pathophysiology of respiration

1. COLLEGE OF MEDICINE AND HEALTH SCIENCES
SCHOOL OF MEDICINE AND PHARMACY
PROF.GAHUTU JEAN BOSCO,MD,PhD,FHEA(UK) , PROFESSOR OF PHYSIOLOGY
CHAPTER VI. DISORDERS OF THE RESPIRATORY FUNCTION
SECTION ONE. DISORDERS OF GAS EXCHANGE
1.1 ALVEOLAR HYPOVENTILATION
1.1.1 DEFINITON
Alveolar hypoventilation is the decrease of the quantity of fresh air which participates to alveolar
gas
exchange.
1.1.2 CAUSES
1.1.2.1 Decrease of tidal volume
- Muscular asthenia
- Chest pain (pleurisy …)
- Thoracic compression (tumor, pregnancy …)
1.1.2.2 Increase of anatomical or physiological dead space
1.1.3 CONSEQUENCES
- There is decreased renewal of alveolar air, hence a decrease of elimination of CO2, accumulation
of
CO2 in the organism: Hypercapnia (increased PaCO2).
- There is decreased oxygenation of blood whereas O2 consumption is unchanged, hence decrease
of
PaO2: hypoxemia.
1.2 ALVEOLAR HYPERVENTILATION
1.2.1 DEFINITION
Alveolar hyperventilation is the increase of the quantity of fresh air which participates to alveolar
gas
exchange.
1.2.2 CAUSES
- Metabolic acidosis
- Hypoxemia
- Voluntary hyperventilation.
1.2.3 CONSEQUENCES
- CO2: increased elimination of CO2 from the organism, hence decreased PaCO2: Hypocapnia
- O2: increased PaO2; however there is normoxemia, because Hb is saturated and the quantity of
dissolved O2 is negligible.
SECTION TWO. VENTILATION – PERFUSION IMBALANCE
In the normal upright human lung, blood flow is unevenly distributed. At normal lung volumes,
blood
flow increases markedly from apex to base. Ventilation also increases down the lung, but the
regional
differences are less marked than those for blood flow. The ventilation-perfusion ratio increases in

2. a
linear fashion from a low value near the base of the lung (0.6 times the ideal value) to a very high
value
near the apex (2.5 times the ideal value). This implies differences in gas exchange.
If the ventilation to an alveolus is reduced relative to its perfusion, the PO2 in the alveolus falls
because
less O2 is delivered to it and the PCO2 rises because less CO2 is expired. Conversely, if perfusion is
reduced relative to ventilation, the PCO2 falls because less CO2 is delivered and the PO2 rises
because
less O2 enters the blood. It is said that the high ventilation/perfusion ratios at the apices account
for
the predilection of tuberculosis for this area because the relatively high alveolar PO2 that results
provides a favorable environment for the growth of the tuberculosis bacteria.
2.1 Ventilation – perfusion imbalance of venous shunt type
There are alveoli which receive blood but are not ventilated.
2.1.1 Causes:
- alveoli filled with fluid, pus … (pulmonary edema, pneumonia)
- obstruction of respiratory ways (foreign body, bronchopneumonia, bronchitis, asthma)
2.1.2 Consequences: hypoxemia and hypercapnia
2.1.3 Reaction of the organism
2.1.3.1 Stimulation of ventilation by hypoxemia and hypercapnia, implying an increase of
ventilation in normal alveoli, improving CO2 elimination and blood oxygenation., hence a decrease
of
PaCO2 and an increase of PaO2.
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2.1.3.2 In areas where there is no gas exchange, the low PaO2 implies a vasoconstriction, which
deviates an important quantity of blood towards normal alveoli and the quantity of blood that
undergoes gas exchange increases.
2.2 Ventilation – perfusion imbalance of dead space type
There are alveoli that are ventilated but do not receive blood for gas exchange.
2.2.1 Causes
- embolism in the branches of the pulmonary artery.
- compression of pulmonary blood vessels by
* fibrosis
* alveolar dilation (in emphysema)
2.2.2 Consequences: there is a decrease of the volume of gas participating to exchange, hence
hypoxemia and hypercapnia.
2.2.3 Reaction of the organism:
- Stimulation of ventilation by hypoxemia and hypercapnia, with increase of PaO2 and decrease
of
PaCO2.
- In the alveoli not participating to gas exchange (not receiving blood), PACO2 is very low, which
implies
a bronchoconstriction in those areas, with the effect of deviating air towards alveoli where gas
exchange occurs.
SECTION THREE. DYSPNEA
3.1 DEFINITION
Dyspnea is defined as an abnormally uncomfortable awareness of breathing.
Although dyspnea is not painful in the usual sense of the word, it is, like pain, involved with both
the
perception of a sensation and the reaction to that perception.
Hyperpnea is the general term for an increase in the rate or depth of breathing regardless of the
patient’s subjective sensations. Tachypnea is rapid, shallow breathing.
3.2 MECHANISMS OF DYSPNEA
Dyspnea occurs whenever the work of breathing is excessive. Increased force generation is
required
of the respiratory muscles to produce a given volume change if the chest wall or lungs are less

3. compliant or if resistance to airflow is increased.
Dyspnea occurs when actual ventilation is ≥ 30 % of maximal ventilation.
Actual Ventilation = Tidal Volume X Respiratory Rate
Maximal Ventilation = Vital Capacity X Maximal Optimal Rate
Dyspnea is produced either by an increase of actual ventilation or by a decrease of maximal
ventilation.
In general, a normal individual is not conscious of respiration until ventilation is doubled, and
breathing is not uncomfortable until ventilation is tripled or quadrupled.
3.2.1 Factors determining an increase of actual ventilation.
3.2.1.1 Chemical factors: hypoxemia, hypercapnia, metabolic acidosis.
3.2.1.2 Non chemical factors, e.g.:
- Stimulation of respiration by muscular exertion
- Stimulation of respiration form psychic origin
- Stimulation of respiration by sensitization of Hering-Breuer reflex, e.g. in pulmonary
fibrosis, pulmonary inflammation, stasis or congestion.
3.2.2 Factors determining a decrease of maximal ventilation.
3.2.2.1 Decrease of Vital Capacity
Diseases accompanied with a decrease of vital capacity are called restrictive diseases.
A. Lesions hindering the expansion of the thorax, e.g., rib fractures, severe thoracic deformity,
painful pleurisy.
B. Lesions hindering pulmonary expansion:
• Disappearance of negative intrapleural pressure due for instance to presence of abnormal
content in the pleural cavity: hydrothorax, hemothorax, pyothorax.
• Pulmonary fibrosis: characterized by replacement of elastic fibers of the alveolar wall by fibrous
tissue, with increased resistance to expansion, hence pulmonary rigidity.
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• Pulmonary emphysema: alveoli have lost their elasticity: dilation of alveoli; the lungs are “fixed
in inspiration”, with little volume decrease during expiration and little volume increase during
inspiration.
C. Reduction of functional pulmonary mass, e.g.:
• Pulmonary resection
• Pulmonary edema, pneumonia: alveoli are filled with fluid.
• Pulmonary congestion (e.g., in left heart failure): there is alveolar compression.
3.2.2.2 Decrease of Maximal Optimal Respiratory Rate: obstructive lesions
The lesions are characterized by an increase of resistance to air flow consecutive to a decrease of
the
diameter of respiratory ways. This is typical of asthma, bronchitis, bronchopneumonia, and
emphysema (in the latter case, the dilated alveoli compress the respiratory ways.)
3.3 OBSTRUCTIVE LUNG DISEASES: asthma and chronic obstructive pulmonary disease
(COPD)
The fundamental physiologic problem in obstructive diseases is increased resistance to airflow as
a
result of caliber reduction of conducting airways. This increased resistance can be caused by
processes (1) within the lumen, (2) in the airway wall, or (3) in the supporting structures
surrounding
the airway. Examples of luminal obstruction include the increased secretions seen in asthma and
chronic bronchitis. Airway wall thickening and airway narrowing can result from the inflammation
seen in both asthma and chronic bronchitis and from the bronchial smooth muscle contraction in
asthma. Emphysema is the classic example of obstruction due to loss of surrounding supporting
structure, with expiratory airway collapse resulting from the destruction of lung elastic tissue.
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Pathophysiology of asthma
Local cellular events in the airways have important effects on lung function. As a consequence of
the
airway inflammation, smooth muscle hyperresponsiveness, and airway narrowing, airway
resistance
increases significantly. Thus, where under normal physiologic circumstances the small-caliber

4. peripheral airways do not contribute significantly to airflow resistance, these airways now are the
site
of increased resistance. This is worsened by the superimposed mucus hypersecretion and by any
additional bronchoconstrictor stimuli. Bronchial neural function also appears to play a role in the
evolution of asthma, though this is probably of secondary importance. Cough and reflex
bronchoconstriction mediated by vagal efferents follows stimulation of bronchial irritant receptors.
Peptide neurotransmitters may also play a role. The proinflammatory neuropeptide substance P
can
be released from unmyelinated afferent fibers in the airways and can induce smooth muscle
contraction and mediator release from mast cells. Vasoactive intestinal peptide (VIP) is the peptide
neurotransmitter of some airway nonadrenergic, non-cholinergic neurons and functions as a
bronchodilator; interruption of its action by cleavage of VIP can promote bronchoconstriction.
Airway obstruction occurs diffusely, though not homogeneously, throughout the lungs. As a
result,
ventilation of respiratory units becomes non uniform and the matching of ventilation to perfusion
is
altered. Areas of both abnormally low and abnormally high ventilation/perfusion ratios exist, with
the
low ventilation/perfusion ratio regions contributing to hypoxemia. Pure shunt is unusual in
asthma
even though mucus plugging is a common finding, particularly in severe, fatal asthma. Arterial
CO2
pressure is usually normal to low, given the increased ventilation seen with asthma exacerbations.
Hypercapnia is seen as a late and ominous sign, indicating progressive airway obstruction, muscle
fatigue, and falling alveolar ventilation.
3.4 OTHER PULMONARY CAUSES OF DYSPNEA
3.4.1 Pneumonia
Several mechanisms contribute to dyspnea:
- Restrictive factor: certain alveoli are filled with fluid; there is decrease of the functional mass,
vital capacity, and maximal ventilation.
- As the alveoli filled with fluid receive blood for gas exchange but are not ventilated, there is a
ventilation-perfusion imbalance of venous shunt type, hence hypercapnia and hypoxemia. The
increased PaCO2 and the decreased PaO2 stimulate ventilation, hence an increase of actual
ventilation.
- There is sensitization of the Hering-Breuer reflex.
3.4.2 Bronchopneumonia
In broncopneumonia, there are lesions not only in the lungs but also in the respiratory ways, with
a
decrease of the diameter of the bronchial lumen.
The mechanisms contributing to dyspnea in case of pneumonia also intervene in case of
bronchopneumonia. There is an additional obstructive factor, with decrease of maximal
ventilation.
3.4.3 Pulmonary fibrosis
The mechanisms of dyspnea involve:
• Restrictive factor: decrease of vital capacity, decrease of maximal ventilation
• Decrease of pulmonary expansion, which corresponds to alveolar hypoventilation
• Vascular compression by fibrosis resulting in a ventilation-perfusion imbalance of dead space
type: alveoli are ventilated but do not receive blood for gas exchange, hence an increase of
PaCO2 and a decrease of PaO2, which stimulate ventilation with increased actual ventilation.
• Sensitization of the Hering-Breuer reflex with increased actual ventilation.
3.4.4 Emphysema
The mechanisms of dyspnea involve:
• Restrictive factor: limited pulmonary expansion, hence decrease of vital capacity, decrease of
maximal ventilation
• Obstructive factor: compression of respiratory ways by dilated alveoli, hence decrease of
maximal optimal respiratory frequency, decrease of maximal ventilation.
• As volume modifications are limited during respiration, there is alveolar hypoventilation

5. resulting in increased PaCO2 and decreased PaO2, which stimulate ventilation, hence an
increase of actual ventilation.
3.5 EXTRAPULMONARY CAUSES OF DYSPNEA
3.5.1 Heart failure: Cf. Part III, Chap 4, section one, 1.4.3.1
Nocturnal episodes of severe paroxysmal dyspnea are characteristic of left ventricular failure.
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Dyspnea upon assuming the supine posture, orthopnea, is mainly characteristic of congestive
heart
failure.
3.5.2 Increased metabolism, e.g., in fever, hyperthyroidism, physical exertion. Increase of
ventilation
corresponds to increased needs in O2.
3.5.3 Anemia: Dyspnea occurs during physical exertion. Due to decreased Hb content in the
blood,
O2 transport capacity is decreased and cardiac output is increased at rest in order to satisfy
metabolic
needs in O2. During physical exertion, further increase of cardiac output is limited and tissue
oxygenation is insufficient, hence hypoxemia and stimulation of ventilation.
3.5.4 Metabolic acidosis, e.g. in case of:
- renal failure (insufficient elimination of acids)
- diabetic ketoacidosis: cf. Part VII. Chap VII, Section three.
SECTION FOUR. HYPOXIA
4.1 DEFINITION
Hypoxia is O2 deficiency at the tissue level. It is a more correct term than anoxia, there rarely
being no
O2 at all left in the tissues.
4.2 TYPES
Traditionally, hypoxia has been divided into four types. Numerous other classifications have been
used, but the four-type system still has considerable utility if the definitions of the terms are kept
clearly in mind.
The four categories are
(1) hypoxic hypoxia, in which the PO2 of the arterial blood is reduced, resulting in hypoxemia due
to
insufficient saturation of Hb in O2;
(2) anemic hypoxia, in which the arterial PO2 is normal but the amount of hemoglobin available
to
carry O2 is reduced, which results in hypoxemia (blood content in O2 is low);
(3) stagnant or ischemic hypoxia, in which the blood flow to a tissue (in case of vascular spasm,
thrombosis or embolism) or the global blood flow (in case of heart failure) is so low that adequate
O2 is
not delivered to it despite a normal PaO2 and hemoglobin concentration (normoxemia); and
(4) histotoxic hypoxia, in which the amount of O2 delivered to a tissue is adequate but, because
of
the
action of a toxic agent (e.g. CN-, which inhibits cytochrome oxidase), the tissue cells cannot make
use
of the O2 supplied to them.
4.3 HYPOXIC HYPOXIA
4.3.1 CAUSES
A. Inadequate oxygenation of the lungs because of extrinsic reasons
a. Deficiency of oxygen in atmosphere
b. Hypoventilation (neuromuscular disorders)
B. Pulmonary disease
a. Hypoventilation due to increased airway resistance or decreased pulmonary compliance
b. Alveolar ventilation-perfusion imbalance (cf. chapter two)
c. Diminished respiratory membrane diffusion.
C. Venous-to-arterial shunts (“right-to-left” cardiac shunts)

6. 4.3.2 EFFECTS OF HYPOXIA ON THE BODY
Hypoxia causes tachypnea: respiration is stimulated by a low PaO2 at the peripheral
chemoreceptors
(carotid and aortic bodies).
Hypoxia, if severe enough, can cause death of the cells, but in less severe degrees it results
principally
in:
(1) depressed mental activity, sometimes culminating in coma, and
(2) reduced work capacity of the muscles.
Hypoxia also produces chronic effects:
A. Polycythemia: increase of erythrocyte total mass. Hypoxia is the main stimulus for
erythropoietin
secretion by the kidneys and at a lesser extent by the liver; erythropoietin stimulates
erythropoiesis.
B.Pulmonary hypertension, which can lead to hypertrophy and failure of the right heart.
Mechanism: Pulmonary hypoxia provokes a pulmonary vasoconstriction, increase of resistance in
the
pulmonary circulation, hence pulmonary hypertension.
C. Cyanosis
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Reduced hemoglobin has a dark color, and a dusky bluish discoloration of the tissues, called
cyanosis,
appears when the reduced hemoglobin concentration of the blood in the capillaries is more than 5
g/dL. Its occurrence depends upon the total amount of hemoglobin in the blood, the degree of
hemoglobin unsaturation, and the state of the capillary circulation. Cyanosis is most easily seen
in
the nail beds and mucous membranes and in the lips and fingers. Cyanosis does not occur in
anemic
hypoxia, because the total hemoglobin content is low; in carbon monoxide poisoning, because the
color
of reduced hemoglobin is obscured by the cherry-red color of carbonmonoxyhemoglobin; or in
histotoxic hypoxia, because the blood O2 content is normal. A discoloration of the mucous
membranes
similar to cyanosis is produced by high circulating levels of methemoglobin.
D. Blunted hypoxic ventilatory response
Long-term residence at high altitude – or sleep apnea with repeated episodes of severe oxygen
desaturation – may blunt the hypoxic ventilatory response. In such individuals, the development
of
lung disease and hypercapnia may remove any endogenous stimulus to breathing. This pattern is
seen in patients with obesity-hypoventilation syndrome.
SECTION FIVE. HYPOCAPNIA
5.1 Hypocapnia is the decrease of PaCO2, as a result of hyperventilation. During voluntary
hyperventilation, the arterial PCO2 falls from 40 (at sea level) to as low as 15 mm Hg while the
alveolar
PO2 rises to 120–140 mm Hg.
The more chronic effects of hypocapnia are seen in neurotic patients who chronically
hyperventilate.
Cerebral blood flow may be reduced 30% or more because of the direct constrictor effect of
hypocapnia
on the cerebral vessels. The cerebral ischemia causes light-headedness, dizziness, and
paresthesias.
Hypocapnia also increases cardiac output. It has a direct constrictor effect on many peripheral
vessels, but it depresses the vasomotor center, so that the blood pressure is usually unchanged or
only
slightly elevated.
Other consequences of hypocapnia are due to the associated respiratory alkalosis, the blood pH
being

7. increased to 7.5 or 7.6. The plasma HCO3- level is low, but HCO3- reabsorption is decreased
because of
the inhibition of renal acid secretion by the low PCO2. The plasma total calcium level does not
change,
but the plasma Ca2+ level falls because plasma proteins release H+ to keep normal [H+] in the
plasma
and Ca2+ replaces H+ ions on the negatively charged proteins. As Ca2+ is a membrane potential
stabilizer, the lowering of [Ca2+] results in an increased neuromuscular excitability and
hypocapnic
individuals develop carpopedal spasm and signs of tetany.
The reaction of the organism to respiratory alkalosis is:
- Increased elimination of HCO3- in order to renormalize the pH.
• There is increased production, in the brain and the erythrocytes, of fixed acids (e.g., lactic acid)
which dissociate and H+ neutralize HCO3-.
• Decreased reabsorption of HCO3- in the kidneys, consecutive to a decrease of H+ excretion.
- Stimulation of Na+/K+ exchange in the kidneys (distal convoluted tubule), as the Na+/H+
exchange
is inhibited, leading to hypokalemia.
SECTION SIX. HYPERCAPNIA
6.1 Definition: Hypercapnia means excess carbon dioxide in the body fluids, due to retention of
CO2
in the body.
6.2 Causes: It is caused by a decrease of pulmonary expansion, a ventilation-perfusion
imbalance, or
a
diffusion abnormality (in extreme cases of alveolo-capillary block, because CO2 diffusion capacity
is
high).
6.3 Consequences: Retention of CO2 in the body initially stimulates respiration. Retention of
larger
amounts produces symptoms due to depression of the central nervous system: confusion,
diminished
sensory acuity, and, eventually, coma with respiratory depression and death. In patients with
these
symptoms, the PCO2 is markedly elevated, there is severe respiratory acidosis, and the plasma
HCO3-
may exceed 40 meq/L.
6.4 Reaction of the organism: Large amounts of HCO3- are excreted, but more HCO3- is
reabsorbed,
raising the plasma HCO3- and partially compensating for the acidosis. Coupled with increased
HCO3-
reabsorption, there is increased renal H+ elimination.
In the brain, buffer systems trap H+ as CO2 is hydrated and carbonic acid dissociated, so that
[HCO3-]
increase is very important and can renormalize pH.
There is inhibition of the renal Na+/K+ exchange in the distal convoluted tubule (in favor of Na+/H+
exchange), leading to hyperkalemia.
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6.5 Chronic hypercapnia and oxygenotherapy
In patients with chronic hypercapnia, brain pH is returned toward normal by compensatory
changes
in
bicarbonate levels. This makes the central chemoreceptors less sensitive to further changes in
PaCO2.
In this instance, a patient’s minute ventilation may depend on tonic stimuli from the carotid
bodies. If
such a patient were given high concentrations of inspired oxygen, it could reduce carotid body

8. output
and lead to a fall in minute ventilation. In rare cases, this can be extreme enough to cause a rapid
rise
in PaCO2 and coma.