CHAPTER

2
Pulmonary Physiology
Pnina Weiss, MD, MHPE, FAAP

Introduction
The primary function of the respiratory system is to provide oxygen to arterial
blood to nourish the body’s tissues and to remove carbon dioxide from the
returning venous blood. Gas exchange takes place at the level of the alveoli
surrounded by a network of thin capillaries. Oxygen and carbon dioxide move
between the air and blood by a process of diffusion. Air is brought to the alveoli
by branching bronchi and bronchioles. The muscles of respiration act as a pump
to move air in and out of the lungs. Elastic properties of the lung and chest wall
and airway resistance affect the work and efficiency of the system. Disease
processes that alter these relationships can lead to respiratory failure, defined
as failure of the lungs to oxygenate and/or ventilate adequately.

Gas Exchange
The tensions or pressures of dissolved oxygen or carbon dioxide in the blood are
designated as Po2 and Pco2 (individual partial pressures of the gases), respec-
tively. Table 2-1 shows the partial pressures of gases in the atmosphere and the
lung. Dry atmospheric air is composed primarily of nitrogen. Oxygen consti-
tutes 20.93% of the atmosphere; there is a minimal amount of carbon dioxide.1
Table 2‑1. Partial Pressure of Gases in the Atmosphere and the Lung
Gas Air (mm Hg) Humidified Air (mm Hg) Alveoli (mm Hg)
Oxygen 159 149 104
Carbon dioxide 0.3 0.3 40
Nitrogen 600.6 564 569
Water vapor 0 47 47
Adapted with permission from Levitzky M. Pulmonary Physiology. 4th ed. McGraw-Hill, Inc; 1995:74–75.

Dry atmospheric air is humidified as it travels down the airways into the lungs.
The Po2 in the alveoli is determined by the balance between the amount that
flows in and the amount that is removed by the pulmonary capillaries. It will
be decreased if barometric pressure is low (ie, high altitude), if there is no
fresh supply of air (ie, atelectasis), or if Pco2 is elevated (ie, hypoventilation).
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As gas moves in and out of the alveolus, blood flows through the pulmonary
capillary vessels, which provide a large surface for gas exchange. Figure 2-1
depicts how gas exchange occurs in the alveolus. The driving force for gas
exchange is the difference in pressures of Po2 and Pco2 between the venous
blood and alveoli. Under normal conditions, the gases equilibrate fully, and
the Po2 and Pco2 of pulmonary capillary blood equal those of the alveoli.2

PO2 = 149
PCO2 = 0.3

Alveolus

PO2 = 104
PCO2 = 40

Venous Arterial
blood blood
PO2 = 100
PCO2 = 40
PO2 = 40
PCO2 = 45 Pulmonary capillary blood

Figure 2-1. Gas exchange in the alveolus (values in mm Hg). Oxygen and carbon dioxide diffuse
across the alveolar-capillary membrane. There is little carbon dioxide in the atmosphere. The Po2
in the alveolus is high, and oxygen diffuses into the capillary blood. Pco2 is high in the venous
blood, and carbon dioxide diffuses into the alveolus.
Oxygen Consumption and Carbon Dioxide Production
The total amount of oxygen taken up by the body in 1 minute is called the
oxygen consumption, and the amount of carbon dioxide produced is the
carbon dioxide production. Oxygen consumption and carbon dioxide pro-
duction increase with exercise. The ratio between them is known as the
respiratory quotient and is approximately 0.8. The respiratory quotient
increases (ie, more carbon dioxide is produced for each molecule of oxygen
consumed) on a high carbohydrate diet. For patients in respiratory failure,
low carbohydrate and high lipid formulas are suggested to decrease the
respiratory quotient and decrease carbon dioxide production.3

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Chapter 2—Pulmonary Physiology

Ventilation
The process of ventilation brings air in and out of the lungs. During inspira-
tion, the size of the thoracic cavity increases and air moves into the lungs.
The fresh air is carried through conducting airways to the alveoli, which
are responsible for gas exchange.

Alveolar and Dead Space Ventilation

The volume of a breath is known as the tidal volume.2 However, only part of
the breath is used for gas exchange. Only the air that reaches the alveolus is
involved in gas exchange; this is known as alveolar volume and is shown in
Figure 2‑2. The conducting airways are not involved in gas exchange, and
the volume of air in them is known as dead space. About 30% of each breath
ends up in dead space.4 In some disease processes, the dead space volume
increases, and less air is available in each breath for gas exchange.

Dead
space

Tidal
volume

Alveolar
volume

Venous
blood
Pulmonary
capillary

Figure 2‑2. The relationship of tidal volume to dead space and alveolar volume. In each breath
(tidal volume), some of the air goes into the alveoli (alveolar volume) and is available for gas
exchange. The rest remains in the conducting airways and is known as dead space.

Total ventilation is the total volume of fresh air that reaches the lung each
minute. It is determined by the volume of each breath multiplied by the
number of breaths per minute. The relationship of tidal volume, respira-
tory rate, and total ventilation is shown in Figure 2‑3. If a child has a tidal
volume of 100 mL and is breathing 15 breaths/min, then the total ventilation
is 1,500 mL/min. Alveolar ventilation is the total volume of air that reaches
the alveoli and is available for gas exchange each minute. Thus, if a disease
process decreases the respiratory rate and/or the volume of each breath or
increases the dead space, it will decrease the effective ventilation. Total

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ventilation is easy to quantify because tidal volume is easily measured;

alveolar ventilation is more difficult to quantify because dead space is more
difficult to measure.

Tidal 100
volume mL

15 breaths/min Dead space

Alveolar
ventilation
1,000 mL
Total
ventilation
1,500 mL

Dead space
ventilation
500 mL

Figure 2‑3. Components of total ventilation: tidal volume, respiratory rate, alveolar ventilation,
and dead space ventilation. Total ventilation is determined by the volume of each breath
multiplied by the number of breaths per minute. In this diagram, dead space is one-third of
total volume.

Relationship of Ventilation to Arterial Pco2

The removal of carbon dioxide from the blood depends on alveolar ventilation.
If alveolar ventilation increases, then the elimination of carbon dioxide in-
creases, and its concentration in the arterial blood decreases.1 This relationship
is shown in Figure 2‑4. If alveolar ventilation decreases, then the elimination
of carbon dioxide decreases, and it accumulates in the arterial blood. There is
an inverse relationship between the alveolar ventilation and the arterial carbon
dioxide concentration: if alveolar ventilation doubles, the arterial carbon
dioxide concentration is halved. If the alveolar ventilation decreases by
50%, then the arterial carbon dioxide concentration doubles.
The effect of changes in respiratory rate, tidal volume, and dead space on
ventilation and arterial carbon dioxide level are depicted in Table 2‑2. A wide
variety of factors can cause decreased alveolar ventilation with an increase in
arterial carbon dioxide tension. A decrease in respiratory rate or tidal volume
can result from drugs such as opiates, benzodiazepines, or alcohol; central
nervous system infection; trauma; seizures; or sepsis. Preterm infants can
have cessation of breathing or apnea of prematurity. In congenital central hypo-
ventilation syndrome, children have a decreased central drive to breathe and,
consequently, hypoventilation. Children with obstructive sleep apnea have a

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relative decrease in their tidal volume because they cannot effectively breathe
in. Chest wall trauma or deformity, neuromuscular weakness, and lung
disease can also decrease the tidal volume and impair ventilation. Disease
processes, such as acute respiratory distress syndrome, scoliosis, pulmonary
embolus, or general anesthesia, can increase the dead space and thus impair
the proportion of effective ventilation.
150 Figure 2‑4. The relationship
between ventilation and carbon
dioxide levels in the lung.
Increases in alveolar ventilation
100 will decrease carbon dioxide
PACO2 (mm Hg)

levels; conversely, decreases in

ventilation will increase
carbon dioxide levels. Paco2
50 is the Pco2 in the alveolus.
Adapted from Lumb AB. Nunn’s Applied
Respiratory Physiology.
5th ed. Edinburgh, Scotland:
0 Butterworth Heinemann;
0 2 4 6 8 10 2000, with permission.
Alveolar Ventilation (L/min)

Table 2‑2. Effect of Changes in Respiratory Rate, Tidal Volume, and Dead Space on Total
Ventilation and Arterial Carbon Dioxide Level
Respiratory Rate Tidal Dead Total Arterial
(breaths/min) Volume Space Ventilation Pco2 Causes
Medications, alcohol,
 ↔ ↔ ↓ ↑ central nervous system
infections, seizures, apnea
Chest wall trauma,
↔  ↔ ↓ ↑ neuromuscular weakness,
lung disease
Acute respiratory distress
↔ ↔  ↔ ↑ syndrome, scoliosis,
pulmonary embolus
Metabolic acidosis,
 ↔ ↔ ↑ ↓ salicylate overdose,
anxiety, pain
Metabolic acidosis,
↔  ↔ ↑ ↓ salicylate overdose,
anxiety, pain

↔ ↔  ↔ ↓
Mechanical ventilation,
deep breathing
The primary events are shown in bold arrows; the effects on total ventilation and arterial PCO2 are listed.
Decreases in respiratory rate and tidal volume decrease total ventilation and increase arterial carbon dioxide
tension. Increases in respiratory rate and tidal volume increase total ventilation and decrease arterial carbon
dioxide tension. Changes in dead space do not affect total ventilation; they will, however, affect alveolar
ventilation and carbon dioxide levels.

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Increased alveolar ventilation results in a decrease in Pco2. Causes for

increasing respiratory rate and tidal volume are depicted in Table 2‑2. The
most common causes include metabolic acidosis, salicylate ingestion, anxiety,
central nervous system disorders, and pain. There are also some instances in
which the dead space can be decreased.

Regulation of Arterial Pco2

The arterial carbon dioxide concentration reflects a balance between carbon
dioxide production and elimination. More carbon dioxide is produced when
the metabolic rate is increased. Fever or increased muscle activity (shivering,
seizures) produces more carbon dioxide and can produce elevations in arterial
carbon dioxide levels unless ventilation is increased.
Ventilation is controlled by sensors called chemoreceptors, which are located
in the brain and aortic bodies (at the common carotid artery and aortic arch,
respectively). These receptors sense changes in arterial carbon dioxide concen-
tration. They respond by activating effectors that alter ventilation to keep
arterial carbon dioxide concentration normal.

Acid-Base Status
Carbon dioxide is transported in the blood in 3 forms: dissolved, bicarbonate,
and combined with proteins such as carbamino compounds. In arterial blood,
most carbon dioxide is carried as bicarbonate (90%).5
Carbonic Anhydrase
↓
CO2 + H2O D H2CO3 D H+ + HCO-3
Carbon dioxide and water are converted to carbonic acid by the enzyme car-
bonic anhydrase in red blood cells. Carbonic acid spontaneously dissociates
into hydrogen ions (acid) and bicarbonate.
The pH of the blood depends on the relationship of bicarbonate and carbon
dioxide. As the arterial Pco2 increases, the pH decreases, which is known as
respiratory acidosis. As the arterial Pco2 decreases, the pH increases, which
is known as respiratory alkalosis.
The lungs regulate the concentration of carbon dioxide, and the kidneys control
the bicarbonate concentration. In response to respiratory acidosis, the kidneys
will compensate over 3 to 5 days by conserving bicarbonate and will create a
secondary metabolic alkalosis. Table 2‑3 provides a list of primary acid-base
disorders and their secondary compensation. In contrast, in response to
respiratory alkalosis, the kidneys will eliminate excess bicarbonate and
create a secondary metabolic acidosis in compensation.

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Chapter 2—Pulmonary Physiology

Table 2‑3. Primary Acid-Base Disorders and Compensation

Carbon Dioxide Bicarbonate
Disorder Level pH Level
Acute respiratory acidosis

Chronic respiratory acidosis

Acute respiratory alkalosis

Chronic respiratory alkalosis

Metabolic acidosis

Metabolic alkalosis

The primary events are shown in bold arrows; the secondary effects are listed, and the arrow lengths
are proportional to the magnitude of the change. For example, in acute respiratory acidosis, the primary
event is an elevation in arterial Pco2. There is a concomitant decrease in pH and a very small increase in
bicarbonate. In chronic respiratory acidosis, there is renal compensation and bicarbonate increases. As
a result, the Pco2 is still elevated, but the pH is not as dramatically low as in acute respiratory acidosis.

It is possible to determine the primary acid-base disorder and the compensa-

tion by plotting the values on a nomogram as exemplified in Figure 2‑5.6
In general, for acute respiratory acidosis, an increase in Pco2 of 10 mm Hg
will decrease the pH by 0.08 and the bicarbonate by 1 mmol/L (1 mEq/L).
In chronic respiratory acidosis, after renal compensation, the bicarbonate
will increase by a total of 4 mmol/L (4 mEq/L) for each increase in Pco2 of
10 mm Hg. In acute and chronic respiratory alkalosis, similar changes in the
opposite direction occur. Remembering the relationship between change in
Pco2 and pH can be useful in determining whether a patient has compensated,
partially compensated, or uncompensated respiratory acidosis. For example,
a patient with a severe acute asthma exacerbation may present to the emergen-
cy department with a pH of 7.24, Pco2 of 60 mm Hg, and bicarbonate level of
22 mmol/L (22 mEq/L), which indicates acute uncompensated respiratory
acidosis. If the patient’s ventilation does not improve, over the course of 2 to
3 days the kidneys will start to compensate, and a follow-up blood gas mea-
surement may have a pH of 7.30, Pco2 of 60 mm Hg, and bicarbonate level of
25 mmol/L (25 mEq/L), which reflects partial compensation. In contrast, an
infant with bronchopulmonary dysplasia who has chronic respiratory failure
may have a blood gas measurement with a pH of 7.35, Pco2 of 60 mm Hg, and
bicarbonate level of 28 mmol/L (28 mEq/L), which indicates compensated
respiratory acidosis.

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Pediatric Pulmonology

A B

Figure 2‑5. Nomogram of acid-base abnormalities. From this nomogram, the primary acid-
base abnormality can be determined. A. Patient A has a pH of 7.18, Pco2 of 80 mm Hg, and
bicarbonate (HCO-3) of 26 mmol/L, which is consistent with acute respiratory acidosis.
B. Patient B has a pH of 7.3, Pco2 of 80 mm Hg, and HCO-3 of 37 mmol/L, which is consistent
with chronic respiratory acidosis.
Adapted from DuBose TD. Disorders of acid-base balance. In: Brenner BM, ed. Brenner and Rector’s The Kidney.
Philadelphia, PA: Saunders Elsevier; 2007, with permission from Elsevier.

Oxygenation
Oxygen reaches the alveoli through the conducting airways, where it diffuses
across the very thin membrane to the capillary blood. Under normal circum-
stances, oxygen composes approximately 21% of air. The amount of oxygen
in the alveolus is determined by the presence of other gases such as carbon
dioxide, a supply of fresh air, and changes in barometric pressure. The Po2
decreases when the Pco2 increases. The Po2 depends on a fresh flow of air; if
there is no airflow, such as in cases of mucous plugging, atelectasis, or apnea,
then the Po2 in the alveolus decreases. In addition, the Po2 depends on the
atmospheric pressure. At high altitudes, the atmospheric pressure is lower,

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Chapter 2—Pulmonary Physiology

and there is less oxygen available, which accounts for the development of
hypoxemia, or low arterial oxygen level, at Mount Everest or when flying.
Oxygen is primarily bound to hemoglobin in the red blood cell; a small
amount is dissolved in plasma. A red blood cell takes about three-quarters of
a second to transverse the pulmonary capillary bed; under normal conditions,
it takes about one-quarter of a second for oxygen to be transferred fully to the
red blood cell.2 If the capillary membrane is thickened, then transfer may take
longer and may not be complete by the end of its transit time. This delay may
be aggravated by exercise; as the blood moves more quickly through the
lungs, it may not have adequate time to become fully saturated.7

Mechanisms of Hypoxemia
The primary processes that contribute to hypoxemia are hypoventilation;
diffusion impairment; shunt; ventilation/perfusion (V̇/Q̇) mismatch; and,
under some conditions, low venous blood saturation.8 These processes are
depicted in Figure 2‑6. In addition, as mentioned in the prior section,
hypoxemia may result from low inspired Po2 , which may occur at high
altitudes or in the laboratory under experimental conditions.
Hypoventilation
If ventilation is inadequate, the Pco2 in the alveoli increases and the Po2
decreases. Inadequate ventilation may be caused by depressed respiratory
drive (medications, sepsis, brain trauma), damage to the chest wall, or
weakness of the respiratory muscles.
The relationship between the increase in arterial carbon dioxide and decrease
in oxygen tension can be seen from the alveolar gas equation, which is often
simplified as follows:
Pao2 = Pio2 – Paco2/R,
where Pao2 is the alveolar Po2 , Pio2 is the inspired Po2 , Paco2 is the arterial
Pco2 , and R is the respiratory exchange ratio of carbon dioxide and oxygen,
which is estimated to be 0.8 for the whole lung. Therefore, every increase
in alveolar Pco2 of 10 mm Hg would decrease the Po2 by approximately
12.5 mm Hg. For example, if a child without lung disease with a resting
Pco2 of 40 mm Hg and Po2 of 100 mm Hg has an episode of apnea and
the Pco2 increases to 80 mm Hg, the Po2 will decrease to 50 mm Hg.

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Pediatric Pulmonology

↑PCO2

↑PCO
↑P CO2
↓PO2 ↑PCO2 2 ↑PCO2
↓POO2
↓P
↓PO2 ↓PO2 PO2
↓↓PO2 ↓PO2 2 ↓↓PO2 ↓PO2
↓↓POO2 ↓POO2 ↓↓POO2 PPOO22 ↓PO
↓↓P ↓P ↓↓P PO2 PO↓P
2 O22
↓↓PO2 2 ↓↓PO2 ↓PO2 2 ↓PO2 2
↓↓PO2 ↓↓PO2 ↓PO2 ↓PO2
A. Hypoventilation B. Diffusion impairment

A.Hypoventilation
A. Hypoventilation B.Diffusion
B. Diffusionimpairment
impairment
A. Hypoventilation
A. Hypoventilation B. Diffusion
B. Diffusion
impairment
impairment
x x
xxx x xxx xPO
x x x
xx x
2 PO2

↓↓PO2 xx ↓↓PO2

↓↓PPOO22 ↓↓POO2
↓↓PO2

↓↓POO2
↓↓P
↓
PO2

↓↓PO2 2 ↓↓PO2
↓↓
↓
PPOO22
PO2

PPOO22
PO2
PO2
↓
PPOO22
PO2 OP2O2
↓↓P PO2

↓↓POO2
↓↓P
↓↓ ↓↓P 2 ↓P O
↓↓PO2 2 ↓↓PO2
↓↓PO2 ↓↓PO2 ↓↓PO2 ↓↓PO2 2
C. Shunt D. Ventilation/perfusion mismatch
↓POO2
↓P
C. Shunt ↓PO2 2 ↓P
D.Ventilation/perfusion
Ventilation/perfusion O2
mismatch
C. Shunt D. mismatch
C. Shunt
C. Shunt D. Ventilation/perfusion
D. Ventilation/perfusion
mismatch
mismatch

PO2

PPOO22
PO2 PO2
↓↓↓PO2 ↓PO2
↓↓↓POO2
↓↓↓P ↓POO2
↓P
↓↓↓PO2P↓↓↓P
E. Low venous 2O O2 ↓PO2 2 ↓PO2
2

E.Low
E. Lowvenous
venousPPOO2
Figure 2‑6. Causes of hypoxemia. A, Hypoventilation:
E. Low E.
venous PO2 2 Ventilation
Low venous PO2 is decreased, and Pco2 is
increased. Consequently, the Po2 in the alveolus decreases. B, Diffusion impairment: Diffusion
across the alveolar-capillary membrane to the hemoglobin in the red blood cells is decreased.
C, Shunt: Pulmonary venous blood bypasses the lung without being oxygenated. This may
occur in congenital cardiac disease or arteriovenous malformation where there is a right-to-left
shunt. D, Ventilation/perfusion mismatch: Some areas of the lung are nonfunctional and poorly
oxygenate the venous blood. Blood from functioning alveolar units mixes with the venous
blood. E, Low venous Po2: The Po2 in the venous blood may be abnormally low because of
anemia, fever, or decreased cardiac output. In the presence of lung disease, shunt, or exercise,
the venous blood may not be fully oxygenated as it completes its course through the lung.

Diffusion Defects
Pediatric patients can have problems with diffusion. Diffusion of a gas through
tissues depends on the cross-sectional area, the partial pressure difference
across the tissue and the thickness of the tissue, and inherent characteristics
of the gas (its solubility and molecular weight). Diffusion can be impaired if the
surface area of the lung is decreased (such as in a lobectomy or emphysema) or

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the capillary basement membrane is thickened (such as in pulmonary edema or

interstitial fibrosis). Problems with diffusion can be detected by using carbon
monoxide as a surrogate marker and testing the diffusing capacity of the lung
for carbon monoxide (Dlco). The Dlco may be low in the aforementioned
conditions and also with reduced thoracic blood volume or reduced hemoglobin.
Infants and children have lower diffusion capacities, related to their smaller body
length and lung volumes, than adults do. Infants and children with chronic lung
disease of prematurity have a decrease in Dlco likely related to arrested alveolar-
ization and decreased surface area.9–11 Despite immature alveolarization, it does
not appear as though prematurity per se is associated with a decrease in Dlco.12
Shunt
Shunt occurs when deoxygenated blood bypasses the lungs and flows directly
into the arterial circulation.2 Small shunts exist under normal physiological
conditions. Deoxygenated blood
from the bronchial arteries drains
directly into the pulmonary veins,
and the coronary veins drain directly
into the left ventricle through the
Thebesian veins. In some circum-
stances, there can be an abnormal
connection between the veins and
arteries (arteriovenous malformation).
In addition, a right-to-left shunt
can occur with congenital heart
disease (eg, pulmonary atresia with
ventriculoseptal defect, pulmonary
hypertension with an atrial septal
defect or patent foramen ovale).
The amount of blood going through
the shunt can be calculated from the
following equation:
Q̇ s = Cc'o2 – Cao2
Q̇ t Cc'o2 – Cv̄ o2

Figure 2‑7. Effect of changing inspired oxygen

where Q̇ s/Q̇ t is the fraction of blood
concentration on arterial Po2 in lungs with shunts going through the shunt, Cc'o2 is the
of varying degrees from 10% to 50%. In larger pulmonary capillary oxygen content,
shunts, administering supplemental oxygen Cao2 is the arterial oxygen content,
has little effect on arterial Po2. Addition of
100% oxygen has little effect on arterial Po2 and Cv̄ o2 is the mixed venous oxy-
when the shunt is greater than 30%. gen content. Shunt fractions can also
From Dantzker DR. Gas exchange in the adult respiratory be calculated from nomograms
distress syndrome. Clin Chest Med. 1982;3:57–67, with
permission from Elsevier. (Figure 2‑7).

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A shunt will result in decreased oxygen concentration but does not usually pro-
duce elevated arterial carbon dioxide levels. The chemoreceptors normally sense
the elevation of arterial carbon dioxide and respond by increasing ventilation.
Mismatch
V̇ /Q̇ mismatch is one of the most difficult of the causes of hypoxemia to
understand. If blood flow and ventilation are not matched in areas of the lung,
then inadequate gas exchange occurs. If an area of the lung is perfused but not
ventilated, as in the case of pneumonia or atelectasis (lung collapse), then it acts Sho
like a small shunt. Deoxygenated blood goes through the nonfunctional lung new
without being oxygenated and then mixes with blood from other areas of the 2-8
lung that are oxygenated.
ack
A shunt can be distinguished from V̇ /Q̇ mismatch by the hyperoxia test. In
the case of the latter, addition of 100% oxygen will increase the arterial oxygen
lue
saturation. However, if a true shunt exists, the supplemental oxygen will raise
the arterial saturation by only a small amount (usually < 5%).2
Low Venous Po2
The normal Po2 of venous blood is 45 mm Hg and has a saturation of 75%. If
venous blood has an unusually low Po2, then the blood may not be fully oxygen-
ated by the time it finishes its course through the pulmonary capillaries. Low
venous Po2 may result when the body extracts more oxygen from the blood than
usual, such as in anemia, fever, and low cardiac output. Normally, the lung can
compensate for the abnormally low venous Po2. However, it may not during exer-
cise or if there is another superimposed problem, such as V̇ /Q̇ mismatch, shunt,
or diffusion impairment.

Oxygen Transport
Oxygen is primarily carried in the blood bound to hemoglobin; a very small
amount is dissolved in plasma. The total amount carried by the blood is called
the oxygen content. The maximum amount of oxygen that can be combined
with hemoglobin is called the oxygen capacity. One gram of hemoglobin can
combine with 1.34 mL of oxygen.2 The oxygen capacity for a normal child
with a hemoglobin concentration of 14 g/100 mL is 19.5 mL oxygen/100 mL
of blood.
The oxygen saturation is the percentage of binding sites of hemoglobin that
have oxygen attached. The normal oxygen saturation is 98% for arterial blood
and 75% for venous blood. In general, oxygen saturation increases as the Po2
of the blood increases. The dissociation curve for oxygen is S-shaped and is
shown in Figure 2-8. Between an oxygen tension of 20 and 75 mm Hg, there
is a sharp, linear increase in oxygen saturation. After that, large increases in
arterial Po2 cause small increases in oxygen saturation. The P50 is the oxygen
tension at which 50% of the hemoglobin is saturated.

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At high oxygen tension, relatively large

changes in PO2 will lead to only small
changes in SpO2 (flat part of the curve)

100

90
↑ pH
↓ DPG
80
↓ Temp
Oxyhemoglobin (% Saturation)

70 ↓ pH
↑ DPG
60 ↑ Temp

At SpO2 90% or lower, small reduction

50 in SpO2 may result in dangerous falls
in PO2 (steep part of the curve)
40

30

20

10

0
0 10 20 30 40 50 60 70 80 90 100
PO2 (mmHg)

Figure 2‑8. Oxygen dissociation curve. The oxygen dissociation curve is shown for a pH of
7.4, Pco2 of 40 mm Hg, temperature of 37 °C, and hemoglobin concentration of 15 g/100 mL
(dashed line). Many factors can shift the oxygen dissociation curve to the right and cause
oxygen to bind less avidly to hemoglobin (dotted line): increased temperature, acidosis,
hypercarbia, and increased 2,3-diphosphoglycerate (2,3-DPG) levels. Conversely, decreased
temperature, alkalosis, low carbon dioxide levels, and decreased 2,3-DPG levels shift the
curve to the left (solid line); thus, oxygen binds more avidly to the hemoglobin, and the effect
is decreased delivery to the tissues. Spo2, oxygen saturation as measured by pulse oximetry. P50 is
the oxygen tension when hemoglobin is 50% saturated with oxygen. When hemoglobin-
oxygen affinity increases, the oxyhemoglobin dissociation curve shifts to the left and decreases
P50. When hemoglobin-oxygen affinity decreases, the oxyhemoglobin dissociation curve shifts
to the right and increases P50.
Adapted from Krishnan S. Oximetry and capnography. In: Stokes DC, Dozor AJ, eds. Pediatric Pulmonology, Asthma,
and Sleep Medicine: A Quick Reference Guide. Itasca, IL: American Academy of Pediatrics; 2018: 63–67.

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Factors That Alter the Affinity of Hemoglobin for Oxygen

Many factors can affect the affinity of hemoglobin for oxygen. Acidosis,
hypercarbia, hyperthermia, and increased 2,3-diphosphoglycerate (2,3-DPG)
levels can decrease the affinity. The result is a shift in the oxygen dissociation
curve to the right, which is shown in Figure 2‑8. As a result, the hemoglobin
is less saturated at a given oxygen tension. The converse is also true: alkalosis,
hypocarbia, hypothermia, and decreased 2,3-DPG levels shift the oxygen
dissociation curve to the left, and the hemoglobin has a higher saturation
at a given oxygen tension.
Another common reason for altered oxygen affinity is alterations in the
hemoglobin itself. The hemoglobin in patients with sickle cell disease has
less affinity for oxygen than that in those with normal hemoglobin, so patients
with sickle cell disease may have a lower oxygen saturation in room air.13,14
In contrast, fetal hemoglobin or red blood cells that have been stored in a
blood bank have a higher affinity for oxygen because of a decreased level
of 2,3-DPG.15 The saturation of oxygen can also be lower because it is
bound by other molecules, such as in carbon monoxide poisoning
or methemoglobinemia.
Decreases in oxygen capacity and, consequently, impaired oxygen delivery
to tissues can be caused by a decrease in oxygen saturation or anemia. As
previously described, decreases in oxygen saturation can be caused by
decreases in arterial oxygen concentration (pneumonia, atelectasis, lung
disease, high altitude), decreases in affinity of hemoglobin for oxygen,
or sites on the hemoglobin being bound by other molecules.

Assessment of Oxygenation and Ventilation

It is extremely difficult to assess the adequacy of oxygenation and ventilation
by means of physical examination. The most specific sign of impaired oxygen-
ation is cyanosis, which can usually be detected at an oxyhemoglobin satura-
tion of 80%.16 However, it may be difficult to assess in children with anemia
or dark-colored skin. Signs of hypoxemia include tachypnea and tachycardia,
and progression may be associated with confusion, motor incoordination, and
agitation. Impaired ventilation is even more difficult to determine. Certainly,
when a patient is apneic or has an extremely low respiratory rate, an impair-
ment of ventilation is likely. Tidal volume is difficult to determine from
examination of chest excursion; dead space cannot be assessed.17 Other late
signs of impaired ventilation are hypotension, flushed skin, diaphoresis,
tachycardia, and lethargy.
Noninvasive Monitoring of Oxygen and Carbon Dioxide
Both oxygenation and ventilation can be assessed noninvasively. Pulse oxi-
metry is the most common way to assess oxygenation and is based on the
principle that oxyhemoglobin and reduced hemoglobin have different light

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absorption spectra. Pulse oximetry detects arterial pulsations and measures the
arterial oxygen saturation. However, it has a few deficiencies. It is insensitive to
changes at high arterial Po2 (because of the shape of the oxygen dissociation
curve) and inaccurate at low arterial oxygen saturation (Sao2). Pulse oximetry
may be less sensitive to hypoxemia in patients with more darkly pigmented
skin. There is also a delay in response to changes in Sao2, particularly when the
oximeter is placed on an extremity. In addition, a number of factors can give
spurious results; these factors are listed in Box 2‑1.18,19
Box 2‑1
Causes of Inaccuracies in Pulse Oximetry
Carboxyhemoglobin Intravenous dyes
Methemoglobin ū Methylene blue
High-intensity ambient light ū Indigo carmine
ū Indocyanine green
Impaired perfusion
Nail polish and artificial nails

End-tidal carbon dioxide monitoring (capnography) can be used to assess

ventilation.20 The carbon dioxide in exhaled air is measured by means of in-
frared light absorption or mass spectrometry. A representative capnograph is
shown in Figure 2‑9. In healthy individuals, the carbon dioxide in the exhaled
50
End-tidal CO2

40

30
PCO2 mm Hg

20

10

0
0 1 2 3 4 5
Expiration Inspiration
starts starts

Time (sec)

Figure 2‑9. Normal capnograph. Carbon dioxide is measured in the exhaled air. The beginning
of the breath is filled with dead space volume. At the end of the breath, the end-tidal Pco2
reflects alveolar Pco2. It is a noninvasive way of monitoring arterial Pco2.
From Levitzky M. Pulmonary Physiology. 4th ed. New York: McGraw-Hill, Inc; 1995:73, with permission.

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air will be slightly less than the arterial Pco2. Larger differences may occur in
disease states in which there is more dead space, such as in patients who are
anesthetized or those with pulmonary embolism.21
Another noninvasive method to estimate arterial Po2 and Pco2 is by using
a transcutaneous monitor, which measures skin-surface Po2 and Pco2. The
transcutaneous monitor increases the local temperature of the skin, produc-
ing hyperperfusion, and determines the Po2 and Pco2 by using a sensor.22
Because of the widespread use of pulse oximetry and the potential risk of
thermal injury, the transcutaneous monitor is usually used only to estimate
arterial Pco2 and is referred to as transcutaneous Pco2 (TcPco2). This tech-
nique has advantages and disadvantages. TcPco2 values are typically higher
than the true arterial Pco2. Inaccurate readings may occur in patients with
hyperoxemia, hypoperfusion, or skin edema and from improper electrode
placement.22 However, TcPco2 values may provide a better estimate of arterial
Pco2 than does end-tidal Pco2 , particularly in neonates and preterm infants in
whom end-tidal Pco2 measurements often lead to underestimation of the true
arterial Pco2.23 Transcutaneous Pco2 monitoring is especially useful in
neonatal and pediatric intensive care units, sleep laboratories, and operating
rooms.22–25
Arterial Blood Gas Analysis
The gold standard for assessing both oxygenation and ventilation is arterial
blood gas analysis.26 The actual value of measured arterial Po2 is important.
However, in patients with hypoventilation or receiving supplemental oxygen,
it is also useful to compare it with what it should ideally be. The difference
between the predicted arterial Po2 , calculated from the alveolar Po2 (Pao2),
and what is measured is known as the alveolar-arterial (A-a) gradient; it is
usually less than 10 mm Hg.27 The Pao2 can be calculated from the simplified
alveolar gas equation as follows:
Pao2 = Pio2 – Paco2/R,
and because Pio2 = Fio2 (Patm – Ph2o),
Pao2 = Fio2 (Patm – Ph2o) – Paco2/R,
where Pao2 is the alveolar Po2 , Pio2 is the inspired Po2 , Paco2 is the arterial
Pco2 , and R is the respiratory exchange ratio of carbon dioxide and oxygen
(which is estimated to be 0.8 for the whole lung). Fio2 is the percentage of
oxygen, Patm is atmospheric pressure (760 mm Hg at sea level), and Ph2o is
water vapor pressure (47 mm Hg at 37° C). So, for example, a patient breath-
ing 40% oxygen with an arterial Pco2 of 35 mm Hg has a Po2 of 100 mm Hg.
However, on the basis of the equation, the patient should have an arterial
Po2 of 240 mm Hg at sea level. The A-a gradient is extremely elevated at
140 mm Hg. There are other ways to assess impairment of oxygenation by
using the Pao2 as well as other variables27–31 (Table 2‑4).

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The adequacy of ventilation can be assessed by measuring arterial blood

gas; there is an inverse correlation between ventilation and the arterial Pco2.
However, the number must be assessed in the context of the clinical picture.
For example, a patient with asthma who is in severe distress with a respiratory
rate of 60 breaths/min has a Pco2 of 40 mm Hg. Although this is a normal
value, it implies impending respiratory failure in a patient with this degree
of tachypnea and work of breathing.
Measurement of arterial blood gases is invasive and may be technically diffi-
cult and painful. Surrogate measures involve using either a venous or a capil-
lary blood sample. In the latter, a finger or toe is pierced with a lancet and the
blood collected. Neither measure is useful for assessing arterial oxygenation
because the samples are mixed with venous blood. Because venous blood has
a higher Pco2 , both samples will lead to overestimation of the true arterial
Pco2 (and indicate the worst-case scenario). In cases of cardiac arrest, the
discrepancy between the 2 values widens.32

Table 2‑4. Measures of Impairment in Oxygenation

Name of Index Equation Normal Values
A-a oxygen gradient Pao2 – Pao2 < 10 mm Hg
A-a oxygen ratio Pao2/Pao2 > 0.75
Pao2:Fio2 ratio Pao2/Fio2 300–500 mm Hg
Oxygenation index Fio2 × mean airway pressure × 100/Pao2 <5
Oxygen saturation index Fio2 × mean airway pressure × 100/Spo2 < 6.5
Normal values are from references 27–31.

Mechanics of Breathing
The muscles of respiration act like a pump to move air in and out of the lungs.
The efficiency of the pump is determined by the elastic properties of the chest
wall and lungs and the resistance of the airways. Disease processes can alter
these relationships and lead to respiratory failure.

Muscles of Breathing
The muscles of breathing are depicted in Figure 2‑10. The diaphragm is the
primary muscle of inspiration. It is a dome-shaped muscle and is responsible
for two-thirds of the air that enters the lungs during quiet breathing. When
it contracts, it forces the abdominal contents down and widens the rib cage.
When it is paralyzed, as in the case of phrenic nerve or cervical spine injury,
it moves up instead of down during inspiration. Other muscles of inspiration
are the external intercostal muscles and other accessory muscles, such as the
scalene and sternocleidomastoid muscles.

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Pediatric Pulmonology

In normal quiet breathing, expiration is passive; the recoil of the lungs forces
the air out. However, in active breathing, such as with exercise, coughing, or
singing, or in lower airway obstruction, expiratory muscles are recruited.1
The muscles of expiration are the abdominal and internal intercostal muscles.
Neuromuscular disease, abdominal muscle weakness, or postoperative
abdominal pain may impair cough, leading to a decreased ability to
clear secretions.

INSPIRATION ACTIVE EXPIRATION

Accessory
muscles

External
intercostals

Internal
intercostals

Diaphragm

Abdominal
muscles

Posterior Anterior

Figure 2‑10. Muscles of breathing. The inspiratory muscles are

the diaphragm, external intercostals, and accessory muscles such
as the sternocleidomastoid and scalene. Expiration with quiet
breathing is passive. Active expiration requires the use of the
abdominal and internal intercostal muscles.

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Chapter 2—Pulmonary Physiology

Elastic Properties of the Lung and Chest Wall

The interaction of the lungs and chest wall determines the effectiveness
of the pump. The lungs and individual alveoli act like balloons. Pressure is
required to inflate the lungs; without it, they would tend to collapse. At low
volumes, it is difficult to overcome the elastic forces and to inflate the lung;
high pressures are required. At medium volumes, less pressure is required to
inflate the lungs. At high volumes, it is again more difficult, and higher pres-
sures are required. The ease with which the lungs can be stretched is known
as compliance. Reduced lung compliance can be seen in conditions such as
fibrosis, pulmonary edema, and acute respiratory distress syndrome. Increased
lung compliance is seen in emphysema and aging. One of the important func-
tions of surfactant, a phospholipid produced by the lung, is to increase lung
compliance by reducing the surface tension of the alveoli. Consequently, in
preterm neonates in whom there is a developmental decrease in surfactant
production, there is a decrease in lung compliance and the development of
neonatal respiratory distress syndrome.
The chest wall has elastic properties and its own compliance. Its inherent
tendency is to expand, which counterbalances the tendency of the lungs to
collapse. The relationship between the forces of the chest wall and lung
volume is shown in Figure 2‑11. The resting lung volume (functional residual
capacity) represents the equilibrium between the 2 forces (Figure 2‑11A).
Lung volumes are smaller if the compliance of either the chest wall
(Figure 2‑11B) or the lung (Figure 2‑11C) is decreased.

A B C

Figure 2‑11. Interactions of the chest wall and lung. A, In the normal lung, the outward recoil
of the chest wall balances the inward recoil of the lung. The final volume of the lung depends
on the equilibrium between them. B, If the chest wall becomes less compliant and more stiff,
there is less outward force to balance out the inward recoil of the lungs. The result is a smaller
lung volume. Examples include obesity, neuromuscular weakness, and trauma to or defects in
the chest wall. C, If the lungs become less compliant, they overcome the outward force of the
chest wall and have a smaller resting volume. Examples include pulmonary edema, interstitial
fibrosis, and acute respiratory distress syndrome.

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Airway Resistance
Resistance is the force that opposes the forward motion of the airflow.
Approximately 25% to 40% of the total resistance to airflow is located in the
upper airway: nose and mouth passages and larynx.1,5 The airways and lung
tissue provide the remainder of the resistance. Air flows through the airways
as if they were tubes. In some areas, the flow is very orderly and is known as
laminar flow. In some places, such as in narrowed or branch points, it is dis-
organized and is known as turbulent flow. In laminar flow, resistance is directly
proportional to the radius4 of the airways. Consequently, if the radius of an air-
way is narrowed by one-half, the resistance increases by 16-fold. In an infant’s
or child’s airway, which is already narrow relative to an adult’s, small changes
in caliber produce large changes in the degree of obstruction. Turbulent flow
depends on gas density. Thus, gases with a low density, such as helium, are
administered to decrease resistance in patients with airway obstruction.33

Work of Breathing
The work involved in breathing is proportional to the tidal volume and the
change in pressure required to move the air. The work of breathing increases
when the compliance of the chest wall or lung is decreased; more negative
pressure is required to breathe. In addition, the work of breathing increases
with increased airway resistance, such as with asthma or upper airway
obstruction. Infants and young children are at a mechanical disadvantage;
their respiratory system works less efficiently than an adult’s. Their chest
walls are more compliant, and their diaphragms are flatter and more likely
to fatigue, which predisposes them to respiratory failure.

Assessment of Lung Mechanics

An alteration in lung mechanics may result in signs of respiratory distress.
Decreases in lung and chest wall compliance are usually heralded by tachy-
pnea. Increased effort of breathing is manifested by recruitment of accessory
muscles, such as the sternocleidomastoid or scalene muscles. Retractions,
bowing in of the muscle and soft tissue of the chest wall with inspiration,
indicate that high pressures are generated to move air through the airways.
They can be seen subcostally, intercostally, and in the suprasternal notch.
The higher the retractions, the more severe the respiratory distress. Nasal
flaring is an attempt to decrease the resistance of breathing by decreasing
the resistance of the nasal passages.
Airflow, lung volumes, and airway resistance can be measured by means
of pulmonary function testing and will be further described in Chapter 6,
Pulmonary Function Testing.

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Chapter 2—Pulmonary Physiology

key po ints
Gas Exchange
} The Po2 in the alveoli is determined by the balance between the amount that
flows in and the amount that is removed in the pulmonary capillaries.
Ventilation
} In each breath (tidal volume), some of the air goes into the alveoli (alveolar
volume) and is available for gas exchange, while the rest remains in the
conducting airways and is known as dead space.
} The arterial Pco2 is inversely proportional to alveolar ventilation.
} Increases in arterial Pco2 can be caused by decreased tidal volume, decreased
respiratory rate, increased dead space, or increased carbon dioxide production.
} In chronic respiratory acidosis, after renal compensation, the bicarbonate will
increase by a total of 4 mEq/L for each 10-mm increase in Pco2.
} Arterial Pco2 can be approximated noninvasively by end-tidal carbon dioxide or
transcutaneous carbon dioxide monitoring.
Oxygenation
} Hypoxemia, or low arterial Po2, may be caused by low inspired partial pressure of
oxygen (ie, high altitude), hypoventilation, diffusion impairment, shunt, V/Q
mismatch, and abnormally low venous blood saturation (under certain conditions).
} Oxygen is primarily carried in the blood bound to hemoglobin; a very small
amount is dissolved in plasma.
} The P50 is the oxygen tension at which 50% of the hemoglobin is saturated.
} The affinity of hemoglobin for oxygen can by altered by changes in blood pH,
Pco2, temperature, and 2,3-DPG levels.
} Arterial oxygen saturation can be approximated noninvasively by using pulse
oximetry.
} The degree of impairment in oxygenation can be assessed by calculating the
A-a oxygen gradient or other indexes such as A-a oxygen ratio, Pao2:Fio2 ratio,
oxygenation index, and oxygen saturation index.
Mechanics of Breathing
} The diaphragm is the primary muscle of inspiration.
} The ease with which the lungs can be stretched is known as compliance, which
is decreased in conditions such as pneumonia, pulmonary edema, and acute
respiratory distress syndrome.
} In laminar airflow, which normally occurs only in small airways, resistance is
directly proportional to the radius4 of the airways, and small changes in the
airway caliber produce large changes in resistance.
} The work of breathing increases when the compliance of the chest wall or lung
is decreased or airway resistance is increased.
} Infants and young children are at higher risk of respiratory failure in part
because their chest walls are more compliant and their diaphragms are flatter
and more prone to fatigue.

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