Hypoxia (medical)
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Hypoxia Medical
Hypoxia
Other namesHypoxiation, lack of, low blood oxygen, oxygen starvation
Cyanosis of the hand in an elderly person with low oxygen saturation
SpecialtyPulmonology, toxicology
SymptomsCyanosis, numbness or pins and needles feeling of the extremities
ComplicationsGangrene, necrosis
Risk factorsDiabetes, coronary artery disease, heart attack, stroke, embolism, thrombosis, deep-vein thrombosis, tobacco smoking

Hypoxia[1] is a condition in which the body or a region of the body is deprived of adequate oxygen supply at the tissue level. Hypoxia may be classified as either generalized, affecting the whole body, or local, affecting a region of the body.[2] Although hypoxia is often a pathological condition, variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise..

Hypoxia differs from hypoxemia and anoxemia, in that hypoxia refers to a state in which oxygen received by a tissue or the whole body is insufficient, whereas hypoxemia and anoxemia refer specifically to states that have low or no oxygen in the blood.[3] Hypoxia in which there is complete absence of oxygen supply is referred to as anoxia.

Hypoxia can be due to external causes, when the breathing gas is hypoxic, or internal causes, such as reduced effectiveness of gas transfer in the lungs, reduced capacity of the blood to carry oxygen, compromised general or local perfusion, or inability of the affected tissues to process an adequately oxygenates blood supply.

Generalized hypoxia occurs in healthy people when they ascend to high altitude, where it causes altitude sickness leading to potentially fatal complications: high altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE).[4] Hypoxia also occurs in healthy individuals when breathing inappropriate mixtures of gases with a low oxygen content, e.g., while diving underwater, especially when using malfunctioning closed-circuit rebreather systems that control the amount of oxygen in the supplied air. Mild, non-damaging intermittent hypoxia is used intentionally during altitude training to develop an athletic performance adaptation at both the systemic and cellular level.[5]

Hypoxia is a common complication of preterm birth in newborn infants. Because the lungs develop late in pregnancy, premature infants frequently possess underdeveloped lungs. To improve blood oxygenation, infants at risk of hypoxia may be placed inside incubators that provide warmth, humidity, and supplemental oxygen. More serious cases are treated with continuous positive airway pressure (CPAP).[6]

Classification

Hypoxia exists when there is a reduced amount of oxygen in the tissues of the body. Hypoxemia refers to a reduction in arterial oxygenation below the normal range, regardless of whether gas exchange is impaired in the lung, arterial oxygen content (CaO2 - which represents the amount of oxygen delivered to the tissues) is adequate, or tissue hypoxia exists.[7]

By cause

Intermittent hypoxic training induces mild generalized hypoxia for short periods as a training method to improve sporting performance.[14]

By extent

Hypoxia may affect the whole body, or just some parts.

Generalized hypoxia

The term generalized hypoxia may refer to hypoxia affecting the whole body,[] or may be used as a synonym for hypoxic hypoxia, which occurs when there is insufficient oxygen in the breathing gas to oxygenate the blood to a level that will adequately support normal metabolic processes,[9][13][8] and which will inherently affect all perfused tissues.

The symptoms of generalized hypoxia depend on its severity and acceleration of onset. In the case of altitude sickness, where hypoxia develops gradually, the symptoms include fatigue, numbness / tingling of extremities, nausea, and cerebral hypoxia.[15] These symptoms are often difficult to identify, but early detection of symptoms can be critical.[16][17]

In severe hypoxia, or hypoxia of very rapid onset, ataxia, confusion, disorientation, hallucinations, behavioral change, severe headaches, reduced level of consciousness, papilloedema, breathlessness,[15] pallor,[18] tachycardia, and pulmonary hypertension eventually leading to the late signs cyanosis, slow heart rate, cor pulmonale, and low blood pressure followed by heart failure eventually leading to shock and death.[19][20]

Because hemoglobin is a darker red when it is not bound to oxygen (deoxyhemoglobin), as opposed to the rich red color that it has when bound to oxygen (oxyhemoglobin), when seen through the skin it has an increased tendency to reflect blue light back to the eye.[21] In cases where the oxygen is displaced by another molecule, such as carbon monoxide, the skin may appear 'cherry red' instead of cyanotic.[22] Hypoxia can cause premature birth, and injure the liver, among other deleterious effects.[]

Local hypoxia

If tissue is not being perfused properly, it may feel cold and appear pale; if severe, hypoxia can result in cyanosis, a blue discoloration of the skin. If hypoxia is very severe, a tissue may eventually become gangrenous. Extreme pain may also be felt at or around the site.[23]

Tissue hypoxia from low oxygen delivery may be due to low haemoglobin concentration (anaemic hypoxia), low cardiac output (stagnant hypoxia) or low haemoglobin saturation (hypoxic hypoxia).[24] The consequence of oxygen deprivation in tissues is a switch to anaerobic metabolism at the cellular level. As such, reduced systemic blood flow may result in increased serum lactate.[25] Serum lactate levels have been correlated with illness severity and mortality in critically ill adults and in ventilated neonates with respiratory distress.[25]

Signs and symptoms

Arterial oxygen tension can be measured by blood gas analysis of an arterial blood sample, and less reliably by pulse oximetry, which is not a complete measure of circulatory oxygen sufficiency. If there is insufficient blood flow or insufficient hemoglobin in the blood (anemia), tissues can be hypoxic even when there is high arterial oxygen saturation.

Complications

• Local tissue death, gangrene
• Brain damage

Causes

Oxygen passively diffuses in the lung alveoli according to a concentration gradient, also referred to as a partial pressure gradient. Inhaled air rapidly reaches saturation with water vapour, which slightly reduces the partial pressures of the other components. Oxygen diffuses from the inhaleded air, to arterial blood, where its partial pressure is around 100 mmHg (13.3 kPa).[29] In the blood, oxygen is bound to hemoglobin, a protein in red blood cells. The binding capacity of hemoglobin is influenced by the partial pressure of oxygen in the environment, as described by the oxygen-hemoglobin dissociation curve. A smaller amount of oxygen is transported in solution in the blood.[]

In systemic tissues, oxygen again diffuses down a concentration gradient into cells and their mitochondria, where it is used to produce energy in conjunction with the breakdown of glucose, fats, and some amino acids.[30] Hypoxia can result from a failure at any stage in the delivery of oxygen to cells. This can include low partial pressures of oxygen in the breathing gas, problems with diffusion of oxygen in the lungs through the interface between air and blood, insufficient available hemoglobin, problems with blood flow to the end user tissue, problems with the breathing cycle regarding rate and volume, and physiological and mechanical dead space Experimentally, oxygen diffusion becomes rate limiting when arterial oxygen partial pressure falls to 60 mmHg (5.3 kPa) or below.[clarification needed][31]

Almost all the oxygen in the blood is bound to hemoglobin, so interfering with this carrier molecule limits oxygen delivery to the perfused tissues. Hemoglobin increases the oxygen-carrying capacity of blood by about 40-fold,[32] with the ability of hemoglobin to carry oxygen influenced by the partial pressure of oxygen in the local environment, a relationship described in the oxygen-hemoglobin dissociation curve. When the ability of hemoglobin to carry oxygen is degraded, a hypoxic state can result.[33]

Ischemia

Ischemia, meaning insufficient blood flow to a tissue, can also result in hypoxia in the affected tissues. This is called 'ischemic hypoxia'. This can be caused by an embolism, a heart attack that decreases overall blood flow, or trauma to a tissue that results in damage reducing perfusion. A consequence of insufficient blood flow causing local hypoxia is gangrene that occurs in diabetes.[34]

Diseases such as peripheral vascular disease can also result in local hypoxia. For this reason, symptoms are worse when a limb is used, increasing the oxygen demand in the actve muscles. Pain may also be felt as a result of increased hydrogen ions leading to a decrease in blood pH (acidosis) created as a result of anaerobic metabolism.[35]

Hypoxemic hypoxia

This refers specifically to hypoxic states where the arterial content of oxygen is insufficient.[36] This can be caused by alterations in respiratory drive, such as in respiratory alkalosis, physiological or pathological shunting of blood, diseases interfering in lung function resulting in a ventilation-perfusion mismatch, such as a pulmonary embolus, or alterations in the partial pressure of oxygen in the environment or lung alveoli, such as may occur at altitude or when diving.[]

Carbon monoxide poisoning

Carbon monoxide competes with oxygen for binding sites on hemoglobin molecules. As carbon monoxide binds with hemoglobin hundreds of times tighter than oxygen, it can prevent the carriage of oxygen.[37] Carbon monoxide poisoning can occur acutely, as with smoke intoxication, or over a period of time, as with cigarette smoking. Due to physiological processes, carbon monoxide is maintained at a resting level of 4-6 ppm. This is increased in urban areas (7-13 ppm) and in smokers (20-40 ppm).[38] A carbon monoxide level of 40 ppm is equivalent to a reduction in hemoglobin levels of 10 g/L.[38][note 1]

Carbon monoxie 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.[clarification needed] In so doing, the hemoglobin is less likely to release its oxygen at the peripheral tissues.[clarification needed][32] Certain abnormal hemoglobin variants also have higher than normal affinity for oxygen, and so are also poor at delivering oxygen to the periphery.[clarification needed][]

Altitude

Atmospheric pressure reduces with altitude and proportionally, so does the oxygen content of the air.[39] The reduction in the partial pressure of inspired oxygen at higher altitudes lowers the oxygen saturation of the blood, ultimately leading to hypoxia.[39] The clinical features of altitude sickness include: sleep problems, dizziness, headache and oedema.[39]

Hypoxic breathing gases

The breathing gas may contain an insufficient partial pressure of oxygen. Such situations may lead to unconsciousness without symptoms since carbon dioxide levels remain normal and the human body senses pure hypoxia poorly. Hypoxic breathing gases can be defined as mixtures with a lower oxygen fraction than air, though gases containing sufficient oxygen to reliably maintain consciousness at normal sea level atmospheric pressure may be described as normoxic even when the oxygen fraction is slightly below normoxic. Hypoxic breathing gas mixtures in this context are those which will not reliably maintain consciousness at sea level pressure.[40]

One of the most widespread circumstances of exposure to hypoxic breathing gas is ascent to altitudes where the ambient pressure drops sufficiently to reduce the partial pressure of oxygen to hypoxic levels.[39]

Gases with as little as 2% oxygen by volume in a helium diluent are used for deep diving operations. The ambient pressure at 190 msw is sufficient to provide a partial pressure of about 0.4 bar, which is suitable for saturation diving. As the divers are decompressed, the breathing gas must be oxygenated to maintain a breathable atmosphere/.[41]

It is also possible for the breathing gas for diving to have a dynamically controlled oxygen partial pressure, known as a set point, which is maintained in the breathing gas circuit of a diving rebreather by addition of oxygen and diluent gas to maintain the desired oxygen partial pressure at a safe level between hypoxic and hyperoxic at the ambient pressure due to the current depth. A malfunction of the control system may lead to the gas mixture becoming hypoxic at the current depth.[42]

A special case of hypoxic breathing gas is encountered in deep freediving where the partial pressure of the oxygen in the lung gas is depleted during the dive, but remains sufficient at depth, and when it drops during ascent, it becomes too hypoxic to maintain consciousness, and the diver loses consciousness before reaching the surface.[43][11]

Hypoxic gases may also occur in industrial, mining, and firefighting environments. Some of these may also be toxic or narcotic, others are just asphyxiant. Some are recognisable by smell, others are odourless.

Inert gas asphyxiation may be deliberate with use of a suicide bag. Accidental death has occurred in cases where concentrations of nitrogen in controlled atmospheres, or methane in mines, has not been detected or appreciated.[44]

Other

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[45][unreliable medical source?] as well as certain drugs and other chemicals.[46]

Anemia

Hemoglobin plays a substantial role in carrying oxygen throughout the body,[32] and when it is deficient, anemia can result, causing 'anaemic hypoxia' if tissue perfusion is decreased. Iron deficiency is the most common cause of anemia. As iron is used in the synthesis of hemoglobin, less hemoglobin will be synthesised when there is less iron, due to insufficient intake, or poor absorption.[33]

Anemia is typically a chronic process that is compensated over time by increased levels of red blood cells via upregulated erythropoetin. A chronic hypoxic state can result from a poorly compensated anaemia.[33]

Histotoxic hypoxia

Histotoxic hypoxia (also called histoxic hypoxia) is the inability of cells to take up or use oxygen from the bloodstream, despite physiologically normal delivery of oxygen to such cells and tissues.[47] Histotoxic hypoxia results from tissue poisoning, such as that caused by cyanide (which acts by inhibiting cytochrome oxidase) and certain other poisons like hydrogen sulfide (byproduct of sewage and used in leather tanning).[48]

Diagnosis

Differential diagnosis

Treatment will depend on severity and may also depend on the cause, as some cases are due to external causes and removing them and treating acute symptoms may be sufficient, but where the symptoms are due to underlying pathology, treatment of the obvious symptoms may only provide temporary or partial relief, so differential diagnosis can be important in selecting definitive treatment.

Hypoxemic hypoxia: Low oxygen tension in the arterial blood (PaO2) is generally an indication of inability of the lungs to properly oxygenate the blood. Internal causes include hypoventilation, impaired alveolar diffusion, and pulmonary shunting. External causes include hypoxic environment, which could be caused by low ambient pressure or unsuitable breathing gas.[9]

Circulatory Hypoxia: Caused by insufficient perfusion of the affected tissues by blood which is adequately oxygenated. This may be generalised, due to cardiac failure or hypovolemia, or localised, due to infarction or localised injury.[9]

Anemic Hypoxia is caused by a deficit in oxygen-carrying capacity, usually due to low hemoglobin levels, leading to generalised inadequate oxygen delivery.[9]

Histotoxic Hypoxia (Dysoxia) is a consequence of cells being unable to utilize oxygen effectively. A classic example is cyanide poisoning which inhibits the enzyme cytochrome C oxidase in the mitochondria, blocking the use of oxygen to make ATP.[9]

Physiological compensation

Acute

If oxygen delivery to cells is insufficient for the demand (hypoxia), electrons will be shifted to pyruvic acid in the process of lactic acid fermentation. This temporary measure (anaerobic metabolism) allows small amounts of energy to be released. Lactic acid build up (in tissues and blood) is a sign of inadequate mitochondrial oxygenation, which may be due to hypoxemia, poor blood flow (e.g., shock) or a combination of both.[49] If severe or prolonged it could lead to cell death.[50]

In humans, hypoxia is detected by the peripheral chemoreceptors in the carotid body and aortic body, with the carotid body chemoreceptors being the major mediators of reflex responses to hypoxia.[51] This response does not control ventilation rate at normal p, but below normal the activity of neurons innervating these receptors increases dramatically, so much so to override the signals from central chemoreceptors in the hypothalamus, increasing p despite a falling pCO2[]

In most tissues of the body, the response to hypoxia is vasodilation. By widening the blood vessels, the tissue allows greater perfusion.

By contrast, in the lungs, the response to hypoxia is vasoconstriction. This is known as hypoxic pulmonary vasoconstriction, or "HPV".[52]

Chronic

When the pulmonary capillary pressure remains elevated chronically (for at least 2 weeks), the lungs become even more resistant to pulmonary edema because the lymph vessels expand greatly, increasing their capability of carrying fluid away from the interstitial spaces perhaps as much as 10-fold. Therefore, in patients with chronic mitral stenosis, pulmonary capillary pressures of 40 to 45 mm Hg have been measured without the development of lethal pulmonary edema.[Guytun and Hall physiology]

There are several potential physiologic mechanisms for hypoxemia, but in patients with chronic obstructive pulmonary disease (COPD), ventilation/perfusion (V/Q) mismatching is most common, with or without alveolar hypoventilation, as indicated by arterial carbon dioxide concentration. Hypoxemia caused by V/Q mismatching in COPD is relatively easy to correct, and relatively small flow rates of supplemental oxygen (less than 3 L/min for the majority of patients) are required for long term oxygen therapy (LTOT). Hypoxemia normally stimulates ventilation and produces dyspnea, but these and the other signs and symptoms of hypoxia are sufficiently variable in COPD to limit their value in patient assessment. Chronic alveolar hypoxia is the main factor leading to development of cor pulmonale -- right ventricular hypertrophy with or without overt right ventricular failure -- in patients with COPD. Pulmonary hypertension adversely affects survival in COPD, proportional to resting mean pulmonary artery pressure elevation. Although the severity of airflow obstruction as measured by forced expiratory volume tests FEV1 correlates best with overall prognosis in COPD, chronic hypoxemia increases mortality and morbidity for any severity of disease. Large-scale studies of long term oxygen therapy in patients with COPD show a dose-response relationship between daily hours of supplemental oxygen use and survival. Continuous, 24-hours-per-day oxygen use in appropriately selected patients may produce a significant survival benefit.[7]

Treatment and management

Treatment and management depend on circumstances. For most high altitude situations the risk is known, and prevention is appropriate. At low altitudes hypoxia is more likely to be associated with a medical problem or an unexpected contingency, and treatment is more likely to be provided to suit the specific case.

Treatment of acute and chronic cases

There are three main aspects of treatment: maintaining patent airways, providing sufficient oxygen content of the inspired air, and improving the diffusion in the lungs.[9] In some cases treatment may extend to improving oxygen capacity of the blood, which may include volumetric and circulatory intervention and support, hyperbaric oxygen therapy and treatment of intoxication.

Invasive ventilation may be necessary or an elective option in surgery. This generally involves a positive pressure ventilator connected to an endotracheal tube, and allows precise delivery of ventilation, accurate monitoring of FiO2, and positive end-expiratory pressure, and can be combined with anaesthetic gas delivery. In some cases a tracheotomy may be necessary.[9] Decreasing metabolic rate by reducing body temperature lowers oxygen demand and consumption, and can minimise the effects of tissue hypoxia, especially in the brain, and therapeutic hypothermia based on this principle may be useful.[9]

Where the problem is due to respiratory failure. it is desirable to treat the underlying cause. In cases of pulmonary edema, diuretics can be used to reduce the oedems. Steroids may be effective in some cases of interstitial lung disease, and in extreme cases, extracorporeal membrane oxygenation (ECMO) can be used.[9]

Hyperbaric oxygen has been found useful for treating some forms of localized hypoxia, including poorly perfused trauma injuries such as Crush injury, compartment syndrome, and other acute traumatic ischemias.[53][54] It is the definitive treatment for severe decompression sickness, which is largely a condition involving loclized hypoxia initially caused by inert gas embolism and inflammatory reactions to extravascular bubble growth.[55][56][57] It is also effective in Carbon monoxide poisoning.[58] and diabetic foot.[59][60]

A prescription renewal for home oxygen following hospitalization requires an assessment of the patient for ongoing hypoxemia.[61]

Prevention of altitude induced hypoxia

To counter the effects of high-altitude diseases, the body must return arterial p toward normal. Acclimatization, the means by which the body adapts to higher altitudes, only partially restores p to standard levels. Hyperventilation, the body's most common response to high-altitude conditions, increases alveolar p by raising the depth and rate of breathing. However, while p does improve with hyperventilation, it does not return to normal. Studies of miners and astronomers working at 3000 meters and above show improved alveolar p with full acclimatization, yet the p level remains equal to or even below the threshold for continuous oxygen therapy for patients with chronic obstructive pulmonary disease (COPD).[62] In addition, there are complications involved with acclimatization. Polycythemia, in which the body increases the number of red blood cells in circulation, thickens the blood, raising the danger that the heart can't pump it.[]

In high-altitude situations, only oxygen enrichment or compartment pressurisation can counteract the effects of hypoxia. Pressurisation is practicable in vehicles, and for emergencies in ground installations. By increasing the concentration of oxygen in the at ambient pressure, the effects of lower barometric pressure are countered and the level of arterial p is restored toward normal capacity. A small amount of supplemental oxygen reduces the equivalent altitude in climate-controlled rooms. At 4000 m, raising the oxygen concentration level by 5 percent via an oxygen concentrator and an existing ventilation system provides an altitude equivalent of 3000 m, which is much more tolerable for the increasing number of low-landers who work in high altitude.[63] In a study of astronomers working in Chile at 5050 m, oxygen concentrators increased the level of oxygen concentration by almost 30 percent (that is, from 21 percent to 27 percent). This resulted in increased worker productivity, less fatigue, and improved sleep.[62]

Oxygen concentrators are suited for high altitude oxygen enrichment of climate-controlled environments. They require little maintenance and electricity, utilise a locally available source of oxygen, and eliminate the expensive task of transporting oxygen cylinders to remote areas. Offices and housing often already have climate-controlled rooms, in which temperature and humidity are kept at a constant level.[]

Outcomes

Prognosis is strongly affected by cause, severity, treatment, and underlying pathology.

Epidemiology

Silent hypoxia

Silent hypoxia (also known as happy hypoxia)[64][65] is generalised hypoxia that does not coincide with shortness of breath.[66][67][68] This presentation is known to be a complication of COVID-19,[69][70] and is also known in atypical pneumonia,[71] altitude sickness,[72][73][74] and rebreather malfunction accidents.[75][76]

Localized hypoxia may be a complication of diabetes, decomression sickness, and of trauma that affects blood supply to the extremities.

Generalized hypoxia is an occupational hazard in several high-risk occupations, including firefighting, professional diving, mining and underground rescue.

History

The 2019 Nobel Prize in Physiology or Medicine was awarded to William G. Kaelin Jr., Sir Peter J. Ratcliffe, and Gregg L. Semenza in recognition of their discovery of cellular mechanisms to sense and adapt to different oxygen concentrations, establishing a basis for how oxygen levels affect physiological function.[77][78]

Notes

1. ^ The formula ${\displaystyle Hb_{CO}(\%)={\frac {CO-2.34}{5.09}}}$ can be used to calculate the amount of carbon monoxide-bound hemoglobin. For example, at carbon monoxide level of 5 ppm, ${\displaystyle ={\frac {5-2.34}{5.09}}=.5\%}$, or a loss of half a percent of their blood's hemoglobin.[38]

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