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Hypoxia (medical)

March 22, 2023

Hypoxia is a condition in which the body or a region of the body is deprived of adequate oxygen supply at the tissue level.[1] 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
Other namesHypoxiation, lack of oxygen, low blood oxygen (technically hypoxemia), 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 differs from hypoxemia and anoxemia, in that hypoxia refers to a state in which oxygen present in 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 extract oxygen from, or metabolically process, an adequate supply of oxygen from an adequately oxygenated 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).

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.[6] The classification categories are not always mutually exclusive, and hypoxia can be a consequence of a wide variety of causes.

By cause

  • Hypoxic hypoxia, sometimes also referred to as generalised hypoxia. Generalised, or hypoxic hypoxia may be caused by:
  • Hypoxemic hypoxia is a lack of oxygen caused by low oxygen tension in the arterial blood, due to the inability of the lungs to sufficiently oxygenate the blood. Causes include hypoventilation, impaired alveolar diffusion, and pulmonary shunting.[8] This definition overlaps considerably with that of hypoxic hypoxia.
  • Pulmonary hypoxia is hypoxia from hypoxemia due to abnormal pulmonary function, and occurs when the lungs receive adequately oxygenated gas which does not oxygenate the blood sufficiently. It may be caused by:[7]
    • Ventilation perfusion mismatch (V/Q mismatch), which can be either low or high.[8] A reduced V/Q ratio can be caused by impaired ventilation, which may be a consequence of conditions such as bronchitis, obstructive airway disease, mucus plugs, or pulmonary edema, which limit or obstruct the ventilation. In this situation there is not enough oxygen in the alveolar gas to fully oxygenate the blood volume passing through, and PaO2 will be low. Conversely, an increased V/Q ratio tends to be a consequence of impaired perfusion, in which circumstances the blood supply is insufficient to carry the available oxygen, PaO2 will be normal, but tissues will be insufficiently perfused to meet the oxygen demand. A V/Q mismatch can also occur when the surface area available for gas exchange in the lungs is decreased.[8]
    • Pulmonary shunt, in which blood passes from the right to the left side of the heart without being oxygenated. This may be due to anatomical shunts, in which the blood bypasses the alveoli, via intracardiac shunts, pulmonary arteriovenous malformations, fistulas, and hepatopulmonary syndrome, or physiological shunting, in which blood passes through non-ventilated alveoli.[8]
    • Impaired diffusion, a reduced capacity for gas molecules to move between the air in the alveoli and the blood, which occurs when alveolar–capillary membranes thicken. This can happen in interstitial lung diseases such as pulmonary fibrosis, sarcoidosis, hypersensitivity pneumonitis, and connective tissue disorders.[7]
  • Circulatory hypoxia,[8] also known as ischemic hypoxia or stagnant hypoxia is caused by abnormally low blood flow to the lungs, which can occur during shock, cardiac arrest, severe congestive heart failure, or abdominal compartment syndrome, where the main dysfunction is in the cardiovascular system, causing a major reduction in perfusion. Arterial gas is adequately oygenated in the lungs, and the tissues are able to accept the oxygen available, but the flow rate to the tissues is insufficient. Venous oxygenation is particularly low.[7][11]
  • Anemic hypoxia or hypemic hypoxia is the lack of capacity of the blood to carry the normal level of oxygen.[8] It can be caused by anemia or:[7]
    • Carbon monoxide poisoning, in which carbon monoxide combines with the hemoglobin, to form carboxyhemoglobin (HbCO) preventing it from transporting oxygen.[7][12]
    • Methemoglobinemia, a change in the hemoglobin molecule from a ferrous ion (Fe2+) to a ferric ion (Fe3+), which has a lesser capacity to bind free oxygen molecules, and a greater affinity for bound oxygen. This causes a left shift in the O2–Hb curve. It can be congenital or caused by medications, food additives or toxins, including chloroquine, benzene, nitrites, benzocaine.[7]
  • Histotoxic hypoxia (Dysoxia)[8] or Cellular hypoxia occurs when the cells of the affected tissues are unable to use oxygen provided by normally oxygenated hemoglobin.[7] Examples include cyanide poisoning which inhibits cytochrome c oxidase, an enzyme required for cellular respiration in mitochondria. Methanol poisoning has a similar effect, as the metabolism of methanol produces formic acid which inhibits mitochondrial cytochrome oxidase.[7][13][clarification needed]

Intermittent hypoxic training induces mild generalized hypoxia for short periods as a training method to improve sporting performance. This is not considered a medical condition.[14] Acute cerebral hypoxia leading to blackout can occur during freediving. This is a consequence of prolonged voluntary apnea underwater, and generally occurs in trained athletes in good health and good physical condition.[15]

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,[citation needed] 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,[8][13][7] 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.[16][17] These symptoms are often difficult to identify, but early detection of symptoms can be critical.[18]

In severe hypoxia, or hypoxia of very rapid onset, ataxia, confusion, disorientation, hallucinations, behavioral change, severe headaches, reduced level of consciousness, papilloedema, breathlessness,[16] pallor,[19] 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.[20][21]

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.[22] In cases where the oxygen is displaced by another molecule, such as carbon monoxide, the skin may appear 'cherry red' instead of cyanotic.[23] Hypoxia can cause premature birth, and injure the liver, among other deleterious effects.[citation needed]

Localized hypoxia

See also: Ischemia

 
Vascular ischemia of the toes with characteristic cyanosis

Hypoxia that is localized to a region of the body, such as an organ or a limb. is usually the consequence of ischemia, the reduced perfusion to that organ or limb, and may not necessarily be associated with general hypoxemia. A locally reduced perfusion is generally caused by an increased resistance to flow through the blood vessels of the affected area.

Ischemia is a restriction in blood supply to any tissue, muscle group, or organ, causing a shortage of oxygen.[24][25] Ischemia is generally caused by problems with blood vessels, with resultant damage to or dysfunction of tissue i.e. hypoxia and microvascular dysfunction.[26][27] It also means local hypoxia in a given part of a body sometimes resulting from vascular occlusion such as vasoconstriction, thrombosis, or embolism. Ischemia comprises not only insufficiency of oxygen, but also reduced availability of nutrients and inadequate removal of metabolic wastes. Ischemia can be a partial (poor perfusion) or total blockage.

Compartment syndrome is a condition in which increased pressure within one of the body's anatomical compartments results in insufficient blood supply to tissue within that space.[28][29] There are two main types: acute and chronic.[28] Compartments of the leg or arm are most commonly involved.[30]

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.

By affected tissues and organs

Any living tissue can be affected by hypoxia, but some are particularly sensitive, or have more noticeable or notable consequences.

Cerebral hypoxia
Main article: Cerebral hypoxia

Cerebral hypoxia is hypoxia specifically involving the brain. The four categories of cerebral hypoxia in order of increasing severity are: diffuse cerebral hypoxia (DCH), focal cerebral ischemia, cerebral infarction, and global cerebral ischemia. Prolonged hypoxia induces neuronal cell death via apoptosis, resulting in a hypoxic brain injury.[31][32]

Oxygen deprivation can be hypoxic (reduced general oxygen availability) or ischemic (oxygen deprivation due to a disruption in blood flow) in origin. Brain injury as a result of oxygen deprivation is generally termed hypoxic injury. Hypoxic ischemic encephalopathy (HIE) is a condition that occurs when the entire brain is deprived of an adequate oxygen supply, but the deprivation is not total. While HIE is associated in most cases with oxygen deprivation in the neonate due to birth asphyxia, it can occur in all age groups, and is often a complication of cardiac arrest.[33][34][35]

Corneal hypoxia

Long term use of some types of contact lenses can result in hypoxia damage to the corneas. The corneas are not perfused and get their oxygen from the atmosphere by diffusion. Impermeable contact lenses form a barrier to this diffusion and this can cause damage to the corneas.

Intrauterine hypoxia
Main article: Intrauterine hypoxia

Intrauterine hypoxia, also known as fetal hypoxia, occurs when the fetus is deprived of an adequate supply of oxygen. It may be due to a variety of reasons such as prolapse or occlusion of the umbilical cord, placental infarction, maternal diabetes (prepregnancy or gestational diabetes)[36] and maternal smoking. Intrauterine growth restriction may cause or be the result of hypoxia. Intrauterine hypoxia can cause cellular damage that occurs within the central nervous system (the brain and spinal cord). This results in an increased mortality rate, including an increased risk of sudden infant death syndrome (SIDS). Oxygen deprivation in the fetus and neonate have been implicated as either a primary or as a contributing risk factor in numerous neurological and neuropsychiatric disorders such as epilepsy, attention deficit hyperactivity disorder, eating disorders and cerebral palsy.[37][38][39][40][41][42]

Tumor hypoxia
Main article: Tumor hypoxia

Tumor hypoxia is the situation where tumor cells have been deprived of oxygen. As a tumor grows, it rapidly outgrows its blood supply, leaving portions of the tumor with regions where the oxygen concentration is significantly lower than in healthy tissues. Hypoxic microenvironements in solid tumors are a result of available oxygen being consumed within 70 to 150 μm of tumour vasculature by rapidly proliferating tumor cells thus limiting the amount of oxygen available to diffuse further into the tumor tissue. In order to support continuous growth and proliferation in challenging hypoxic environments, cancer cells are found to alter their metabolism. Furthermore, hypoxia is known to change cell behavior and is associated with extracellular matrix remodeling and increased migratory and metastatic behavior.[43][44] Tumour hypoxia is usually associated with highly malignant tumours, which frequently do not respond well to treatment.[45]

Vestibular system

In acute exposure to hypoxic hypoxia on the vestibular system and the visuo-vestibular interactions, the gain of the vestibulo–ocular reflex (VOR) decreases under mild hypoxia at altitude. Postural control is also disturbed by hypoxia at altitude, postural sway is increased, and there is a correlation between hypoxic stress and adaptive tracking performance.[46]

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.

  • Cyanosis[47]
  • Headache[47][48][49]
  • Decreased reaction time,[50] disorientation, and uncoordinated movement.[47]
  • Impaired judgment, confusion, memory loss and cognitive problems.[47][48]
  • Euphoria or dissociation[47]
  • Visual impairment[48] A moderate level of hypoxia can cause a generalized partial loss of color vision affecting both red-green and blue-yellow discrimination at an altitude of 12,000 feet (3,700 m).[51]
  • Lightheaded or dizzy sensation, vertigo[47]
  • Fatigue, Drowsiness or tiredness[47]
  • Shortness of breath[47]
  • Palpitations may occur in the initial phases. Later, the heart rate may reduce significantly degree. In severe cases, abnormal heart rhythms may develop.
  • Nausea and vomiting[47]
  • Initially raised blood pressure followed by lowered blood pressure as the condition progresses.[47]
  • Severe hypoxia can cause loss of consciousness, seizures or convulsions, coma and eventually death. Breathing rate may slow down and become shallow and the pupils may not respond to light.[47]
  • Tingling in fingers and toes[48]
  • Numbness[48]

Complications

  • Local tissue death and gangrene is a relatively common complication of ischaemic hypoxia. (diabetes, etc.)
  • Brain damage – cortical blindness is a known but uncommon complication of acute hypoxic damage to the cerebral cortex.[52]
  • Obstructive sleep apnea syndrome is a risk factor for cerebrovascular disease and cognitive dysfunction.[49]

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).[53] 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.[citation needed]

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.[54] 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][55]

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,[56] 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.[57]

Ischemia

Main article: Ischemia

Ischemia, meaning insufficient blood flow to a tissue, can also result in hypoxia in the affected tissues. This is called 'ischemic hypoxia'. Ischemia can be caused by an embolism, a heart attack that decreases overall blood flow, trauma to a tissue that results in damage reducing perfusion, and a variety of other causes. A consequence of insufficient blood flow causing local hypoxia is gangrene that occurs in diabetes.[58]

Diseases such as peripheral vascular disease can also result in local hypoxia. Symptoms are worse when a limb is used, increasing the oxygen demand in the active 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.[59]

G-LOC, or g-force induced loss of consciousness, is a special case of ischemic hypoxia which occurs when the body is subjected to high enough acceleration sustained for long enough to lower cerebral blood pressure and circulation to the point where loss of consciousness occurs due to cerebral hypoxia. The human body is most sensitive to longitudinal acceleration towards the head, as this causes the largest hydrostatic pressure deficit in the head.[60]

Hypoxemic hypoxia

Main article: Hypoxemia

This refers specifically to hypoxic states where the arterial content of oxygen is insufficient.[61] 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.[citation needed]

Common disorders that can cause respiratory disfunction include trauma to the head and spinal cord, nontraumatic acute myelopathies, demyelinating disorders, stroke, Guillain–Barré syndrome, and myasthenia gravis. These dysfunctions may necessitate mechanical ventilation. Some chronic neuromuscular disorders such as motor neuron disease and muscular dystrophy may require ventilatory support in advanced stages.[49]

Carbon monoxide poisoning

Main article: 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.[62] 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).[63] A carbon monoxide level of 40 ppm is equivalent to a reduction in hemoglobin levels of 10 g/L.[63][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][56] 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][citation needed]

Altitude

Main article: Altitude sickness

Atmospheric pressure reduces with altitude and proportionally, so does the oxygen content of the air.[64] The reduction in the partial pressure of inspired oxygen at higher altitudes lowers the oxygen saturation of the blood, ultimately leading to hypoxia.[64] The clinical features of altitude sickness include: sleep problems, dizziness, headache and oedema.[64]

Hypoxic breathing gases

Main articles: Inert gas asphyxiation and Asphyxiant 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.[65]

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.[64]

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/.[66]

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.[67]

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.[15][10]

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.[68]

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[69][unreliable medical source?] as well as certain drugs and other chemicals.[70]

Anemia

Main article: Anemia

Hemoglobin plays a substantial role in carrying oxygen throughout the body,[56] and when it is deficient, anemia can result, causing 'anaemic hypoxia' if tissue oxygenation 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.[57]: 997–99 

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.[57]: 997–99 

Histotoxic hypoxia

Main article: 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.[71] 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).[72]

Mechanism

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).[73] 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.[74] Serum lactate levels have been correlated with illness severity and mortality in critically ill adults and in ventilated neonates with respiratory distress.[74]

Physiological responses

All vertebrates must maintain oxygen homeostasis to survive, and have evolved physiological systems to ensure adequate oygenation of all tissues. In air breathing vertebrates this is based on lungs to acquire the oxygen, hemoglobin in red corpuscles to transport it, a vasculature to distribute, and a heart to deliver. Short term variations in the levels of oxygenation are sensed by chemoreceptor cells which respond by activating existing proteins, and over longer terms by regulation of gene transcription. Hypoxia is also involved in the pathogenesis of some common and severe pathologies.[75]

The most common causes of death in an aging population include myocardial infarction, stroke and cancer. These diseases share a common feature that limitation of oxygen availability contributes to the development of the pathology. Cells and organisms are also able to respond adaptively to hypoxic conditions, in ways that help them to cope with these adverse conditions. Several systems can sense oxygen concentration and may respond with adaptations to acute and long-term hypoxia.[75] The systems activated by hypoxia usually help cells to survive and overcome the hypoxic conditions. Erythropoietin, which is produced in larger quantities by the kidneys under hypoxic conditions, is an essential hormone that stimulates production of red blood cells, which are the primary transporter of blood oxygen, and glycolytic enzymes are involved in anaerobic ATP formation.[45]

Hypoxia-inducible factors (HIFs) are transcription factors that respond to decreases in available oxygen in the cellular environment, or hypoxia.[76][77] The HIF signaling cascade mediates the effects of hypoxia on the cell. Hypoxia often keeps cells from differentiating. However, hypoxia promotes the formation of blood vessels, and is important for the formation of a vascular system in embryos and tumors. The hypoxia in wounds also promotes the migration of keratinocytes and the restoration of the epithelium.[78] It is therefore not surprising that HIF-1 modulation was identified as a promising treatment paradigm in wound healing.[79]

Exposure of a tissue to repeated short periods of hypoxia, between periods of normal oxygen levels, influences the tissue's later response to a prolonged ischaemic exposuret. Thus is known as ischaemic preconditioning, and it is known to occur in many tissues.[45]

Acute

See also: Hypoxic ventilatory response § Acute hypoxic ventilatory response

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.[80] If severe or prolonged it could lead to cell death.[81]

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.[82] This response does not control ventilation rate at normal PO2, but below normal the activity of neurons innervating these receptors increases dramatically, so much as to override the signals from central chemoreceptors in the hypothalamus, increasing PO2 despite a falling PCO2[citation needed]

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", and has the effect of redirecting blood away from poorly ventilated regions, which helps match perfusion to ventilation, giving a more even oxygenation of blood from different parts of the lungs.[75] In conditions of hypoxic breathing gas, such as at high altitude, HPV is generalized over the entire lung, but with sustained exposure to generalized hypoxia, HPV is suppressed.[83] Hypoxic ventilatory response (HVR) is the increase in ventilation induced by hypoxia that allows the body to take in and transport lower concentrations of oxygen at higher rates. It is initially elevated in lowlanders who travel to high altitude, but reduces significantly over time as people acclimatize.[4][84]

Chronic

See also: Hypoxic ventilatory response § Chronic hypoxic ventilatory response, and High-altitude adaptation in humans

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.[85]

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.[6]

Pathological responses

Cerebral ischemia

The brain has relatively high energy requirements, using about 20% of the oxygen under resting conditions, but low reserves, which make it specially vulnerable to hypoxia. In normal conditions, an increased demand for oxytgen is easily compensated by an increased cerebral blood flow. but under conditions when there is insufficient oxygen available, increased blood flow may not be sufficient to compensate, and hypoxia can result in brain injury. A longer duration of cerebral hypoxia will generally result in larger areas of the brain being affected. The brainstem, hippocampus and cerebral cortex seem to be the most vulnerable regions. Injury becomes irreversible if ogygenation is not soon restored. Most cell death is by necrosis but delayed apoptosis also occurs. In addition, presynaptic neurons release large amounts of glutamate which further increases Ca2+ influx and causes catastrophic collapse in postsynaptic cells. Although it is the only way to save the tissue, reperfusion also produces reactive oxygen species and inflammatory cell infiltration, which induces further cell death. If the hypoxia is not too severe, cells can suppress some of their functions, such as protein synthesis and spontaneous electrical activity, in a process called penumbra, which is reversible if the oxygen supply is resumed soon enough.[75]

Myocardial ischemia

Parts of the heart are exposed to ischemic hypoxia in the event of occlusion of a coronary artery. Short periods of ischaemia are reversible if reperfused within about 20 minutes, without development of necrosis, but the phenomenon known as stunning is generally evident. If hypoxia continues beyond this period, necrosis propagates through the myocardial tissue.[75] Energy metabolism in the affected area shifts from mitochondrial respiration to anaerobic glycolysis almost immediately, with concurrent reduction of effectiveness of contractions, which soon cease. Anaerobic products accumulate in the muscle cells, which develop acidosis and osmotic load leading to cellular edema. Intracellular Ca2+ increases and eventually leads to cell necrosis. Arterial flow must be restored to return to aerobic metabolism and prevent necrosis of the affected muscle cells, but this also causes further damage by reperfusion injury. Myocadial stunning has been described as "prolonged postischaemic dysfunction of viable tissue salvaged by reperfusion", which manifests as temporary contractile failure in oxygenated muscle tissue. This may be caused by a release of reactive oxygen species during the early stages of reperfusion.[75]

Tumor angiogenesis

As tumors grow, regions of relative hypoxia develop as the oxygen supply is unevenly utilized by the tumor cells. The formation of new blood vessels is necessary for continued tumor growth, and is also an important factor in metastasis, as the route by which cancerous cells are transported to other sites.[75]

Diagnosis

Physical examination and history

Hypoxia can present as acute or chronic.

Acute presentation may include dyspnea (shortness of breath) and tachypnea (rapid, often shallow, breathing). Severity of symptom presentation is commonly an indication of severity of hypoxia. Tachycardia (rapid pulse) may develop to compensate for low arterial oxygen tension. Stridor may be heard in upper airway obstruction, and cyanosis may indicate severe hypoxia. Neurological symptoms and organ function deterioration occur when the oxygen delivery is severely compromised. In moderate hypoxia, restlessness, headache and confusion may occur, with coma and eventual death possible in severe cases.[8]

In chronic presentation, dyspnea following exertion is most commonly mentioned. Symptoms of the underlying condition that caused the hypoxia may be apparent, and can help with differential diagnosis. A productive cough and fever may be present with lung infection, and leg edema may suggest heart failure.[8]

Lung auscultation can provide useful information.[8]

Tests

An arterial blood gas test (ABG) may be done, which usually includes measurements of oxygen content, hemoglobin, oxygen saturation (how much of the hemoglobin is carrying oxygen), arterial partial pressure of oxygen (PaO2), partial pressure of carbon dioxide (PaCO2), blood pH level, and bicarbonate (HCO3)[86]

  • An arterial oxygen tension (PaO2) less than 80 mmHg is considered abnormal, but must be considered in context of the clinical situation.[8]
  • In addition to diagnosis of hypoxemia, the ABG may provide additional information, such as PCO2, which can help identify the etiology. The arterial partial pressure of carbon dioxide is an indirect measure of exchange of carbon diozide with the air in the lungs, and is related to minute ventilation. PCO2 is raised in hypoventilation.[8]
  • The normal range of PaO2:FiO2 ratio is 300 to 500 mmHg, if this ratio is lower than 300 it may indicate a deficit in gas exchange, which is particularly relevant for identifying acute respiratory distress syndrome (ARDS). A ratio of less than 200 indicates severe hypoxemia.[8]
  • The alveolar–arterial gradient (A-aO2,[87] or A–a gradient), is the difference between the alveolar (A) concentration of oxygen and the arterial (a) concentration of oxygen. It is a useful parameter for narrowing the differential diagnosis of hypoxemia.[88] The A–a gradient helps to assess the integrity of the alveolar capillary unit. For example, at high altitude, the arterial oxygen PaO2 is low, but only because the alveolar oxygen PAO2 is also low. However, in states of ventilation perfusion mismatch, such as pulmonary embolism or right-to-left shunt, oxygen is not effectively transferred from the alveoli to the blood which results in an elevated A-a gradient. PaO2 can be obtained from the arterial blood gas analysis and PAO2 is calculated using the alveolar gas equation.[8]
  • An abnormally low hematocrit (volume percentage of red blood cells) may indicate anemia.

X-rays or CT scans of the chest and airways can reveal abnormalities that may affect ventilation or perfusion.[89]

A ventilation/perfusion scan,[90] also called a V/Q lung scan, is a type of medical imaging using scintigraphy and medical isotopes to evaluate the circulation of air and blood within a patient's lungs,[91][92] in order to determine the ventilation/perfusion ratio. The ventilation part of the test looks at the ability of air to reach all parts of the lungs, while the perfusion part evaluates how well blood circulates within the lungs.

Pulmonary function testing[89] may include:

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.[8] Both acute and chronic hypoxia and hypercapnia caused by respiratory dysfunction can produce neurological symptoms such as encephalopathy, seizures, headache, papilledema, and asterixis.[49] Obstructive sleep apnea syndrome may cause morning headaches[49]

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.[8]

Anemic Hypoxia is caused by a deficit in oxygen-carrying capacity, usually due to low hemoglobin levels, leading to generalised inadequate oxygen delivery.[8]

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.[8]

Critical illness polyneuropathy or myopathy should be considered in the intensive care unit when patients have difficulty coming off the ventilator.[49]

Prevention

Prevention can be as simple as risk management of occupational exposure to hypoxic environments, and commonly involves the use of environmental monitoring and personal protective equipment. Prevention of hypoxia as a predictable consequence of medical conditions requires prevention of those conditions. Screening of demographics known to be at risk for specific disorders may be useful.

Prevention of altitude induced hypoxia

To counter the effects of high-altitude diseases, the body must return arterial PaO2 toward normal. Acclimatization, the means by which the body adapts to higher altitudes, only partially restores PO2 to standard levels. Hyperventilation, the body's most common response to high-altitude conditions, increases alveolar PO2 by raising the depth and rate of breathing. However, while PO2 does improve with hyperventilation, it does not return to normal. Studies of miners and astronomers working at 3000 meters and above show improved alveolar PO2 with full acclimatization, yet the PO2 level remains equal to or even below the threshold for continuous oxygen therapy for patients with chronic obstructive pulmonary disease (COPD).[94] 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 risk of blood clots.[95]

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 PO2 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% 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.[96] 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.[94]

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.[citation needed]

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. It is necessary to identify persons who need oxygen therapy, as supplemental oxygen is required to treat most causes of hypoxia, but different oxygen concentrations may be appropriate.[97]

Treatment of acute and chronic cases

Treatment will depend on the cause of hypoxia. If it is determined that there is an external cause, and it can be removed, then treatment may be limited to support and returning the system to normal oxygenation. In other cases a longer course of treatment may be necessary, and this may require supplemental oxygen over a fairly long term or indefinitely.

There are three main aspects of oxygenation treatment: maintaining patent airways, providing sufficient oxygen content of the inspired air, and improving the diffusion in the lungs.[8] 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.[8] 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.[8] 

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.[8]

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.[98][99] It is the definitive treatment for severe decompression sickness, which is largely a condition involving localized hypoxia initially caused by inert gas embolism and inflammatory reactions to extravascular bubble growth.[100][101][102] It is also effective in Carbon monoxide poisoning.[103] and diabetic foot.[104][105]

A prescription renewal for home oxygen following hospitalization requires an assessment of the patient for ongoing hypoxemia.[106]

Outcomes

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

Hypoxia leading to reduced capacity to respond appropriately, or to loss of consciosness, has been implicated in incidents where the direct cause of death was not hypoxia. This is recorded in underwater diving incidents, where drowning has often been given as cause of death, high altitude mountaineering, where exposure, hypothermia and falls have been consequences, flying in unpressurized aircraft, and aerobatic maneuvers, where loss of control leading to a crash is possible.

Epidemiology

Hypoxia is a common disorder but there are many possible causes.[8] Prevalence is variable. Some of the causes are very common, like pneumonia or chronic obstructive pulmonary disease; some are quite rare like hypoxia due to cyanide poisoning. Others, like reduced oxygen tension at high altitude, may be regionally distributed or associated with a specific demographic.[8]

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

Potentially life-threatening hypoxemia is common in critically ill patients.[107]

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

Hypoxia due to underdeveloped lung function is a common complication of premature birth. In the United States, intrauterine hypoxia and birth asphyxia were listed together as the tenth leading cause of neonatal death.[108]

Silent hypoxia

Main article: Silent hypoxia

Silent hypoxia (also known as happy hypoxia)[109][110] is generalised hypoxia that does not coincide with shortness of breath.[111][112][113] This presentation is known to be a complication of COVID-19,[114][115] and is also known in atypical pneumonia,[116] altitude sickness,[117][118][119] and rebreather malfunction accidents.[120][121]

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.[122][123]

See also

  • Asphyxia – Condition of severely deficient supply of oxygen to the body caused by abnormal breathing
  • Cerebral hypoxia – Oxygen shortage of the brain
  • Erotic asphyxiation – Intentional restriction of oxygen to the brain for sexual arousal
  • Fink effect, also known as diffusion hypoxia – Changes of oxygen partial pressure in the pulmonary alveoli caused by a soluble anesthetic gas
  • G-LOC – Loss of consciousness due to sustained high acceleration
  • Histotoxic hypoxia – Medical condition in which cells cannot use oxygen
  • Hyperoxia – Exposure of tissues to abnormally high concentrations of oxygen.
  • Hypoventilation training – Physical training method
  • Hypoxemia – Abnormally low level of oxygen in the blood
  • Hypoxia in fish – Response of fish to environmental hypoxia
  • Hypoxia-inducible factor – Protein that responds to low oxygen
  • Hypoxic hypoxia – Medical condition of oxygen deprivation, a result of insufficient oxygen available to the lungs
  • Hypoxic ventilatory response – Biological reaction to increased altitude
  • Hypoxicator – Device for providing breathing air with reduced oxygen content a device intended for hypoxia acclimatisation in a controlled manner
  • Intermittent hypoxic training – Technique aimed at improving human performance by adaptation to reduced oxygen.
  • Intrauterine hypoxia – Medical condition when the fetus is deprived of sufficient oxygen, when a fetus is deprived of an adequate supply of oxygen
  • Latent hypoxia – Lung gas and blood oxygen concentration sufficient to support consciousness only at depth
  • Pseudohypoxia, increased cytosolic ratio of free NADH to NAD+ in cells
  • Rhinomanometry – Method used in evaluation of respiratory function of the nasal cavity
  • Sleep apnea – Disorder involving pauses in breathing during sleep
  • Time of useful consciousness – Duration of effective performance in a hypoxic environment
  • Tumor hypoxia – Situation where tumor cells have been deprived of oxygen

Notes

  1. ^ The formula   can be used to calculate the amount of carbon monoxide-bound hemoglobin. For example, at carbon monoxide level of 5 ppm,  , or a loss of half a percent of their blood's hemoglobin.[63]

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March 22, 2023
hypoxia, medical, hypoxia, condition, which, body, region, body, deprived, adequate, oxygen, supply, tissue, level, hypoxia, classified, either, generalized, affecting, whole, body, local, affecting, region, body, although, hypoxia, often, pathological, condit. Hypoxia is a condition in which the body or a region of the body is deprived of adequate oxygen supply at the tissue level 1 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 HypoxiaOther namesHypoxiation lack of oxygen low blood oxygen technically hypoxemia oxygen starvationCyanosis of the hand in an elderly person with low oxygen saturationSpecialtyPulmonology toxicologySymptomsCyanosis numbness or pins and needles feeling of the extremitiesComplicationsGangrene necrosisRisk factorsDiabetes coronary artery disease heart attack stroke embolism thrombosis deep vein thrombosis tobacco smokingHypoxia differs from hypoxemia and anoxemia in that hypoxia refers to a state in which oxygen present in 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 extract oxygen from or metabolically process an adequate supply of oxygen from an adequately oxygenated 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 Contents 1 Classification 1 1 By cause 1 2 By extent 1 2 1 Generalized hypoxia 1 2 2 Localized hypoxia 1 2 3 By affected tissues and organs 1 2 3 1 Cerebral hypoxia 1 2 3 2 Corneal hypoxia 1 2 3 3 Intrauterine hypoxia 1 2 3 4 Tumor hypoxia 1 2 3 5 Vestibular system 2 Signs and symptoms 2 1 Complications 3 Causes 3 1 Ischemia 3 2 Hypoxemic hypoxia 3 2 1 Carbon monoxide poisoning 3 2 2 Altitude 3 2 3 Hypoxic breathing gases 3 2 4 Other 3 3 Anemia 3 4 Histotoxic hypoxia 4 Mechanism 4 1 Physiological responses 4 2 Acute 4 3 Chronic 4 4 Pathological responses 4 4 1 Cerebral ischemia 4 4 2 Myocardial ischemia 4 4 3 Tumor angiogenesis 5 Diagnosis 5 1 Physical examination and history 5 2 Tests 5 3 Differential diagnosis 6 Prevention 6 1 Prevention of altitude induced hypoxia 7 Treatment and management 7 1 Treatment of acute and chronic cases 8 Outcomes 9 Epidemiology 9 1 Silent hypoxia 10 History 11 See also 12 Notes 13 ReferencesClassification EditHypoxia 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 6 The classification categories are not always mutually exclusive and hypoxia can be a consequence of a wide variety of causes By cause Edit Hypoxic hypoxia sometimes also referred to as generalised hypoxia Generalised or hypoxic hypoxia may be caused by Hypoventilation 7 insufficient ventilation of the lungs due to any cause fatigue excessive work of breathing barbiturate poisoning pneumothorax sleep apnea etc Low inspired oxygen partial pressure which may be caused by breathing normal air at low ambient pressures due to altitude 7 8 by breathing hypoxic breathing gas at an unsuitable depth by breathing inadequately re oxygenated recycled breathing gas from a rebreather 9 life support system or anesthetic machine hypoxia of ascent latent hypoxia in freediving and rebreather diving 10 Airway obstruction choking 7 drowning Chronic obstructive pulmonary disease COPD 11 Neuromuscular diseases or interstitial lung disease Malformed vascular system such as an anomalous coronary artery citation needed Hypoxemic hypoxia is a lack of oxygen caused by low oxygen tension in the arterial blood due to the inability of the lungs to sufficiently oxygenate the blood Causes include hypoventilation impaired alveolar diffusion and pulmonary shunting 8 This definition overlaps considerably with that of hypoxic hypoxia Pulmonary hypoxia is hypoxia from hypoxemia due to abnormal pulmonary function and occurs when the lungs receive adequately oxygenated gas which does not oxygenate the blood sufficiently It may be caused by 7 Ventilation perfusion mismatch V Q mismatch which can be either low or high 8 A reduced V Q ratio can be caused by impaired ventilation which may be a consequence of conditions such as bronchitis obstructive airway disease mucus plugs or pulmonary edema which limit or obstruct the ventilation In this situation there is not enough oxygen in the alveolar gas to fully oxygenate the blood volume passing through and PaO2 will be low Conversely an increased V Q ratio tends to be a consequence of impaired perfusion in which circumstances the blood supply is insufficient to carry the available oxygen PaO2 will be normal but tissues will be insufficiently perfused to meet the oxygen demand A V Q mismatch can also occur when the surface area available for gas exchange in the lungs is decreased 8 Pulmonary shunt in which blood passes from the right to the left side of the heart without being oxygenated This may be due to anatomical shunts in which the blood bypasses the alveoli via intracardiac shunts pulmonary arteriovenous malformations fistulas and hepatopulmonary syndrome or physiological shunting in which blood passes through non ventilated alveoli 8 Impaired diffusion a reduced capacity for gas molecules to move between the air in the alveoli and the blood which occurs when alveolar capillary membranes thicken This can happen in interstitial lung diseases such as pulmonary fibrosis sarcoidosis hypersensitivity pneumonitis and connective tissue disorders 7 Circulatory hypoxia 8 also known as ischemic hypoxia or stagnant hypoxia is caused by abnormally low blood flow to the lungs which can occur during shock cardiac arrest severe congestive heart failure or abdominal compartment syndrome where the main dysfunction is in the cardiovascular system causing a major reduction in perfusion Arterial gas is adequately oygenated in the lungs and the tissues are able to accept the oxygen available but the flow rate to the tissues is insufficient Venous oxygenation is particularly low 7 11 Anemic hypoxia or hypemic hypoxia is the lack of capacity of the blood to carry the normal level of oxygen 8 It can be caused by anemia or 7 Carbon monoxide poisoning in which carbon monoxide combines with the hemoglobin to form carboxyhemoglobin HbCO preventing it from transporting oxygen 7 12 Methemoglobinemia a change in the hemoglobin molecule from a ferrous ion Fe2 to a ferric ion Fe3 which has a lesser capacity to bind free oxygen molecules and a greater affinity for bound oxygen This causes a left shift in the O2 Hb curve It can be congenital or caused by medications food additives or toxins including chloroquine benzene nitrites benzocaine 7 Histotoxic hypoxia Dysoxia 8 or Cellular hypoxia occurs when the cells of the affected tissues are unable to use oxygen provided by normally oxygenated hemoglobin 7 Examples include cyanide poisoning which inhibits cytochrome c oxidase an enzyme required for cellular respiration in mitochondria Methanol poisoning has a similar effect as the metabolism of methanol produces formic acid which inhibits mitochondrial cytochrome oxidase 7 13 clarification needed Intermittent hypoxic training induces mild generalized hypoxia for short periods as a training method to improve sporting performance This is not considered a medical condition 14 Acute cerebral hypoxia leading to blackout can occur during freediving This is a consequence of prolonged voluntary apnea underwater and generally occurs in trained athletes in good health and good physical condition 15 By extent Edit Hypoxia may affect the whole body or just some parts Generalized hypoxia Edit The term generalized hypoxia may refer to hypoxia affecting the whole body citation needed 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 8 13 7 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 16 17 These symptoms are often difficult to identify but early detection of symptoms can be critical 18 In severe hypoxia or hypoxia of very rapid onset ataxia confusion disorientation hallucinations behavioral change severe headaches reduced level of consciousness papilloedema breathlessness 16 pallor 19 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 20 21 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 22 In cases where the oxygen is displaced by another molecule such as carbon monoxide the skin may appear cherry red instead of cyanotic 23 Hypoxia can cause premature birth and injure the liver among other deleterious effects citation needed Localized hypoxia Edit See also Ischemia Vascular ischemia of the toes with characteristic cyanosis Hypoxia that is localized to a region of the body such as an organ or a limb is usually the consequence of ischemia the reduced perfusion to that organ or limb and may not necessarily be associated with general hypoxemia A locally reduced perfusion is generally caused by an increased resistance to flow through the blood vessels of the affected area Ischemia is a restriction in blood supply to any tissue muscle group or organ causing a shortage of oxygen 24 25 Ischemia is generally caused by problems with blood vessels with resultant damage to or dysfunction of tissue i e hypoxia and microvascular dysfunction 26 27 It also means local hypoxia in a given part of a body sometimes resulting from vascular occlusion such as vasoconstriction thrombosis or embolism Ischemia comprises not only insufficiency of oxygen but also reduced availability of nutrients and inadequate removal of metabolic wastes Ischemia can be a partial poor perfusion or total blockage Compartment syndrome is a condition in which increased pressure within one of the body s anatomical compartments results in insufficient blood supply to tissue within that space 28 29 There are two main types acute and chronic 28 Compartments of the leg or arm are most commonly involved 30 This section needs expansion with local trauma edema allergic reactions etc You can help by adding to it December 2022 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 By affected tissues and organs Edit Any living tissue can be affected by hypoxia but some are particularly sensitive or have more noticeable or notable consequences Cerebral hypoxia Edit Main article Cerebral hypoxia Cerebral hypoxia is hypoxia specifically involving the brain The four categories of cerebral hypoxia in order of increasing severity are diffuse cerebral hypoxia DCH focal cerebral ischemia cerebral infarction and global cerebral ischemia Prolonged hypoxia induces neuronal cell death via apoptosis resulting in a hypoxic brain injury 31 32 Oxygen deprivation can be hypoxic reduced general oxygen availability or ischemic oxygen deprivation due to a disruption in blood flow in origin Brain injury as a result of oxygen deprivation is generally termed hypoxic injury Hypoxic ischemic encephalopathy HIE is a condition that occurs when the entire brain is deprived of an adequate oxygen supply but the deprivation is not total While HIE is associated in most cases with oxygen deprivation in the neonate due to birth asphyxia it can occur in all age groups and is often a complication of cardiac arrest 33 34 35 Corneal hypoxia Edit Long term use of some types of contact lenses can result in hypoxia damage to the corneas The corneas are not perfused and get their oxygen from the atmosphere by diffusion Impermeable contact lenses form a barrier to this diffusion and this can cause damage to the corneas This section needs expansion You can help by adding to it December 2022 Intrauterine hypoxia Edit Main article Intrauterine hypoxia Intrauterine hypoxia also known as fetal hypoxia occurs when the fetus is deprived of an adequate supply of oxygen It may be due to a variety of reasons such as prolapse or occlusion of the umbilical cord placental infarction maternal diabetes prepregnancy or gestational diabetes 36 and maternal smoking Intrauterine growth restriction may cause or be the result of hypoxia Intrauterine hypoxia can cause cellular damage that occurs within the central nervous system the brain and spinal cord This results in an increased mortality rate including an increased risk of sudden infant death syndrome SIDS Oxygen deprivation in the fetus and neonate have been implicated as either a primary or as a contributing risk factor in numerous neurological and neuropsychiatric disorders such as epilepsy attention deficit hyperactivity disorder eating disorders and cerebral palsy 37 38 39 40 41 42 Tumor hypoxia Edit Main article Tumor hypoxia Tumor hypoxia is the situation where tumor cells have been deprived of oxygen As a tumor grows it rapidly outgrows its blood supply leaving portions of the tumor with regions where the oxygen concentration is significantly lower than in healthy tissues Hypoxic microenvironements in solid tumors are a result of available oxygen being consumed within 70 to 150 mm of tumour vasculature by rapidly proliferating tumor cells thus limiting the amount of oxygen available to diffuse further into the tumor tissue In order to support continuous growth and proliferation in challenging hypoxic environments cancer cells are found to alter their metabolism Furthermore hypoxia is known to change cell behavior and is associated with extracellular matrix remodeling and increased migratory and metastatic behavior 43 44 Tumour hypoxia is usually associated with highly malignant tumours which frequently do not respond well to treatment 45 Vestibular system Edit In acute exposure to hypoxic hypoxia on the vestibular system and the visuo vestibular interactions the gain of the vestibulo ocular reflex VOR decreases under mild hypoxia at altitude Postural control is also disturbed by hypoxia at altitude postural sway is increased and there is a correlation between hypoxic stress and adaptive tracking performance 46 Signs and symptoms EditArterial 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 Cyanosis 47 Headache 47 48 49 Decreased reaction time 50 disorientation and uncoordinated movement 47 Impaired judgment confusion memory loss and cognitive problems 47 48 Euphoria or dissociation 47 Visual impairment 48 A moderate level of hypoxia can cause a generalized partial loss of color vision affecting both red green and blue yellow discrimination at an altitude of 12 000 feet 3 700 m 51 Lightheaded or dizzy sensation vertigo 47 Fatigue Drowsiness or tiredness 47 Shortness of breath 47 Palpitations may occur in the initial phases Later the heart rate may reduce significantly degree In severe cases abnormal heart rhythms may develop Nausea and vomiting 47 Initially raised blood pressure followed by lowered blood pressure as the condition progresses 47 Severe hypoxia can cause loss of consciousness seizures or convulsions coma and eventually death Breathing rate may slow down and become shallow and the pupils may not respond to light 47 Tingling in fingers and toes 48 Numbness 48 Complications Edit Local tissue death and gangrene is a relatively common complication of ischaemic hypoxia diabetes etc Brain damage cortical blindness is a known but uncommon complication of acute hypoxic damage to the cerebral cortex 52 Obstructive sleep apnea syndrome is a risk factor for cerebrovascular disease and cognitive dysfunction 49 This section needs expansion You can help by adding to it December 2022 Causes EditOxygen 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 53 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 citation needed 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 54 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 55 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 56 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 57 Ischemia Edit Main article Ischemia Ischemia meaning insufficient blood flow to a tissue can also result in hypoxia in the affected tissues This is called ischemic hypoxia Ischemia can be caused by an embolism a heart attack that decreases overall blood flow trauma to a tissue that results in damage reducing perfusion and a variety of other causes A consequence of insufficient blood flow causing local hypoxia is gangrene that occurs in diabetes 58 Diseases such as peripheral vascular disease can also result in local hypoxia Symptoms are worse when a limb is used increasing the oxygen demand in the active 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 59 G LOC or g force induced loss of consciousness is a special case of ischemic hypoxia which occurs when the body is subjected to high enough acceleration sustained for long enough to lower cerebral blood pressure and circulation to the point where loss of consciousness occurs due to cerebral hypoxia The human body is most sensitive to longitudinal acceleration towards the head as this causes the largest hydrostatic pressure deficit in the head 60 Hypoxemic hypoxia Edit Main article Hypoxemia This refers specifically to hypoxic states where the arterial content of oxygen is insufficient 61 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 citation needed Common disorders that can cause respiratory disfunction include trauma to the head and spinal cord nontraumatic acute myelopathies demyelinating disorders stroke Guillain Barre syndrome and myasthenia gravis These dysfunctions may necessitate mechanical ventilation Some chronic neuromuscular disorders such as motor neuron disease and muscular dystrophy may require ventilatory support in advanced stages 49 Carbon monoxide poisoning Edit Main article 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 62 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 63 A carbon monoxide level of 40 ppm is equivalent to a reduction in hemoglobin levels of 10 g L 63 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 56 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 citation needed Altitude Edit Main article Altitude sickness Atmospheric pressure reduces with altitude and proportionally so does the oxygen content of the air 64 The reduction in the partial pressure of inspired oxygen at higher altitudes lowers the oxygen saturation of the blood ultimately leading to hypoxia 64 The clinical features of altitude sickness include sleep problems dizziness headache and oedema 64 Hypoxic breathing gases Edit Main articles Inert gas asphyxiation and Asphyxiant 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 65 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 64 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 66 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 67 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 15 10 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 68 Other Edit 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 69 unreliable medical source as well as certain drugs and other chemicals 70 Anemia Edit Main article Anemia Hemoglobin plays a substantial role in carrying oxygen throughout the body 56 and when it is deficient anemia can result causing anaemic hypoxia if tissue oxygenation 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 57 997 99 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 57 997 99 Histotoxic hypoxia Edit Main article 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 71 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 72 Mechanism EditTissue 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 73 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 74 Serum lactate levels have been correlated with illness severity and mortality in critically ill adults and in ventilated neonates with respiratory distress 74 Physiological responses Edit All vertebrates must maintain oxygen homeostasis to survive and have evolved physiological systems to ensure adequate oygenation of all tissues In air breathing vertebrates this is based on lungs to acquire the oxygen hemoglobin in red corpuscles to transport it a vasculature to distribute and a heart to deliver Short term variations in the levels of oxygenation are sensed by chemoreceptor cells which respond by activating existing proteins and over longer terms by regulation of gene transcription Hypoxia is also involved in the pathogenesis of some common and severe pathologies 75 The most common causes of death in an aging population include myocardial infarction stroke and cancer These diseases share a common feature that limitation of oxygen availability contributes to the development of the pathology Cells and organisms are also able to respond adaptively to hypoxic conditions in ways that help them to cope with these adverse conditions Several systems can sense oxygen concentration and may respond with adaptations to acute and long term hypoxia 75 The systems activated by hypoxia usually help cells to survive and overcome the hypoxic conditions Erythropoietin which is produced in larger quantities by the kidneys under hypoxic conditions is an essential hormone that stimulates production of red blood cells which are the primary transporter of blood oxygen and glycolytic enzymes are involved in anaerobic ATP formation 45 Hypoxia inducible factors HIFs are transcription factors that respond to decreases in available oxygen in the cellular environment or hypoxia 76 77 The HIF signaling cascade mediates the effects of hypoxia on the cell Hypoxia often keeps cells from differentiating However hypoxia promotes the formation of blood vessels and is important for the formation of a vascular system in embryos and tumors The hypoxia in wounds also promotes the migration of keratinocytes and the restoration of the epithelium 78 It is therefore not surprising that HIF 1 modulation was identified as a promising treatment paradigm in wound healing 79 Exposure of a tissue to repeated short periods of hypoxia between periods of normal oxygen levels influences the tissue s later response to a prolonged ischaemic exposuret Thus is known as ischaemic preconditioning and it is known to occur in many tissues 45 Acute Edit See also Hypoxic ventilatory response Acute hypoxic ventilatory response 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 80 If severe or prolonged it could lead to cell death 81 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 82 This response does not control ventilation rate at normal PO2 but below normal the activity of neurons innervating these receptors increases dramatically so much as to override the signals from central chemoreceptors in the hypothalamus increasing PO2 despite a falling PCO2 citation needed 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 and has the effect of redirecting blood away from poorly ventilated regions which helps match perfusion to ventilation giving a more even oxygenation of blood from different parts of the lungs 75 In conditions of hypoxic breathing gas such as at high altitude HPV is generalized over the entire lung but with sustained exposure to generalized hypoxia HPV is suppressed 83 Hypoxic ventilatory response HVR is the increase in ventilation induced by hypoxia that allows the body to take in and transport lower concentrations of oxygen at higher rates It is initially elevated in lowlanders who travel to high altitude but reduces significantly over time as people acclimatize 4 84 Chronic Edit See also Hypoxic ventilatory response Chronic hypoxic ventilatory response and High altitude adaptation in humans 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 85 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 6 Pathological responses Edit Cerebral ischemia Edit The brain has relatively high energy requirements using about 20 of the oxygen under resting conditions but low reserves which make it specially vulnerable to hypoxia In normal conditions an increased demand for oxytgen is easily compensated by an increased cerebral blood flow but under conditions when there is insufficient oxygen available increased blood flow may not be sufficient to compensate and hypoxia can result in brain injury A longer duration of cerebral hypoxia will generally result in larger areas of the brain being affected The brainstem hippocampus and cerebral cortex seem to be the most vulnerable regions Injury becomes irreversible if ogygenation is not soon restored Most cell death is by necrosis but delayed apoptosis also occurs In addition presynaptic neurons release large amounts of glutamate which further increases Ca2 influx and causes catastrophic collapse in postsynaptic cells Although it is the only way to save the tissue reperfusion also produces reactive oxygen species and inflammatory cell infiltration which induces further cell death If the hypoxia is not too severe cells can suppress some of their functions such as protein synthesis and spontaneous electrical activity in a process called penumbra which is reversible if the oxygen supply is resumed soon enough 75 Myocardial ischemia Edit Parts of the heart are exposed to ischemic hypoxia in the event of occlusion of a coronary artery Short periods of ischaemia are reversible if reperfused within about 20 minutes without development of necrosis but the phenomenon known as stunning is generally evident If hypoxia continues beyond this period necrosis propagates through the myocardial tissue 75 Energy metabolism in the affected area shifts from mitochondrial respiration to anaerobic glycolysis almost immediately with concurrent reduction of effectiveness of contractions which soon cease Anaerobic products accumulate in the muscle cells which develop acidosis and osmotic load leading to cellular edema Intracellular Ca2 increases and eventually leads to cell necrosis Arterial flow must be restored to return to aerobic metabolism and prevent necrosis of the affected muscle cells but this also causes further damage by reperfusion injury Myocadial stunning has been described as prolonged postischaemic dysfunction of viable tissue salvaged by reperfusion which manifests as temporary contractile failure in oxygenated muscle tissue This may be caused by a release of reactive oxygen species during the early stages of reperfusion 75 Tumor angiogenesis Edit As tumors grow regions of relative hypoxia develop as the oxygen supply is unevenly utilized by the tumor cells The formation of new blood vessels is necessary for continued tumor growth and is also an important factor in metastasis as the route by which cancerous cells are transported to other sites 75 This section needs expansion You can help by adding to it December 2022 Diagnosis EditPhysical examination and history Edit Hypoxia can present as acute or chronic Acute presentation may include dyspnea shortness of breath and tachypnea rapid often shallow breathing Severity of symptom presentation is commonly an indication of severity of hypoxia Tachycardia rapid pulse may develop to compensate for low arterial oxygen tension Stridor may be heard in upper airway obstruction and cyanosis may indicate severe hypoxia Neurological symptoms and organ function deterioration occur when the oxygen delivery is severely compromised In moderate hypoxia restlessness headache and confusion may occur with coma and eventual death possible in severe cases 8 In chronic presentation dyspnea following exertion is most commonly mentioned Symptoms of the underlying condition that caused the hypoxia may be apparent and can help with differential diagnosis A productive cough and fever may be present with lung infection and leg edema may suggest heart failure 8 Lung auscultation can provide useful information 8 Tests Edit An arterial blood gas test ABG may be done which usually includes measurements of oxygen content hemoglobin oxygen saturation how much of the hemoglobin is carrying oxygen arterial partial pressure of oxygen PaO2 partial pressure of carbon dioxide PaCO2 blood pH level and bicarbonate HCO3 86 An arterial oxygen tension PaO2 less than 80 mmHg is considered abnormal but must be considered in context of the clinical situation 8 In addition to diagnosis of hypoxemia the ABG may provide additional information such as PCO2 which can help identify the etiology The arterial partial pressure of carbon dioxide is an indirect measure of exchange of carbon diozide with the air in the lungs and is related to minute ventilation PCO2 is raised in hypoventilation 8 The normal range of PaO2 FiO2 ratio is 300 to 500 mmHg if this ratio is lower than 300 it may indicate a deficit in gas exchange which is particularly relevant for identifying acute respiratory distress syndrome ARDS A ratio of less than 200 indicates severe hypoxemia 8 The alveolar arterial gradient A aO2 87 or A a gradient is the difference between the alveolar A concentration of oxygen and the arterial a concentration of oxygen It is a useful parameter for narrowing the differential diagnosis of hypoxemia 88 The A a gradient helps to assess the integrity of the alveolar capillary unit For example at high altitude the arterial oxygen PaO2 is low but only because the alveolar oxygen PAO2 is also low However in states of ventilation perfusion mismatch such as pulmonary embolism or right to left shunt oxygen is not effectively transferred from the alveoli to the blood which results in an elevated A a gradient PaO2 can be obtained from the arterial blood gas analysis and PAO2 is calculated using the alveolar gas equation 8 An abnormally low hematocrit volume percentage of red blood cells may indicate anemia X rays or CT scans of the chest and airways can reveal abnormalities that may affect ventilation or perfusion 89 A ventilation perfusion scan 90 also called a V Q lung scan is a type of medical imaging using scintigraphy and medical isotopes to evaluate the circulation of air and blood within a patient s lungs 91 92 in order to determine the ventilation perfusion ratio The ventilation part of the test looks at the ability of air to reach all parts of the lungs while the perfusion part evaluates how well blood circulates within the lungs Pulmonary function testing 89 may include Tests that measure oxygen levels during the night 89 The six minute walk test which measures how far a person can walk on a flat surface in six minutes to test exercise capacity by measuring oxygen levels in response to exercise 89 Diagnostic measurements that may be relevant include 93 Lung volumes including lung capacity airway resistance respiratory muscle strength diffusing capacity Other pulmonary function tests which may be relevant include 93 Spirometry body plethysmography forced oscillation technique for calculating the volume pressure and air flow in the lungs bronchodilator responsiveness carbon monoxide diffusion test DLCO oxygen titration studies cardiopulmonary stress test bronchoscopy and thoracentesisDifferential diagnosis Edit 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 8 Both acute and chronic hypoxia and hypercapnia caused by respiratory dysfunction can produce neurological symptoms such as encephalopathy seizures headache papilledema and asterixis 49 Obstructive sleep apnea syndrome may cause morning headaches 49 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 8 Anemic Hypoxia is caused by a deficit in oxygen carrying capacity usually due to low hemoglobin levels leading to generalised inadequate oxygen delivery 8 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 8 Critical illness polyneuropathy or myopathy should be considered in the intensive care unit when patients have difficulty coming off the ventilator 49 This section needs expansion You can help by adding to it December 2022 Prevention EditPrevention can be as simple as risk management of occupational exposure to hypoxic environments and commonly involves the use of environmental monitoring and personal protective equipment Prevention of hypoxia as a predictable consequence of medical conditions requires prevention of those conditions Screening of demographics known to be at risk for specific disorders may be useful This section needs expansion with more detail You can help by adding to it December 2022 Prevention of altitude induced hypoxia Edit To counter the effects of high altitude diseases the body must return arterial PaO2 toward normal Acclimatization the means by which the body adapts to higher altitudes only partially restores PO2 to standard levels Hyperventilation the body s most common response to high altitude conditions increases alveolar PO2 by raising the depth and rate of breathing However while PO2 does improve with hyperventilation it does not return to normal Studies of miners and astronomers working at 3000 meters and above show improved alveolar PO2 with full acclimatization yet the PO2 level remains equal to or even below the threshold for continuous oxygen therapy for patients with chronic obstructive pulmonary disease COPD 94 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 risk of blood clots 95 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 PO2 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 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 96 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 94 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 citation needed Treatment and management EditTreatment 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 It is necessary to identify persons who need oxygen therapy as supplemental oxygen is required to treat most causes of hypoxia but different oxygen concentrations may be appropriate 97 Treatment of acute and chronic cases Edit Treatment will depend on the cause of hypoxia If it is determined that there is an external cause and it can be removed then treatment may be limited to support and returning the system to normal oxygenation In other cases a longer course of treatment may be necessary and this may require supplemental oxygen over a fairly long term or indefinitely There are three main aspects of oxygenation treatment maintaining patent airways providing sufficient oxygen content of the inspired air and improving the diffusion in the lungs 8 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 8 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 8 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 8 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 98 99 It is the definitive treatment for severe decompression sickness which is largely a condition involving localized hypoxia initially caused by inert gas embolism and inflammatory reactions to extravascular bubble growth 100 101 102 It is also effective in Carbon monoxide poisoning 103 and diabetic foot 104 105 A prescription renewal for home oxygen following hospitalization requires an assessment of the patient for ongoing hypoxemia 106 Outcomes EditPrognosis is strongly affected by cause severity treatment and underlying pathology Hypoxia leading to reduced capacity to respond appropriately or to loss of consciosness has been implicated in incidents where the direct cause of death was not hypoxia This is recorded in underwater diving incidents where drowning has often been given as cause of death high altitude mountaineering where exposure hypothermia and falls have been consequences flying in unpressurized aircraft and aerobatic maneuvers where loss of control leading to a crash is possible This section needs expansion You can help by adding to it November 2022 Epidemiology EditHypoxia is a common disorder but there are many possible causes 8 Prevalence is variable Some of the causes are very common like pneumonia or chronic obstructive pulmonary disease some are quite rare like hypoxia due to cyanide poisoning Others like reduced oxygen tension at high altitude may be regionally distributed or associated with a specific demographic 8 Generalized hypoxia is an occupational hazard in several high risk occupations including firefighting professional diving mining and underground rescue and flying at high altitudes in unpressurised aircraft Potentially life threatening hypoxemia is common in critically ill patients 107 Localized hypoxia may be a complication of diabetes decompression sickness and of trauma that affects blood supply to the extremities Hypoxia due to underdeveloped lung function is a common complication of premature birth In the United States intrauterine hypoxia and birth asphyxia were listed together as the tenth leading cause of neonatal death 108 This section needs expansion You can help by adding to it December 2022 Silent hypoxia Edit Main article Silent hypoxia Silent hypoxia also known as happy hypoxia 109 110 is generalised hypoxia that does not coincide with shortness of breath 111 112 113 This presentation is known to be a complication of COVID 19 114 115 and is also known in atypical pneumonia 116 altitude sickness 117 118 119 and rebreather malfunction accidents 120 121 History EditThe 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 122 123 See also EditAsphyxia Condition of severely deficient supply of oxygen to the body caused by abnormal breathing Cerebral hypoxia Oxygen shortage of the brain Erotic asphyxiation Intentional restriction of oxygen to the brain for sexual arousal Fink effect also known as diffusion hypoxia Changes of oxygen partial pressure in the pulmonary alveoli caused by a soluble anesthetic gas G LOC Loss of consciousness due to sustained high acceleration Histotoxic hypoxia Medical condition in which cells cannot use oxygen Hyperoxia Exposure of tissues to abnormally high concentrations of oxygen Hypoventilation training Physical training method Hypoxemia Abnormally low level of oxygen in the blood Hypoxia in fish Response of fish to environmental hypoxia Hypoxia inducible factor Protein that responds to low oxygen Hypoxic hypoxia Medical condition of oxygen deprivationPages displaying short descriptions of redirect targets a result of insufficient oxygen available to the lungs Hypoxic ventilatory response Biological reaction to increased altitude Hypoxicator Device for providing breathing air with reduced oxygen content a device intended for hypoxia acclimatisation in a controlled manner Intermittent hypoxic training Technique aimed at improving human performance by adaptation to reduced oxygen Intrauterine hypoxia Medical condition when the fetus is deprived of sufficient oxygen when a fetus is deprived of an adequate supply of oxygen Latent hypoxia Lung gas and blood oxygen concentration sufficient to support consciousness only at depth Pseudohypoxia increased cytosolic ratio of free NADH to NAD in cells Rhinomanometry Method used in evaluation of respiratory function of the nasal cavity Sleep apnea Disorder involving pauses in breathing during sleep Time of useful consciousness Duration of effective performance in a hypoxic environment Tumor hypoxia Situation where tumor cells have been deprived of oxygenNotes Edit The formula H b C O C O 2 34 5 09 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 5 2 34 5 09 5 displaystyle frac 5 2 34 5 09 5 or a loss of half a percent of their blood s hemoglobin 63 References Edit Samuel Jacob Franklin Cory 2008 Common Surgical Diseases New York Springer pp 391 94 doi 10 1007 978 0 387 75246 4 97 ISBN 978 0387752457 Das K K Honnutagi R Mullur L Reddy R C Das S Majid D S A Biradar M S 2019 Heavy metals and low oxygen microenvironment its impact on liver metabolism and dietary supplementation Dietary Interventions in Liver Disease Academic Press pp 315 32 West John B 1977 Pulmonary Pathophysiology The Essentials Williams amp Wilkins p 22 ISBN 978 0 683 08936 3 a b Cymerman A Rock P B Medical Problems in High Mountain Environments A Handbook for Medical Officers Technical Report USARIEM TN94 2 Report US Army Research Inst of Environmental Medicine Thermal and Mountain Medicine Division Gore C J Clark S A Saunders P U September 2007 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