REGULATION OF RESPIRATION

Ventilation is the movement of air in and out of the lungs which facilitates gas
exchange. It occurs via the respiratory muscles, which contract and relax rhythmically to fill
the lungs with air in inspiration and empty them in expiration. Spontaneous respiration is
produced by the rhythmic discharges from brain to the motor neurons that innervate the
respiratory muscles and is regulated by 2 mechanisms. They are:

1. Nervous/ neural regulatory mechanism

2. Chemical regulatory mechanism

NERVOUS/ NEURAL REGULATION OF RESPIRATION

Nervous regulation of respiration occurs in 2 ways. They are:

1. Involuntary/ Automatic control

2. Voluntary control

Involuntary/ Automatic control of respiration

Involuntary respiration is under the subconscious control. The diaphragm and

intercostal muscles, the primary respiratory muscles, are stimulated by a group of neurons
located in the medulla and pons. They are together called the Respiratory Centers that send
impulses via the phrenic and intercostal nerves causing the contraction of respiratory muscles.
The neuron groups or respiratory centers are:

a. Medullary Respiratory centers: Dorsal Respiratory Group (DRG) and Ventral

Respiratory Group (VRG)
b. Pontine Respiratory Centers: Apneustic Center and Pneumotaxic Center

DRG and Apneustic center control Inspiration and VRG and Pneumotaxic center control
expiration. VRG is inactive during respiration and gets activated only during forced expiration.

Rhythmic respiration is initiated by a small group of pacemaker cells in the pre- Botzinger
complex, located in the medulla. Rhythmic impulses from this complex stimulates the DRG
and VRG and is responsible for the rhythmicity of respiration.

Medullary Respiratory Centers

Dorsal Respiratory Group (DRG): DRG is located in the medulla near the nucleus of tractus
solitaries (NTS), made up of neurons that control Inspiration. These neurons maintain the
normal rhythm of respiration by the rhythmic discharge of impulses. Formerly these neurons
were collectively called Inspiratory center because they generate inspiratory ramp by virtue of
their auto- rhythmic property. Inspiratory ramp is the pattern of discharge from the DRG
neurons characterized by steady increase in amplitude of action potential. The impulses from
DRG are not produced continuously but only for a period of two seconds during which
inspiration occurs. After 2 seconds the ramp signals stop abruptly and do not appear for another
3 seconds. The switching off ramp signals causes expiration. At the end of 3 seconds the
inspiratory ramp signals reappear in the same pattern and the cycle is repeated. Normally during
inspiration the DRG inhibit expiratory neurons and during expiration the expiratory neurons
inhibit inspiratory neurons. Thus the medullary respiratory centers control each other through
reciprocal innervation.

Ventral Respiratory Group (VRG): VRG is located at the ventral part of the medulla. Earlier
the VRG was called Expiratory center. Ventral group has both inspiratory and expiratory
neurons. The inspiratory neurons are found in the central area of the group. The expiratory
neurons are in the caudal and rostral area of the group. Normally the VRG are inactive during
quiet breathing and become active during forced breathing. During forced breathing these
neurons stimulate both inspiratory muscles and expiratory muscles.

Pontine Centers

Although the rhythmic discharge of neurons in the medullary respiratory center is

spontaneous, it is modified by Pontine centers and afferents coming from receptors in airways
and lungs through vagus.

Apneustic center: It is situated in reticular formation of lower pons. This center increases the
depth of inspiration by acting directly on DRG. The pneumotaxic center inhibits the apneustic
center and restricts the duration of inspiration.

Pneumotaxic center: It is situated in the dorsolateral part of the reticular formation in the
upper pons. The primary function of the pneumotaxic center is to control the medullary
respiratory centers particularly the DRG. It acts through the apneustic center. The pneumotaxic
center inhibits the apneustic center so that the DRG is inhibited. Because of this, inspiration
stops and expiration starts. Thus the pneumotaxic center influences the switching between
inspiration and expiration. The pneumotaxic center increases the respiratory rate by reducing
the duration of inspiration.
The switch- off mechanism coming from pneumotaxic center and vagus are the key factors that
determine the rate and rhythm of respiration.

Reflexes that control/ affect respiration:

1. Hering Breuer Inflation and Deflation reflexes: Inflation and deflation reflexes occur
as a result of the impulses sent by stretch receptors on the surface of lungs.
When lungs stretch than the normal, the stretch receptors are stimulated to a greater
extend thereby increasing the rate of afferent impulses passing through the vagus to
inspiratory center (DRG and Apneustic center). The impulses reaching here through the
vagus nerve inhibit the center, leading to the inhibition of discharge of impulses to the
inspiratory muscles. Inspiration stops and expiration begins. This brings back the lungs
to its normal volume and prevents overstretching of lungs. This reflex is called Hering
Breuer Inflation Reflex.
Similarly when the lungs deflate excessively, there will be no impulses from the stretch
receptors of lungs. So no inhibitory impulses reach the Inspiratory center through vagus
nerve to supress them. Inspiration occurs automatically leading to filling and stretching
of lungs, thereby bringing back the lungs to its normal volume. This reflex is called
Hering Breuer Deflation Reflex and prevents the lungs from collapsing.
2. J- Reflex (pulmonary chemoreflex): Excessive inflation of lungs stimulates
unmyelinated vagus afferent nerve endings called J- receptors or Juxta- pulmonary
capillary receptors located in the alveolar wall. These receptors better respond to
pulmonary congestion or edema, inhalation of strong irritants or chemicals etc. they do
not function during normal respiration and the effects of stimulation of J receptors are-
Hypotension, bradycardia, tachypnea (shallow, rapid breathing) and dyspnea
(decreased breathing) due to bronchospasm and weakness of skeletal muscles.
3. Cough and Sneezing reflex: These are protective reflexes that occur due to stimulation
of irritant receptors of larynx, trachea and respiratory bronchioles. These reflexes begin
with a deep inspiration followed by forced expiration against a closed glottis. The
glottis is suddenly opened and air is expelled at high velocity. In sneezing reflex,
expiration is with a continuously open glottis.

Voluntary control of Respiration

Voluntary respiration is under conscious control. It is controlled via the motor cortex
in the cerebrum which receives inputs from the limbic system and hypothalamus. The
respiration can be modified in rate and depth only for a specific time period. The pathway for
such a control is via corticospinal tract which originates from the cerebral cortex and ends on
the spinal neurons innervating the respiratory groups of muscles. Thus this pathway bypasses
the medullary respiratory neurons.

CHEMICAL REGULATION OF RESPIRATION

Chemical regulation of respiration occurs when the levels of PO2, PCO2 or pH changes.
These changes act on the respiratory centers to bring back the blood chemistry to normal. It is
brought about by a set of receptors called Chemoreceptors that respond to changes in the
oxygen, carbon dioxide or pH.

Chemoreceptors are of two types:

1. Central/ Medullary chemoreceptors

2. Peripheral chemoreceptors

PERIPHERAL CHEMORECEPTORS

Peripheral chemoreceptors are located in the carotid sinus and aortic arch and respond
to changes in blood levels of Oxygen and Carbon dioxide. Carotid sinus is innervated by carotid
sinus nerve branch of glossopharyngeal nerve and aortic body in the aortic arch is innervated
by the aortic nerve branch of vagus nerve.

Mechanism of action

Decrease in PO2 (hypoxia) or increase in PCO2 (hypercapnia) stimulates peripheral

chemoreceptors which in turn stimulates the Inspiratory centers (DRG and Apneustic Center).
As a result, there will be rise in pulmonary ventilation and wash out of excess carbon dioxide.

CENTRAL CHEMORECEPTORS

Central or medullary chemoreceptors are located in the ventral surface of medulla near
to medullary respiratory centers. They get stimulated by the H+ concentration of CSF and brain
interstitial fluid.

Mechanism of action (mechanism of H+ formation)

When pH of blood decreases, i.e. H+ concentration in blood increases, it cannot cross

the blood- brain barrier. So it gets converted to CO2 in the following way:

H+ + HCO3- H2CO3 CO2 + H2O

This carbon dioxide readily penetrates the blood- brain and blood- CSF barriers and produces
H+ ions in the following way:

CO2 + H2O H2CO3 H+ + HCO3-

Hydrogen ions formed directly stimulates the central chemoreceptors that stimulates the
Inspiratory centers thereby increasing pulmonary ventilation. Central chemoreceptors respond
only to abrupt changes in blood carbon dioxide. They are inhibited by anesthesia, cyanide,
sleep etc.

TRANSPORT OF GASES

TRANSPORT OF OXYGEN

O2 is transported from lungs to tissues by the cardiovascular system. Amount of O2

delivered to the tissues depends on:

1. Amount of O2 in the inspired air

2. Gaseous exchange in the lungs
3. Blood flow to tissues
4. Amount of O2 carried by the blood to tissues and the ability of tissues to extract the O2
from blood.

Distribution of O2 in the body

Medium pO2 (mm Hg) O2 content

Inspired air 158 21 mL/ dL
Expired air 116 16 mL/ dL
Alveolar air 100-104 13- 14 mL/ Dl
Arterial blood 98- 100 19 mL/ Dl
Venous blood 40 14 mL/ dL

O2 is transported in 2 ways/ forms:

1. Dissolved form- 3% of O2 is transported in the dissolved form, i.e. 0.3 mL/ 100ml.
amount of dissolved O2 increases with increase in arterial PO2.
2. Combined with hemoglobin- in the form of Oxy- hemoglobin- 97%

Each hemoglobin molecule has four heme groups with an iron atom in the ferrous form.
Oxygenation of hemoglobin takes place rather than oxidation because Oxygen combines
with hemoglobin very loosely and is reversible and iron remains in the ferrous form itself.
Hemoglobin accepts oxygen readily and releases it very rapidly. The O2 carrying power of
hemoglobin is given by the Oxygen- Hemoglobin Dissociation Curve, a curve relating to
the percentage of O2 saturation of hemoglobin to PO2.

Oxygen Carrying Capacity of Blood: The O2 carrying capacity of blood refers to the
amount of O2 transported by blood. 1G of Hb carries 1.34 ml of O2. It is called O2 carrying
capacity of Hb. The normal Hb content in blood is 15g%. So the blood with 15g% of Hb
must carry 20.1 ml% of O2. But, the blood with 15g% of Hb carries only 19ml % of O2.
The O2 carrying capacity of blood is only 19ml % because the Hb is not fully saturated with
O2. It is saturated only for about 95%. This is due to physiological shunt.

Oxygen- Hemoglobin Dissociation Curve (ODC)

ODC is a sigmoid curve showing the relationship between partial pressure of Oxygen
and percentage of Hemoglobin saturation. The combination of O2 with hemoglobin is a
stepwise process and the affinity for O2 is different at different steps, i.e. combination of
1st heme of the hemoglobin with O2 increases the affinity of the next and so on.

The lower part of the curve indicates association of O2 with Hb. The upper part of the curve
indicates the dissociation of O2 from Hb depending upon the PO2.

The graph has 3 phases:

1. Flat top- When PO2 falls from 100 mm Hg to 60 mm Hg, there is not much change in
the % saturation of Hb and almost 90% saturation is there. This is sufficient for normal
activities. This is a protective measure for a person going to high altitude. Upto 60 mm
Hg, he does not develop hypoxic symptoms.
 2. Steep fall (dissociation)- Below 60mm Hg, there is a steep fall in the curve which
represents the rapid release of O2 from Hb and this is the tissue phase. In the tissue,
pO2 is 40mm Hg, so Oxygen dissociates rapidly and tissues extract oxygen rapidly.
3. Flat bottom- at low levels of Oxygen, oxygen dissociation becomes difficult.

P50

P50 is the pO2 at which haemoglobin is 50% saturated with O2. Normal value is 26mm Hg. It
is an index used to indicate the affinity of Hb to O2. Higher the P50, lower the affinity of Hb
for O2, i.e. dissociation is favoured.

Factors that Influence Oxygen Binding

A RIGHT SHIFT can be caused by an increase in 4 factors:

• Increased Temperature

• Increased [H+] concentration

• Increased pCO2 (the shifting of curve to right side due to increased PCO2 is called Bohr
effect where the Hb shows more affinity towards CO2)

• Increased 2,3 DPG level.

A LEFT SHIFT is caused by- decreased PCO2, increased PO2, decreased temperature
and decreased hydrogen ion concentration.

TRANSPORT OF CARBONDIOXIDE

CO2 is transported by the blood from tissues to the alveoli. CO2 is transported in the blood in 4
ways:

1. As dissolved form
2. As carbonic acid
3. As bicarbonate
4. As carbamino compounds.
 Transport of CO2 as dissolved form: CO2 diffuses into the blood and dissolves in the
fluid of plasma forming a simple solution. Only about 3 ml/100ml of plasma of CO2 is
transported as dissolved state. It is about 8% of total CO2 in the blood.
 Transport of CO2 as carbonic acid: Part of dissolved CO2 in plasma combines with
water to form carbonic acid (H2CO3). Though CO2 is transported in this form, this
 reaction is very slow and is negligible.
CO2 + H2 O ------------> H2 CO 3

 Transport of CO2 as bicarbonate: About 67% of CO2 is transported as bicarbonate.

From plasma, the CO2 enters the RBCs, CO2 combines with water to form carbonic
acid. The reaction inside RBC is very rapid. The rapid formation of H2CO3 inside the
RBC is due to the presence of an enzyme called carbonic anhydrase ( It is present only
inside the RBCs, not in the plasma). H2CO3 is very unstable. It gets dissociated into
bicarbonate and Hydrogen ions. The concentration of HCO3- inside the RBC causes
diffusion of HCO3- through the cell membrane into the plasma.
Chloride Shift or Hamburger Phenomenon: It is the exchange of a chloride ion for a
bicarbonate ion across the erythrocyte membrane. Chloride shift occurs when CO2 enters the
blood from tissues. In plasma plenty of NaCl is present. It dissociates into Na+ and Cl-. When
the negatively charged HCO3- ion moves out of RBC into the plasma, the negatively charged
chloride move into the RBC in order to maintain the electrolyte equilibrium. The HCO3-
combine with the Na+ in the plasma and form NaHCO3. In this form it is transported in the
blood.

Reverse Chloride Shift: It is the process by which the Cl- are moved back in to the plasma
from RBC. It occurs when blood reaches the lungs and flows through pulmonary capillaries.
It helps in elimination of CO2 from the blood. The H2CO3 is converted back into CO2, which
has to be expelled out.

When the blood reaches the alveoli, sodium bicarbonate in the plasma dissociates into
sodium and bicarbonate ions. Bicarbonate ion moves in to the RBC. It makes Cl- to move out
of the RBC in to the plasma where it combines with sodium and forms NaCl. At the same time
O2 also enters the RBC. It displaces H ions from Hb. The H+ combines with H2Co3 and forms
HCO3 - , which dissociates in to H2O and CO2. The CO2 is expelled out.

 Transport of CO2 as carbamino compounds: About 25% CO2 is transported as

carbamino compounds. CO2 combines with Hb to form carbamino Hemoglobin. And
it combines with plasma proteins to form carbamino proteins. The carbamino proteins
and carbamino hemoglobin are together called as carbamino compounds. This
combination of CO2 with proteins and Hb is a reversible one.
HYPOXIA

It is defined as the reduced availability of O2 in the tissues. It is classified in to four types based on
four different characteristics.

Hypoxic hypoxia - Decreased O2 content in blood caused due to low oxygen tension in the inspired air
and low oxygen tension in arterial blood, respiratory disorders associated with decreased
pulmonary ventilation, inadequate oxygenation in lungs and congestive heart failure. Low oxygen
tension in inspired air occurs at high altitudes, while breathing in closed space etc. Decreased
pulmonary ventilation occurs in asthma, poliomyelitis, brain tumors, pneumothorax. Inadequate
oxygenation occurs in emphysema, fibrosis of alveoli, pulmonary edema, hemorrhage,
pneumonia, bronchial obstruction, lack of surfactant etc.

Anemic hypoxia - It is characterized by inability of blood to carry oxygen due to decreased RBC or
decreased Hb content. Oxygen availability will be normal. It may be caused due to decreased RBC or
Hb content, formation of altered Hb by poisoning with chlorates, oxidation of iron to ferric producing
methemoglobin, combination of Hb with gases other than O2 and CO2 like CO, CH 4 etc.

Stagnant hypoxia - Caused due to decreased flow rate of blood. It is caused due to congestive heart
failure, hemorrhage, surgical shock, vasospasm, thrombosis, embolism etc.

Histotoxic hypoxia - Inability of the tissues to utilize oxygen. Cyanide or sulphide poisoning destroys
the cellular oxidative enzyme that causes complete paralysis of cytochrome oxidase system. So
utilization of oxygen by tissues decreases.

Effects of Hypoxia

1. It causes increased production of erythropoietin by stimulating kidney thereby increasing RBC

production.
2. Increase in the rate and force of contraction of heart initially.
3. Increase in the rate of respiration.
4. Loss of appetite, nausea, vomiting etc; feeling of thirst.
5. Disorientation, loss of power of judgment, impaired memory, weakness, lack of co-ordination
and fatigue of muscles, unconsciousness etc.
Hyperbaric O2 therapy with 2-3atm is tolerated by the patient for about 5 hours. During this period,
the dissolved O2 increases in the arterial blood because the O2 carrying capacity of Hb is limited. At
this level tissue, O2 tension also increases to about 200 mm Hg. However, tissues tolerate the high P O2
without much adverse effects but O2 toxicity develops when pure O2 is administered for long periods.
O2 toxicity is the increases O2 content in tissues beyond certain critical level.
ARTIFICIAL RESPIRATION
METHODS
1. Manual methods:
a. Mouth to mouth method
b. Back pressure arm lift method (Holger- Neilsen method)
Mouth to mouth method:
This is the most superior to all other methods and is the only manual method capable of
producing adequate ventilation.
The patient is placed in supine position with the neck extended and jaw elevated. The rescuer
should place one hand behind the neck of the subject which will eliminate the obstruction of
airway due to falling back of the tongue. The rescuer takes a deep inspiration, places his mouth
over the patient’s mouth and expires into the patient’s mouth. While doing this the patient’s
nostrils should be closed. Expiration should be forceful and twice the tidal volume. This helps
in inflation of the lungs and expansion of chest wall. The rescuer then removes his mouth and
allows the patient to breath passively. The procedure is repeated about 12-20 times/min.
Holger- Neilsen method:
This is a prone position method where the patient is placed in prone position with arms
abducted at the shoulders and elbows remaining flexed. The face is turned to one side and rests
on the hands. The rescuer kneels down in front of the patient facing towards the head and hands
placed on the sides of chest, palms on the patient’s scapula and bends forward to apply deep
pressure on the chest. This causes expiration. Then the rescuer pulls his arms up to bring about
inspiration.
2. Mechanical methods:
a. Drinker’s method
b. Ventilator method
Drinker’s method:
It involves the use of an air tank called tank respirator into which the patient is placed with his
head outside. Alternate negative and positive pressures are obtained in the tank which produces
movements of chest wall resembling normal inspiration and expiration. Negative pressure pulls
on chest and causes inspiration and positive pressure compresses the chest and causes
expiration.
Ventilator method:
Now ventilators are used from which pulses of air or mixtures of respiratory gases are delivered
after intubation the patient.