exercise than at rest. This is accomplished because of the following
reasons: the diffusion gradient in muscle PO2 which results from the increase in
metabolic rate and the affinity of hemoglobin for oxygen is decreased by the higher
temperature of the exercising muscle and by the release of the carbon dioxide and
hydrogen ions from the muscle.

Muscle itself contains an oxygen –binding, myoglobin, that provides a small store of
oxygen. But unlike hemoglobin it contains only one heme group, so the dissociation
curve is not sigmoid but is a rectangular hyperbola.

Thus, in exercise the increased demand for oxygen is met by changes in blood flow,
hematocrit, and oxygen extraction from blood, and to a smaller degree, by oxygen
release from myoglobin. These mechanisms are available whenever unusual demands
for gas exchange arise.

RESPIRATORY REFLEXES
Reflex refers to an involuntary, qualitatively unvarying response of the nervous system to a
stimulus. It is a mechanism by which a sensory impulse is automatically converted into a
motor effect through the involvement of central nervous system. The following are the
respiratory reflexes:

1. Hering-Breuer (HB) Reflexes

It is a volume reflex and operates due to inflation and deflation of lungs. Accordingly, it is of
two types: Hering-Breuer inflation reflex and Hering-Breuer deflation reflex. Mechanical
receptors for both the varieties are situated in between the smooth muscles of small airways.
The receptors are unmyelinated nerve endings which are stimulated due to change of shape of
the airways. So, these receptors are also called mechanoreceptors.

a. Hering-Breuer Inflation Reflex

In the muscular portions of the walls of the bronchi and bronchioles throughout the lungs are
stretch receptors that transmit signals through the vagi into the dorsal respiratory group of
neurons. When air enters inside the lungs during inspiration the airways are stretched and the
receptors are stimulated. The impulse is then rapidly conduced to the respiratory centers by
myelinated vagal afferents which cut down inspiratory activity. So, this “switches off
inspiratory ramp and thus stops further inspiration or inflation and then expiration starts. This
is
called the Hering-Breuer inflation reflex.

This reflex also increases the rate of respiration, the same as is true for signals from the
pneumotaxic center. The effect of HB inflation reflex is to increase the rate of breathing when
the tidal volume is high as in case of physical exercise. As the inflation here is quick, there is
quick stretching, and the inspiration is quickly inhibited by the reflex, thus inspiration time is
decreased though the drive is more. Expiration follows and the next inspiration starts very
quickly as the respiratory demand are very high. In this way the respiratory rate increases.
This HB inflation reflex cuts down inspiration before the lung volume increases very much
and thus helps the lungs to operate the lower volume. This reflex is mainly a protective
mechanism for preventing excess lung inflation rather than an important ingredient in the
normal control of ventilation.

b. Hering-Breuer Deflation Reflex

It operates when the lungs are deflated very much and stimulates inspiration. The receptors
may be described as compression receptors located probably in the alveolar septa. The
afferent fibers through these receptors are carried in the vagi to the respiratory center. These
receptors are stimulated due to change of shape of the small airways in a collapsed area. They
are stimulated during expiration and reflexly inhibit expiration and reciprocally stimulate
inspiration. So, this reflex does not operate during normal condition. This reflex also probably
prevents collapse of the lungs (atelectasis) and helps to open a collapsed portion.

The Cough Reflex

Cough is a protective reflex by means of which respiratory passages are kept free
from foreign matter. It is the process where respiration is modified and utilized to
expel the unwanted materials from the respiratory passage. It usually results due to
stimulation of lung irritant receptors.

The bronchi and the trachea are so sensitive to light touch that excessive amount of
any foreign matter or any other causes of irritation initiates the cough reflex. Sensory
stimulus necessary for this reflex is either physical or chemical irritation of the
respiratory tract. The larynx and the area of bifurcation of the trachea are especially
sensitive, and the terminal bronchioles and even the alveoli are sensitive to corrosive
chemical stimuli such as sulfur dioxide gas or chlorine gas.

The afferent nerve impulses pass from the respiratory passages mainly through the
vagus nerves to the medulla of the brain. Then the automatic sequence of events is
triggered by the neuronal circuits of the medulla causing following events-
a.First, a deep inspiration is taken.
b. Second, the epiglottis closes, and the vocal cords shut tightly to entrap the
large amount of air within the lungs.
c.Third, the abdominal muscles contract forcefully; pushing against the
diaphragm while other expiratory muscles, such as the internal intercostals,
also contract forcefully.
d. Consequently, the pressure in the lungs rises greatly (to 100 mm Hg or
more).
e.Fourth, the vocal cords and the epiglottis suddenly open widely and thus the
lung air under high pressure comes out with explosive violence (at a velocity
of about 900 km per hour).
f. This act thus helps in clearing out the noxious irritating agents from the
respiratory passage.
The Sneeze Reflex

Sneeze reflex is very much like the cough reflex but the air outflow occurs through
the nose without any closure of the glottis. So, it applies to the nasal passageways
instead of the lower respiratory passages. The initiating stimulus of the sneeze reflex
is irritation in the nasal passageways, the afferent impulses passing in the trigeminal
nerve to the medulla, where the reflex is triggered. A series of reactions similar to
those for the cough reflex takes place; however, large amounts of the air pass rapidly
through the nose, thus helping to clear the nasal passages of foreign matter.

HYPOXIA
Hypoxia

Hypoxia is a condition characterized by reduced level of oxygen supply to the tissues

and the tissues suffer due to it. Less oxygen in blood is called hypoxemia. Absence of
oxygen is anoxia. Different conditions such as less oxygen in the inspired air,
decreased alveolar ventilation, reduced exchange due to defect in respiratory
membrane, anemia, slowness of circulation and defects in the use of oxygen in the
cells may lead to serious degrees of cellular hypoxia.

Hypoxia may be divided into following four types:

Hypoxic Hypoxia
It is the hypoxia resulting from the inadequate aeration of blood (reduced PO2 level in
the arterial blood) due to one or more of the following reasons:
a. Deficiency of oxygen in the inspired air (e.g., high altitude, in a closed room,
etc.)
b. Hypoventilation as in respiratory paralysis, asthma, emphysema, airway
obstruction, etc.
c. Defective transfer of oxygen due to problems in the respiratory membrane
(e.g., pulmonary edema, pneumoconiosis, etc.)

In all these cases there is a decreased Pao2 and also a low O2 content of the arterial
blood which is further reduced in venous blood. It results in diminished saturation of
hemoglobin with oxygen. Naturally the tissues also get less amount of O 2 and they
suffer. Various symptoms arise due to this tissue hypoxia. Most of the symptoms are
due to hypoxia in brain and there may be death if the hypoxia is severe and sudden.

Compensatory changes in case of hypoxic hypoxia are:

a. Hypoxic stimulation of respiration leading to hyperventilation with an aim to
raise the Pao2
b. Rise of BP and there is polycythemia with increased Hb.
c. Increased 2, 3-DPG content in red cells.

The aim of these changes is to increase the O2 carrying capacity of blood and also to
increase the ability to release more O2. The immediate treatment is O2 therapy. The
next step of the treatment is the removal of cause.

Anemic Hypoxia
It results due to decrease in the oxygen-carrying capacity of the blood because of
reduced level of hemoglobin. Anemia of any cause may bring about this type of
hypoxia. The O2 capacity of the blood becomes less, so also the O2 content but PO2
remains normal because there is nothing against the O2 to be dissolve in plasma in
this case. In venous blood O2 content is very low.
The partial pressure of oxygen is normal and the percentage saturation of the
hemoglobin is also normal, but an insufficient volume of oxygen is delivered to the
tissues.

Anemic hypoxia is seen after hemorrhage, in various anemias, and in conditions

where a part of the hemoglobin is changed to methemoglobin or is combined with
carbon monoxide. Acute variety of anemic hypoxia occurs in carbon monoxide
poisoning where CO combines with Hb irreversibly thus O2 cannot combine with Hb.

Compensatory changes in cases of chronic anemic hypoxia are: hyerdynamic

circulation increased cardiac output, increased heart rate, etc. All these lead to a
hyperdynamic (increased speed of the blood flow) so that the same Hb can be used
repeatedly to transport oxygen. There is also rise of 2, 3-DPG in RBC.
Erythropoietin production is increased leading to increase erythropoiesis in an
attempt to correct the anemia.

Stagnant or Ischemic Hypoxia

Stagnant hypoxia results due to reduced flow of blood in the tissues. O2 reaching the
tissue per unit time is less, so the tissues suffer, though the O2 content of arterial
blood is normal. Venous blood shows very low O2 as the blood stays for longer time
in tissue capillaries and more O2 is extracted from it. Naturally the arteriovenous
(AV) difference of O2 content is very high in this condition. It may be a general or
local failure of the circulation. Stagnant hypoxia occurs in congestive heart failure,
shock, and obstruction to venous return, paralytic dilatation of capillaries as in
irreversible shock and so on.
Histotoxic Hypoxia

Histotoxic hypoxia follows if the tissues are unable to utilize oxygen in the
physiological oxidations. It is the most dangerous type and very difficult to treat as
well. It is due to paralysis of the enzymes required for O 2 utilization. So, even if there
is normal O2 status of the arterial blood, the tissues cannot use O 2 and suffer. The O2
status of the venous blood is almost like the arterial blood and therefore the AV
difference of O2 is practically absent. The blood is bright red in color.

Histotoxic hypoxia is typically seen in cyanide poisoning. Cyanide inhibits

cytochrome oxidase and possibly other enzymes and results in hypoxic condition.
Table: O2 status in different hypoxias

Pao2 Arterial Blood Venous Blood AV Difference

of O2
O2% O2%
Hypoxic hypoxia ↓ ↓ ↓ unchanged

Anemic hypoxia = ↓ ↓ unchanged

Stagnant hypoxia = = ↓↓ very high

Histotoxic hypoxia = = ↑ very very low

 (=Normal, ↑more than normal, ↓ Less

Oxygen Therapy in Different Types of Hypoxia

Administration of oxygen-rich gas mixture is of very limited value in stagnant,
anemic, and histotoxic hypoxia because all that can be accomplished in this way
is an increase in the amount of dissolved oxygen in the arterial blood.
This is also true in hypoxic hypoxia when it is due to shunting of deoxygenated
venous blood past the lungs. In hypoxic hypoxia, oxygen treatment is of great
benefit.

ACCLIMATIZATION
If an animal is brought to high altitude sufficiently slowly (taking several weeks) then
some changes occur in its body. This is called acclimatization. These changes help the
body to adjust or acclimatize to high altitude. These changes are seen at a height of
3000 m and above. It is important in mountain climbers. The main problem in high
altitude is hypoxia, so the changes in acclimatization are directed against the hypoxia.
These are as follows:

Hyperventilation
This helps to increase the PaO2. It occurs due to stimulation by hypoxia in high
altitude and it also causes washing out of Co2 at the same time. So, alkalosis develops
-
and respiration is inhibited, and to compensate, HCO3 is excreted in urine (thus
producing alkaline urine). When the pH gets corrected the respiration starts again. In
fact, washing out of CO2 makes the room for O2 in alveolar air and Pao2 increases.
This helps the transfer of more O2 to blood.

Polycythaemia
This is caused by erythropoietin mechanism activated due to the effect of hypoxia on
kidney. So, RBC count may be as high as 15 million/cmm and Hb up to 19.8 g%. This
helps to carry more O2 even in the conditions of less Pao2 and even with
undersaturation of blood.

Changes in O2 dissociation curve

A shift of the curve to the right occurs due to increased 2, 3-DPG in the RBCs. So,
more O2 can be delivered at the tissue level. When the blood is in the pulmonary
capillaries, comparatively more O2 leaves due to low Paco2 caused by the associated
hyperventilation and the curve is shifted to the left, so more O 2 can be taken up even
in presence of high 2, 3-DPG in the RBCs.
Number of capillaries in the tissues also increases so that the intercapillary distance is
decreased and even with low Pao2, tissues can be supplied with enough O2.

d. Number of mitochondria, mitochondrial enzymes all increase so that O2 in the

tissues can be used more effectively.

e. Polycythaemia and hypoxic vasoconstriction also lead to pulmonary

hypertension and right ventricular hypertrophy.

f. Hyperdynamic circulation results due to hypoxic condition.

ROLE OF RESPIRATION IN REGULATION OF ACID-BASE

BALANCE
An acid is defined as a molecule or an ion that acts as a proton donor and proton is
actually the hydrogen ion (H+), thus acid is a molecule or an ion that can contribute a
+
hydrogen ion (H ) to a solution. A base is defined as a molecule or an ion that can
function as a proton accepter, or a base is a molecule or an ion that will combine with
+
hydrogen ions (H ) to remove them form a solution. Most of the acids and bases
concerned with normal regulation of acid base balance in the body are weak acids and
bases. pH is defined as the negative logarithms of hydrogen ion concentration. The
normal pH of arterial plasma is around 7.4. The regulation of acid base balance means
+
the regulation of H concentration in the body fluids.
-14
The hydrogen ion concentration in different solutions can vary from less than 10
Eq/liter to higher than 100 Eq/liter. On a logarithmic basis, the hydrogen ion
concentration in the body is approximately midway between these two extremes.
Changes in the hydrogen ion concentration from the normal value can cause marked
change in the rate of the chemical reactions in the cells; some of the reactions are
depressed while some may be accelerated. pH is very much important for life. Any
change leads to problem. Most of the body proteins can function normally only at a
particular pH range. So, the enzymes, receptors, channels, etc., all are affected by pH
change. Serum calcium (Ca2+) is also dependent on pH and hence the various
physiological functions of Ca2+. So, various body functions including the metabolic
reactions are very much affected by a change in metabolic reactions are very much
affected by a change in pH. That is why the body tries to maintain the pH rigidly
though the pH is continuously threatened by various processes.

To prevent acidosis or alkalosis, several defense mechanisms are available. All the
body fluids are supplied with acid base buffer systems (e.g., bicarbonate, phosphate,
hemoglobin, plasma proteins, etc.) that immediately combine with any acid or base
and thereby prevent excessive changes in hydrogen ion concentration. If the hydrogen
ion concentration does not change measurably, the respiratory centre is immediately
stimulated to alter the rate of breathing. As a result the carbon dioxide level in the
blood is changed and the hydrogen ion concentration is returned towards normal.
When the hydrogen ion concentration changes from normal, the kidneys excrete either
acidic or alkaline urine, thereby helping to readjust the hydrogen ion concentration of
the body fluids back to normal. The buffer system acts within a fraction of second to
prevent excessive change in hydrogen ion concentration. Respiratory centre takes 1-
12 minutes to make acute adjustments and another day or so to make still additional
chronic adjustments. Finally the kidneys, providing most powerful of all the acid
base regulatory system, require many hours to several days to readjust the hydrogen
ion concentration. The kidneys which can excrete either acid or alkaline urine, thereby
readjusting the extracellular fluid H+ concentration towards normal during acidosis or
alkalosis.
Role of respiration in acid base balance
Respiratory system controls the CO2 concentration through lungs. CO2 is the most
important volatile acid in the body produced from the aerobic metabolism of the cells.
CO2 combines with the H2O to form H2CO3 which dissociates into hydrogen and
bicarbonate ions. Carbonic anhydrase enzyme catalyses the reaction since it is
abundantly present in the walls of alveoli, where carbon dioxide is released.
Respiratory regulation of acid base balance is a physiological type of buffer system
because it acts rapidly and keeps the hydrogen ion concentration from changing too
much until the much more slowly responding kidneys can eliminate the imbalance. In
general, the buffering power of the respiratory system is one to two times higher than
that of all other chemical buffers in the ECF (extracellular fluid) combined. However,
the buffer power of lungs decreases in case of abnormalities of respiration like
impairment of lung function. In such cases CO 2 accumulates and respiratory acidosis
occurs.

It is clear that pH is inversely proportional CO 2 concentration and directly

proportional to bicarbonate ion. This means that an increase in carbon dioxide
concentration can decrease the pH towards the acidic side, whereas the decrease in the
carbon dioxide concentration will turn the pH towards the alkaline side. Carbon
dioxide is continually formed in the tissues by the intracellular metabolic processes;
which is then passed to the atmosphere by diffusion from the alveolar capillaries. The
passage requires several minute as the carbon dioxide has to pass from the cells to the
alveoli, thus normally 1.2 mmol/ liter of dissolved carbon dioxide is normally present
in the extracellular fluids (ECF) at all times. Hence, by adjusting PCO2 either up or
down, the lungs can effectively regulate the hydrogen ion concentration in
extracellular fluid. An increase in ventilation eliminates CO2 from the ECF, which
reduces the hydrogen ion concentration. Conversely, decrease ventilation increases
CO2, thus also increasing the hydrogen ion concentration in ECF.

If the rate of metabolism is increased, carbon dioxide production is increased with

increased extracellular volume, whereas in decreased metabolism the carbon dioxide
in the extracellular space is reduced. When the rate of the pulmonary ventilation is
increased, then there is increased carbon dioxide blown off and the amount of carbon
dioxide in the extracellular fluids is decreased. Thus, increased pulmonary ventilation
is present in the conditions of acidosis and decreased pulmonary ventilation is present
in alkalosis.

Effect of hydrogen ion concentration on alveolar ventilation

The hydrogen ion present in the extracellular fluid will directly act on the respiratory
centre in the medulla oblongata where the chemoreceptor present will then change the
rate of respiration as per its concentration. When the hydrogen ion concentration is
very high it will cause increased ventilation, so that more of the carbon dioxide will
be expelled out and the pH of the fluid will be turned towards normal. Similarly, in
reduced hydrogen ion concentration, the respiration rate is reduced so that hydrogen
ion concentration will rise back towards normal.

Acid-Base Imbalance
Acid-Base imbalance due to respiratory causes is categorized into respiratory
acidosis and respiratory alkalosis. And those due to non-respiratory cause are termed
as metabolic acidosis and metabolic alkalosis.
1. Respiratory Acidosis
Respiratory acidosis is caused by alveolar hypoventilation , which can be due to
damage to or depression of the respiratory centers, injury to the respiratory pump
(e.g., fractured ribs or bloated abdomen), or reverse respiratory disease that either
obstructs the airways or excessively stiffens the lungs. This results when the Paco2 is
above the upper limit of normal 45 mm Hg.

Respiratory acidosis is most commonly due to decreased alveolar ventilation causing

decreased excretion of CO2. Less commonly it is due to excessive production of CO2
by aerobic metabolism.

a. Inadequate CO2 excretion: The causes of decreased alveolar ventilation are

numerous as stated above.

b. Excess CO2 production: Respiratory acidosis is rarely caused by excess

production of CO2. This may occur in syndromes such as malignant
hyperpyrexia, though a metabolic acidosis usually predominates. More
commonly, modest overproduction of CO2 in the face of moderately depressed
ventilation may result acidosis. For example in patients with severe lung
disease a pyrexia or high carbohydrate diet may result in respiratory acidosis.

Compensation of respiratory acidosis:

Here compensation is not possible by the lungs as the defect lies there. Kidneys
increase HCO3-recovery so that the HCO3-/CO2 ratio returns towards its normal value
-
and after some days, if high PCO2 is maintained, there is rise of [HCO 3 ] with pH
returning towards normal.

2. Respiratory alkalosis
Respiratory alkalosis is caused by alveolar hyperventilation, which is due to
stimulation of the chemoreceptor by hypoxia or to stimulation of intrapulmonary
receptors by lung injury or inflammation. Overly vigorous use of a ventilator can
cause hyperventilation in an anesthetized animal. This results from the excessive
excretion of CO2, and occurs when the PaCo2 is less than 34 mm Hg. This is
commonly seen in hyperventilation due to anxiety states. In more serious states, such
as severe asthma or moderately pulmonary embolism, respiratory alkalosis may occur.
A physiologic type of respiratory alkalosis occurs when an individual ascends to
high altitude.

Compensation of respiratory alkalosis:

Here, pulmonary compensation is limited as too much decrease of respiration leads to
hypoxia; compensation occurs by kidney by elimination of HCO 3-/CO2 ratio returns
to normal. So, after compensation there is decreased CO2, decreased HCO3- and
slightly increased pH.
3. Metabolic Acidosis
Metablolic acidosis is caused by either excessive hydrogen ion production (e.g. hypoxic
conditions produce lactic or pyruvic acid), ingestion of acids (e.g. ethylene glycol or
ammonium chloride poisoning) inadequate excretion of hydrogen ion production (e.g. renal
tubular dysfunction, renal failure) or excessive loss of bicarbonate ion (e.g. excessive
diarrhea, gastrointestinal secretions are high in sodium bicarbonate). It is the commonest
disturbance of acid-base balance observed clinically. Some conditions that cause metabolic
acidosis are diabetes mellitus, starvation, violent exercise, severe diarrhea, renal tubular
acidosis etc.

4. Metabolic Alkalosis
Metabolic alkalosis caused by either excessive reabsorption of bicarbonate ions (e.g. loss of
chlorine ions such as during prolonged vomiting and diuretics like thiazide therapy promotes
bicarbonate ion reabsorption), excessive loss of hydrogen ion concentration( e.g. prolonged
vomiting, pyloric stenosis) or excessive ingestion of alkalis (e.g. alkaline antacids).

RESPIRATION IN BIRDS

Avian respiratory system has several very distinctive features:

a. Lungs are small and attached to the ribs making them relatively less
expandable.
b. Large, discrete, poorly vascularized air sacs are present.
c. Contraction of respiratory muscles occurs both during inspiration and
expiration so both phases are active in birds.
d. No structures homologous to diaphragm are present.
e. In mammalian lungs, the exchange of oxygen and carbon dioxide occurs in
microscopic sacs in the lungs, called 'alveoli.' In the avian lung, the gas
exchange occurs in the walls of microscopic tubules, called air capillaries.

Anatomy of respiratory system in birds

The respiratory system begins with the external nares, which open into nasal
cavities.
These cavities are separated from each other by a septum in most birds but not all
(e.g. vultures). The two nasal cavities communicate posteriorly with the mouth
and the pharynx by a common slit-like opening.
The nasal cavities contain nasal glands. The glottis leads to the trachea and is
present at the base of the tongue.
The trachea is formed by about 115 complete cartilaginous rings.
The point of bifurcation of trachea into two primary bronchi is dilated to form a
cartilaginous compartment, called syrinx.

Syrinx is the organ responsible for the production of sound in birds. Air passing
over the membranes inside the syrinx produces the variety of sound characteristics
of birds. The trachea divides into right and left primary bronchi. Each bronchus
leads to the corresponding lung where further branching forms secondary and
tertiary bronchi. The primary bronchi also pass through the lungs to connect
directly to the abdominal air sacs. The lung is connected to the other air sacs via
secondary bronchi, which may arise, from the primary bronchi or by the joining
together of a group of terminal bronchi.

Recurrent bronchi lead from the air sacs back to the lung.

Lungs
The lungs are small and are attached to the ribs, making them relatively less
 expandable.
Within the lungs, air conduits (channels or tubes) provide a complicated system of
anastomosis.
Bronchi: The smallest conduits, the tertiary bronchi, are arranged as parallel
connectors between the secondary bronchi within the lung. This arrangement
permits the continuous flow of air between the secondary bronchi and through the
lung. The functional respiratory exchange regions of the avian lung, the air
capillaries, surround the tertiary bronchi and make up the bulk of the lung.
Spiral smooth muscles bands line the walls of the tertiary bronchi. These muscles
constrict the bronchi for regular airflow. Atria open off from the spiral bands and
air capillaries leads from these atria.
The atria may divide into several smaller atria after branching off the tertiary
bronchus.
Air capillaries extend perpendicularly either from the main atrium or from its
subdivisions and connect with other air capillaries. Blood capillaries lie adjacent
to air capillaries but blood and air flow in opposite direction. This
countercurrent flow permits a more thorough exchange of gases than is achieved
in the alveoli of the mammalian lung.

Air sacs
The air sacs lie outside the lungs in the body cavity. Depending upon the
species, the bird has seven or nine air sacs. They function principally as
airways and as they are avascular they are not capable for gas exchange.
These air sacs are in communication with the bronchus on one side and air
spaces in the bone cavities on the other side. They confer lightness to the
body of birds.

There are 9 air sacs; out of these, cervical (may be absent in some species),
anterior thoracic, posterior thoracic and abdominal are paired, and the clavicular
single.These air sacs are divided as anterior set and posterior set of air sacs.The
anterior set includes clavicular, paired cervical, and paired anterior thoracic, The
posterior set includes paired posterior thoracic and paired abdominal air sacs.
The abdominal sacs are the largest air sacs and extend from the lungs to cloacae.
The air sacs of birds extend into the humerus (the bone between the shoulder and
elbow), the femur (the thigh bone), the vertebrae and even the skull.
 Diagram: respiratory system in birds: structural illustration

Diaphragm

There is no structure homologous to the mammalian diaphragm in birds. Two membranes

called pulmonary aponeurosis and the oblique septum having some muscular components
occur in birds and function during respiration. But these structures do not divide the body
cavity of bird into thoracic and abdominal cavities, so the pressures occurring during the
respiratory cycle are referred thoraco-abdominal as pressure.

Mechanics of respiration and air circulation

Birds do not have a diaphragm; instead, air is moved in and out of the respiratory system
through pressure changes in the air sacs. Muscles in the chest cause the sternum to be
pushed outward. This creates a negative pressure in the air sacs, causing air to enter the
respiratory system. Expiration is not passive, but requires certain muscles to contract to
increase the pressure on the air sacs and push the air out. Because the sternum must move
during respiration, it is essential that it is allowed to move freely when a bird is being
restrained. Holding a bird "too tight" can easily cause the bird to suffocate.
Because birds have air sacs that reach into the bones, and have no diaphragm, respiratory
infections can spread to the abdominal cavity and bones.

Respiration in birds requires two respiratory cycles (inspiration, expiration, inspiration and
expiration) to move the air through the entire respiratory system. In mammals, only one
respiratory cycle is necessary.

Respiratory cycle of a bird

During the first inspiration, the air travels through the nostrils, also called nares, of a bird,
which are located at the junction between the top of the upper beak and the head. The fleshy
tissue that surrounds them, in some birds, is called the cere. As in mammals, air moves
through the nostrils into the nasal cavity. From there it passes through the larynx and into the
trachea. Air moves through the trachea to the syrinx, which is located at the point just before
the trachea divides in two. It passes through the syrinx and then the air stream is divided in
two as the trachea divides. The air does not go directly to the lung, but instead travels to the
caudal (posterior) air sacs. A small amount of air will pass through the caudal air sacs to the
lung.
During the first expiration, the air is moved from the posterior air sacs through the
ventrobronchi and dorsobronchi into the lungs. The bronchi continue to divide into smaller
diameter air capillaries. Blood capillaries flow through the air capillaries and this is where
the oxygen and carbon dioxide are exchanged.

When the bird inspires the second time, the air moves to the cranial air sacs. On the second
expiration, the air moves out of the cranial air sacs, through the syrinx into the trachea,
through the larynx, and finally through the nasal cavity and out of the nostrils.

In birds, the contraction of respiratory muscles occurs during both inspiration and
expiration so that both phases are active. Airflow is primarily unidirectional and continuous
through a system of primary, secondary, and tertiary bronchi. Gaseous exchange occurs
across the walls of air capillaries which branch off the tertiary bronchi.
During inspiration, the size of the thoracic area increases in both transverse and dorsoventral
directions. During expiration, the muscles of the pulmonary aponeurosis contract, expanding
the lung. In mammals, expansion of the lung occurs during inspiration.

Pressure drops in all air sacs during inspiration, that is their volume increases, and upon
expiration pressure increases in all air sacs. These changes in volume cause the sacs to act as
a “bellows”. The lungs are compressed during inspiration and expand during expiration.

A generalized concept of airflow in the avian respiratory system has been derived, but airflow
probably varies somewhat between species. Upon inhalation, all air sacs are filled and the
lungs are emptied. The posterior sacs are filled primarily with fresh atmospheric air plus dead
space air left in the trachea from the previous exhalation. The anterior sacs are filled
primarily with air left in the lung from the previous respiratory cycle. Upon exhalation all
sacs empty and the lungs are filled. The air in the posterior sacs goes into the lungs primarily,
and the air in the anterior sacs is exhaled through the trachea. Thus both the lungs and air sacs
are thoroughly ventilated. However, the anterior air sacs are ventilated mainly with air that
has gone through the lungs.

Transport of Blood Gases

Exchange of gases in the bird lung, as in the mammalian lung, results from diffusion and is
governed by physical laws. While there are some differences in the manner in which gases
are transported and handled, the differences are not great.

Chemoreceptors
Pulmonary receptors sensitive to carbon dioxide are apparently very important in the
regulation of avian respiration. Most of the receptors (95 %) are in the caudal parts of the
lung; none are in extrapulmonary airways. The receptors detect carbon dioxide levels in lung
air, not in the blood flowing through the lung. The afferent pathways from these receptors are
in the vagus nerves and the maximal activity of these afferents is associated with the lowest
concentrations of carbon dioxide in the lung. This is the opposite of the situation with arterial
chemoreceptors, which increase their activity in response to high concentration of carbon
dioxide in arterial blood. Activity of these lung chemoreceptor afferents, however, inhibits
respiration. That is, stimulation of these pulmonary chemoreceptors with low levels of carbon
dioxide produces a rapid decrease in respiratory rate.
Carotid and aortic chemoreceptors have also been described in birds. In normal ducks, higher
than normal arterial pO2 produced decreased respiratory ventilation and lower than normal
arterial pO2 levels caused increased ventilation. High arterial pCO2 also increased ventilation
in these ducks. Studies indicate the probable existence of cranial chemoreceptors as are found
in mammals.