Measures of oxygenation and mechanisms of hypoxemia

INTRODUCTION — Understanding the mechanisms of hypoxemia is critical for evaluating patients with hypoxemia. Identifying the main contributing mechanism to hypoxemia helps narrow the differential so that investigations and therapy are appropriately targeted.

In this topic review, measures of oxygenation and mechanisms of hypoxemia are discussed. Oxygen delivery and consumption and management of acute hypoxemia are discussed separately. (See "Oxygen delivery and consumption" and "Evaluation and management of the nonventilated, hospitalized adult patient with acute hypoxemia".)

TERMINOLOGY — The process of taking oxygen from the inspired air and using it to sustain aerobic cellular metabolism throughout the body involves the following:

●Oxygenation

●Oxygen delivery

●Oxygen consumption

Low levels of oxygen in the blood can result in hypoxemia or hypoxia.

Oxygenation — Oxygenation is the process of oxygen diffusing passively from the alveolus to the pulmonary capillary, where it mostly binds to hemoglobin in red blood cells (oxyhemoglobin); a small proportion directly dissolves into the plasma. Measures of oxygenation are discussed below. (See 'Measures of oxygenation' below.)

Oxygen delivery and consumption — Oxygen delivery is the rate of oxygen transport from the lungs to the peripheral tissues. Oxygen consumption is the rate at which oxygen is removed from the blood for use by the tissues. Further details on these processes are described separately (See "Oxygen delivery and consumption", section on 'Oxygen delivery'.)

Hypoxemia — Hypoxemia is defined by an arterial oxygen tension <60 mmHg (ie, insufficient oxygenation). Hypoxemia does not necessarily always indicate tissue hypoxia.

Hypoxia — Hypoxia is defined as a condition where the oxygen supply is inadequate either to the body as a whole (general hypoxia) or to a specific region (tissue hypoxia). Hypoxia can be due to reduced oxygen delivery and/or increased oxygen consumption by tissue.

MEASURES OF OXYGENATION — When impaired oxygenation is present, peripheral tissues are at risk for unmet metabolic requirements. There are numerous ways to measure whether oxygenation is impaired. Commonly used measures are arterial oxygen saturation (SaO₂) and peripheral oxygen saturation (SpO₂), arterial oxygen tension (PaO₂), the alveolar-arterial (A-a) gradient, and arterial oxygen tension:fraction of inspired oxygen (PaO₂:FiO₂) ratio. SaO₂, SpO₂, and PaO₂ are general measures of oxygenation while the A-a gradient and PaO₂:FiO₂ ratio are used in select situations.

Commonly used

Arterial and peripheral oxygen saturation (SaO2 and SpO2) — Most of the oxygen that diffuses from the alveolus to the pulmonary capillary binds to hemoglobin in red blood cells (approximately 98 percent). The percent of saturated hemoglobin (ie, oxyhemoglobin) can be determined by measuring SaO₂ or SpO₂.

●SaO₂ – SaO₂ is a direct measurement of the percent of oxyhemoglobin in arterial blood. It is commonly reported as part of an arterial blood gas sample that also measures PaO₂. (See 'Arterial oxygen tension (PaO2)' below and "Arterial blood gases", section on 'Interpretation'.)

●SpO₂ – SpO₂ is a noninvasive estimate of the percent of oxyhemoglobin in the capillary bed that uses co-oximetry and a pulse oximeter. (See "Pulse oximetry".)

The SpO₂ is most commonly used to measure oxygenation in patients since it is noninvasive and generally correlates well with the SaO₂, although accuracy decreases when the SaO₂ is <90 percent. Since SaO₂ is a more accurate measure of oxygenation, it is prudent that the clinician checks the SaO₂ on an arterial blood gas when uncertainty exists (ie, dark skin tone, an error in the SpO₂ is suspected such as methemoglobinemia or carbon monoxide poisoning). Further details regarding errors associated with SpO₂ including racial differences in SpO₂ measurements are listed in the table (table 1) and discussed separately. (See "Pulse oximetry", section on 'Troubleshooting sources of error'.)

Abnormal SpO₂ or SaO₂ has not been defined because an exact threshold below which tissue hypoxia occurs has not been identified. This reflects the multifactorial nature of tissue hypoxia. It is reasonable to consider a resting SpO₂ or SaO₂ ≤95 percent or exercise desaturation ≥5 percent from baseline as abnormal, although these values should not be considered in isolation [1,2]. As an example, a resting SaO₂ of 95 percent could be abnormal if a patient previously had a resting SaO₂ of 99 percent. Ideal target oxygen saturation goals are discussed separately. (See "Evaluation and management of the nonventilated, hospitalized adult patient with acute hypoxemia", section on 'Oxygen saturation goals'.)

Arterial oxygen tension (PaO2) — The PaO₂ reflects the small amount of the oxygen that diffuses from the alveolus to the pulmonary capillary and dissolves into the plasma (approximately 2 percent). The PaO₂ is measured in arterial blood. We measure PaO₂ when an accurate assessment of gas exchange is needed and when we suspect that the SpO₂ is falsely low, normal, or high; these conditions are listed in the table (table 1). (See "Pulse oximetry", section on 'Troubleshooting sources of error'.)

An abnormal PaO₂ has not been precisely defined because a threshold below which tissue hypoxia predictably occurs has not been identified. However, it is reasonable to consider a PaO₂ <80 mmHg as abnormal, with the understanding that the threshold varies with the A-a gradient (which widens with age), that the value should not be considered in isolation, and that an approximate value <60 mmHg typically represents hypoxemia [3]. (See "Arterial blood gases" and "Arterial blood gases", section on 'Normal values' and "Arterial blood gases", section on 'Oxygenation' and 'Alveolar-arterial (A-a) oxygen gradient' below.)

Alveolar-arterial (A-a) oxygen gradient — The A-a oxygen gradient (also known as A-a difference) is a common measure of oxygenation ("A" denotes alveolar and "a" denotes arterial oxygenation). The A-a gradient is a nonspecific indicator of the integrity of the alveolocapillary membrane. Thus, any pathology of the alveolocapillary unit widens the gradient. Hypoxemia due to ventilation-perfusion (V/Q) mismatch, diffusion limitation, and shunt are associated with a widened gradient, whereas hypoxemia due to hypoventilation has a normal gradient.

We typically use the A-a gradient to narrow the differential in patients with hypoxemia, the details of which are discussed separately (table 2). (See "Evaluation and management of the nonventilated, hospitalized adult patient with acute hypoxemia", section on 'Narrowing the differential'.)

The A-a gradient is calculated as the difference between the amount of the oxygen in the alveoli (ie, the alveolar oxygen tension [PAO₂]) and the amount of oxygen dissolved in the plasma (PaO₂) (calculator 1):

PaO₂ is measured by arterial blood gas, while PAO₂ is calculated using the alveolar gas equation:

where FiO₂ is the fraction of inspired oxygen (0.21 at room air), Patm is the atmospheric pressure (760 mmHg at sea level; 633 mmHg at 5000 feet; 523 mmHg at 10,000 feet), PH₂O is the partial pressure of water (47 mmHg at 37°C), PaCO₂ is the arterial carbon dioxide tension, and R is the respiratory quotient. The respiratory quotient is approximately 0.8 at steady state but varies according to the relative utilization of carbohydrate, protein, and fat. The A-a gradient calculated using the alveolar gas equation may deviate from the true gradient by up to 10 mmHg. This reflects the equation's simplification from a more rigorous full calculation and the imprecision of several independent variables (eg, FiO₂ and R).

There is no single cutoff for a normal or abnormal A-a gradient since it varies with age and the FiO₂ [4,5]:

●Age – The normal A-a gradient increases with age due to a rise in V/Q mismatch with age and can be estimated from the following equation, assuming the patient is breathing room air (calculator 1) [4]:

●FiO₂ – The A-a gradient increases with higher FiO₂. When a patient receives a high FiO₂, both PAO₂ and PaO₂ increase. However, the PAO₂ increases disproportionately, causing the A-a gradient to widen.

Proper determination of the A-a gradient requires exact measurement of the FiO₂. Thus, the most accurate measurement of the A-a gradient is in patients breathing room air at sea level or in patients receiving mechanical ventilation. Since the FiO₂ can only be estimated in patients receiving supplemental oxygen by nasal cannula or face mask the A-a gradient can only be approximated in such patients leading to large variations and limiting its usefulness. However, when used to assess the contribution of shunt to hypoxemia in spontaneously breathing patients (eg, in a pulmonary function laboratory or hospital floor), despite relative inaccuracy, a 100 percent nonrebreathing mask is typically used since it is the only suitable noninvasive alternative. Further details on this evaluation are provided separately. (See 'Ventilation-perfusion mismatch' below and 'Right-to-left shunt' below and "Pulmonary arteriovenous malformations: Clinical features and diagnostic evaluation in adults", section on 'Shunt fraction assessment'.)

Arterial oxygen tension: fraction of inspired oxygen (PaO2/FiO2) ratio — The PaO₂/FiO₂ ratio is another common measure of oxygenation and is most often employed in ventilated patients. The Berlin criteria for defining acute respiratory distress syndrome (ARDS) includes calculating the PaO₂/FiO₂ ratio (calculator 2) and can help make decisions regarding ventilator management in ARDS, the details of which are described elsewhere. (See "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults", section on 'Clinical diagnosis' and "Acute respiratory distress syndrome: Ventilator management strategies for adults".)

PaO₂/FiO₂ ratio is calculated by dividing the PaO₂ by the FiO₂ (calculator 2). For example, a patient whose PaO₂ is 60 mmHg while receiving an FiO₂ of 0.5 (ie, 50 percent) has a PaO₂/FiO₂ ratio of 120 mmHg. A normal PaO₂/FiO₂ ratio is 300 to 500 mmHg, with values less than 300 mmHg indicating abnormal gas exchange and values less than 200 mmHg indicating moderate to severe hypoxemia [6].

Mixed and central venous oxygen saturation (SvO2, ScvO2) — Mixed venous oxygen saturation (SvO₂) and central venous oxygen saturation (ScvO₂) measure the percentage of oxygen bound to hemoglobin in mixed venous and central venous blood, respectively. ScvO₂ measures central venous oxygen saturation level from veins draining the head and upper body and can be readily obtained from a central venous catheter (if in place), while the SvO₂ measures mixed venous oxygen saturation from the entire body and requires placement of a pulmonary artery catheter. ScvO₂ measurements obtained from internal jugular or subclavian catheters are often used as a surrogate for the SvO₂.

SvO₂ and ScvO₂ reflect the degree of oxygen extraction by the tissues. Normal SvO₂ is 60 to 80 percent. Normal ScvO₂ (from an internal jugular or subclavian vein) is >70 percent. They are low in patients with increased oxygen extraction due to high metabolic states or decreased cardiac output but may be either high or low in sepsis.

Less commonly used

Arterial-alveolar (a-A) oxygen ratio — The a-A oxygen ratio is typically used to predict the change in PaO₂ that will result when the FiO₂ is changed.

The a-A oxygen ratio is determined by dividing the PaO₂ by the PAO₂ ("A" denotes alveolar and "a" denotes arterial oxygenation) [6-8]:

where the PaO₂ is derived from an arterial blood gas and the PAO₂ is derived from the alveolar gas equation above. (See 'Alveolar-arterial (A-a) oxygen gradient' above.)

Its lower limit of normal is 0.77 to 0.82, and it is most reliable when the FiO₂ is less than 0.55 (ie, 55 percent) [7]. However, it is rarely used since the FiO₂ and positive end-expiratory pressure can be easily adjusted based upon SpO₂ measurements. (See "Acute respiratory distress syndrome: Ventilator management strategies for adults", section on 'Positive end-expiratory pressure (PEEP), fraction of inspired oxygen, oxygenation target'.)

Oxygenation index — The oxygenation index (OI) is most commonly used in neonates with persistent pulmonary hypertension of the newborn (PPHN). The OI is used to determine the severity of hypoxemia and to guide the timing of interventions, such as inhaled nitric oxide [9,10].

The OI is calculated as follows (calculator 3):

A high OI (eg, ≥25) indicates severe hypoxemic respiratory failure.

The value of OI in the management of newborns with PPHN is discussed in detail separately. (See "Persistent pulmonary hypertension of the newborn (PPHN): Management and outcome", section on 'Severity of hypoxemia'.)

Arterial oxygen content — The oxygen content of arterial blood (CaO₂) includes bound and dissolved oxygen and is calculated as the following:

CaO₂ (mL O₂/dL) = (1.34 x hemoglobin concentration x SaO₂) + (0.0031 x arterial oxygen tension [PaO₂]).

The CaO₂ is sometimes used to determine the shunt fraction and oxygen delivery. (See 'Right-to-left shunt' below and "Oxygen delivery and consumption".)

The contribution of the dissolved oxygen to CaO₂ is minimal (approximately 2 percent). Since PaO₂ depends on dissolved oxygen, PaO₂ may remain normal in the presence of anemia but CaO₂ is low.

MECHANISMS OF HYPOXEMIA — Hypoxemia can be caused by ventilation-perfusion (V/Q) mismatch, right-to-left shunt, hypoventilation, diffusion impairment, reduced inspired oxygen tension [11], and reduced oxygen content or oxygen carrying capacity. While V/Q mismatch is the most common mechanism involved, most disease states have more than one mechanism contributing to hypoxemia. The mechanisms, etiology, and management of acute hypoxemia are listed in the table (table 2). Evaluation of the hypoxemic patient is discussed in detail elsewhere. (See "Evaluation and management of the nonventilated, hospitalized adult patient with acute hypoxemia".)

Ventilation-perfusion mismatch — V/Q mismatch refers to an imbalance of ventilation and blood flow in the lung (figure 1).

●In the normal lung, there is V/Q mismatch because perfusion and ventilation are heterogeneous. Both ventilation and perfusion are greater in the bases than in the apices (when in an upright position). However, the difference between apical and basilar ventilation is smaller than the difference between apical and basilar perfusion. As a result, the V/Q ratio is higher in the apices than in the bases. Normal V/Q mismatch is responsible for the normal physiologic occurring A-a gradient. (See 'Alveolar-arterial (A-a) oxygen gradient' above.)

●In the diseased lung, V/Q mismatch increases because heterogeneity of both ventilation and perfusion worsen. The net effect is hypoxemia. V/Q mismatch causes the composition of alveolar gas to vary among lung regions:

•Lung regions with low ventilation compared with perfusion (low V/Q mismatch) will have a low alveolar oxygen content and high carbon dioxide (CO₂) content.

•Lung regions with high ventilation compared with perfusion (high V/Q mismatch) will have a low CO₂ content and high oxygen content.

Etiologies where V/Q mismatch contributes to hypoxemia include patients with embolic diseases, pulmonary vascular diseases, obstructive and interstitial lung diseases, and low flow cardiac output states (reduced perfusion globally, including reduced perfusion to the pulmonary capillary bed) (table 2). Hypoxemia due to V/Q mismatch typically corrects with oxygen supplementation, with the exception of shunt, which is an extreme form of low V/Q mismatch (see 'Right-to-left shunt' below). V/Q mismatch is characterized by an increased alveolar-arterial (A-a) gradient and is not typically associated with hypercapnia unless dead space is increased or hypoventilation is also present.

Physiologic dead space and shunt are extreme forms of V/Q mismatch:

●Physiologic dead space (high V/Q mismatch) – Physiologic dead space is areas that are ventilated and not perfused (ie, high V/Q mismatch; eg, large saddle pulmonary embolism, severe obstructive lung disease with loss of capillary-alveoli structures).

●Physiologic shunt (low V/Q mismatch) – Shunt is the opposite of dead space and is comprised of areas that are perfused but not ventilated (ie, low V/Q mismatch; eg, lobar pneumonia, significant atelectasis). (See 'Right-to-left shunt' below.)

Right-to-left shunt — A right-to-left shunt exists when blood passes from the right to the left side of the heart without being oxygenated. Right-to-left shunts cause extremely low V/Q mismatch, with a V/Q ratio of zero in some lung regions. The net effect is hypoxemia, which is classically difficult to correct with supplemental oxygen and is associated with a widened A-a gradient. Hypercapnia is uncommon in shunt until the shunt fraction reaches 50 percent or more [6].

There are two types of right-to-left shunt that are associated with several etiologies (table 2):

●Anatomic shunt – Anatomic shunts exist when the alveoli are bypassed anatomically. Examples include intracardiac shunts, pulmonary arteriovenous malformations, and hepatopulmonary syndrome. The clinical manifestations and assessment of shunt in these conditions are discussed elsewhere. (See "Clinical manifestations and diagnosis of atrial septal defects in adults" and "Pulmonary arteriovenous malformations: Clinical features and diagnostic evaluation in adults" and "Hepatopulmonary syndrome in adults: Prevalence, causes, clinical manifestations, and diagnosis".)

●Physiologic shunt – Physiologic shunts exist when nonventilated alveoli are perfused (ie, low V/Q mismatch). Examples include atelectasis and diseases with alveolar filling (eg, blood, pus, cells, water, or microbes).

The degree of physiologic shunt (ie, shunt fraction) in healthy lung is typically 2 to 3 percent of the cardiac output [12]. It occurs since bronchial veins drain into pulmonary veins and some of the coronary veins may also drain directly into the left ventricle.

The physiologic shunt fraction can be quantified from the shunt equation:

where Qs/Qt is the shunt fraction, CcO₂ is the end-capillary oxygen content, CaO₂ is the arterial oxygen content, and CvO₂ is the mixed venous oxygen content. CaO₂ and CvO₂ are calculated from arterial and mixed venous blood gas measurements, respectively (see 'Arterial oxygen content' above). CcO₂ is estimated from the alveolar oxygen tension (PAO₂) (see 'Alveolar-arterial (A-a) oxygen gradient' above). Since this calculation is complicated, as a rough estimate, some experts use the arterial oxygen tension:fraction of inspired oxygen (PaO₂:FiO₂) ratio (eg, if PaO₂/FiO₂ is <200, shunt fraction is more than 20 percent). (See "Oxygen delivery and consumption", section on 'Definitions'.)

Hypoventilation — Hypoventilation refers to alveolar underventilation. Hypoxemia due to global hypoventilation is less common than hypoxemia due to V/Q mismatch or shunt. Abnormalities that cause pure hypoventilation are central and peripheral neuromuscular disorders, thoracic cage disorders, and several drugs. These and other causes of hypercapnia are listed in the table (table 3).

In healthy lung, hypoxemia due to hypoventilation is generally mild but may be severe in those with diseased lung. It is distinguished from V/Q mismatch and shunt by the presence of hypercapnia. Typically, the A-a gradient is unchanged unless hypercapnia is prolonged [13] or there is coexisting dead space. Hypoxemia due to global hypoventilation generally corrects easily with supplemental oxygen.

The lung alveolus is a space in which gas makes up 100 percent of the contents. This means that once the partial pressure of one gas rises, the other must decrease. Both arterial carbon dioxide tension (PaCO₂) and alveolar carbon dioxide tension (PACO₂) increase during hypoventilation, which causes the PAO₂ to decrease. As a result, diffusion of oxygen from the alveolus to the pulmonary capillary declines with a net effect of hypoxemia and hypercapnia. Because the respiratory quotient (defined as CO₂ eliminated/O₂ consumed) is assumed to be 0.8, hypoventilation affects PaCO₂ more than the PaO₂. (See "Mechanisms, causes, and effects of hypercapnia", section on 'Formula for arterial carbon dioxide tension'.)

Diffusion limitation — Diffusion limitation exists when the movement of oxygen from the alveolus to the pulmonary capillary is impaired. It is usually a consequence of alveolar and/or interstitial inflammation, fibrosis, or destruction, such as that due to interstitial lung disease or emphysema. In such diseases, diffusion limitation usually coexists with V/Q mismatch, which makes the relative contribution of each to the patient's hypoxemia uncertain. However, diffusion limitation is classically more apparent during exercise than at rest, whereas hypoxemia due to V/Q mismatch is usually associated with hypoxemia at rest.

Abnormalities that are associated with diffusion are listed in the table (table 2). Although diffusion abnormalities impair the diffusion of both oxygen and CO₂, hypercapnia is uncommon since CO₂ is 20 times more soluble in water than oxygen and therefore diffuses more readily across the alveolar capillary membrane.

Diffusion limitation is characterized by exercise-induced hypoxemia, which is physiologically explained by the following:

●Reduced transit time – During rest, blood traverses the lung relatively slowly. Capillary transit time is typically 0.75 second with gas exchange occurring in 0.25 second. Thus, there is usually sufficient time for oxygenation to occur even if diffusion limitation exists. However, during exercise, cardiac output increases and blood traverses the lung more quickly. As a result, there is less time for oxygenation resulting in hypoxemia.

●Altered compensatory mechanisms – In healthy individuals during exercise, pulmonary capillaries dilate, which increases the surface area available for gas exchange by perfusing additional regions of lung. PAO₂ also increases, which promotes oxygen diffusion by increasing the oxygen gradient from the alveolus to the artery. The net effect is that full oxygenation is sustained. In contrast, in patients with diffusion limitation, the ability to recruit additional surface area for gas exchange is limited, resulting in hypoxemia.

Reduced inspired oxygen tension — A reduced inspired oxygen tension (PiO₂) is most commonly associated with high altitude and, less commonly, a reduction in cabin pressure during aircraft travel. (See "Acute mountain sickness and high-altitude cerebral edema" and "High-altitude pulmonary edema".)

It can be determined by the equation:

where FiO₂ is the fraction of inspired oxygen (0.21 at room air), Patm is the atmospheric pressure (760 mmHg at sea level), and PH₂O is the partial pressure of water (47 mmHg at 37°C).

Reduction of the PiO₂ will decrease the PAO₂. This impairs oxygen diffusion by decreasing the A-a oxygen gradient. The net effect is hypoxemia.

It has been estimated that the mean decrease in PaO₂ is 1.60 kPa (12 mmHg) per 1000 meters of vertical ascent [14].

Reduced oxygen content or carrying capacity — Rare causes of hypoxemia tend to affect oxygen content or oxygen carrying capacity, which then affect oxygen delivery:

●Genetic causes of severe anemia or hemoglobinopathies (low hemoglobin values affect oxygen delivery). (See "Hemoglobin variants that alter hemoglobin-oxygen affinity".)

●Cyanide toxicity, carboxyhemoglobinemia, or methemoglobinemia. (See "Cyanide poisoning" and "Carbon monoxide poisoning" and "Methemoglobinemia".)

Increased oxygen extraction — Increased oxygen extraction refers to the removal of excess amounts of oxygen from capillary blood by metabolically active tissue. When extraction is high, the level of oxygenated blood returning to the venous side is significantly lower than usual. This mechanism generally contributes to, rather than being sole reason for, hypoxemia.

Increased oxygen extraction is associated with a normal PaCO₂ and a widened A-a gradient and is usually suspected when the mixed and central venous oxygen saturation are low. (See 'Mixed and central venous oxygen saturation (SvO2, ScvO2)' above.)

Examples of high extraction states include low flow cardiac output states and sepsis (table 2). Anemia must be severe to be associated with increased oxygen extraction (eg, hemoglobin <7.5 g/dL). (See "Use of blood products in the critically ill", section on 'Restrictive strategy as the preferred approach'.)

Oxygen consumption and oxygen extraction can be calculated, but such calculations are not frequently used in practice for clinical management. (See "Oxygen delivery and consumption", section on 'Oxygen consumption' and "Oxygen delivery and consumption", section on 'Oxygen extraction'.)

SPURIOUS HYPOXEMIA — Spurious hypoxemia (also known as pseudohypoxemia) is characterized by a low arterial oxygen tension (PaO₂) on arterial blood gas analysis but an actual normal oxygen saturation (SaO₂) in the patient.

The two most common conditions causing spurious hypoxemia are leukocyte larceny, which occurs with leukemic polymorphonuclear leukocyte counts higher than 55,200, or platelet larceny, with counts more than 2,000,000 [15,16]. The low PaO₂ is due to increased oxygen consumption by the high number of leukemic white blood cells or platelets prior to laboratory blood analysis or by mechanical blockage of the sensing electrode by the numerous cells interfering with readings.

When spurious hypoxemia is suspected, we follow the peripheral oxygen saturation and arterial oxygen saturation since these measurements reflect oxyhemoglobin and are unaffected by leukocyte or platelet larceny.

EFFECTS OF HYPOXEMIA — Hypoxemia can adversely affect every tissue in the body. Cellular hypoxia may result in organ failure, shock, encephalopathy, and even cardiac arrest.

Cellular tolerance of hypoxia is variable. As examples, skeletal muscle cells can recover fully after 30 minutes of hypoxia, but irreversible damage occurs in brain cells after only four to six minutes of similar hypoxic stress [17,18]. Therefore, life-threatening hypoxemia needs to be treated with the administration of oxygen (and sometimes with red cell transfusion) while measures are being initiated to treat the primary cardiopulmonary insult.

Cellular mechanisms that contribute to hypoxic cell injury include depletion of adenosine triphosphate, development of intracellular acidosis, increased concentrations of metabolic by-products, generation of oxygen free radicals, and destruction of membrane phospholipids. There is also a dramatic increase in intracellular calcium concentration, contributing to cellular injury via a variety of mechanisms, including direct damage to the cytoskeleton and induction of genes that contribute to apoptosis [17]. Hypoxia also induces an inflammatory reaction characterized by neutrophilic infiltration, thus augmenting cellular damage via release of cytokine mediators and oxygen free radicals and by intensifying ischemia due to disruption of the microcirculation.

SUMMARY AND RECOMMENDATIONS

●Terminology – Oxygenation is the process of oxygen diffusing passively from the alveolus to the pulmonary capillary, where it binds to hemoglobin in red blood cells as oxyhemoglobin (98 percent) or directly dissolves into the plasma (2 percent). Hypoxemia is defined as an arterial oxygen tension (PaO₂) of <60 mmHg in the blood. Hypoxia is a condition where the oxygen supply is inadequate either to the body as a whole (general hypoxia) or to a specific region (tissue hypoxia). Hypoxemia does not necessarily always indicate tissue hypoxia. (See 'Terminology' above.)

●Measures of oxygenation – There are numerous ways to assess oxygenation:

•The arterial oxygen saturation (SaO₂), peripheral oxygen saturation (SpO₂), and PaO₂ are commonly used to globally assess the level of oxygenation in the blood. SpO₂ noninvasively measures oxygenation using a pulse oximeter, while SaO₂ and PaO₂ require arterial blood. (See 'Arterial and peripheral oxygen saturation (SaO2 and SpO2)' above and 'Arterial oxygen tension (PaO2)' above.)

•The alveolar-arterial (A-a) oxygen gradient (calculator 1) is used to narrow the differential of hypoxemia; the PaO₂:fraction of inspired oxygen (FiO₂) ratio (calculator 2) is used in ventilated patients with acute respiratory distress syndrome (ARDS) to determine the severity of ARDS and direct management. (See 'Measures of oxygenation' above and 'Alveolar-arterial (A-a) oxygen gradient' above and 'Arterial oxygen tension: fraction of inspired oxygen (PaO2/FiO2) ratio' above.)

●Mechanisms of hypoxemia – Ventilation-perfusion (V/Q) mismatch is the most common mechanism underlying hypoxemia, although more than one mechanism often contributes to hypoxemic states. The mechanisms, etiology, and management of hypoxemia are listed in the table (table 2).

•V/Q mismatch – V/Q mismatch refers to an imbalance of ventilation and blood flow in the lung (figure 1). V/Q mismatch contributes to hypoxemia in patients with embolic diseases, pulmonary vascular diseases, obstructive and interstitial lung diseases, and low flow cardiac output states. Hypoxemia due to V/Q mismatch typically responds well to oxygen supplementation (unless shunt is present), is associated with a widened A-a gradient, and is not typically associated with hypercapnia unless dead space is increased or hypoventilation is also present. (See 'Ventilation-perfusion mismatch' above.)

•Right-to-left shunt – A right-to-left shunt exists when blood passes from the right to the left side of the heart without being oxygenated. Physiologic or anatomic right-to-left shunts cause extremely low V/Q mismatch. Hypoxemia is difficult to correct with supplemental oxygen and is associated with a widened A-a gradient. Hypercapnia is uncommon unless the shunt fraction is >50 percent. (See 'Right-to-left shunt' above.)

•Hypoventilation – Hypoventilation refers to alveolar underventilation. Hypoxemia due to hypoventilation is generally mild but may be severe in those with diseased lung. It is characterized by hypercapnia and a normal A-a gradient (unless there is underlying lung disease). Hypoxemia generally responds easily to supplemental oxygen. Abnormalities that cause pure hypoventilation are central and peripheral neuromuscular disorders, thoracic cage disorders, and several drugs (table 3). (See 'Hypoventilation' above.)

•Diffusion limitation – Diffusion limitation exists when the movement of oxygen from the alveolus to the pulmonary capillary is impaired. It reflects alveolar capillary membrane pathology due to alveolar and/or interstitial inflammation, fibrosis, or destruction (eg, interstitial lung disease or emphysema). The A-a gradient is usually widened and hypercapnia is uncommon. Hypoxemia due to diffusion limitation may not be evident at rest but is most pronounced during exercise. (See 'Diffusion limitation' above.)

•Others – Other mechanisms include the following:

-Reduced inspired oxygen tension (eg, altitude, unpressurized aircraft). (See 'Reduced inspired oxygen tension' above.)

-Reduced oxygen content or oxygen carrying capacity (eg, hemoglobin variants, cyanide toxicity, carboxyhemoglobinemia, or methemoglobinemia). (See 'Reduced oxygen content or carrying capacity' above and "Hemoglobin variants that alter hemoglobin-oxygen affinity" and "Cyanide poisoning" and "Carbon monoxide poisoning" and "Methemoglobinemia".)

-Increased oxygen extraction (See 'Increased oxygen extraction' above.)

●End-organ effects of hypoxemia – Hypoxemia can adversely affect every tissue in the body. Cellular hypoxia can result in organ failure, shock, encephalopathy, and even cardiac arrest. (See 'Effects of hypoxemia' above.)