Hypoxemia (or hypoxaemia) was originally defined as a deficiency of oxygen in arterial blood, and standard manuals take this to mean an abnormally low partial pressure of oxygen (mm Hg), content of oxygen (ml oxygen per dl blood) or percent saturation of hemoglobin with oxygen, either found singly or in combination.^{[1] [2]} One simple rule is that hypoxemia becomes very serious when the decreased partial pressure of oxygen in blood is less than 60 mm Hg, because that point is the beginning of the steep portion of the hemoglobin dissociation curve, where a small decrease in the partial pressure of oxygen results in a large decrease in the oxygen content of the blood.^[3] or when hemoglobin oxygen saturation is less than 90%.

The distinction between hypoxemia, hypoxia and anemia[link]

While the term hypoxemia is limited to low oxygen in the blood, the more general term is hypoxia, which is an abnormally low oxygen content in any tissue or organ. It will be seen that hypoxemia can cause hypoxia (the hypoxemic hypoxia) along with other mechanisms (e.g. anemic hypoxia or histotoxic hypoxia).^[4] Informally, hypoxemic hypoxia is sometimes informally given as hypoxic hypoxia.

Disagreements exist concerning the scope of the term hypoxemia. At one extreme, there is nearly universal agreement that a blood gas determination which shows that the partial pressure of oxygen in a good arterial sample of whole blood is lower than normal constitutes hypoxemia. ^{[1] [3] [5]} One important condition that tests this rule is carbon monoxide poisoning, where the arterial partial pressure of oxygen is normal, but the content is much reduced. ^[2] (The content is reduced because the hemoglobin is tightly bound by the carbon monoxide, which effectively excludes oxygen.)

There is also nearly universal agreement that an abnormally low percent saturation of arterial hemoglobin with oxygen constitutes hypoxemia. This concept has given rise to a ready measurement of percent saturation by pulse oximetry. However this measurement can be very misleading when blood flow is slowed or interrupted, leading to a local tissue hypoxia even though arterial blood in patent blood vessels is normal.

There is less agreement concerning whether the oxygen content of blood is relevant to hypoxemia, particularly because the measurement of oxygen content requires tonometry, a method that is not always available. Pulmonary medical specialists would say yes^{[1] [2]}, as would the more technical dictionaries^[6], but in so doing they include severe anemia as a cause of hypoxemia due to the disease's greatly reduced quantity of hemoglobin, the oxygen binding protein within the red blood cell. Trauma Critical Care specialists tend to say no, conforming to the simpler definition of hypoxemia being a low partial pressure of oxygen only, reserving the concept of oxygen content to discussions of oxygen delivery to the tissues. ^[5][7][8].

Finally, the term was initially proposed to describe the low blood oxygen seen at high altitude and, had a general, non-technical definition - a defective oxygenation of the blood ^[9] Current dictionaries and web sites track the original definition, generally defining the term as insufficient oxygenation of the (arterial) blood.^[10][11] Other sites speak of "level" of oxygen^[12][13] but this non-technical usage sidesteps the contentious details, and does not offer a definitive solution to the problem of whether to include anemia in the scope of hypoxemia. With this caveat, the following article will include low oxygen content as a cause of hypoxemia because it is a functionally and clinically important reason why tissues become hypoxic and must be considered when there are symptoms of tissue hypoxia.

Causes[link]

Many of the causes for hypoxemia fall into the general category of problems that concern the lung and heart.The most common source of an individual's hypoxemia is the lung, where inspired air is wasted by going to regions that are poorly supplied with blood and (conversely) blood is perfusing areas of the lung that receive little of the inspired air; this is termed ventilation-perfusion mismatch. A second category includes those causes where the ventilatory drive is inadequate for some reason. Finally, the blood might be incapable of carrying sufficient oxygen for the body's needs for reasons such as anemia or carbon monoxide poisoning; remember, this final category is for those whose definition of hypoxemia includes situations where the quantity of oxygen is deficient, as well as when the partial pressure and/or the percent saturation is reduced.

The lung and the heart as the source of hypoxemia[link]

In addition to the two common reasons (ventilation-perfusion mismatch and shunt), a diffusion limitation in the lung may also cause hypoxemia. (Incidentally, this order of presentation is different from that found in a textbook because - didactically - it is more effective for them to present the ideas in the reverse order of how common they really are.^[14])

Key to understanding whether the lung is involved in a particular case of hypoxemia is the difference between the alveolar and the arterial oxygen levels; this A-a difference is often called the A-a gradient and is normally small. The arterial oxygen partial pressure is obtained directly from an arterial blood gas determination. The oxygen contained in the alveolar air can be calculated because it will be directly proportional to its fractional composition in air. Since the airways humidify (and so dilute) the inhaled air, the barometric pressure of the atmosphere is reduced by the vapor pressure of water.

[edit] Ventilation-perfusion mismatch

When alveolar ventilation (in liters of air per minute) and alveolar capillary blood flow (in liters of blood per minute) are approximately equal, oxygen equilibrates across the alveolar-capillary membrane well before the blood has traversed the alveolus. This equilibration does not occur when the alveolus is insufficiently ventilated, and as a consequence the blood exiting that alveolus is relatively hypoxemic. When such blood is added to blood from well ventilated alveoli, the mix has a lower oxygen partial pressure than the alveolar air, and so the A-a difference develops.

• Activity and modest levels of exercise improve ventilation-perfusion matching.^[15]

• Aging. Each of us faces a decline in the oxygen content of our arterial blood as we age:

Failed to parse (Missing texvc executable; please see math/README to configure.): P_{a_{O_2}}=-0.28 * Age + 0.11 * P_B + 14.6

[1]

with age in years and P_B being barometric pressure in mm Hg.

This decline is due to an increasingly poor match between ventilation and perfusion in the lung as we age^[16], making ventilation-perfusion abnormalities the most common reason for a reduced arterial oxygen content.

• Acute lung injury and the more severe acute respiratory distress syndrome (ARDS) is marked by hypoxemia due to impaired ventilation-perfusion matching. With widespread tissue injury, blood flow is shunted through poorly ventilated areas.^[17]

• Cirrhosis can be complicated by refractory hypoxemia due to high rates of blood flow through the lung, resulting in ventilation-perfusion mismatch. ^[18]

• As a limit, a ventilation/perfusion ratio of zero is a physiological shunt.

Shunt[link]

Some venous blood never circulates by alveoli before returning to the arterial vasculature, thus diluting the freshly oxygenated blood and reducing its oxygen content. The shunt may be intracardiac or may be intrapulmonary, and cannot be corrected by administering 100% oxygen.

• Some anatomic shunting is normal, as the bronchial circulation provides nutrition to the lung and is not oxygenated before it returns to the left heart. Additionally, some of the through the smallest cardiac veins empty back into the left heart directly.

• Shunting of blood from the right side to the left side of the circulation (right-to-left shunt) through a still patent atrial or ventricular septal defect or other congenital malformation is a powerful cause of hypoxemia. In the fetus, this is the normal circulation; newborn babies with a large anatomic shunt are cyanotic and fail to thrive.

• Blood passing through alveoli that have a ventilation/perfusion ratio of zero is a physiologic shunt. The physiologic shunt grows much larger in acute lung injury and especially in adult respiratory distress syndrome. Administering 100% oxygen can convert regions of the lung that have especially low ventilation to regions with physiologic shunt as affected alveoli collapse.

• Recently, the anatomic use ^[19] of the term intrapulmonary shunt has returned.^[20] In this use, an intrapulmonary shunt is defined according to its ability to pass micro-bubbles or microspheres through the lung, signifying that some fraction of the bloodflow is passing through vessels larger than capillaries. Such a shunt is normally absent at rest or when exercising while breathing 100% oxygen, but appears during strenuous exercise or when breathing air low in oxygen. The quantitative and functional importance of bubble-defined shunts is being vigorously debated, as is the relationship between physiologic shunt and these bubble-defined shunts. ^{[21] [22]}

Impaired diffusion[link]

Impaired diffusion across the blood-gas barrier in the lung can cause hypoxemia. However this is a rare cause as it is a problem only in extremely unusual circumstances. Most of the past cases once thought to be due to a diffusion problem are now recognized as being due to ventilation-perfusion inequality.

• Mount Everest presents its climbers with the lowest oxygen partial pressure on earth. Blood gas determinations obtained from subjects breathing ambient air at Camp 2, above the Ice Fall (6300 M) demonstrated hypoxemia due to a diffusion limitation in the uptake of oxygen.^{[23] [24]}

• Hypoxemia developing during vigorous exercise. It is possible to become hypoxemic during exercise with certain lung diseases due to impaired diffusion of oxygen across the alveolar-capillary membrane. ^[25] This is particularly true with idiopathic pulmonary fibrosis, where even at rest a fifth of the hypoxemia is due to diffusion limitations (on average). During exercise, almost half of the hypoxemia is due to diffusion limitations (again, on average).^[26]

Inadequate ventilation[link]

If the alveolar ventilation is insufficient, there will not be enough oxygen delivered to the alveoli for the body's use. This can cause hypoxemia even if the lungs are normal, as the cause is in the brainstem's control of ventilation or in the body's inability to breathe effectively.

Reduced ventilatory drive[link]

The rate of breathing and the depth of each breath is controlled by the brainstem and are generally controlled by the blood level of carbon dioxide, as determined by chemoreceptors in the aorta. Hypoxia occurs when the breathing center doesn't function correctly or when the signal is not appropriate.

• Central sleep apnea. During sleep, the breathing centers of the brain can pause their activity, leading to prolonged periods of apnea with potentially serious consequences. Infants also have periods of apnea during their sleep.

• Prolonged breath-holding post-hyperventilation. The duration of breath-holding during swimming or diving is greatly prolonged by first hyperventilating to blow off the carbon dioxide, thus reducing the urge to breathe. However, this maneuver is dangerous as it can lead to death because the falling blood oxygen levels are not sensed, and tissue hypoxia can ensue.^[27]

Mechanical blockade of the airflow[link]

A variety of conditions that physically limit airflow can lead to hypoxemia.

• Suffocation can occur in many ways; for instance, temporary interruption of breathing can occur during sleep when the upper airways fall shut (obstructive sleep apnea), while bedclothes may interfere with breathing in infants (SIDS).

• Structural deformities of the chest (scoliosis an kyphosis) can severely restrict breathing, leading to hypoxemia towards the end of life.

• Congenital and acquired causes of muscle weakness may be severe enough to limit breathing and cause hypoxemia, as can muscle weakness and then fatigue in extreme cases of COPD.

Deficient oxygen in the inspired air[link]

The oxygen contained in the alveolar air is directly proportional to its fractional composition in air. The oxygen content also depends on the barometric pressure, so altitude reduces alveolar oxygen. For calculations, the barometric pressure of the atmosphere is reduced by the vapor pressure of the water that comes to saturate the air in the lung, since the airways humidify the inhaled air:

Failed to parse (Missing texvc executable; please see math/README to configure.): P_{A_{O_2}} = F_{I_{O_2}}*(P_B-P_{H_2O})

Failed to parse (Missing texvc executable; please see math/README to configure.): = F_{I_{O_2}}*(P_B-47)

.^[14]

and at sea level:Failed to parse (Missing texvc executable; please see math/README to configure.): = 21%*(760-47) = 150 mm Hg

.

and in Denver, Colorado: Failed to parse (Missing texvc executable; please see math/README to configure.): = 21%*(640-47) = 125 mm Hg

.

and on the top of Pikes Peak, Colorado:Failed to parse (Missing texvc executable; please see math/README to configure.): = 21%*(450-47) = 85 mm Hg

.

and on the top of Mount Everest, Nepal:Failed to parse (Missing texvc executable; please see math/README to configure.): = 21%*(253-47) = 43 mm Hg

.^[28]

• Flying does too, since cabin pressure is maintained at 7,000 to 8,000 feet, which is greater than Denver and almost that of Vail, Colorado. The effects of altitude can be reversed by pressurizing the cabin or by supplementing inhaled air with 100% oxygen.

• Air depleted of oxygen has also proven fatal. In the past, anesthesia machines have malfunctioned, delivering low-oxygen gas mixtures to patients. Additionally, oxygen in a confined space can be consumed if carbon dioxide scrubbers are used without sufficient attention to supplementing the oxygen which has been consumed.

Limited oxygen carrying ability of blood[link]

Almost all the oxygen in the blood is bound to hemoglobin, so interfering with this carrier molecule limits oxygen delivery to the periphery.

[edit] Anemia

In blood, most of the oxygen is carried by hemoglobin. The following calculations demonstrate the quantitative difference between the quantity of oxygen dissolved in the blood and that carried by oxygen. First, the dissolved oxygen is calculated as the product of the gas solubility times the partial pressure of the gas, and is given as ml of gas per 100 ml blood.

Failed to parse (Missing texvc executable; please see math/README to configure.): O_2(plasma) = 0.003*P_{a_{O_2}}

The partial pressure of oxygen in the alveoli is the product of its fractional composition (21% in air) times the barometric pressure (less the water vapor pressure):

Failed to parse (Missing texvc executable; please see math/README to configure.): P_{A_{O_2}}=0.21*(P_B-47)

for example, at sea level, Failed to parse (Missing texvc executable; please see math/README to configure.): P_{A_{O_2}} = 0.21*(760-47) = 150 mm Hg.

So Failed to parse (Missing texvc executable; please see math/README to configure.): O_2(plasma) = 0.003*150 = 0.5 ml

.^[2]

The quantity of oxygen carried by hemoglobin depends on its concentration (Hb) and the fraction of the hemoglobin that is actually carrying oxygen (the percent saturation). If Hb is 15 g/dl and it is 98% saturated:

Failed to parse (Missing texvc executable; please see math/README to configure.): O_2(hemoglobin) =1.34*S_{a_{O_2}}*Hb

Failed to parse (Missing texvc executable; please see math/README to configure.): ={1.34*0.98*15} = 20 ml

.^[2]

These two calculations illustrate that hemoglobin increases the amount of oxygen that the blood can carry by ~40-fold. Such a large improvement means that any substantial degree of anemia will have a large impact on the oxygen carrying capacity of the blood.

[edit] Carbon monoxide (CO) poisoning

Carbon monoxide poisoning can occur acutely, as with smoke intoxication, or over a period of time, as with cigarette smoking. Hemoglobin binds CO hundreds of times tighter than oxygen, so very low concentrations of CO will occupy hemoglobin binding sites, excluding oxygen.^[29] The quantity of CO in the blood is never zero since metabolic processes have CO as a waste product, giving us 4 ppm to 6 ppm at all times. Urban dwellers have 7 ppm to 13 ppm, but smokers have 20 ppm to 40 ppm!^[30] To calculate some consequences of these values, we can calculate (for urban dwellers at 5 ppm CO in their blood):

Failed to parse (Missing texvc executable; please see math/README to configure.): Hb_{CO}(%) = \frac {CO - 2.34} {5.09}

Failed to parse (Missing texvc executable; please see math/README to configure.): = \frac {5 - 2.34} {5.09} = .5%

or a loss of half a percent of their blood's hemoglobin.

For heavy smokers (40 ppm):

Failed to parse (Missing texvc executable; please see math/README to configure.): Hb_{CO}(%) = \frac {CO - 2.34} {5.09}

Failed to parse (Missing texvc executable; please see math/README to configure.): = \frac {40 - 2.34} {5.09} = 7.4%

.^[30] This is equivalent to reducing the Hb from 15 to 14.

CO has a second toxic effect, namely removing the allosteric shift of the oxygen dissociation curve and shifting the foot of the curve to the left. In so doing, the hemoglobin is less likely to release its any of its oxygens at the peripheral tissues.^[2] Certain abnormal hemoglobin variants also have higher than normal affinity for oxygen, and so are also poor at delivering oxygen to the periphery.

Chemical modifications of hemoglobin[link]

Hemoglobin's function can also be lost by chemically oxidizing its iron atom to its ferric form. This form of inactive hemoglobin is called methemoglobin and can be made by ingesting sodium nitrite^[31] as well as certain drugs and other chemicals.

Oxygen demand[link]

The final word is that the body may be able to compensate for hypoxemia due to any of these causes, and so symptoms may be overlooked initially. However, further disease or a stress such as any increase in oxygen demand may finally unmask the existing hypoxemia.

Notes[link]

References[link]

• West, John B. (2012). Pulmonary Pathophysiology: The Essentials (8th ed.). Lippincott Williams & Wilkins. ISBN 978-1-4511-0713-5. 
• Anderson, Kenneth N. (ed) (2002). Mosby's Medical, Nursing & Allied Health Dictionary (6th ed.). C.V. Mosby. ISBN 978-0-323-01430-4. 
• Dean R. Hess, Neal R. MacIntyre, Shelley C. Mishoe, William F. Galvin, Alexander B. Adams (2012) Respiratory Care: Principles and Practice. (eds.) (2nd ed). Jones and Bartlet Learning ISBN 978-0-7637-6003-8
• Jacob Samuel and Cory Frankling, "Hypoxemia and Hypoxia" in Jonathan A. Myers, Keith W. Millikan and Theodore J. Saclarides (eds) (2008) Common Surgical Diseases. (2nd ed.). 391-394 ISBN 978-0-387-75245-7