Lung India. 2017 Jan-Feb; 34(1): 47–60.

PMCID: PMC5234199
doi: 10.4103/0970-2113.197116 PMID: 28144061

Mechanisms of hypoxemia
Malay Sarkar, N Niranjan,1 and PK Banyal2

Department of Pulmonary Medicine, Indira Gandhi Medical College, Shimla, Himachal Pradesh, India
1
Navodaya Medical College Hospital and Research Center, Raichur, Karnataka, India
2
Community Health Center, Kupvi, Nerwa, Shimla, Himachal Pradesh, India
Address for correspondence: Dr. Malay Sarkar, Department of Pulmonary Medicine, Indira Gandhi Medical College, Shimla, Himachal
Pradesh, India. E-mail: [email protected]

Copyright : © 2017 Indian Chest Society

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License,
which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are
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Abstract Go to: Go to:

Oxygen is an essential element for life and without oxygen humans can survive for few minutes only.
There should be a balance between oxygen demand and delivery in order to maintain homeostasis within
the body. The two main organ systems responsible for oxygen delivery in the body and maintaining
homeostasis are respiratory and cardiovascular system. Abnormal function of any of these two would lead
to the development of hypoxemia and its detrimental consequences. There are various mechanisms of
hypoxemia but ventilation/perfusion mismatch is the most common underlying mechanism of hypoxemia.
The present review will focus on definition, various causes, mechanisms, and approach of hypoxemia in
human.

KEY WORDS: Diffusion limitation, hypoxemia, shunt, ventilation-perfusion mismatch

INTRODUCTION Go to: Go to:

The term hypoxia and hypoxemia are not synonymous. Hypoxemia is defined as a decrease in the partial
pressure of oxygen in the blood whereas hypoxia is defined by reduced level of tissue oxygenation. It can
be due to either defective delivery or defective utilization of oxygen by the tissues. Hypoxemia and
hypoxia do not always coexist. Patients can develop hypoxemia without hypoxia if there is a compensatory
increase in hemoglobin level and cardiac output (CO). Similarly, there can be hypoxia without hypoxemia.
In cyanide poisoning, cells are unable to utilize oxygen despite having normal blood and tissue oxygen
level.

MECHANISMS OF HYPOXEMIA Go to: Go to:

There are various mechanisms of hypoxemia. These are V/Q mismatch, right-to-left shunt, diffusion
impairment, hypoventilation, and low inspired PO2.

Alveolar-arterial oxygen gradient

It is the difference between alveolar oxygen level (PAO2) and arterial oxygen level (PaO2) and is
represented by the following equation: Alveolar to arterial (A-a) oxygen gradient = PAO2 – PaO2. The A-a
oxygen gradient indicates the integrity of the alveolocapillary membrane and effectiveness of gas
exchange. Pathology of the alveolocapillary unit widens the gradient. Therefore, hypoxemia due to V/Q
mismatch, diffusion limitation, and shunt will have widened gradient, whereas hypoxemia due to
hypoventilation would have normal gradient. The word gradient is a misnomer, and ideally, it should be
referred to as A-a oxygen difference as the difference between alveolar and arterial oxygen is not due to
any diffusion gradient. The difference between alveolar and arterial oxygen tensions is due to other factors:
(1) V/Q imbalance in various parts of the lungs, (2) small right to left shunt (bronchial vein, thebesian
vein, and small pulmonary arteriovenous anastomosis), and (3) resistance to the diffusion of oxygen across
the alveolar membrane.[1,2]

Unlike PaO2, PAO2 is not measured but calculated by using the alveolar gas equation:

PAO2 = FiO2× (Pb − PH2O) − (PACO2/R).

PAO2 is the mean alveolar oxygen pressure.

FiO2 is the fractional concentration of inspired oxygen. It is 0.21 at room air.

Pb is the barometric pressure (760 mmHg at sea level).

PH2O is the water vapor pressure (47 mmHg at 37°C).

PaCO2 is the alveolar carbon dioxide tension. It is assumed to be equal to arterial PCO2.

R is the respiratory quotient and is approximately 0.8 at steady state on standard diet.

Normal PAO2 is:

PAO2 = FiO2× (Pb − PH2O) − (PACO2/R).

=0.21× (760 − 47) − (40/0.8).

=100 mmHg.

In young person, the A-a oxygen difference is <10 mmHg. The A-a oxygen difference increases with age.
It is primarily due to age-induced decrease in the PaO2 level because of the rise in V/Q mismatch. The
drop in PaO2 after 70 years is about 0.43 mmHg per year.[3] High FiO2 by increasing both the alveolar
and arterial oxygen level widens the gradient. The rise in gradient is due to disproportionate increase in
alveolar oxygen level. The arterial blood oxygen level does not rise to the same proportion as the alveolar
oxygen level due to its admixing with unoxygenated blood coming from bronchial veins, mediastinal
veins, and thebesian veins.[1]

Ventilation/perfusion mismatch
V/Q mismatch is the most common cause of hypoxemia.[4] Normal V/Q level is 0.8. Ventilation,
perfusion and V/Q ratio are not uniform in the human lungs. There is regional heterogeneity of V/Q ratio
caused by variable subatmospheric intrapleural pressure and gravity. Ventilation and perfusion is higher at
the base and lower at the apex of the lungs. However, V/Q ratio is higher at the apex and lower at the base.
The ratio is low at the base as the rise in perfusion is much more than the rise in ventilation. The V/Q ratio
is higher at apex because the fall in perfusion is higher than the fall in ventilation at the apex. Since
ventilation is responsible for gas exchange, apical region with high ratio has low alveolar CO2 content and
high oxygen content and the basal region, on the other hand, has low alveolar oxygen content and high
CO2 content. Only low V/Q ratio produces hypoxemia by decreasing the alveolar oxygen level (PAO2)
and subsequently arterial oxygen level [Figure 1].[5] There is an important compensatory mechanism due
to hypoxemia, particularly when chronic. The human body will try to restrict perfusion in areas of the
lungs with reduce ventilation. This is done by hypoxic pulmonary vasoconstriction (HPV) which is unique
to pulmonary vasculature. By reducing perfusion to areas of the lungs with reduce ventilation, blood is
diverted to the well-ventilated lung regions.[6,7] The basic goal is to maintain matching between
ventilation and perfusion. The pulmonary selectivity of hypoxia can be explained by the presence of an
oxygen-sensitive channel in the pulmonary circulation. The vessels mainly involved in HPV are the small
pulmonary arteries.[8] Arteries with an internal diameter of 200–400 µm are most commonly involved in
the animal study.[9] HPV also possesses negative consequences when chronic. Chronic HPV causes
vascular structural remodeling and subsequent development of sustained pulmonary hypertension.[10] The
inhibition of oxygen-sensitive potassium channel initiates the process of HPV. Patel et al. subsequently
revealed that the K+ channels involved are voltage-gated K+ channels (KV), particularly KV1.5.[11]
Hypoxia inhibits the voltage-gated K+ channels present in the pulmonary artery leading to accumulation of
intracellular K+ and depolarization of the cells. Depolarization opens up the voltage-gated L-Type Ca2+
channels resulting in Ca2+ influx and vasoconstriction [Figure 2].[12,13]

High ventilation/perfusion ratio

High V/Q ratios develop when ventilation is excess in proportion to perfusion. Figure 3 is showing an
example of high V/Q ratio in pulmonary embolism (PE). It can produce a dead space like effect.[14] Since
perfusion is less; removal of CO2 by high V/Q unit is low. Although the impact of high V/Q unit on blood
oxygenation is minimal, it can cause hypoxemia if the compensatory rise in total ventilation is absent.
Since the high V/Q unit receiving less perfusion, blood from this area is diverted to other areas leading to
the development of low V/Q in other areas of the lungs. It results in the development of hypoxemia unless
the compensatory rise in total ventilation is impaired. The compensatory rise in ventilation can lead to
normalization of V/Q ratio of the low V/Q areas.

Effects of beta-2 agonist on ventilation/perfusion ratio Beta-2 agonist can produce mild hypoxemia by
causing V/Q mismatch. Wagner et al.[15] in a multiple inert gas elimination technique (MIGET)-based
study in asymptomatic asthma patients reported transient deterioration in V/Q ratio and PaO2 after
nebulized isoproterenol therapy. These changes happen despite the forced expiratory volume in one second
(FEV1) and forced expiratory flow between 25% and 75% returning to normal. Polverino et al.[16] could
not find any gas exchange abnormality after salbutamol therapy in chronic obstructive pulmonary disease
(COPD) patients with severe exacerbations requiring hospitalization but detected small decrement in PaO2
during convalescence period only. The worsening V/Q ratio is due to increase perfusion of poorly
ventilated areas due to salbutamol-induced release of HPV. Moreover, diversion of perfusion from adjacent
well-ventilated areas creates new areas with low V/Q ratio.[17] Ballester et al.[18] reported different
effects of intravenous and inhaled bronchodilator on cardiopulmonary parameters. Intravenous salbutamol,
but not inhaled salbutamol, caused a significant increase in heart rate, CO, and V/Q inequality. However,
PaO2 remained unchanged during salbutamol administration by both the routes. Normal PaO2 along with
worsened V/Q ratio may be explained by the elevated CO in the intravenous salbutamol group. However,
all these studies should not be a deterrent for its use in acute bronchospasm as the benefits of reversing
bronchospasm far outweighs its small detrimental effect on arterial oxygenation and V/Q ratio.
Characteristic features of ventilation/perfusion mismatch
1. Hypoxemia due to V/Q mismatch can be easily corrected by supplemental oxygen therapy
2. Widened A-a oxygen gradient is another feature of V/Q mismatch.

Some common causes of hypoxemia due to V/Q mismatch include asthma, COPD, bronchiectasis, cystic
fibrosis, interstitial lung diseases (ILDs), and pulmonary hypertension.

Shunt
The shunt is a condition whereby blood from the right side of the heart enters the left side without taking
part in any gas exchange. Figure 4 is showing an example of shunt. Normally, we have a small fraction of
the shunt (2–3% of CO). It occurs when bronchial veins drain into pulmonary veins. Some of the coronary
veins may also drain directly into the left ventricle and is called the thebesian veins. Shunt is the extreme
degree of V/Q mismatch where there is no ventilation. Poor response to oxygen therapy is the feature that
differentiates shunt from other mechanisms of hypoxemia. Failure to improve PaO2 by oxygen therapy is
due to the inability of oxygen to improve PAO2 in unventilated lung units.[11] Hypercapnia is uncommon
in shunt until the shunt fraction reaches 50%.[1] Lack of hypercapnia is due to stimulation of the
respiratory center by chemoreceptor as the PCO2 in the arterial blood leaving the shunt unit is high.
PaO2/FiO2 is a rough estimate of shunt fraction. If PaO2/FiO2 is <200, shunt fraction is more than 20%,
whereas a PaO2/FiO2 of more than 200 indicates a shunt fraction of <20%.[19]

Characteristics of pulmonary shunt

1. P (A-a) O2 is elevated
2. Poor response to oxygen therapy
3. PCO2 is normal.

Causes of shunt include pneumonia, pulmonary edema, acute respiratory distress syndrome (ARDS),
alveolar collapse, and pulmonary arteriovenous communication.

Pulmonary shunt can be calculated by the following equation [Figure 5].

Q'T is the total pulmonary blood flow.

Q'S is the blood flow to the nonventilated or shunt area.

CaO2 is the oxygen content of the arterial blood.

CecO2 is the end-capillary oxygen content of the effective gas exchanging unit.

Cec'O2 is the end-capillary oxygen content of the shunt area.

Cv Ō 2 is the mixed venous blood oxygen content.

The total amount of oxygen leaving this unit is equal to the sum of oxygen content of shunted blood and
effective gas exchanging unit.

CaO2 × Q'T = Cv–O2 × Q'S + CecO2 × (Q'T − Q'S).

Rearranging the equation, amount of shunt fraction (Q'S/ Q'T)

Diffusion limitation
It occurs when the oxygen transport across the alveolocapillary membrane is impaired. Diffusion
limitation may be due to decrease in lung surface area for diffusion, inflammation, and fibrosis of the
alveolocapillary membrane, low alveolar oxygen, and extremely short capillary transit time. Since both
oxygen and carbon dioxide transport occur through the alveolar-capillary membrane, theoretically it
should cause both hypoxemia and hypercapnia. However, hypercapnia is uncommon due to diffusion
limitation. Since CO2 is 20 times more soluble in water than O2, it is less likely to be affected by diffusion
limitation.[20] Another reason could be hypoxemia-mediated stimulation of ventilation, leading to CO2
washout. Normal pulmonary capillary transit time is 0.75 s, and the time required to complete gas
exchange is 0.25 s. One important characteristics of diffusion limitation is the development or worsening
of hypoxemia during exercise. During exercise, the capillary transit time is shortened due to rise in CO.
Moreover, mixed venous oxygen level also falls due to increase oxygen extraction by the tissues.
However, hypoxemia usually does not develop due to the following reasons: Recruitment of capillaries,
distension of capillaries, and rise in alveolar oxygen. Patients with pulmonary fibrosis fail to recruit
additional capillaries and develop exercise-induced/exaggerated hypoxemia. Important causes of diffusion
limitation are emphysema and ILDs.

Characteristics
1. Hypoxemia shows good response to oxygen therapy
2. P (A-a) O2 is elevated
3. PaCO2 is usually normal.

Hypoventilation
The hallmark of hypoventilation is a high PaCO2 level as adequate ventilation is necessary for the removal
of CO2. Ventilation is also required for oxygenation, and hypoventilation leads to low PAO2 and
subsequent low PaO2. Another unique feature of hypoventilation is normalP(A-a)O2 gradient as the
alveolar – capillary membrane is intact in this condition. Prolonged hypoventilation, however, may lead to
atelectasis of some parts of the lungs and widening ofP(A-a)O2 gradient.[21] Hypoventilation does not
produce significant hypoxemia in healthy lung, but in the presence of lung diseases, hypoxemia can be
severe. One characteristic feature of hypoventilation induced hypoxemia is that it is easily correctible by
supplemental oxygen. Oxygen therapy corrects hypoxemia even when hypoventilation and hypercapnia
persists. Normal pulse oximetry in a patient breathing room air indicates adequacy of ventilation (normal
PaCO2). However, it cannot be used to judge the adequacy of ventilation in patients on supplemental
oxygen if hypoventilation persists.[14] Patients of COPD, asthma, ILD, and other lung diseases initially
cause Type-1 respiratory failure but after certain period of time may develop Type-2 respiratory failure due
to alveolar hypoventilation.

Alveolar gas equation describes the relationship between PACO2 level and alveolar ventilation (VA).
Reduced VA increases the PCO2 level and increase in VA decreases the PCO2 level.

Alveolar gas equation

Equation-1:

V'CO2 is the CO2 production in the body.

V'A is alveolar ventilation.

Factor k (0.863) is constant.

We can also rearrange the equation in the following ways.

V'A = V'E − V'D.

V'E is the minute ventilation and V'D is the dead space ventilation. V'E is the amount of air inhaled per
minute and is derived by multiplying respiratory frequency and with tidal volume (VT). VA can be
decreased either by a reduction in VT or an increase in VD.

Equation-2:

Rearranging the equation-2

Equation-3:

There are several causes of high CO2 level. It can be due to high VCO2 production without compensatory
rise in VA, rise in VD and fall in VT and/or RR. A-a oxygen gradient can help differentiating whether the
high PaCO2 is due to reduction in VT or increase in VD. Gradient will be normal in the former and high in
the latter. Increase VCO2 normally does not contribute to raise PaCO2 level if the ventilatory
compensating mechanism is functioning normally.[22] In certain conditions, CO2 production is increased
in the body, for example, burns, sepsis, exercise, hyperthermia, intake of carbohydrate rich diet, tetanus,
seizures, and tremor. Various causes of rise in VD/VT leading to high CO2 level are PE, acute reduction in
CO, COPD, ARDS, and bronchiectasis.

Hypoventilation occurs due to dysfunction of the respiratory pump at various levels: Respiratory center in
the brainstem, spinal cord, nerves supplying the respiratory muscles, neuromuscular junction, respiratory
muscles, and chest wall bellows. One characteristic feature of hypoventilation is the fact that both PaO2
and PaCO2 moves in opposite direction to same extent. If they do not move to same extent, rule out other
causes of hypoxemia.[1]

Various causes of hypoventilations are given below:

1. Impaired central drive

Drug overdose: Opioids, benzodiazepines, alcohol
Brainstem hemorrhage, infarction
Primary alveolar hypoventilation
2. Spinal cord level: Amyotrophic lateral sclerosis, cervical spinal cord injury
3. Nerve supplying respiratory muscle: Guillain–Barre syndrome
4. Neuromuscular junction: Myasthenia gravis, Lambert–Eaton syndrome
5. Respiratory muscles: Myopathy
6. Defects in chest wall: Kyphoscoliosis, thoracoplasty, fibrothorax.

Characteristics
1. Hypoxemia shows good response to oxygen therapy
2. P(A-a)O2 is usually normal
3. PaCO2 is high
4. PaO2 and PaCO2 move in opposite direction to the same extent.

Various mechanisms and differentiating features of hypoxemia are given in Figure 6.

ASTHMA Go to: Go to:

The most common gas exchange abnormality in asthma is respiratory alkalosis. Carbon dioxide retention
may occur with worsening asthma and development of respiratory muscle fatigue. V/Q mismatch is the
main mechanism of gas exchange abnormality in asthma. Wagner et al. reported a bimodal pattern of V/Q
distribution in patients of asthma: Majority of V/Q ratio lies within the normal range, and about 25% of the
CO confines to a low V/Q ratio of ≤0.1.[15] Other characteristics features of Wagner's series were the
absence of high V/Q ratio and shunt. There is also a poor correlation between V/Q mismatch and
spirometric parameters. Wagner et al.[23] in another paper studied the relationship between V/Q mismatch
and indices of airflow obstruction across the various clinical spectrum of asthma. They noted abnormal
V/Q ratio despite the spirometric indices being well preserved. At this stage, PaO2 may also remain
normal despite the presence of V/Q mismatch and highP(A-a)O2 gradient. The V/Q ratio remains stable
till FEV1 falls to 40% of predicted. Below this level of FEV1, PaO2 falls significantly. The presence of
normal PaO2 despite the clear evidence of gas exchange abnormality is due to the buffering action of high
CO. This study clearly questions the utility of spirometry alone in the management of asthma. This
dissociation between indices airflow obstruction and gas exchange abnormality is due to the following
reasons. FEV1 reflects the function of more central airways, and peripheral airway obstruction has a
greater influence on the degree of V/Q mismatch. Second, lung units with low V/Q ratio contribute little to
the lung function measured at the mouth. Contribution to FEV1 is mainly from lung units with good
ventilation. Despite the presence of moderately severe V/Q mismatch, PaO2 level can be normal. Large
amount of CO and/or ventilation can explain this phenomenon. Shunt is also uncommon in stable asthma
due to the presence of collateral ventilation between normal alveoli and the region distal to the obstruction.

Roca et al.[24] studied the V/Q distribution in 10 patients with acute severe asthma requiring
hospitalization and the following recovery. All patients had a severe airflow obstruction and moderate to
severe hypoxemia at the time of admission. The majority of their patients showed bimodal blood flow
distributions. They also reported a lack of correlation between V/Q mismatch and spirometric criteria.
Moreover, the improvement in V/Q mismatch lags behind spirometric and clinical criteria. Clinical and
spirometric improvement occurred at the time of discharge, whereas maximum improvement in V/Q
mismatch occurs at the end of 4 weeks. The lack of correlation between the two variables indicates that
different pathophysiologic processes are involved. Spirometric abnormalities reflect a narrowing of large-
and middle-sized bronchi, and V/Q mismatch reflects abnormalities involving peripheral small airways.
The role of peripheral airways in V/Q mismatch is further strengthened by the fact that administration of
beta-2 agonist was associated with transient worsening of V/Q mismatch despite relief of airway
obstruction.[15] In future, there is a need to evaluate the role of gas exchange abnormalities in the follow-
up of patients with asthma along with conventional parameters of clinical and spirometric criteria.[25]
High V/Q and shunt are uncommon in all these studies except in children following an exercise challenge
and in patients with acute severe asthma. Freyschuss et al.[26] evaluated the mechanisms of hypoxemia in
children with exercise-induced asthma (EIA). The majority of children with EIA developed bimodal
distribution: Normal V/Q ratio and high V/Q ratios. Shunt or a low V/Q ratio (V/Q <0.1) was not detected.
High V/Q developed due to hyperinflated lungs impeding local blood flow.

CHRONIC OBSTRUCTIVE PULMONARY DISEASE Go to: Go to:

COPD is a lifestyle related lung diseases characterized by progressive loss of lung function and gas
exchange abnormality. The major sites of airflow obstruction in COPD is the small airways (<2 mm in
internal diameter).[27] Alveolar walls maintain patency of the small airway by exerting radial traction by
the elastic fibers. Alveolar wall destruction leads to loss of these elastic fibers, resulting in airflow
obstruction. Alveolar wall destruction also causes loss of the alveolar surface area and pulmonary
capillaries, resulting in gas exchange abnormalities. Other mechanisms of airflow obstruction include
bronchial mucosal inflammation, edema or fibrosis, and mucus hypersecretion.[28] The most common gas
exchange abnormalities in COPD patients include arterial hypoxemia, with or without hypercapnia. The
major mechanism of hypoxemia in COPD is V/Q mismatch.[29] Gas exchange abnormality depends on
the phenotype of COPD. Phenotyping in COPD is not new as Burrows distinguished the two phenotypes
of COPD as early as 1963.[30] He proposed the following classification of COPD based on clinical,
roentgenologic, and physiologic characteristics: Type A (predominant emphysema/pink puffer), Type B
(predominant chronic bronchitis/blue bloater), or type X (indeterminate type). Type A patients show
hyperinflation decreased elastic recoil of the lung, mild hypoxemia and rarely hypercapnia, whereas, Type
B patients develop worse hypoxemia and hypercapnia. They also develop cor pulmonale more frequently.

Ventilation/perfusion mismatch in advanced chronic obstructive pulmonary disease

Wagner et al. evaluated the V/Q distribution in 23 patients with stable but advanced COPD and showed
the following three patterns of V/Q mismatch.[31]

1. Predominantly high V/Q ratio (H-type)

2. Predominantly low V/Q ratio (L-type)
3. Mixture of both low and high V/Q ratio (HL-type).

Shunt is characteristically absent. Most of the Type A emphysematous patients had high V/Q ratio, but it
was also noted in Type B patients. High V/Q ratio is characterized by significant ventilation in the poorly
perfused area. High V/Q ratio develops in emphysematous patients due to high compliance and reduced
blood flow. Low V/Q ratio develops predominantly in bronchitis phenotype due to bronchial obstruction
leading to reduced ventilation. Diffusion impairment is not important factor for hypoxemia development in
COPD as exercise or breathing 100% oxygen produces only minimal changes in V/Q distributions.

Ventilation/perfusion mismatch in mild chronic obstructive pulmonary disease

V/Q mismatch can be present even in patients with mild COPD. Barbera et al.[32] reported V/Q mismatch
in 23 mild COPD patients with mean predicted FEV1 of 76 ± 3%. Since the correlation between FEV1 and
V/Q mismatch is poor, the authors also studied the structural basis of V/Q mismatch in mild COPD and
found both pulmonary emphysema and small airways abnormalities as a contributor to V/Q mismatch.
However, the major correlate of the increase in P (A-a) O2 is the morphological severity of emphysema.
The V/Q mismatch in mild COPD may even produce pulmonary vascular remodeling.[33] Morphological
changes in pulmonary vessels are greater in patients with airflow obstruction and poor response to oxygen
therapy. Intimal changes are seen mainly in arteries of <500 µm in diameter. The intimal thickening may
reduce the response to oxygen therapy. Barberà et al.[33] also reported positive correlation between
degrees of V/Q mismatch with mean intimal area thickening. Dead space or wasted ventilation develops
quite early in the natural history of COPD. Elbehairy et al.[34] evaluated 11 stable patients with Global
Initiative for Chronic Obstructive Lung Disease (GOLD) grade 1B COPD and 11 age-matched healthy
control subjects by physiological testing and a symptom-limited incremental cycle exercise test. The P(A-
a)O2 gradient and dead space to the tidal volume ratio (VD/VT) are seen significantly higher level in
COPD both at rest and exercise than in healthy control. Dead space or wasted ventilation represents almost
40% of total VE at rest in mild COPD compared with 28% in control subjects. The mechanism of dead
space development is overventilation of alveolar units relative to perfusion. Reduced perfusion may be due
to reduced pulmonary capillary density or blood flow, impaired vessel recruitment and distension and
smoking associated pulmonary vascular inflammation.[35,36,37]

The V/Q mismatch worsens along with the progression of COPD. Rodríguez-Roisin et al.[29] evaluated
the V/Q mismatch in 150 patients with COPD of various severities and reported a steady worsening of
both V/Q mismatch and arterial blood gas disturbances with the progression of COPD. However, in GOLD
Stage IV, the V/Q mismatch was only modestly worse compared to Stage 1 despite the FEV1 value fallen
to 20% of predicted. One factor could be that V/Q mismatch is already at its worst in Stage 1, so there is
less scope for further deterioration. Patients with GOLD Stage 1 COPD with minimum spirometric
abnormalities developed substantial V/Q mismatch. It indicates that pulmonary gas exchange
abnormalities occur quite early in the natural history of COPD even before lung function abnormalities
develop. The second factor could be simultaneous decrease in both VA and pulmonary blood flow
producing a buffering effect. Airway obstruction causes reduced ventilation and alveolar dilatation and
HPV causes reduced perfusion.

There is also no correlation between the radiological extent of emphysema and degree of V/Q mismatch.
Sandek et al.[38] studied the relationship between V/Q ratios and extent of emphysema by high-resolution
computed tomography (HRCT) in twenty patients of moderate to severe COPD. Similar to Wagner et al.
[31] study, main V/Q defect in emphysema patients in this study was high V/Q ratio due to preferential
ventilation to lung areas with poor perfusion. Shunt and low V/Q ratio were minimal. There was no
correlation between V/Q ratios and the radiological extent of emphysema, diffusing capacity, and arterial
blood gas levels. Severe V/Q mismatch does not develop in COPD patients as the destruction of the
alveolar surface is associated with a reduction in perfusion also. Brudin et al.[39] measured blood volume
on the basis of positron emission tomography scan and found lower tissue density and peripheral vascular
volume within lungs in emphysematous patients. Morrison et al.[40] also reported reduced pulmonary
capillary blood volume across all spectrum of emphysema. The reduced perfusion causes modest V/Q
mismatch and explains the lack of correlation with extent of emphysema. Blood flow is also reduced due
to compression by the overinflated alveolar walls.[40] Another characteristic of Sandek et al.[38] study is
the presence of normal or near normal PaO2 in 80% of patients despite having moderate to severe
emphysema on HRCT in 75% of patients. It may be due to the lesser involvement of small airway as small
airway obstruction may cause atelectasis resulting in the perfusion of poorly ventilated lung areas and
development of hypoxemia. In the COPD gene study, female sex, higher body mass index, lower FEV1
were independent risk factors for hypoxemia development in patients with moderate to very severe COPD.
However, emphysema severity on quantitative chest computed tomography scan did not predict
hypoxemia.[41] The shunt is an uncommon mechanism of hypoxemia in COPD patients. The factor that
prevents the development of shunt is collateral ventilation. Collateral ventilation in the obstructed
segments prevents absorption atelectasis and subsequent shunt formation by keeping the alveoli ventilated.
[42]

Ventilation/perfusion mismatch in acute exacerbation of chronic obstructive pulmonary

disease
Mechanisms responsible for the development of low V/Q ratio in patients with AE-COPD include airway
narrowing due to bronchial inflammation, bronchospasm, or mucous accumulation. Shunt fraction is not
increased during acute exacerbation probably due to the absence of complete airway occlusion or the
presence of collateral ventilation.

Barberà et al.[43] evaluated the mechanism of hypoxemia in 13 male patients admitted to hospital with
acute exacerbations COPD (AE-COPD). Both V/Q mismatch and reduced PvO2 are responsible for
hypoxemia development in AE-COPD. PvO2 is an important contributor to hypoxemia and for a given
level of V/Q mismatch; reduced PvO2 is associated with reduced level of PaO2.[44] PvO2 is reduced due
to greater consumption of oxygen by the overactive respiratory muscles. CO is one extrapulmonary factor
that can modulate the impact of low PvO2 on resulting hypoxemia by improving the PvO2 value.
Therefore, we should be cautious in using drugs that can reduce CO in COPD patients during AE.[39]

PULMONARY EMBOLISM Go to: Go to:

Hypoxemia, hypocapnia, and an increase in the A-a oxygen tension gradient are the classical gas exchange
abnormalities in patients with PE.[45,46] Patients with PE may also present with hypocapnia alone.[47]
Hypocapnia develops due to hyperventilation. The exact mechanism of hyperventilation is not known but
hypoxemia is probably not the only mechanism as correction of hypoxemia with supplemental oxygen
does not always correct hyperventilation mediated respiratory alkalosis.[48] Proprioceptors and other
receptors such as irritant and juxtacapillary sensors may be responsible for stimulation of ventilation.[48]

The main mechanisms of hypoxemia in PE are V/Q mismatch and low level of mixed venous blood
oxygen (PvO2).[49] V/Q mismatch occurs due to redistribution of blood from occluded pulmonary arteries
to the nonoccluded vessels. This results in extremely high or infinite V/Q units in the embolized areas and
low V/Q units in the nonembolized regions due to over perfusion.[50] Overperfusion of nonembolized
regions leads to the development of hypoxemia. The second important mechanism causing hypoxemia is
fall in PvO2 due to reduction in CO.[51] Itti et al.[52] reported the following bimodal distribution of V/Q
ratios in 99 consecutive patients with suspected PE. There was 15.5% increase in high V/Q ratios (>1.2)
and 34.5% increase in low V/Q ratios (<0.8).

Patients of PE may also develop diffusion limitation due to a reduction in pulmonary blood flow by
vascular obstruction and reduced CO. Normal PaO2 and normal A-a oxygen gradient does not rule out
acute PE. Stein et al. reported a Pa02 >80 mmHg in 25% of patients with PE and no prior cardiopulmonary
disease and 15% of patients with PE and prior cardiopulmonary disease. In the same series, 12% of 280
patients with acute PE had an A-a gradient <20 mm.[53] Dantzker et al.[51] reported a PaO2 ≥90 mmHg
in 6% of the patients and a PaO2 ≥80 mmHg in 14%. Normal PaO2 can be explained by hyperventilation
mediated hypocapnia leading to increase in PaO2 level according to the alveolar gas equation. High PAO2
results in maintenance of PaO2 level.

BRONCHOCONSTRICTION AND DEAD SPACE VENTILATION Go to: Go to:

Another physiological change in patients with PE is bronchoconstriction. Stein et al. in an animal model
first reported bronchoconstriction and increased pulmonary resistance due to PE.[54] Gurewich et al.
subsequently reported bronchoconstriction in a group of seven patients with PE.[55] Bronchoconstriction
may be due to the release of substances with bronchoconstriction properties at the sites of thromboemboli,
such as acetylcholine, histamine, serotonin, platelet-activating factor, prostaglandins and the plasma kinins
leading to reflex bronchoconstriction.[56,57,58,59] Pulmonary artery obstruction by thromboemboli also
reduces the elimination of CO2, leading to reduced alveolar CO2 tension and hypocapnia-induced
bronchoconstriction.[60] Patients with PE may develop surfactant deficiency leading to development of
alveolar collapse. Various factors are responsible for surfactant deficiency: Pulmonary gas exchange
abnormalities, inflammation, ischemia and reperfusion and alteration in lung mechanics.[61,62] Patients of
PE may also develop shunt, and it is particularly common in the presence of large emboli.[63] It may
occur due to perfusion of unventilated areas due to surfactant deficiency, pulmonary edema, and
pulmonary arteriovenous anastomosis or patent foramen ovale.[64,65] Preexisting pulmonary arterial-
venous anastomosis may open up by the elevated pulmonary artery pressure.[66] PE may lead to the
development of right ventricular failure and elevated right atrial pressure and when the right atrial pressure
exceeds left atrial pressure, shunting occurs through the foramen ovale which remains patent in
approximately 15% of patients. Recanalization of thrombi occurs earlier than the clearance red blood cells
and debris from the infracted alveolar area and improved perfusion to this underventilated area may cause
shunt formation.[49,65] Although PE reduces the elimination of CO2, hypercapnia is rare except in large
emboli. Hyperventilation of normally functioning alveoli eliminates CO2. Dantzker and Bower in the
animal study had shown that the development of hypoxemia depends on the size of the V/Q units.
Embolization of smaller units leads to diversion of blood to larger unit with little impact, but embolization
of the larger unit leads to significant reduction of V/Q ratio of smaller unit and development of significant
hypoxemia.[67] Another factor that may lead to hypoxemia development in PE is reduced mixed venous
oxygen level (PvO2). PVO2 may be reduced in PE due to a decrease in CO. The impact of PvO2 has been
noted in both V/Q mismatch and shunt.[68] Diffusion impairment is not a common mechanism of
hypoxemia in PE.[69]

Mechanisms:

1. V/Q mismatching:
a. Development of high V/Q ratio in areas with occluded pulmonary vessels
b. Development of low V/Q areas caused by redistribution of pulmonary blood flow from
obstructed vascular areas to adjacent normal areas
c. Development of low V/Q areas following restoration of perfusion in areas with reduced
ventilation due to pulmonary infarction
d. Development of bronchoconstriction by various mediators locally released and alveolar
hypocapnia
e. Development of alveolar collapse due to surfactant loss
f. Decrease PvO2 due to reduced CO
2. Shunt: Surfactant deficiency or opening of pulmonary arteriovenous anastomosis or patent foramen
ovale or delayed clearance of alveolar exudates
3. Decreased diffusion capacity: Decrease in pulmonary blood flow.

IDIOPATHIC PULMONARY FIBROSIS Go to: Go to:

Idiopathic pulmonary fibrosis (IPF) is the most common type of idiopathic interstitial pneumonia. Most
common gas exchange abnormality in IPF is hypoxemia without hypercapnia.[70] Hypoxemia is usually
mild at rest until disease progresses to advanced stages. Another hallmark of IPF is the exercise-induced
worsening of hypoxemia.[71] Hypercapnia may develop if FEV1 falls below 1.0 L/s. Patients of IPF often
adopt rapid shallow breathing pattern due to low VT and stimulation of mechanoceptors. The increase
ventilation is responsible for maintaining eucapnia even in the presence of severe restriction.[72] The
mechanisms of hypoxemia in IPF may be a combination of V/Q mismatch, shunt, and diffusion limitation;
however, V/Q mismatch is the most common cause of hypoxemia both at rest and during exercise.[73]
Diffusion limitation contributes to 19% of hypoxemia at rest but plays a major role during exercise-
induced hypoxemia. During exercise, Agustí et al.[73] did not notice any increase in V/Q mismatch,
explaining a greater role of diffusion limitation during exercise. Diffusion limitation worsens during
exercise due to reduced PvO2 and short capillary transit time and contributes to 40% of hypoxemia at
exercise. They also studied the role of pulmonary vascular tone in hypoxemia. There are basically two
types of vascular involvement: Functional and fixed. Patients with functional vascular obstruction show
better vascular response to oxygen therapy, less pulmonary hypertension during exercise, less V/Q
mismatch and higher PaO2 during exercise than patients with fixed vascular obstruction. Shunting is not
very common in IPF patients.

ACUTE RESPIRATORY DISTRESS SYNDROME Go to: Go to:

The ARDS is a noncardiogenic pulmonary edema characterized by respiratory failure, development of new
bilateral pulmonary infiltrates and severe hypoxemia and low lung compliance. It is associated with
significant mortality. The main mechanism of hypoxemia in ARDS is the development of intrapulmonary
shunting. The mechanism of shunting is due to alveolar flooding with exudates or alveolar collapse. Lamy
et al.[74] in an elegant study of 45 consecutive patients of ARDS correlated gas exchange abnormalities
with pathological changes. They divided the patients into three distinct groups. Group 1 developed most
severe hypoxia and fixed shunt as PaO2 changes is minimal despite a 10 mmHg increase in positive end-
expiratory pressure (PEEP). Pathologically, they show consolidation. Group 2 patients had less severe
hypoxemia and a moderate and slowly increased PaO2 response to a 10 mmHg increase in PEEP.
Pathologically, they show extensive fibrosis. The Group 3 patients had less severe hypoxemia and rapid
response to PEEP therapy. They also show consolidation but less severe than those in Group 1. The V/Q
mismatch and DL is responsible for hypoxemia in Group 2 and 3. Dantzker et al.[75] also reported
predominant presence of shunt along with low V/Q units. Many ARDS patients develop increase shunting
after high FiO2 administration. Santos et al.[76] reviewed the response to 100% oxygen therapy in eight
patients with acute lung injury (ALI) and four patients with COPD. In ALI patients there was a moderate
increase in intrapulmonary shunt. The oxygen induced increment in shunt is due to reabsorbsion
atelectasis. It usually involves the low unstable V/Q units. No increment in intrapulmonary shunt occurred
in COPD patients and the main mechanism of gas exchange abnormalities in COPD is the release of HPV
leading to increase perfusion to areas with low ventilation creating a dead space effects. The gas exchange
abnormalities may persist long after resolution of ARDS. Elliott et al.[77] evaluated the lung function and
exercise gas exchange in 13 survivors of ARDS. The FVC, and total lung capacity returned to normal by
4–6 months but pulmonary gas exchange abnormalities persisted longer, particularly after exercise. ARDS
patients with very high percentage of shunting (~50%) show poor response to oxygen therapy due to
extensive lung damage.[78] Matamis et al.[79] evaluated the effects on PEEP therapy in eight patients
with acute respiratory failure (ARF). One prevailing mechanism of improvement in hypoxemia is the
PEEP-induced fall in CO leading to reduced perfusion to shunt areas. However, reduction in CO is not the
only mechanism. To negate the effect of low CO, Matamis et al. maintained the CO at control level by
dopamine infusion. PEEP therapy reduced the shunt fraction significantly. There was also a redistribution
of pulmonary blood flow from shunt area to areas with normal V/Q ratio.

Pleural effusion
Pleural effusion is a common clinical entity in pulmonary medicine and often causes symptoms and
abnormal gas exchange. Agustí et al.[80] evaluated the mechanism of hypoxemia and the impact of
thoracocentesis in nine patients with recent onset pleural effusion. The main mechanism of hypoxemia was
the presence of intrapulmonary shunt. After thoracocentesis of significant amount of fluid (693 ± 424 ml),
the PaO2, P(A-a)O2 and shunt remained unchanged. Intrapulmonary shunt develops due to continued
perfusion in collapse lungs. The lack of improvement in gas exchange parameters after thoracocentesis can
be explained by various factors. First, re-expansion of collapsed lungs does not occur immediately after
aspiration of pleural fluid.[81] Second, patients may develop mild ex-vacuo pulmonary edema.
Sonnenblick et al.[82] studied the effect of body position on oxygenation status of patients with unilateral
pleural effusion. The mean PaO2 was better when the affected side was superior compared to PaO2 when
the affected side was positioned dependent. The mean PaO2 when the affected side superior was 71.9 ± 9.3
mmHg compared with 66.7 ± 8.7 mmHg when the affected side dependent with the mean difference in
PaO2 between the two positions of 5.1 ± 1 mmHg (P < 0.005). When the affected side up, there is less
perfusion going to the collapsed lung, thereby reducing the amount of shunt. Pneumothorax is also
associated with arterial hypoxemia. Norris et al.[83] studied the pulmonary gas exchange in a series of 12
patients with spontaneous pneumothorax. Nine patients developed a PaO2 below 80 mmHg and 10 patients
developed widened A-a oxygen tension difference. With 100% oxygen, the majority of patients developed
anatomical shunt. There is a negative correlation between the degree of shunt and Pneumothorax volume.
When the pneumothorax volume is <25%, it is not associated with increased shunts. The minimal
pneumothorax volume at which anatomical shunt appears is 35%. The effect of pleural aspiration on PaO2,
PaCO2, P (A-a) O2, dead space and an anatomical shunt was variable.

Liver disease
Arterial hypoxemia is a common clinical feature in patients with chronic liver disease. Fluckiger[84] in
1884 first reported the presence of cyanosis, and digital clubbing in a female with cirrhosis of liver.
Hoffbauer and Rydell et al.[85] in a lung necropsy based study demonstrated intrapulmonary vascular
dilatations and distinct anatomic arteriovenous communications that resulted in the development of severe
hypoxemia in chronic liver disease patients. Eriksson et al.[86] in 1988 first coined the term
“hepatopulmonary syndrome” (HPS) characterized by the triad of liver disease, arterial hypoxemia, and
intrapulmonary vascular dilatation. The intrapulmonary vascular dilatation is responsible for the
development of arterial hypoxemia. The mechanisms of hypoxemia include diffusion limitation, V/Q
mismatch, and right to left intrapulmonary shunt. However, the main mechanism is V/Q mismatch. The
V/Q mismatch occurs due to increase perfusion in the presence of normal ventilation.[87] Increased
perfusion is due to intrapulmonary vascular dilatation and hyperdynamic circulation often seen in cirrhotic
patients. The normal diameter of pulmonary capillaries at the alveolar level is 7–15 microns[88] and
capillary diameters as large as 500 microns have been detected.[89] Dilatation of capillary produces
diffusion defects. Erythrocytes carrying hemoglobin usually travels through the center of the capillaries
and oxygen from adjacent alveoli fail to reach to the center of the dilated vessel in time leading to
inadequate oxygenation and development of hypoxemia. High CO further reduces the capillary transit
time. Diffusion limitation occurs in the advanced stages of HPS.[87] P(A-a)O2 gradient is helpful in early
diagnosis of disease. Patients of HPS often develop platypnoea characterized by increase dyspnea on
standing position. The objective feature of platypnoea is orthodeoxia defined by a decrease in PaO2 of ≥4
mmHg or ≥5% from the supine position to the upright position.[90] On standing position, preferential
perfusion occurs to the basal area of the lungs due to gravity. It leads to further dilatation of vasculature
and worsening of V/Q mismatch. Krowka and Cortese discussed two patterns of intrapulmonary vascular
dilatations. Type 1 lesions include diffuse pulmonary vascular dilatations at the precapillary level close to
the gas exchange units and Type 2 lesions consist of localized dilatations away from the gas exchange
units. Type 2 category show a poor response to oxygen.[91]

Oxygen induced hypercapnia

Uncontrolled oxygen therapy to correct hypoxemia in patients of COPD with ARF may lead to
development or worsening of existing hypercapnia. This phenomenon has been observed since long time
in the field of medicine.[92,93] However, there is controversy regarding the exact mechanism leading to
the development of oxygen induced hypercapnia in COPD patients. The mechanism proposed initially and
still being taught in the medical school is the hypoxic drive theory. According to this theory, COPD
patients depend on hypoxic ventilatory drive as the hypercapnic drive is blunted in chronically
hypercapnic COPD patients.

Rudolf proposed that prolonged hypoxemia in patients with COPD in ARF leads to lactate accumulation in
the brain and establishes the hypoxic drive of breathing.[94]

Therefore, uncontrolled oxygen therapy may abolish the hypoxic drive resulting in fall in VE and
development of hypercapnia. However, there is an upper limit to the effect of oxygen therapy on VE as any
rise in PaO2 above 100 mmHg have no impact on VE. It occurs due to attenuation of carotid sinus
discharge above 100 mmHg.[95] However, Aubier et al. did not find any correlation between oxygen
therapy induced hypercapnia and changes in ventilation.[96] They administered oxygen to 22 patients with
ARF due to COPD and studied the time course of changes in arterial blood gases, VE, and respiratory rate.
Oxygen therapy initially decreases VE in all patients, and the nadir occurred 71 ± 9 s after initiation of
oxygen therapy. The mean decrease in VE was 18 ± 2%. However, with continued oxygen therapy there is
a significant improvement in VE reaching a plateau after about 12 min of oxygen therapy. Surprisingly
PaCO2 showed a rising trend despite the recovery in VE. At the end of 15 min of oxygen therapy, average
fall in VE was 7% compared to patients breathing room air and this can explain a PaCO2 increase of 5
mmHg of the total 23 mmHg only. In another study, Aubier et al.[97] measured the respiratory drive by
mouth occlusion pressure in the first 100 ms of inspiratory effort (P0.1) in twenty COPD patients with
ARF. The P0.1 after oxygen therapy reduced to 4.9 ± 0.7 cm H2O from a value of 8.3 ± 0.8 cm H2O seen
in patients on room air. However, this value is still greater than that of normal subjects, thereby clearly
indicating that reduction in VE alone cannot explain the rise in PaCO2. PaCO2 level is influenced by VT,
RR, VCO2, and VD. Since VE cannot explain the rise, it must be either rise in VCO2 or VD responsible for
the rise in PCO2. The VD/VT ratio increased from 77 ± 2 while breathing room air to 82 ± 2 after 15 min
of O2 inhalation (P < 0.01). Therefore, the oxygen-induced hypercapnia is due to V/Q mismatch. Oxygen
therapy can lead to further worsening of V/Q mismatch by relieving HPV, thereby increasing perfusion to
low ventilated areas. Since the alveolar-capillary unit remains poorly ventilated, CO2 removal would be
poor leading to rise in PaCO2. On the other hand, blood from the adjacent better-ventilated unit would be
diverted to the poorly ventilated unit due to the abolition of HPV, the former unit would become a high
V/Q units. Another detrimental effect of uncontrolled oxygen therapy is the development of absorption
atelectasis. It may happen with FiO2 as low as 30–50%.[98] The increase in FiO2 can cause nitrogen
washout of the alveoli thereby leading to alveolar collapse as oxygen is absorbed rapidly distal to the
obstruction in the airways. Another mechanism of oxygen-induced hypercapnia is Haldane effect. Haldane
effect says that increasing FiO2 displaces the CO2 molecules from hemoglobin and can also explain the
rise in PaCO2 level.[99] Robinson et al.[100] evaluated the V/Q mismatch by MIGET in 22 patients
during an acute exacerbation of COPD and studied the underlying mechanism of hypercapnia. They
grouped the patients into CO2 retainer and non-retainer group. The features that differentiate the two
groups are depression of ventilation and increase in alveolar dead space in the retainer groups. V/Q
mismatch was equally distributed in both the groups. They proposed hypercapnia induced
bronchodilatation as the mechanism for the increase in dead space. Therefore, the mechanism of oxygen-
induced hypercapnia in COPD is still controversial. However, COPD patients should be treated with
controlled oxygen therapy with a SaO2 goal from 88% to 92% to avoid the risk of hypercapnia.[95]

The risk of hypercapnia following oxygen therapy has also been observed with other conditions: Morbid
obesity, asthma, pneumonia, chest wall deformities and neuromuscular disorders.[95,100] Perrin et al.
[101] in a randomized controlled trial of high versus controlled oxygen therapy in patients with severe
exacerbations of asthma reported an increase in the transcutaneous partial pressure of carbon dioxide
(PtCO2) in patients on high concentration oxygen therapy. Similar to COPD patients, a controlled oxygen
regime should be used in the treatment of severe asthma. The mechanism is the release of HPV by high
concentration of oxygen therapy leading to dead space effect.[18,102] Hutchison et al.[103] proposed an
interesting hypothesis that the response to hypoxia may be mediated in part by familial factor and those
with this risk are at risk of developing respiratory failure after an asthma attack. Hollier et al.[104]
reported hypoventilation and acidemia development after using moderate concentration of supplemental
oxygen (FiO2) in patients with obesity hypoventilation syndrome (OHS). The risk is higher in patients
with a high baseline level of PaCO2 and HCO3. Both high PaCO2 and HCO3 level may blunt the
hypercapnic ventilatory responses in OHS patients.[105,106]

Measurement of hypoxemia
Arterial oxygen tension (PaO2) The PaO2 is the partial pressure of oxygen that indicates the dissolved
oxygen in the plasma and not the oxygen bound to hemoglobin. It is measured by arterial blood gas
analyzer. Mixed venous blood partial pressure of oxygen (PVO2) is 40 mmHg and it is 75% saturated. The
PaO2 in the systemic artery after gas exchange at the alveolar level is 97%. It does not become 100% due
to the presence of an anatomical shunt. The goal in oxygen therapy is to raise the PaO2 above 60 mmHg as
the oxygen-hemoglobin curve is flattened after a PaO2 of 60 mmHg. The normal PaO2 level varies from
80 to 100 mmHg.

Arterial oxygen content (CaO2) It is the combination of hemoglobin bound oxygen plus the dissolved
oxygen in the arterial blood. It is calculated by the following equation:

CaO2= (Hgb × 1.34 × SaO2) + (0.0031 × PaO2).

PaO2 and the SaO2 do not provide information on the number of oxygen molecules in the blood. CaO2
quantifies the amount of oxygen in the blood-both bound and unbound fraction to hemoglobin. The
contribution of the dissolved oxygen to CaO2 is normally minimal. Since PaO2 depends on dissolved
oxygen, PaO2 may remain normal in the presence of anemia.

Arterial oxygen saturation (SaO2) It is defined as the percentage of hemoglobin saturated with oxygen. It
can be measured by both pulse oximetry and arterial blood gas analysis (SaO2). Pulse oximetry is widely
used in the assessment of patients and should be regarded as the fifth vital sign.[107] Measurement of
oxygen saturation by pulse oximetry (SpO2) is based on the Beer–Lambert–Bouguer law which states that
the attenuation of light depends on the properties of the materials through which the light is traveling.
Pulse oximeter contains light-emitting diodes that transmit light energies at two wavelengths of 660 nm
(red light) and 940 nm (infrared) respectively. Oxy-hemoglobin (O2Hb) and deoxy-hemoglobin (HHb)
differentially absorb red and near-infrared (IR) light.[108]
PaO2/FiO2 ratio It is the ratio of partial pressure of oxygen to fractional inspired oxygen and is also known
as Carrico index. The PaO2/FiO2 ratio assesses the hypoxemia at a different level of FiO2. The normal
ratio varies from 300 to 500 mmHg. It is a commonly used index because of the ease of measurement and
its prognostic value in ARDS patients. According to Berlin definition, ARDS is differentiated into three
subcategories based on the degree of hypoxemia measured by PaO2/FiO2 ratio: Mild (200 mmHg
PaO2/FiO2 ≤300 mmHg), moderate (100 mmHg PaO2/FiO2 ≤200 mmHg), and severe (PaO2/FIO2 ≤100
mmHg). In all the subcategories, PEEP or continuous positive airway pressure ≥5 cm H2O was used.[109]
It can also be used for rough estimation of shunt fraction.[19] A PaO2/FiO2 ratio of <200 indicates a shunt
fraction is more than 20%. In a healthy person who is breathing room air, the PaO2 is 100 mmHg and FiO2
is 0.21%. Therefore, the PaO2/FiO2 ratio is 100/0.21 or 500.

There are limitations of PaO2/FiO2 ratio also. A-a gradient can differentiate whether hypoxemia is due to
alveolar hypoventilation or V/Q mismatch but PaO2/FiO2 ratio is unable to determine the underlying
mechanism of hypoxemia. Gowda et al.[110] in a modeling study assessed the variability of PaO2/FiO2
ratio in ARDS patients. They observed that in ARDS patients, all the indices of hypoxemia are influenced
by changes in extra-pulmonary factor like FiO2. In ARDS patients with moderate shunts (<30%),
PaO2/FiO2 ratio is better at extremes of FiO2 than at intermediate FiO2. In patients with large shunts
(>30%) PaO2/FiO2 ratio is greater at low FiO2. A stable PaO2/FiO2 ratio is seen with a FiO2 of ≥0.5 and a
PaO2 of ≤100 mmHg. Karbing et al.[111] showed that PaO2/FiO2 ratio varied with FiO2 in both
mechanically ventilated and spontaneously breathing patients and proposed that the FiO2 level at which
the PaO2/FiO2 ratio is measured should be specified. They also advocated the replacement of the
conventional single-parameter variable like PaO2/FiO2 ratio with two parameters model of hypoxemia
development due to V/Q mismatch and shunt.

The arterial/alveolar oxygen tension ratio (a-A oxygen tension ratio)

The arterial to alveolar oxygen ratio is measured by dividing PaO2 by the PaO2. The a-A oxygen ratio is
less dependence on FiO2 unlike the alveolar/arterial oxygen tension difference.[112] Normal ratio varies
between 0.75 and 1.0. The a-A oxygen ratio may be used to calculate the FiO2 required to raise PaO2 to
certain levels. The formula for estimating the required FiO2 can be done by the following formula:

A 65-year-old patients of COPD presented in the emergency with acute exacerbation. His ABGs is
showing a PaO2 of 40 mmHg and a PaCO2 of 55 mmHg on FiO2 28%. What should be the Fio2 to raise
PaO2 to 60 mmHg?

PaO2 = FiO2 (PB − PH2O) − PaCO2/R.

=0.28 (760 − 47) − 55/0.8.

=131.

PaO2/PaO2= 40/131 = 0.30.

60/New PaO2 = PaO2/PaO2= 0.30.

Required FiO2 = 0.37 or 37%.

R is respiratory quotient.
Oxygenation index
The OI is calculated as mean airway pressure (MAP) times FiO2 and whole divided by arterial PO2. The
advantage of OI is that it assesses both the gas exchange and compliance of the lung.[113]

Dechert et al. reported that age-adjusted OI is equivalent to or better than other mortality prediction system
used for ARDS.[114]

Mixed and central venous oxygen saturation

Mixed venous oxygen saturation (SvO2) is the percentage of oxygen bound to hemoglobin in the mixed
venous blood. It gives us idea about the oxygen extraction by the tissues. Normal SvO2 is 60–80%. Central
venous oxygen saturation (ScVO2) is a surrogate of SvO2 and is easier to measure unlike SvO2. The goal
of ScVO2 of more than 70% has been incorporated in the surviving sepsis guidelines.[115] There are other
advantages of ScVO2 measurement. It can be used in estimating CO, shunt fraction. It gives better idea
about adequacy of patient's oxygen delivery.[116]

Financial support and sponsorship

Nil.

Conflicts of interest
There are no conflicts of interest.

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Figures and Tables Go to: Go to:

Figure 1

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The low ventilation/perfusion ratio. Ventilation is reduced but perfusion is normal

Figure 2
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The mechanism of hypoxic pulmonary vasoconstriction. Hypoxia causes closure of voltage-gated potassium channel,
leading to K+ accumulation intracellularly. It leads to depolarization of the cells, opening of voltage-gated calcium
channel and calcium-mediated pulmonary vasoconstriction

Figure 3

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High ventilation/perfusion ratio in a patient with pulmonary embolism

Figure 4

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Shunt where ventilation is zero but perfusion normal

Figure 5

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The calculation of shunt

Figure 6

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Various mechanisms and differentiating features of hypoxemia

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