Hypoxemia

Hypoxemia is a medical term to describe low level of oxygen in your blood ¹. Someone with low blood oxygen is considered hypoxemic. Hypoxemia or low blood oxygen level can cause hypoxia or low oxygen in your tissues or cell when your blood doesn’t carry enough oxygen to your tissues. You may hear the words hypoxia and hypoxemia used interchangeably, but they aren’t the same. The names sound similar because they both involve low levels of oxygen, but in different parts of your body. Hypoxemia is low oxygen levels in your blood and hypoxia is low oxygen levels in your tissues and organs. Hypoxemia can lead to hypoxia and they often both appear together, but not always. You can be hypoxemic but not hypoxic and vice-versa.

Hypoxemia isn’t an illness or a condition. Hypoxemia is a sign of a problem tied to your breathing or blood flow. Hypoxemia can happen if you can’t breathe in enough oxygen or if the oxygen you breathe in can’t get to your blood. Air and blood flow are both important to having enough oxygen in your blood. This is why lung disease and heart disease both increase your risk of hypoxemia.

Oxygen is essential for life and without oxygen humans can survive only for few minutes only. Permanent brain damage begins after only 4 minutes without oxygen, and death can occur as soon as 4 to 6 minutes later ², ³. After five to ten minutes of not breathing, you are likely to develop serious and possibly irreversible brain damage ⁴. There should be a balance between oxygen demand and delivery in order to maintain homeostasis within your body ⁵. The two main organ systems responsible for oxygen delivery in your body and maintaining homeostasis are respiratory (lungs) and cardiovascular (heart and blood vessels) system. Oxygen gets to your blood through your lungs. When you breathe in, oxygen from the air travels through your lungs into small air sacks (alveoli). Blood vessels (capillaries) travel close to the alveoli in your lungs and pick up the oxygen. Finally, oxygen travels through your blood to your tissues with the help of the pumping action of your heart.

Oxygen is carried in your blood in two forms. The vast majority of oxygen in your blood is bound to hemoglobin within red blood cells, while a small amount of oxygen is physically dissolved in the plasma. The regulation of unloading of oxygen from hemoglobin at target tissues is controlled by several factors, including oxygen concentration gradient, temperature, pH, and concentration of the compound 2,3-Bisphosphoglycerate. The most critical measures of adequate oxygen transportation are hemoglobin concentration and oxygen saturation; the latter is often measured clinically using pulse oximetry.

If you use a pulse oximeter at home, be aware of factors that can make the results less accurate:

• Poor circulation.
• Black or brownskin color.
• Skin thickness or temperature.
• Tobacco use.
• Fingernail polish.

Hypoxemia may lead to symptoms such as:

• Shortness of breath.
• Rapid breathing.
• Fast or pounding heartbeat.
• Headaches.
• Confusion.

Depending on the severity and duration of hypoxemia, hypoxemia can lead to mild symptoms or lead to death. Mild hypoxemia symptoms include headaches and shortness of breath. In severe cases, hypoxemia can interfere with heart and brain function. It can lead to a lack of oxygen in your body’s organs and tissues (hypoxia).

Hypoxemia can happen for a short duration leading to “acute respiratory failure”. In situations where it’s a long-term problem over months and years, you may hear it referred to as “chronic respiratory failure”.

Hypoxemia can be a sign of problems such as:

• Less oxygen in the air you breathe, such as at high altitudes.
• Breathing that’s too slow or shallow to meet the lungs’ need for oxygen.
• Either not enough blood flow to the lungs or not enough oxygen to the lungs.
• Trouble with oxygen getting into the bloodstream and the waste gas carbon dioxide getting out.
• A problem with the way blood flows in the heart.
• Unusual changes in the protein called hemoglobin, which carries oxygen in red blood cells.

A healthy level of oxygen in your arteries also known as partial pressure of oxygen in arterial blood (PaO₂) is about 75 to 100 millimeters of mercury (75 to 100 mmHg). Hypoxemia is defined as a partial pressure of oxygen in arterial blood (PaO₂) under 60 mm Hg ⁶. Levels of oxygen and the waste gas carbon dioxide (CO₂) are measured with a blood sample taken from an artery usually in your wrist. This is called a arterial blood gas (ABG) test. ABG or arterial blood gases test measures oxygen (O₂) levels, carbon dioxide (CO₂) levels, and acidity or pH, in your blood.

Most often, the amount of oxygen carried by red blood cells, called oxygen saturation, is measured first. It is measured with a medical device that clips to the finger, called a pulse oximeter. Pulse oximeter uses light absorption through a pulsing capillary bed usually in a toe or finger. Pulse oximeters work on the principle that saturated hemoglobin (oxyhemoglobin or O₂Hb) is a different color from desaturated hemoglobin (deoxyhemoglobin or HHb) and thus absorbs light of a different frequency. Healthy pulse oximeter values often range from 95% to 100% oxygen saturation (SpO2). Values under 90% are considered low.

See your doctor as soon as possible if you:

• Become short of breath after slight physical effort or when you’re at rest.
• Have shortness of breath that you wouldn’t expect from a certain activity and your current fitness and health.
• Wake up at night with a gasp or a feeling that you’re choking. These may be symptoms of sleep apnea.

Seek emergency care if you have shortness of breath that:

• Comes on fast, affects your ability to function or happens with symptoms such as chest pain.
• Happens above 8,000 feet (about 2,400 meters) and occurs with a cough, rapid heartbeat or weakness. These are symptoms of fluid leaking from blood vessels into the lungs, called high-altitude pulmonary edema. This can be deadly.

In general, hypoxemia treatment involves receiving extra oxygen. This treatment is called supplemental oxygen or oxygen therapy. Other treatments focus on the cause of your hypoxemia.

Figure 1. Hypoxemia causes

[Source ¹ ]

Hypoxemia causes

Any condition that reduces the amount of oxygen in your blood or restricts blood flow can cause hypoxemia. Hypoxemia most common cause is an underlying illness that affects blood flow or breathing (like heart or lung conditions). People living with heart or lung diseases such as congestive heart failure, chronic obstructive pulmonary disease (COPD) or asthma, are at an increased risk for hypoxemia. Sleep apnea and mild lung disease can cause nocturnal hypoxemia — when your blood oxygen levels drop during your sleep. Some lung infections, like influenza and pneumonia, can also increase your risk of hypoxemia. Certain medications can slow breathing and lead to hypoxemia. These include certain opioid pain relievers and medicines that prevent pain during surgery and other procedures, called anesthetics.

Being at high altitudes can also cause hypoxemia, which is why it can be hard to breathe when you’re in the mountains.

Hypoxemia can be a sign of problems such as:

• Less oxygen in the air you breathe, such as at high altitudes.
• Breathing that’s too slow or shallow to meet the lungs’ need for oxygen.
• Either not enough blood flow to the lungs or not enough oxygen to the lungs.
• Trouble with oxygen getting into the bloodstream and the waste gas carbon dioxide getting out.
• A problem with the way blood flows in the heart.
• Unusual changes in the protein called hemoglobin, which carries oxygen in red blood cells.

Medical conditions that can lead to hypoxemia include:

• Acute respiratory distress syndrome (ARDS).
• Anemia.
• Asthma.
• Bronchitis.
• Chronic obstructive pulmonary disease (COPD).
• Congenital heart defects.
• Congestive heart failure.
• Emphysema.
• Pneumonia.
• Pneumothorax (air in the space around your lung or collapsed lung).
• Pulmonary edema (fluid on your lungs).
• Pulmonary embolism (blood clot in your lung).
• Pulmonary fibrosis (lung scarring).
• Pulmonary hypertension.

Problems with your blood or blood flow that can cause hypoxemia include:

• Anemia — a condition in which the body doesn’t get oxygen due to a lack of healthy red blood cells.
• Congenital heart defects in children — heart conditions that children were born with.
• Congenital heart disease in adults — heart problems that adults were born with.

Breathing conditions that can lead to hypoxemia include:

• ARDS (acute respiratory distress syndrome) — a lack of air due to a buildup of fluid in the lungs.
• Asthma — a long-term condition that affects airways in the lungs.
• COPD (chronic obstructive pulmonary disease) — the blanket term for a group of diseases that block airflow from the lungs — including emphysema.
• Interstitial lung disease — the blanket term for a large group of conditions that scar the lungs.
• Pneumonia — an infection in one or both lungs.
• Pneumothorax — collapsed lung.
• Pulmonary edema — excess fluid in the lungs.
• Pulmonary embolism — a blood clot in an artery in the lung.
• Pulmonary fibrosis — a disease that happens when lung tissue becomes damaged and scarred.
• Sleep apnea — a condition in which breathing stops and starts many times during sleep.

Hypoxemia pathophysiology

Hypoxemia pathophysiology can involve ventilation-perfusion mismatch (V/Q mismatch), right-to-left shunt, diffusion impairment, hypoventilation, and low inspired PO2 (PiO₂ or partial pressure of inspired oxygen).

Atmospheric air is a mixture of gases, wherein each constituent gas has a partial pressure which is the notional pressure of that gas if it were to occupy the entire volume of the gas mixture at the same temperature. Dalton’s law of partial pressure states that the total pressure of a mixture of gases is equal to the sum of partial pressures of individual gases ⁷. Partial pressure of oxygen within the troposphere (_AtmPO₂) depends on atmosphere’s barometric pressure according to the Dalton’s Law ⁸:

• _AtmPO₂= 0.21 (fraction of inspired oxygen or FiO2) x 760 mmHg (the atmospheric pressure at sea level) = 159.6 mmHg

Normal inspired dry air has a PiO₂ of 160 mmHg or 21 kPa.

Upon entering the lungs inspired PO2 (PiO₂) is reduced, first by addition of water vapor (humidification), to 20 kPa (150 mmHg), and due to the constant removal of oxygen by the pulmonary capillaries, the partial pressure of oxygen in the alveoli (PAO₂) is approximately 14 kPa (100 mmHg) ⁹, ¹⁰.

The alveolar partial pressure of oxygen (PAO2) in the alveoli-capillary barrier at sea level is calculated based on the fraction of inspired oxygen (FiO2 = air contains a standard 20.95% of oxygen). At least in the troposphere, air contains a standard 20.95% of oxygen, the partial pressure of oxygen in the alveoli (PAO₂) is not measured but is calculated by using the alveolar gas equation ¹.

Figure 2. Alveolar Gas Equation

[Source ⁷ ]

The alveolar gas equation

• PAO₂ = FiO₂× (Pb − PH2O) − (PACO₂/R)

PAO₂ is the partial pressure of oxygen in the alveoli.

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 PaCO₂.

R is the respiratory quotient = amount of CO₂ produced/amount of oxygen consumed

R (respiratory quotient) is approximately 0.8 at steady state on standard diet. The value of the R (respiratory quotient) can vary depending upon the type of diet and metabolic state. The R (respiratory quotient) is different for carbohydrates, fats, and proteins (average value is around 0.82 for the human diet). Indirect calorimetry can provide better measurements of R (respiratory quotient) by measuring the VO₂ (oxygen uptake) and VCO₂ (carbon dioxide production).

Normal partial pressure of oxygen in the alveoli (PAO₂) is:

• PAO₂ = FiO₂× (Pb − PH₂O) − (PACO₂/R) = 0.21× (760 − 47) − (40/0.8) = 100 mmHg (14 kPa).

The pressure of water vapor (PH₂O) is constant at 47 mmHg at normal body temperature (37°C), and it is strongly temperature dependent ¹¹. This results in an effective reduction at the alveolar level in the partial pressure of oxygen (PAO₂) from 159 to 149 mmHg that is not likely to be physiologically relevant at sea level, because only represents about 6% of the total _AtmPO₂ ¹². At sea level, during normal conditions, the partial pressure of oxygen in the arteries (PaO₂) is high enough to satisfy the oxygen demands for the entire organism ¹⁰. However, if the barometric pressure (Pb) is already low, such as at high altitude like at the summit of Mount Everest (altitude 8,848 m), a reduction of 47 mmHg (the water vapour pressure or PH2O) represents almost 20% of the available _AtmPO₂, making this reduction life threatening (Figure 2) ¹³, ¹⁴.

Furthermore, once the inspired air has been humidified, there is an additional reduction in partial pressure of oxygen (PO₂) from the trachea to the alveolus, due to the dead space and the mixing of inspired and expired gases ¹⁵. This fall in the pressure of oxygen from the upper airways to the alveolus is almost all accounted for by the alveolar pressure of carbon dioxide (PACO2) ¹⁶. Since inspired PCO2 is zero and the PACO2 is usually in the range of 40 mmHg, the partial pressure of oxygen must fall ¹⁷.

When oxygen is transported into the venous pulmonary capillary, an important gradient of pressure from the upcoming arterial blood pushes the CO2 out to the alveoli ¹⁸.

Once in the lungs, oxygen diffuses across the alveolar-capillary barrier from the alveoli into the arterial blood. Dissolved oxygen in blood also exerts partial pressure. The initial diffusion gradient of pressures in the microcirculation arises when arterial partial pressure of oxygen (PaO₂) with a higher pressure is mixed with the pressure of oxygen within the veins (PVO2) ¹⁹. In the blood, the partial pressure of oxygen in arterial blood (PaO₂) is normally between 80 to 100 mmHg.

The solubility of oxygen in blood is directly proportional to the partial pressure of oxygen that it is exposed to. This relationship is known as Henry’s law. The difference between partial pressure of oxygen in the alveoli (PAO₂) and partial pressure of oxygen in arterial blood (PaO₂) is popularly called “A-a gradient” or alveolar-arterial oxygen gradient.

• Alveolar to arterial (A-a) oxygen gradient = PAO₂ (partial pressure of oxygen in the alveoli) – PaO₂ (partial pressure of oxygen in arterial blood)

The alveolar to arterial (A-a) oxygen gradient indicates the integrity of the alveolocapillary membrane and effectiveness of gas exchange. In young person, the alveolar to arterial (A-a) oxygen difference is <10 mmHg. The alveolar to arterial (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 (ventilation-perfusion mismatch) ¹. The drop in PaO2 after 70 years is about 0.43 mmHg per year ²⁰. High FiO₂ (fraction of inspired oxygen) by increasing both the alveolar and arterial oxygen level widens the alveolar to arterial (A-a) gradient. The rise in alveolar to arterial (A-a) 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 ²¹.

The word alveolar to arterial (A-a) oxygen gradient is a misnomer, and ideally, it should be referred to as alveolar to arterial (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 ²¹, ²²:

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.

Pathology of the alveolocapillary unit widens the gradient. Therefore, hypoxemia due to V/Q mismatch (ventilation-perfusion mismatch), diffusion limitation, and shunt will have widened gradient, whereas hypoxemia due to hypoventilation would have normal gradient ¹.

How much oxygen binds to hemoglobin (Hb), and therefore how much oxygen is carried by blood, is determined by PaO₂. In pulmonary capillaries blood, partial pressure of oxygen (PO₂) is high; therefore, hemoglobin (Hb) takes up oxygen dissolved in plasma ⁷. Plasma in turn draws more oxygen from the alveoli.

Each hemoglobin molecule has four protein chains, carrying a heme molecule. In deoxyhemoglobin, the hemoglobin molecule is in a ‘tense’ conformation having relatively low affinity for oxygen. In oxyhemoglobin, it adopts a relaxed state and the affinity for oxygen increases than in the ‘tense’ state. The combination of oxygen to first heme increases the affinity of second heme for oxygen and so on ⁷.

The relationship between PaO₂ and SaO₂ (oxygen saturation using arterial blood gas analysis) when plotted on a graph results in a sigmoid-shaped curve commonly known as the oxygen hemoglobin dissociation curve (Figure 5). Binding of oxygen to hemoglobin also depends on certain factors like PaCO₂, pH, temperature and 2, 3 Diphosphoglycerate (DPG) levels in red blood cells. These factors lead to either a rightward or leftward shift of the oxygen hemoglobin dissociation curve. The partial pressure of oxygen (PO₂) at which hemoglobin (Hb) is 50% saturated is called the P50 (normally 27 mm Hg in adult) and is used to measure the shift. SaO₂ (oxygen saturation using arterial blood gas analysis) is defined as the percentage of hemoglobin saturated with oxygen. Thus, depending on other variables, SaO₂ (oxygen saturation using arterial blood gas analysis) may vary for the same PaO₂ value. Since PaO2 depends on dissolved oxygen, PaO₂ may remain normal in the presence of anemia. Various physiological parameters that result in a shift in oxygen hemoglobin dissociation curve are illustrated in Figure 5. In the tissue cells, the partial pressure of oxygen (PO₂) is low. As a result, oxygen dissolved in the capillary blood diffuses into the tissues. This reduces the capillary oxygen PO₂, which decreases the affinity of oxygen for hemoglobin. In the capillaries, therefore, oxygen dissociates from hemoglobin and diffuses down the concentration gradient into the cells.

The amount of diffusive oxygen movement depends on the gradient of partial pressure of oxygen (PO₂), the available surface area to diffusion, the permeability and thickness of diffusion barriers and the local metabolic demand ²³, ²⁴.

Tissue partial pressure of oxygen (PtO₂) is regulated by the blood flow, the availability of oxygen and the consumption rate from one region to another ²⁵, ²⁶, ²⁷. The Bohr effect allows that hemoglobin (Hb) releases more oxygen in response to the metabolic rate of that tissue in highly aerobic tissues ²⁸. For example, neurons and cardiac muscle cells are largely aerobic and depend on the presence of oxygen for their survival, although some lactate can be produced within the brain, most of them depended on the metabolic rate of oxygen consumption ²⁹, ³⁰. Other cells, such as the bladder muscle cells or the skeletal muscle cells are more tolerant to hypoxia, and are able to obtain energy without the presence of oxygen for longer periods of time than can neurons in the brain ¹⁰. Once the oxygen reaches the single cells in the tissue, the partial pressure of oxygen (PO₂) goes down to 0.5-2.5 kPa (4-20 mmHg), being the lowest in the mitochondria. Therefore only small changes in oxygen pressure, uptake or delivery can greatly influence the amount of oxygen that can be utilized by the mitochondria for respiration, thereby possibly creating a supply-demand mismatch.

It should be noted that only small amount of oxygen is transported in dissolved form (dissolved O₂). For hemoglobin (Hb) of 15 g/dL, at 100% saturation and PaO₂ of 100 mmHg, approximately 20 mL/dL of oxygen is transported bound to hemoglobin while only 0.3 mL/dL is transported dissolved in blood (1 dL = 100 mL) ⁷. Oxygen content of 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. Oxygen content of blood (CaO₂) may be calculated using the following equation:

• CaO₂ (arterial oxygen content) = Hemoglobin (Hb) bound O₂ + Dissolved O₂
  
• CaO₂ (arterial oxygen content) = (Hb x K x SaO₂) + (α x PaO₂)
• CaO₂ (arterial oxygen content) = (Hb × 1.34 × SaO₂) + (0.0031 × PaO2)

Where K is Huffner’s constant (1.39 mL O₂/gram Hb) – Maximum amount of oxygen that can bind to Hb

Where SaO₂ is arterial oxygen saturation. SaO₂ is defined as the percentage of hemoglobin saturated with oxygen. SaO₂ can be measured by both pulse oximetry and arterial blood gas analysis. Pulse oximetry is widely used in the assessment of patients and should be regarded as the fifth vital sign ³¹. 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 ³².

α is the solubility coefficient for O₂ at 37°C (0.00314 mL/dL/mm Hg).

Figure 3. Relationship between elevation and Barometric pressure

Footnote: Relationship between elevation and Barometric Pressure (filled circles) and Atmospheric Partial Pressure of Oxygen (hollow circles)

[Source ¹⁰ ]

Figure 4.  Arterial oxygen tension (PaO2) at different altitudes in humans

Footnote: Black spots = altitude; Black triangles = Arterial oxygen tension (PaO2)

[Source ¹⁰ ]

Figure 5. Oxygen hemoglobin dissociation curve and factors that results in a shift to right or left

[Source ⁷ ]

Ventilation-perfusion (V/Q) mismatch

V/Q mismatch or ventilation/perfusion mismatch is the most common cause of hypoxemia ³³. For oxygen to get to your blood, you need both airflow into your lungs (ventilation) and blood flow to your lungs (perfusion) to pick up the oxygen. If one of these isn’t working, you’ll end up with plenty of oxygen in your lungs but too little blood flow to pick it up, or vice-versa. This is called ventilation-perfusion, or V/Q, mismatch. It’s usually caused by a heart or lung condition.

Normal V/Q level is 0.8 ¹. Some common causes of hypoxemia due to V/Q mismatch (ventilation/perfusion mismatch) include asthma, COPD, bronchiectasis, cystic fibrosis, interstitial lung diseases, pulmonary embolism (PE) and pulmonary hypertension ¹. Some hypoxemia due to V/Q mismatch can be easily corrected by supplemental oxygen therapy ¹.

Ventilation, perfusion and V/Q ratio are not uniform in the human lungs ¹. 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 ¹. However, V/Q ratio is higher at the apex and lower at the base ¹. The V/Q 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 V/Q ratio has low alveolar CO₂ content and high oxygen content and on the other hand, the basal region, has low alveolar oxygen content and high CO₂ content ¹. Only low V/Q ratio produces hypoxemia by decreasing the alveolar oxygen level (PAO₂) and subsequently arterial oxygen level ³⁴. 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 ¹. This is done by hypoxic pulmonary vasoconstriction which is unique to pulmonary vasculature ¹. By reducing perfusion to areas of the lungs with reduce ventilation, blood is diverted to the well-ventilated lung regions ³⁵, ³⁶. 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 hypoxic pulmonary vasoconstriction are the small pulmonary arteries ³⁷. Arteries with an internal diameter of 200–400 µm are most commonly involved in the animal study ³⁸. Hypoxic pulmonary vasoconstriction also possesses negative consequences when chronic. Chronic hypoxic pulmonary vasoconstriction causes vascular structural remodeling and subsequent development of sustained pulmonary hypertension ³⁹. The inhibition of oxygen-sensitive potassium channel initiates the process of hypoxic pulmonary vasoconstriction. Patel et al. ⁴⁰ subsequently revealed that the K+ channels involved are voltage-gated K+ channels (KV), particularly KV1.5. 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 ⁴¹, ⁴².

Right to left shunting

The right to left shunting is a condition whereby blood from the right side of the heart enters the left side without taking part in any gas exchange ¹. Deoxygenated blood flows into your heart from the right, gets pumped out to your lungs to get oxygen, then comes back in from the left to get pumped out to your body. In some people, deoxygenated blood can get pushed over to the left side of your heart and go out to your tissues without getting oxygen in your lungs first. This is called right-to-left shunting and it’s usually caused by an abnormality in your heart.

Normally, you have a small fraction of the shunt (2–3% of cardiac output). 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 ¹. Causes of right to left shunt include pneumonia, pulmonary edema, acute respiratory distress syndrome (ARDS), alveolar collapse, and pulmonary arteriovenous communication ¹.

Characteristics of pulmonary shunt ¹

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

Poor response to oxygen therapy is the feature that differentiates shunt from other mechanisms of hypoxemia ¹. Failure to improve PaO2 by oxygen therapy is due to the inability of oxygen to improve PAO2 in unventilated lung units ⁴⁰. Hypercapnia (buildup of carbon dioxide in your blood) is uncommon in right to left shunt until the shunt fraction reaches 50% ²¹. Lack of hypercapnia (buildup of carbon dioxide in your blood) 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 ¹. 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% ⁴³.

Diffusion impairment

Diffusion impairment occurs when the oxygen transport across the alveolocapillary membrane is impaired ¹. Even if you have good airflow and good blood flow, sometimes it’s difficult for the oxygen to pass — or diffuse — from your lungs to your blood vessels (diffusion impairment). Diffusion impairment can be caused by emphysema, scarring of your lungs or diseases that impair the blood flow between your heart and lungs.

Diffusion impairment 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 ¹. Since both oxygen and carbon dioxide transport occur through the alveolar-capillary membrane, theoretically it should cause both hypoxemia and hypercapnia (buildup of carbon dioxide in your blood). 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 ⁴⁴. Another reason could be hypoxemia-mediated stimulation of ventilation, leading to CO2 washout ¹. Normal pulmonary capillary transit time is 0.75 second, and the time required to complete gas exchange is 0.25 second ¹. One important characteristics of diffusion limitation is the development or worsening of hypoxemia during exercise ¹. During exercise, the capillary transit time is shortened due to rise in cardiac output. 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 ¹. Patients with pulmonary fibrosis fail to recruit additional capillaries and develop exercise-induced/exaggerated hypoxemia. Important causes of diffusion limitation are emphysema and interstitial lung diseases ¹.

Diffusion limitation characteristics ¹:

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

Hypoventilation

Hypoventilation is when you don’t breathe deeply enough or breathe too slowly. This means not enough oxygen is getting into your lungs. Many lung conditions and some brain diseases can cause 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 ¹. Another unique feature of hypoventilation is normal P(A-a)O2 gradient as the alveolar – capillary membrane is intact in this condition ¹. Prolonged hypoventilation, however, may lead to atelectasis of some parts of the lungs and widening of P(A-a)O2 gradient ⁴⁵. Hypoventilation does not produce significant hypoxemia in healthy lung, but in the presence of lung diseases, hypoxemia can be severe ¹. One characteristic feature of hypoventilation induced hypoxemia is that it is easily correctible by supplemental oxygen ¹. Oxygen therapy corrects hypoxemia even when hypoventilation and hypercapnia persists ¹. 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 ⁴⁶. Patients of COPD, asthma, interstitial lung disease, 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 ¹.

Hypoventilation characteristics ¹:

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.

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 ²¹.

Various causes of hypoventilations are given below ¹:

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.

There are several causes of high CO2 level. It can be due to high CO2 production in the body (VCO2 production) without compensatory rise in alveolar ventilation, rise in dead space ventilation (VD) and fall in tidal volume (VT) and/or respiratory rate ¹. A-a oxygen gradient can help differentiating whether the high PaCO2 is due to reduction in tidal volume (VT) or increase in dead space ventilation (VD) ¹. A-a oxygen gradient will be normal in the former and high in the latter. Increase CO2 production in the body (VCO2 production) normally does not contribute to raise PaCO2 level if the ventilatory compensating mechanism is functioning normally ⁴⁷. 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 ¹.. Various causes of rise in dead space ventilation (VD)/tidal volume (VT) leading to high CO2 level are pulmonary embolism (PE), acute reduction in cardiac output, COPD, ARDS (acute respiratory distress syndrome), and bronchiectasis ¹.

Low environmental oxygen

If there’s not enough oxygen in the air around you to breathe in, your blood can’t get the oxygen it needs to keep your body working. Locations at high altitudes have less oxygen available in the air than those at lower altitudes.

Hypoxemia signs and symptoms

Hypoxemia symptoms vary depending on the severity and underlying cause. Some hypoxemia symptoms include:

• Headache.
• Difficulty breathing or shortness of breath (dyspnea).
• Rapid heart rate (tachycardia).
• Coughing.
• Wheezing.
• Confusion.
• Bluish color in skin, fingernails and lips (cyanosis).

Hypoxemia diagnosis

To diagnose hypoxemia, your doctor will do a physical examination to listen to your heart and lungs. Abnormalities in these organs can be a sign of low blood oxygen. Your doctor may also check to see if your skin, lips or fingernails look bluish (cyanosis).

Your doctor will use tests to check your oxygen levels and determine the underlying cause of hypoxemia, which can include:

• Pulse oximetry: A sensor that slips over your finger measures the amount of oxygen in your blood. Pulse oximetry is painless and noninvasive. Many doctors use it routinely each time you visit.
• Arterial blood gas (ABG) test: A needle is used to take a blood sample from your wrist, arm or groin to measure the levels of oxygen in your blood.
• Pulmonary function test (PFT): You blow out and breathe in to a mouthpiece attached to a machine that measures how well your lungs work.
• Six-minute walk test (6MWT): You see your oxygen levels with exertion and how far you can walk on a flat surface in six minutes. This test helps evaluate lung and heart function.
• Imaging studies: X-rays, CT scans, and V/Q scans all use special equipment to get images of your internal organs. Imaging can help your doctor determine the cause of your hypoxemia.

Pulse Oximetry to Evaluate Arterial Oxygen Saturation (SaO2)

The arterial oxygen saturation (SaO2) refers to the amount of oxygen bound to hemoglobin in arterial blood. The measurement is given as a percentage. Resting SaO2 less than or equal to 95% or exercise desaturation greater than or equal to 5% is considered abnormal. However, clinical correlation is always necessary as the exact cutoff below which tissue hypoxia ensues has not been defined ⁴⁸, ⁴⁹, ⁵⁰.

Arterial Blood Gas

It is a useful tool to evaluate hypoxemia. Aside from the diagnosis of hypoxemia, additional information obtained, such as PCO2, can shed light on the cause of the hypoxia.

• Arterial oxygen tension (PaO2): Partial pressure of oxygen is the amount of oxygen dissolved in the plasma. A PaO2 less than 80 mmHg is considered abnormal. However, this should be in line with the clinical situation.
• The partial pressure of CO2 (PaCO2): It is an indirect measure of exchange of CO2 with the air via the alveoli, its level is related to minute ventilation. PaCO2 is elevated in hypoventilation like in obesity hypoventilation, deep sedation, or maybe in the setting of acute hypoxia secondary to tachypnea and washout of CO2.
• PaO2:FiO2 ratio also known as Carrico index is another way to measure the degree of hypoxia. PaO2/FiO2 ratio is the ratio of partial pressure of oxygen to fractional inspired oxygen ¹. Normal PaO2:FiO2 ratio is 300 to 500, if this ratio drops this may indicate a deterioration in gas exchange, this is particularly important in defining ARDS.

Imaging studies

Imaging studies of the chest, such as chest x-rays or CT help in identifying the cause of the hypoxia, e.g., pneumonia, pulmonary edema, hyperinflated lungs in COPD, and other conditions. CT chest can give more detailed images that outline the exact pathology, CT angiogram of the chest is of particular importance in detecting the pulmonary embolism. Another modality is the VQ scan which can detect the ventilation-perfusion mismatch, which is helpful in diagnostics of acute or chronic pulmonary embolism. VQ scan can be particularly useful when renal failure or allergy to iodinated contrast increases the risks of CT angiography.

Alveolar-arterial (A-a) gradient of oxygen

The first step in evaluating the hypoxia is to calculate the A-a gradient of oxygen. This is the difference in the amount of oxygen between the Alveoli “A” and the amount of oxygen in the blood “a.” In other terms, the A-a oxygen gradient = PAO2 – PaO2.

PaO2 can be obtained from the arterial blood gas; however, PAO2 is calculated using the alveolar gas equation:

The alveolar gas equation

• PAO₂ = FiO₂× (Pb − PH2O) − (PACO₂/R)

PAO₂ is the partial pressure of oxygen in the alveoli.

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 PaCO₂.

R is the respiratory quotient = amount of CO₂ produced/amount of oxygen consumed

R (respiratory quotient) is approximately 0.8 at steady state on standard diet. The value of the R (respiratory quotient) can vary depending upon the type of diet and metabolic state. The R (respiratory quotient) is different for carbohydrates, fats, and proteins (average value is around 0.82 for the human diet). Indirect calorimetry can provide better measurements of R (respiratory quotient) by measuring the VO₂ (oxygen uptake) and VCO₂ (carbon dioxide production).

Normal partial pressure of oxygen in the alveoli (PAO₂) is:

• PAO₂ = FiO₂× (Pb − PH₂O) − (PACO₂/R) = 0.21× (760 − 47) − (40/0.8) = 100 mmHg (14 kPa).

The pressure of water vapor (PH₂O) is constant at 47 mmHg at normal body temperature (37°C), and it is strongly temperature dependent ¹¹. This results in an effective reduction at the alveolar level in the partial pressure of oxygen (PAO₂) from 159 to 149 mmHg that is not likely to be physiologically relevant at sea level, because only represents about 6% of the total _AtmPO₂ ¹². At sea level, during normal conditions, the partial pressure of oxygen in the arteries (PaO₂) is high enough to satisfy the oxygen demands for the entire organism ¹⁰. However, if the barometric pressure (Pb) is already low, such as at high altitude like at the summit of Mount Everest (altitude 8,848 m), a reduction of 47 mmHg (the water vapour pressure or PH2O) represents almost 20% of the available _AtmPO₂, making this reduction life threatening (Figure 2) ¹³, ¹⁴.

The A-a gradient changes with age, and thus it is corrected for age using this equation ⁵¹:

• A-a gradient = (age/4+4)

If the A-a gradient is normal, then the cause of hypoxia is low oxygen content in the alveoli, either due to low O2 content in the air (low FiO2, as in the high altitude) or more commonly due to hypoventilation like the central nervous system (CNS) depression, obesity hypoventilation syndrome or obstructed airways as in COPD exacerbation.

If the A-a gradient is high then the cause of hypoxia is either due to a diffusion defect or perfusion defect (VQ mismatch), an alternative explanation is shunting of blood flow around the alveolar circulation, administering O2 may help differentiate the two, as the oxygenation will improve in VQ mismatch in contrast to cases where right to left shunt physiology is present.

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 ¹. The PaO₂/PAO₂ (a-A oxygen ratio) is less dependence on FiO2 unlike the alveolar to arterial (A-a) oxygen tension difference [PAO₂ (partial pressure of oxygen in the alveoli) – PaO₂ (partial pressure of oxygen in arterial blood)] ⁵². The normal PaO₂/PAO₂ varies between 0.75 and 1.0. The PaO₂/PAO₂ (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:

• PaO₂/PAO₂ = New PaO₂/New PAO₂

For example, 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?

The alveolar gas equation for partial pressure of oxygen in the alveoli (PAO₂) is:

• PAO₂ = FiO₂× (Pb − PH₂O) − (PACO₂/R) = 0.28 x (760 − 47) − (55/0.8) = 131 mmHg.

His arterial to alveolar oxygen ratio is:

• PaO₂/PAO₂ = 40/131 = 0.30.

The formula for estimating the required FiO2 to raise PaO₂ to 60 mmHg can be done by the following formula:

• PaO₂/PAO₂ = New PaO₂/New PAO₂
• PaO₂/PAO₂ = 60/New PAO₂ = 0.30.
• New PAO2 = 200 mmHg
• FiO2 = [PAO2 + (PACO₂/R)] / (Pb − PH₂O)
• FiO2 = [200 mmHg + 68.7] / (713)
• Required FiO2 = 0.378 or 37%

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)

Arterial oxygen content (CaO₂) quantifies the amount of oxygen in the blood-both hemoglobin bound oxygen and unbound fraction to hemoglobin (dissolved oxygen in the arterial blood). The contribution of the dissolved oxygen to CaO₂ is normally minimal. Oxygen content of blood (CaO₂) may be calculated using the following equation:

• CaO₂ (arterial oxygen content) = Hemoglobin (Hb) bound O₂ + Dissolved O₂
  
• CaO₂ (arterial oxygen content) = (Hb x K x SaO₂) + (α x PaO₂)
• CaO₂ (arterial oxygen content) = (Hgb × 1.34 × SaO₂) + (0.0031 × PaO2)

Where K is Huffner’s constant (1.39 mL O₂/gram Hb) – Maximum amount of oxygen that can bind to Hb

Where SaO₂ is arterial oxygen saturation. SaO₂ is defined as the percentage of hemoglobin saturated with oxygen. SaO₂ can be measured by both pulse oximetry and arterial blood gas analysis. Pulse oximetry is widely used in the assessment of patients and should be regarded as the fifth vital sign ³¹. 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 ³².

α is the solubility coefficient for O₂ at 37°C (0.00314 mL/dL/mm Hg).

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)

Arterial oxygen saturation (SaO2) is defined as the percentage of hemoglobin saturated with oxygen. Arterial oxygen saturation (SaO2) can be measured by both pulse oximetry and arterial blood gas analysis (ABG). Pulse oximetry is widely used in the assessment of patients and should be regarded as the fifth vital sign ³¹. 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 ³².

PaO2/FiO2 ratio

PaO2/FiO2 ratio also known as Carrico index is another way to measure the degree of hypoxia. PaO2/FiO2 ratio is the ratio of partial pressure of oxygen to fractional inspired oxygen ¹. The PaO2/FiO2 ratio assesses the hypoxemia at a different level of FiO2. A normal PaO2/FiO2 ratio is about 300 to 500 ⁵¹. 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 ¹. PaO2/FiO2 ratio is a commonly used index because of the ease of measurement and its prognostic value in acute respiratory distress syndrome (ARDS) patients ⁵³.

According to Berlin definition, ARDS (acute respiratory distress syndrome) is differentiated into three subcategories based on the degree of hypoxemia measured by PaO2/FiO2 ratio ⁵³, ⁵⁴:

1. Mild (200 mmHg PaO2/FiO2 ≤300 mmHg),
2. Moderate (100 mmHg PaO2/FiO2 ≤200 mmHg), and
3. Severe (PaO2/FIO2 ≤100 mmHg).

In all the subcategories, positive end-expiratory pressure (PEEP) or continuous positive airway pressure ≥5 cm H2O was used ⁵³. PaO2/FiO2 ratio can also be used for rough estimation of shunt fraction ⁴³. A PaO2/FiO2 ratio of <200 indicates a shunt fraction is more than 20%.

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. ⁵⁵ 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. ⁵⁶ 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 ⁵⁶.

Pulmonary Function Test (PFT)

Pulmonary Function Test (PFT) provides a direct measure of the lung volumes, bronchodilator response, and diffusion capacity, which can help in establishing the diagnosis and guiding the treatment of lung disorders. Aiding the history and physical exam, pulmonary function tests (PFTs) can be used to differentiate between the obstructive (bronchial asthma, COPD, upper airway obstruction) versus restrictive lung diseases (interstitial lung diseases, chest wall abnormalities). Pulmonary Function Tests (PFTs) play a role in the assessment of airway obstruction severity as well as a response to therapy. Keep in mind that pulmonary function tests (PFTs) are effort-dependent and require the patient’s ability to cooperate and understand instructions.

Nocturnal (overnight) Trend Oximetry

It provides information about oxyhemoglobin saturation over a period (usually overnight). This test is primarily used to assess adequacy or need for oxygen supplementation at night. Use of overnight trend oximetry as a surrogate for a diagnostic sleep study is possible, however, is discouraged. A formal sleep study should be used whenever possible.

Six-Minute Walk Test

Six-minute walk test (6MWT) provides information on oxyhemoglobin saturation response to exercise as well as the total distance a patient can walk in 6 minutes on a ground level. This information can be used to titrate oxygen supplementation as well as evaluate the response to therapy. The 6-minutes walk test (6MWT) is frequently used in the preoperative pulmonary evaluation, pulmonary hypertension treatment and assessment of supplemental oxygen need with exercise.

Hemoglobin level

Secondary polycythemia can be an indicator of chronic hypoxemia.

Hypoxemia treatment

Hypoxemia treatment depends on the underlying cause of your hypoxemia. Usually supplemental oxygen, medications or other treatments can help raise your blood oxygen level. To help raise oxygen levels, your doctor might use “supplemental oxygen” via oxygen tanks or oxygen concentrators. These may be needed continuously or only with exertion depending on the severity of your disease.

In the case of severe hypoxemia, especially with acute respiratory distress syndrome (ARDS), healthcare providers may use a machine that breathes for you (ventilator). If hypoxemia doesn’t resolve, a condition known as refractory hypoxemia, additional medications or therapies may be used.

Treatments, which focus on the underlying cause, may include:

• Inhalers with bronchodilators or steroids to help people with lung disease like COPD.
• Medications that help to get rid of excess fluid in your lungs (diuretics).
• Continuous positive airways pressure mask (CPAP) to treat sleep apnea.
• Supplemental oxygen may be used to treat an ongoing risk of hypoxemia. Oxygen devices vary, but you can expect to get a machine that delivers extra oxygen through a breathing mask or small tube (cannula). You may receive oxygen at home, with a portable machine while you travel, or in the hospital.

COPD, sleep apnea and other medical conditions may cause chronic or intermittent hypoxemia with less severe or no symptoms. Talk to your doctor about managing your specific condition to reduce your symptoms and the risk of your oxygen levels dropping too low.

Maintaining Patent Airways

Ensure patency of the upper airways with good suctioning, maneuvers that prevent occlusion of the throat (head tilt and jaw thrust if necessary), sometimes the placement of an endotracheal tube or tracheostomy is necessary ⁵¹.

In chronic conditions like obesity hyperventilation syndrome, maintaining patent airways can be achieved with positive pressure ventilation like continuous positive airways pressure (CPAP) or bilevel positive airways pressure (BiPAP) ⁵¹.

Bronchodilators and aggressive pulmonary hygiene, such as chest physiotherapy, the flutter valve, and incentive spirometry can be used to maintain the patency of the lower airways ⁵¹.

Increase Fraction of the Inspired O2 (FiO2)

This is indicated for low PaO2 less than 60 mmHg or SaO2 less than 90%, and this can be achieved by increasing the percentage of oxygen in the inspired air that reaches the alveoli.

Low-Flow devices

• Nasal Cannula
  • Use: mild hypoxia (with FiO2 approximately 92%)
  • Flow rate: up to 6 L per minute
  • FiO2 delivered: up to 45% (0.45)
  • Advantage: Easy to use and more convenient to the patient (can be used during eating, drinking, talking)
  • Disadvantage: Dry nasal mucosa (humidify if the flow is greater than or equal to 4 L per minute), FiO2 being delivered varies greatly. Mouth breathers derive less benefit from using a nasal cannula.
  • The following formula can be used to approximate the percentage of FiO2; FiO2 = 20% + (4 times oxygen flow liters). For example, oxygen flow 2L/min would deliver approximately FiO2 of 0.3, 6 L per minute would deliver approximately FiO2 of 0.45 (more commonly known as 45%).
• Simple Face Mask
  • Use: Moderate to severe hypoxia, initial treatment
  • Flow rate: up to 10 L per minute
  • FiO2 delivered: 35% to 50%
  • Advantage: provides higher FiO2, no pressures involved, well tolerated by patients
  • Disadvantage: Dry oral mucosa (needs humidification), the flow must be at least 5 L per minute to flush CO2, not high flow. Also, the mask itself can interfere with activities of daily living.
• Reservoir Cannulas (Oxymizer)
  • The device uses a reservoir space, which stores O2 during expiration, making it available as a bolus during the next inspiration. This way the patient gets a higher oxygen delivery without increasing flow.
  • Flow rate: up to 16 L per minute.
  • FiO2 = up to 90% (0.9)
  • Reservoir cannulas are available as mustache configuration (Oxymizer), where the reservoir is located directly beneath the nose, pendant configuration (Oxymizer Pendant) which is connected to a plastic reservoir on the anterior chest
• Partial-rebreather Mask
  • Has a 300 to 500 mL reservoir bag and 2 one-way valves to prevent exhaling into the reservoir
  • Use: Moderate to severe hypoxia, initial treatment
  • Flow rate: 6 to 10 L per minute (flow must be sufficient to keep reservoir bag from collapse during inspiration)
  • FiO2 delivered: 50% to 70%
  • Advantage: Higher FiO2 can be delivered
  • Disadvantage: Interferes with activities of daily living
• Non-rebreather Mask
  • Has a 300 to 500 mL reservoir bag and 2 one-way valves
  • Use: Moderate to severe acute hypoxia, initial treatment
  • Flow rate: 10 to 15 (at least 10 L per minute to avoid bag collapse during inspiration)
  • FiO2 delivered: 85% to 90%
  • Advantage: even higher FiO2 can be achieved
  • Disadvantage: Interferes with activities of daily living

High-Flow Devices

Usually, this requires an oxygen blender, humidifier, and heated tubing.

• Venturi Mask
  • Mask attached an air entrainment valve
  • Use: Moderate to severe hypoxia, initial treatment
  • The flow rate and FiO2: (depends on the color). (Blue = 2 to 4 L per minute = 24% O2, White = 4 to 6 L per minute = 28% O2, Yellow = 8 to 10 L per minute = 35% O2, Red = 10 to 12 L per minute = 40% O2, Green = 12 to 15 L per minute = 60% O2)
  • Advantage: provides the most accurate O2 delivery, high flow
  • Disadvantage: need to be removed for eating. Less accurate at high flow rates
  • Does not guarantee the total flow with O2 percentages above 35% in patients with high inspiratory flow demands; the problem with air entrainment systems is that as this is increased, the air to oxygen ratio decreases
• High-flow Nasal Cannula
  • High-flow oxygen (HFO) consists of a heated, humidified O2
  • Flow rate: 10 to 60 L per minute
  • FiO2 delivered: Up to 100%
  • Advantages: More convenient, Can deliver up to 100% heated and humidified oxygen at a maximum flow of 60 L
  • Disadvantages: Fairly large cannula, can be a source of (although usually rather minimal) discomfort
• Air/oxygen Blender
  • Provides accurate oxygen delivery independent of the patient’s inspiratory flow demands
  • Positive end-expiratory pressure may be generated
  • For approximately every 10 liters of flow delivered, about 1 cm of positive pressure is obtained

Positive Pressure Ventilation

It allows for accurate delivery of any necessary fraction of inspired oxygen (FiO2) and includes the following:

Non-Invasive Ventilation

Non-invasive ventilation is usually used as the last resort to avoid the intubation.

• Continuous Positive Airways Pressure Mask (CPAP)
  • Mainly used in patients with obstructive sleep apnea or in acute pulmonary edema.
  • Delivers oxygen (or air) under pre-determined high pressure via a tightly fitting face mask.
  • Positive pressure is continuous, to ensure that the airways are open (split them).
• Bilevel Positive Airways Pressure (BiPAP)
  • Mainly used in patients with acute Hypercarbia as in patients with COPD exacerbation and ARDS patients.
  • High positive pressure on inspiration and lower positive pressure on expiration.
  • Pressure delivery is variable throughout the respiratory cycle, with high positive pressure on inspiration and lower positive pressure on expiration.

Invasive Ventilation

• Positive pressure ventilator attached to (usually) endotracheal tube.
• Allows for accurate delivery of predetermined minute ventilation as well as accurate FiO2 and positive end-expiratory pressure.
• Can be used electively during surgery.

Improve the Diffusion of Oxygen through the Alveolar Interstitial Tissue

The overall idea is to treat the underlying cause of respiratory failure:

• Diuretics can be used in cases of pulmonary edema.
• Steroids in certain cases of interstitial lung disease.
• Extracorporeal membrane oxygenation (ECMO) can be used as an ultimate method of increasing oxygenation.

Hypoxemia prognosis

Depending on the cause, people with hypoxemia may require treatment once or on an ongoing basis. Your doctor will work with you to manage the condition so you can live an active, healthy life.

These tips could help you cope with ongoing shortness of breath:

• If you smoke, quit. This is one of the most important things you can do if you have a health condition that causes hypoxemia. Smoking makes medical problems worse and harder to treat. If you need help quitting, talk with your doctor.
• Stay away from secondhand smoke. It can cause more lung damage.
• Get regular exercise. Ask your doctor what activities are safe for you. Regular exercise can boost your strength and endurance.

How can I reduce my risk of hypoxemia?

The best way to reduce your risk of hypoxemia is to manage any underlying conditions that can lower your blood oxygen levels. If you’re living with lung or heart conditions, talk to your healthcare provider about your concerns and specific ways to lower your risk.

Even for those without heart or lung conditions, certain medications and situations — like traveling to a higher altitude — can increase your risk of hypoxemia. Ask your provider about any special precautions you need to take while traveling or taking medication. Allow time to safely adjust to higher altitudes when you travel.

Living with hypoxemia

Managing any underlying conditions is the best way to keep your blood oxygen at safe levels and lower your risk of hypoxemia.

• Hypoxemia can be a life-threatening condition, but it’s treatable with prompt medical attention. Hypoxemia can also happen intermittently without obvious symptoms — for instance overnight, if you have sleep apnea. This can cause damage to your heart over time, so it’s important to know your risk and what preventative measures you can take.
• Don’t ignore new symptoms. Trust yourself if you feel something is off. Contact your doctor or go to the emergency room.
• If your doctor prescribes oxygen, use it as directed.
• Practice pulmonary hygiene. If you have COPD or asthma, know your triggers and make sure you always have a rescue inhaler with you if prescribed. Commit to using an incentive spirometer, performing breathing exercises and following any other recommendations for lung health from your doctor .
• Quit smoking. If you smoke, quitting can help increase lung function to bring more oxygen into your lungs. Quitting also helps prevent further damage to your lungs.
• Take any medication as prescribed by your doctor .
• Make a plan for high altitude travel. Even those without heart or lung conditions can have trouble breathing at high altitudes. Understand how it might affect you and make a plan for how to adjust to the change. Know what you will do ahead of time if you should need medical attention. Give yourself plenty of time to adjust if necessary and make sure to bring any extra equipment or medication you might need.

1. Sarkar M, Niranjan N, Banyal PK. Mechanisms of hypoxemia. Lung India. 2017 Jan-Feb;34(1):47-60. doi: 10.4103/0970-2113.197116. Erratum in: Lung India. 2017 Mar-Apr;34(2):220.[↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩]
2. Duff JP, Topjian A, Berg MD, Chan M, Haskell SE, Joyner BL Jr, Lasa JJ, Ley SJ, Raymond TT, Sutton RM, Hazinski MF, Atkins DL. 2018 American Heart Association Focused Update on Pediatric Advanced Life Support: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2018 Dec 4;138(23):e731-e739. doi: 10.1161/CIR.0000000000000612[↩]
3. Panchal AR, Berg KM, Kudenchuk PJ, Del Rios M, Hirsch KG, Link MS, Kurz MC, Chan PS, Cabañas JG, Morley PT, Hazinski MF, Donnino MW. 2018 American Heart Association Focused Update on Advanced Cardiovascular Life Support Use of Antiarrhythmic Drugs During and Immediately After Cardiac Arrest: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2018 Dec 4;138(23):e740-e749. doi: 10.1161/CIR.0000000000000613[↩]
4. https://www.med.umich.edu/trans/transweb/faq/q3.shtml[↩]
5. Chapter 21 – Hypoxia. Complications in Neuroanesthesia 2016, Pages 169-180. https://doi.org/10.1016/B978-0-12-804075-1.00021-3[↩]
6. Gattinoni L, Pesenti A, Matthay M. Understanding blood gas analysis. Intensive Care Med. 2018 Jan;44(1):91-93. doi: 10.1007/s00134-017-4824-y[↩]
7. Arora S, Tantia P. Physiology of Oxygen Transport and its Determinants in Intensive Care Unit. Indian J Crit Care Med. 2019 Sep;23(Suppl 3):S172-S177. doi: 10.5005/jp-journals-10071-23246[↩][↩][↩][↩][↩][↩]
8. Bassett BE, Bennett PB. Introduction to the physical and physiological bases of hyperbaric therapy. Hyperb Oxyg Ther. 1977:11–14.[↩]
9. Hall J. Guyton and Hall textbook of medical physiology (Guyton Physiology) [Internet] Philadelphia, PA: Elsevier; 2016.[↩]
10. Ortiz-Prado E, Dunn JF, Vasconez J, Castillo D, Viscor G. Partial pressure of oxygen in the human body: a general review. Am J Blood Res. 2019 Feb 15;9(1):1-14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420699[↩][↩][↩][↩][↩][↩]
11. West JB. Acclimatization and tolerance to extreme altitude. J Wilderness Med. 1993 Feb;4(1):17-26. doi: 10.1580/0953-9859-4.1.17[↩][↩]
12. Vleck D. Measurement of O2 consumption, CO2 production, and water vapor production in a closed system. J Appl Physiol (1985). 1987 May;62(5):2103-6. doi: 10.1152/jappl.1987.62.5.2103[↩][↩]
13. Mu Y, Nepal S. High mountain adventure tourism: trekkers’ perceptions of risk and death in Mt. Everest region, nepal. Asia Pac J Tour Res. 2016;21:500–511.[↩][↩]
14. Boussuges A, Molenat F, Burnet H, Cauchy E, Gardette B, Sainty JM, Jammes Y, Richalet JP. Operation Everest III (Comex ’97): modifications of cardiac function secondary to altitude-induced hypoxia. An echocardiographic and Doppler study. Am J Respir Crit Care Med. 2000 Jan;161(1):264-70. doi: 10.1164/ajrccm.161.1.9902096[↩][↩]
15. Möller W, Celik G, Feng S, Bartenstein P, Meyer G, Oliver E, Schmid O, Tatkov S. Nasal high flow clears anatomical dead space in upper airway models. J Appl Physiol (1985). 2015 Jun 15;118(12):1525-32. doi: 10.1152/japplphysiol.00934.2014[↩]
16. Mah KK, Cheng HM. Learn Teach Tools Basic Clin Respir Physiol [Internet] Springer; 2015. Diffusion, blood O2, CO2 content and transport; pp. 15–26.[↩]
17. Krogh A, Lindhard J. The volume of the dead space in breathing and the mixing of gases in the lungs of man. J Physiol. 1917 Mar 20;51(1-2):59-90. doi: 10.1113/jphysiol.1917.sp001785[↩]
18. Scheid P, Piiper J. Blood/gas equilibrium of carbon dioxide in lungs. A critical review. Respir Physiol. 1980 Jan;39(1):1-31. doi: 10.1016/0034-5687(80)90011-0[↩]
19. Mayer K, Trzeciak S, Puri NK. Assessment of the adequacy of oxygen delivery. Curr Opin Crit Care. 2016 Oct;22(5):437-43. doi: 10.1097/MCC.0000000000000336[↩]
20. Sorbini CA, Grassi V, Solinas E, Muiesan G. Arterial oxygen tension in relation to age in healthy subjects. Respiration. 1968;25(1):3-13. doi: 10.1159/000192549[↩]
21. Greene KE, Peters JI. Pathophysiology of acute respiratory failure. Clin Chest Med. 1994 Mar;15(1):1-12.[↩][↩][↩][↩]
22. AVIADO DM, DALY MD, LEE CY, SCHMIDT CF. The contribution of the bronchial circulation to the venous admixture in pulmonary venous blood. J Physiol. 1961 Mar;155(3):602-22. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1359878/pdf/jphysiol01270-0187.pdf[↩]
23. Hamer J, Wiedemann K, Berlet H, Weinhardt F, Hoyer S. Cerebral glucose and energy metabolism, cerebral oxygen consumption, and blood flow in arterial hypoxaemia. Acta Neurochir (Wien). 1978;44(3-4):151-60. doi: 10.1007/BF01402057[↩]
24. Spencer JA, Ferraro F, Roussakis E, Klein A, Wu J, Runnels JM, Zaher W, Mortensen LJ, Alt C, Turcotte R, Yusuf R, Côté D, Vinogradov SA, Scadden DT, Lin CP. Direct measurement of local oxygen concentration in the bone marrow of live animals. Nature. 2014 Apr 10;508(7495):269-73. doi: 10.1038/nature13034[↩]
25. Ortiz-Prado E, Natah S, Srinivasan S, Dunn JF. A method for measuring brain partial pressure of oxygen in unanesthetized unrestrained subjects: the effect of acute and chronic hypoxia on brain tissue PO(2). J Neurosci Methods. 2010 Nov 30;193(2):217-25. doi: 10.1016/j.jneumeth.2010.08.019. Epub 2010 Sep 15. Erratum in: J Neurosci Methods. 2011 Mar 30;196(2):327.[↩]
26. Scheufler KM. Tissue oxygenation and capacity to deliver O2 do the two go together? Transfus Apher Sci. 2004 Aug;31(1):45-54. doi: 10.1016/j.transci.2004.06.001[↩]
27. Wang W, Winlove CP, Michel CC. Oxygen partial pressure in outer layers of skin of human finger nail folds. J Physiol. 2003 Jun 15;549(Pt 3):855-63. doi: 10.1113/jphysiol.2002.037994[↩]
28. Malte H, Lykkeboe G. The Bohr/Haldane effect: a model-based uncovering of the full extent of its impact on O2 delivery to and CO2 removal from tissues. J Appl Physiol (1985). 2018 Sep 1;125(3):916-922. doi: 10.1152/japplphysiol.00140.2018[↩]
29. Ortiz-Prado E, León AB, Unigarro L, Santillan P. Oxigenación y flujo sanguíneo cerebral, revisión comprensiva de la literatura. Brain oxygenation and cerebral blood flow, a comprehensive literature review. Rev Ecuat Neurol. 2018:27.[↩]
30. Vlassenko AG, Raichle ME. Brain aerobic glycolysis functions and Alzheimer’s disease. Clin Transl Imaging. 2015 Feb 1;3(1):27-37. doi: 10.1007/s40336-014-0094-7[↩]
31. Neff TA. Routine oximetry. A fifth vital sign? Chest. 1988 Aug;94(2):227. doi: 10.1378/chest.94.2.227a[↩][↩][↩]
32. Chan ED, Chan MM, Chan MM. Pulse oximetry: understanding its basic principles facilitates appreciation of its limitations. Respir Med. 2013 Jun;107(6):789-99. doi: 10.1016/j.rmed.2013.02.004[↩][↩][↩]
33. Belda JF, Soro M, Ferrando C. Pathophysiology of respiratory failure. Trends Anaesth Crit Care. 2013;3:265–9.[↩]
34. Glenny RW. Teaching ventilation/perfusion relationships in the lung. Adv Physiol Educ. 2008 Sep;32(3):192-5. doi: 10.1152/advan.90147.2008[↩]
35. West JB, Dollery CT, Naimark A. Distribution of blood flow in isolated lung; relation to vascular and alveolar pressures. J Appl Physiol. 1964;19:713–24. doi: 10.1152/jappl.1964.19.4.713[↩]
36. Orchard CH, Sanchez de Leon R, Sykes MK. The relationship between hypoxic pulmonary vasoconstriction and arterial oxygen tension in the intact dog. J Physiol. 1983 May;338:61-74. doi: 10.1113/jphysiol.1983.sp014660[↩]
37. Fishman AP. Hypoxia on the pulmonary circulation. How and where it acts. Circ Res. 1976 Apr;38(4):221-31. doi: 10.1161/01.res.38.4.221[↩]
38. Shirai M, Sada K, Ninomiya I. Effects of regional alveolar hypoxia and hypercapnia on small pulmonary vessels in cats. J Appl Physiol (1985). 1986 Aug;61(2):440-8. doi: 10.1152/jappl.1986.61.2.440[↩]
39. Leach RM, Treacher DF. Clinical aspects of hypoxic pulmonary vasoconstriction. Exp Physiol. 1995 Sep;80(5):865-75. doi: 10.1113/expphysiol.1995.sp003894[↩]
40. Patel AJ, Lazdunski M, Honoré E. Kv2.1/Kv9.3, a novel ATP-dependent delayed-rectifier K+ channel in oxygen-sensitive pulmonary artery myocytes. EMBO J. 1997 Nov 17;16(22):6615-25. doi: 10.1093/emboj/16.22.6615[↩][↩]
41. Ward JP, Aaronson PI. Mechanisms of hypoxic pulmonary vasoconstriction: can anyone be right? Respir Physiol. 1999 May 3;115(3):261-71. doi: 10.1016/s0034-5687(99)00025-0[↩]
42. Aaronson PI, Robertson TP, Knock GA, Becker S, Lewis TH, Snetkov V, Ward JP. Hypoxic pulmonary vasoconstriction: mechanisms and controversies. J Physiol. 2006 Jan 1;570(Pt 1):53-8. doi: 10.1113/jphysiol.2005.098855[↩]
43. Covelli HD, Nessan VJ, Tuttle WK 3rd. Oxygen derived variables in acute respiratory failure. Crit Care Med. 1983 Aug;11(8):646-9. doi: 10.1097/00003246-198308000-00012[↩][↩]
44. Gunning JE. Pathophysiology of respiratory failure and indications for respiratory support. Surgery (Oxf) 2003;21:72–6.[↩]
45. Williams AJ. ABC of oxygen: assessing and interpreting arterial blood gases and acid-base balance. BMJ. 1998 Oct 31;317(7167):1213-6. doi: 10.1136/bmj.317.7167.1213[↩]
46. Petersson J, Glenny RW. Gas exchange and ventilation-perfusion relationships in the lung. Eur Respir J. 2014 Oct;44(4):1023-41. doi: 10.1183/09031936.00037014[↩]
47. Roussos C, Koutsoukou A. Respiratory failure. Eur Respir J Suppl. 2003 Nov;47:3s-14s. doi: 10.1183/09031936.03.00038503[↩]
48. Vogelsang H, Botteck NM, Herzog-Niescery J, Kirov J, Litschko D, Weber TP, Gude P. Übertragung einer „Cockpit-Strategie“ in die Anästhesie : Klinisches Beispiel: Einführung von „canned decisions“ zur Lösung von Atemwegsnotfällen [Transfer of a cockpit strategy to anesthesiology : Clinical example: introduction of canned decisions to solve cannot intubate cannot oxygenate situations]. Anaesthesist. 2019 Jan;68(1):30-38. German. doi: 10.1007/s00101-018-0511-9[↩]
49. Grensemann J, Simon M, Kluge S. Atemwegssicherung in der Intensiv- und Notfallmedizin : Was gibt es Neues? [Airway management in intensive care and emergency medicine : What is new?]. Med Klin Intensivmed Notfmed. 2019 May;114(4):334-341. German. doi: 10.1007/s00063-018-0498-7[↩]
50. Gonzalez FJ, Xie C, Jiang C. The role of hypoxia-inducible factors in metabolic diseases. Nat Rev Endocrinol. 2018 Dec;15(1):21-32. doi: 10.1038/s41574-018-0096-z[↩]
51. Bhutta BS, Alghoula F, Berim I. Hypoxia. [Updated 2022 Aug 9]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482316[↩][↩][↩][↩][↩]
52. Doyle DJ. Arterial/alveolar oxygen tension ratio: a critical appraisal. Can Anaesth Soc J. 1986 Jul;33(4):471-4. doi: 10.1007/BF03010973[↩]
53. ARDS Definition Task Force; Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L, Slutsky AS. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012 Jun 20;307(23):2526-33. doi: 10.1001/jama.2012.5669[↩][↩][↩]
54. Fan E, Brodie D, Slutsky AS. Acute Respiratory Distress Syndrome: Advances in Diagnosis and Treatment. JAMA. 2018 Feb 20;319(7):698-710. doi: 10.1001/jama.2017.21907[↩]
55. Gowda MS, Klocke RA. Variability of indices of hypoxemia in adult respiratory distress syndrome. Crit Care Med. 1997 Jan;25(1):41-5. doi: 10.1097/00003246-199701000-00010[↩]
56. Karbing DS, Kjaergaard S, Smith BW, Espersen K, Allerød C, Andreassen S, Rees SE. Variation in the PaO2/FiO2 ratio with FiO2: mathematical and experimental description, and clinical relevance. Crit Care. 2007;11(6):R118. doi: 10.1186/cc6174[↩][↩]