Editing Hypoxia (medicine)

{{Short description|Medical condition of lack of oxygen in the tissues}}
{{distinguish|Hypopnea|Hypoxemia}}
{{Infobox medical condition (new)
| name            = Hypoxia
| image           = Cynosis.JPG
| caption         = [[Cyanosis]] of the hand in an elderly person with low oxygen saturation
| pronounce       =
| field           = [[Pulmonology]], [[toxicology]]
| synonyms        = Hypoxiation, lack of oxygen, low blood oxygen (technically [[hypoxemia]]), oxygen starvation
| symptoms        = [[Cyanosis]], [[numbness]] or [[pins and needles]] feeling of the extremities
| complications   = [[Gangrene]], [[necrosis]]
| onset           =
| duration        =
| types           =
| causes          =
| risks           = [[Diabetes]], [[coronary artery disease]], [[heart attack]], [[stroke]], [[embolism]], [[thrombosis]], [[deep-vein thrombosis]], [[tobacco smoking]]
| diagnosis       =
| differential    =
| prevention      =
| treatment       =
| medication      =
| prognosis       =
| frequency       =
| deaths          =
}}
'''Hypoxia''' is a condition in which the body or a region of the body is deprived of adequate [[oxygen]] supply at the [[tissue (biology)|tissue]] level.<ref name="Samuel and Franklin 2008" /> Hypoxia may be classified as either ''[[Generalized hypoxia|generalized]]'', affecting the whole body, or ''local'', affecting a region of the body.<ref name="Das et al 2019" /> Although hypoxia is often a [[pathological]] condition, variations in [[arterial]] oxygen concentrations can be part of the normal [[physiology]], for example, during strenuous [[physical exercise]].

Hypoxia differs from [[hypoxemia]] and anoxemia, in that hypoxia refers to a state in which oxygen present in a tissue or the whole body is insufficient, whereas hypoxemia and anoxemia refer specifically to states that have low or no [[Oxygen saturation (medicine)|oxygen in the blood]].<ref name="West 1977" /> 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]]).<ref name="Cymerman and Rock" />  Hypoxia also occurs in healthy individuals when breathing inappropriate mixtures of gases with a low oxygen content, e.g., while [[Underwater diving|diving underwater]], especially when using malfunctioning closed-circuit [[Diving rebreather|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.<ref name="Gore et al 2007" />

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

==Classification==
{{anchor|arterial oxygen content}}
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 (C<sub>a<sub>O<sub>2</sub></sub></sub> – which represents the amount of oxygen delivered to the tissues) is adequate, or tissue hypoxia exists.<ref name="Pierson 2000" /> The classification categories are not always mutually exclusive, and hypoxia can be a consequence of a wide variety of causes.

===By cause===
*[[Hypoxic hypoxia]], also referred to as [[generalised hypoxia]], may be caused by:
**[[Hypoventilation]],<ref name="Manninen and Unger 2016" /> which is insufficient ventilation of the lungs due to any cause (fatigue, excessive [[work of breathing]], [[Barbiturate overdose|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,<ref name="Manninen and Unger 2016" /><ref name="Bhutta et al 2022" /> by breathing [[Breathing gas#Classification by oxygen fraction|hypoxic breathing gas]] at an unsuitable depth, by breathing inadequately re-oxygenated recycled breathing gas from a [[rebreather]],<ref name="Elliott 1997" /> [[life support system]], or [[anesthetic machine]].
**[[Hypoxia of ascent]] (latent hypoxia) in [[freediving]] and [[rebreather diving]].<ref name="Lindholm 2006" />
**[[Airway obstruction]], [[choking]],<ref name="Manninen and Unger 2016" /> [[drowning]].
***[[Chronic obstructive pulmonary disease]] (COPD)<ref name="Cleveland" />
***Neuromuscular diseases or [[interstitial lung disease]]<!-- plausible but no ref -->
**Malformed vascular system such as an [[Anomalous left coronary artery from the pulmonary artery|anomalous coronary artery]].{{citation needed|date=November 2022}}
*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.<ref name="Bhutta et al 2022" /> This definition overlaps considerably with that of hypoxic hypoxia.
*{{visible anchor|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:<ref name="Manninen and Unger 2016" />
**[[Ventilation perfusion mismatch]] (V/Q mismatch), which can be either low or high.<ref name="Bhutta et al 2022" /> 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 P<sub>a<sub>O<sub>2</sub></sub></sub> 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, P<sub>a<sub>O<sub>2</sub></sub></sub> 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.<ref name="Bhutta et al 2022" />
**[[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 [[wikt:intracardial|intracardiac]] [[Shunt (medical)|shunts]], [[pulmonary arteriovenous malformation]]s, [[fistula]]s, and [[hepatopulmonary syndrome]], or physiological shunting, in which blood passes through non-ventilated alveoli.<ref name="Bhutta et al 2022" />
**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 disease]]s such as [[pulmonary fibrosis]], [[sarcoidosis]], [[hypersensitivity pneumonitis]], and [[connective tissue]] disorders.<ref name="Manninen and Unger 2016" />
*{{visible anchor|Circulatory hypoxia}},<ref name="Bhutta et al 2022" /> also known as ischemic hypoxia or stagnant hypoxia, is caused by abnormally low blood flow to the lungs, which can occur during [[shock (circulatory)|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.<ref name="Manninen and Unger 2016" /><ref name="Cleveland" />
*{{anchor|Anemic hypoxia}}[[Anemia|Anemic]] hypoxia or hypemic hypoxia is the lack of capacity of the blood to carry the normal level of oxygen.<ref name="Bhutta et al 2022" /> It can be caused by anemia or:<ref name="Manninen and Unger 2016" />
**[[Carbon monoxide poisoning]], in which carbon monoxide combines with the hemoglobin, to form [[carboxyhemoglobin]] (HbCO) preventing it from transporting oxygen.<ref name="Manninen and Unger 2016" /><ref name="Bleecker 2015" />
**[[Methemoglobinemia]], a change in the hemoglobin molecule from a ferrous ion (Fe<sub>2</sub><sup>+</sup>) to a ferric ion (Fe<sub>3</sub><sup>+</sup>), which has a lesser capacity to bind free oxygen molecules, and a greater affinity for bound oxygen. This causes a left shift in the O<sub>2</sub>–Hb curve. It can be congenital or caused by medications, food additives or toxins, including chloroquine, benzene, nitrites, benzocaine.<ref name="Manninen and Unger 2016" />
*[[Histotoxic hypoxia]] (Dysoxia)<ref name="Bhutta et al 2022" /> or {{visible anchor|Cellular hypoxia}} occurs when the cells of the affected tissues are unable to use oxygen provided by normally oxygenated hemoglobin.<ref name="Manninen and Unger 2016" /> 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.<ref name="Manninen and Unger 2016" /><ref name="Mandal" />{{clarify|is there a difference between cellular and histotoxic hypoxia? if so, what exactly? both refer to cyanide poisoning as an example, but the explanations differ|date=December 2022}}

[[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.<ref name="Levine 2002" /> 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.<ref name="Pearn et al 2015" />

===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,<ref>{{Cite journal |last1=Della Rocca |first1=Ylenia |last2=Fonticoli |first2=Luigia |last3=Rajan |first3=Thangavelu Soundara |last4=Trubiani |first4=Oriana |last5=Caputi |first5=Sergio |last6=Diomede |first6=Francesca |last7=Pizzicannella |first7=Jacopo |last8=Marconi |first8=Guya Diletta |date=2022 |title=Hypoxia: molecular pathophysiological mechanisms in human diseases |journal=Journal of Physiology and Biochemistry |volume=78 |issue=4 |pages=739–752 |doi=10.1007/s13105-022-00912-6 |issn=1138-7548 |pmc=9684243 |pmid=35870078}}</ref> 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,<ref name="Bhutta et al 2022" /><ref name="Mandal" /><ref name="Manninen and Unger 2016" /> 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 (medical)|fatigue]], [[Hypoesthesia|numbness]] / tingling of [[Limb (anatomy)|extremities]], [[nausea]], and [[cerebral hypoxia]].<ref name="Oxford University Press" /><ref name="Zhou 2011" /> These symptoms are often difficult to identify, but early detection of symptoms can be critical.<ref name="pia" />

In severe hypoxia, or hypoxia of very rapid onset, [[ataxia]], confusion, disorientation, [[hallucination]]s, behavioral change, severe [[headache]]s, reduced level of consciousness, [[papilloedema]], [[tachypnea|breathlessness]],<ref name="Oxford University Press"/> [[pallor]],<ref name="Illingworth et al 2012" /> [[tachycardia]], and [[pulmonary hypertension]] eventually leading to the late signs [[cyanosis]], [[bradycardia|slow heart rate]], [[cor pulmonale]], and [[hypotension|low blood pressure]] followed by [[heart failure]] eventually leading to [[Shock (circulatory)|shock]] and [[death]].<ref name="Hillman and Bishop 2004" /><ref name="Longmore et al 2006" />

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.<ref name="Ahrens and Rutherford Basham 1993" /> In cases where the oxygen is displaced by another molecule, such as carbon monoxide, the skin may appear 'cherry red' instead of cyanotic.<ref name="Ramratha and Moore 2004" /> Hypoxia can cause [[Preterm birth|premature birth]], and injure the liver, among other deleterious effects.<ref>{{Cite journal |last1=Wang |first1=Bin |last2=Zeng |first2=Hongtao |last3=Liu |first3=Jingliu |last4=Sun |first4=Miao |date=2021-10-25 |title=Effects of Prenatal Hypoxia on Nervous System Development and Related Diseases |journal=Frontiers in Neuroscience |volume=15 |doi=10.3389/fnins.2021.755554 |issn=1662-453X |pmc=8573102 |pmid=34759794 |doi-access=free}}</ref><ref>{{Cite journal |last1=Choudhary |first1=Mukesh |last2=Sharma |first2=Deepak |last3=Dabi |first3=Dhanraj |last4=Lamba |first4=Mamta |last5=Pandita |first5=Aakash |last6=Shastri |first6=Sweta |date=2015-01-12 |title=Hepatic Dysfunction in Asphyxiated Neonates: Prospective Case-Controlled Study |journal=Clinical Medicine Insights. Pediatrics |volume=9 |pages=1–6 |doi=10.4137/CMPed.S21426 |issn=1179-5565 |pmc=4294631 |pmid=25674030}}</ref>

====Localized hypoxia====
{{see also|Ischemia}}{{anchor|Local hypoxia}}
[[File:Ischemia.JPG |thumb|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.<ref name="Merck" /><ref name="auto" />  Ischemia is generally caused by problems with [[blood vessel]]s, with resultant damage to or dysfunction of tissue i.e. hypoxia and [[microvascular dysfunction]].<ref name="Zhai et al 2013" /><ref name="Perico et al 2004" /> 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 [[nutrient]]s and inadequate removal of [[metabolic waste]]s. 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 [[Compartment (anatomy)|anatomical compartments]] results in insufficient blood supply to [[Tissue (biology)|tissue]] within that space.<ref name="PMH 2017" /><ref name="Peitzman et al 2008" /> There are two main types: [[Acute (medicine)|acute]] and [[Chronic (medicine)|chronic]].<ref name="PMH 2017" /> Compartments of the leg or arm are most commonly involved.<ref name="Ferri 2018" />

{{expand section| local trauma, [[edema]], [[allergic reactions]], etc.|date=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====
Any living tissue can be affected by hypoxia, but some are particularly sensitive, or have more noticeable or notable consequences.

=====Cerebral hypoxia=====
{{main|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 [[neuron]]al cell death via [[apoptosis]], resulting in a hypoxic brain injury.<ref name="Malhotra et al 2001" /><ref name="Mattiesen 2009" />

[[Oxygen saturation in medicine|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 [[Perinatal asphyxia|birth asphyxia]], it can occur in all age groups, and is often a complication of [[cardiac arrest]].<ref name="Robinson et al 2003" /><ref name="Geraghty and Torbey 2006" /><ref name="Busl and Greer 2010" />

=====Corneal hypoxia=====
{{expand section|date=December 2022}}
Although corneal hypoxia can arise from any of several causes, it is primarily attributable to the prolonged use of [[Contact lens|contact lenses]].<ref name=":0">{{Citation |last1=Conditions |first1=National Research Council (US) Working Group on Contact Lens Use Under Adverse |title=Hypoxia |date=1991 |url=https://www.ncbi.nlm.nih.gov/books/NBK234101/ |work=Considerations in Contact Lens Use Under Adverse Conditions: Proceedings of a Symposium |access-date=2023-06-11 |publisher=National Academies Press (US) |language=en |last2=Flattau |first2=Pamela Ebert}}</ref>  The corneas are not perfused and get their oxygen from the atmosphere by diffusion. Impermeable contact lenses form a barrier to this [[diffusion]], and therefore can cause damage to the corneas. Symptoms may include irritation, excessive tearing and [[blurred vision]]. The sequelae of corneal hypoxia include punctate [[keratitis]], [[corneal neovascularization]] and epithelial microcysts.<ref name=":0" />

=====Intrauterine hypoxia=====
{{main|Intrauterine hypoxia}}
Intrauterine hypoxia, also known as fetal hypoxia, occurs when the fetus is [[relative deprivation|deprived]] of an adequate supply of [[oxygen]].  It may be due to a variety of reasons such as [[prolapse]] or [[Vascular occlusion|occlusion]] of the [[umbilical cord]], [[placental infarction]], maternal diabetes (prepregnancy or [[gestational diabetes]])<ref name="Tarvonen et al 2021" /> and [[Smoking and pregnancy|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]].<ref name="Maslova et al 2003" /><ref name="Habek et al 2002" /><ref name="Peleg et al 1998" /><ref name="Rosenberg 2008" /><ref name="Gonzalez and Miller 2006" /><ref name="Bulterys et al 1990" />

=====Tumor hypoxia=====
{{main|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. The severity of hypoxia is related to tumor types and varies between different types. Research has shown that the level of oxygenation in hypoxic tumor tissues is poorer than normal tissues and it is reported somewhere between 1%–2% O2.<ref>Nejad, A.E. et al. (2021) The role of hypoxia in the tumor microenvironment and development of Cancer Stem Cell: A novel approach to developing treatment - cancer cell international, BioMed Central. Available at: https://cancerci.biomedcentral.com/articles/10.1186/s12935-020-01719-5#:~:text=Hypoxia%20is%20a%20common%20feature,blood%20vessels%20supplying%20the%20tumor (Accessed: 01 December 2023). </ref> 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.<ref name="Gilkes et al 2014" /><ref name="Spill et al 2016" /> Tumour hypoxia is usually associated with highly malignant tumours, which frequently do not respond well to treatment.<ref name="Lumb 2017" />

=====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.<ref name="Urbani et al 1994" />

==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]]<ref name="Mandal b" />
* [[Headache]]<ref name="Mandal b" /><ref name="FAA" /><ref name="Prasad et al 2021" />
* Increased reaction time,<ref name="Rochester" /> disorientation, and uncoordinated movement.<ref name="Mandal b" />
* Impaired judgment, confusion, memory loss and cognitive problems.<ref name="Mandal b" /><ref name="FAA" />
* [[Euphoria]] or dissociation<ref name="Mandal b" />
* [[Visual impairment]]<ref name="FAA" /> 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 {{convert|12,000|ft|m}}.<ref name="Vingrys and Garner 1987" />
* Lightheaded or dizzy sensation, [[vertigo]]<ref name="Mandal b" />
* [[Fatigue]], [[drowsiness]], or tiredness<ref name="Mandal b" />
* [[Shortness of breath]]<ref name="Mandal b" />
* [[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<ref name="Mandal b" />
* Initially raised [[blood pressure]] followed by lowered blood pressure as the condition progresses.<ref name="Mandal b" />
* 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.<ref name="Mandal b" />
* Tingling in fingers and toes<ref name="FAA" />
* Numbness<ref name="FAA" />

===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.<ref name="Kam et al 1978" />
*Obstructive sleep apnea syndrome is a risk factor for cerebrovascular disease and cognitive dysfunction.<ref name="Prasad et al 2021" />
{{expand section|date=December 2022}}

==Causes==
Oxygen passively diffuses in the lung [[Pulmonary alveolus|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 inhaled air to [[artery|arterial]] blood, where its partial pressure is around 100&nbsp;mmHg (13.3&nbsp;kPa).<ref name="oxygen calculator"/> In the blood, oxygen is bound to hemoglobin, a protein in [[red blood cell]]s. The binding capacity of hemoglobin is influenced by the [[:wikt:partial pressure|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.<ref>{{Citation |last=Patel |first=Sagar |title=Physiology, Oxygen Transport And Carbon Dioxide Dissociation Curve |date=2024 |work=StatPearls |url=https://www.ncbi.nlm.nih.gov/books/NBK539815/ |access-date=2024-08-23 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=30969637 |last2=Jose |first2=Alvin |last3=Mohiuddin |first3=Shamim S.}}</ref>

In systemic tissues, oxygen again diffuses down a concentration gradient into cells and their [[mitochondria]], where it is [[cellular respiration|used to produce energy]] in conjunction with the breakdown of [[glucose]], [[fat]]s, and some [[amino acid]]s.<ref name="Jae-Hwan et al 2015" /> 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 (physiology)|dead space]].
Experimentally, oxygen diffusion becomes [[Rate-determining step|rate limiting]] when arterial oxygen partial pressure falls to 60&nbsp;mmHg (5.3&nbsp;kPa) or below.{{clarify|date=December 2022}}<ref name="Collins et al 2015" />

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,<ref name="MARTIN1999" /> 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.<ref name="DAVIDSONS2010" />

===Ischemia===
{{Main|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 [[embolus|embolism]], a [[myocardial infarction|heart attack]] that decreases overall blood flow, trauma to a tissue that results in damage reducing perfusion, and a variety of [[Ischemia#Causes|other causes]]. A consequence of insufficient blood flow causing local hypoxia is [[gangrene]] that occurs in [[diabetes]].<ref name="Levin O'Neal" />

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]].<ref name="Basbaum et al 2000" />

[[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 [[Syncope (medicine)|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.<ref name="g-LOC" />

===Hypoxemic hypoxia===
{{Main|Hypoxemia}}
This refers specifically to hypoxic states where the arterial content of oxygen is insufficient.<ref name="West 2008" /> 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|date=September 2022}}

Common disorders that can cause respiratory dysfunction 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.<ref name="Prasad et al 2021" />

====Carbon monoxide poisoning====
{{Main|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.<ref name="Douglas et al 1912" />
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).<ref name="CO ppm" />  A carbon monoxide level of 40 ppm is equivalent to a reduction in hemoglobin levels of 10 g/L.<ref name = "CO ppm" />{{notetag|The formula <math> Hb_{CO}(\%) = \frac {CO - 2.34} {5.09} </math> can be used to calculate the amount of carbon monoxide-bound hemoglobin. For example, at carbon monoxide level of 5 ppm, <math>= \frac {5 - 2.34} {5.09} = .5\%</math>, or a loss of half a percent of their blood's hemoglobin.<ref name = "CO ppm"/>}}

Carbon monoxide 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.{{clarify|what does this actually mean?|date=December 2022}}  In so doing, the hemoglobin is less likely to release its oxygen at the peripheral tissues.{{clarify|why?|date=December 2022}}<ref name=MARTIN1999/> Certain [[hemoglobinopathies|abnormal hemoglobin variants]] also have higher than normal affinity for oxygen, and so are also poor at delivering oxygen to the periphery.{{clarify|Is this specifically relevant to carbon monoxide poisoning, or should it be in another section, as it is relevant to hypoxia, but maybe anaemic hypoxia? If relevant, explain more, otherwise move to where relevant, and if necessary, explain more|date=December 2022}}{{citation needed|date=September 2022}}

====Altitude====
{{Main|Altitude sickness}}
[[Vertical pressure variation|Atmospheric pressure reduces with altitude]] and proportionally, so does the oxygen content of the air.<ref name="netzer" /> The reduction in the partial pressure of inspired oxygen at higher altitudes lowers the oxygen saturation of the blood, ultimately leading to hypoxia.<ref name=netzer/> The clinical features of altitude sickness include: sleep problems, dizziness, headache and oedema.<ref name=netzer/>

==== Hypoxic breathing gases ====
{{Main|Inert gas asphyxiation|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.<ref name="Hausserman 2017" />

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.<ref name="netzer" />

Gases with as little as 2% oxygen by volume in a helium diluent are used for deep [[underwater diving|diving]] operations. The ambient pressure at 190 [[metre sea water|msw]] is sufficient to provide a partial pressure of about 0.4 bar, which is suitable for [[saturation diving]]. As the divers are [[Decompression (diving)|decompressed]], the breathing gas must be oxygenated to maintain a breathable atmosphere.<ref name="usn ch15" />

It is also possible for the breathing gas for diving to have a dynamically controlled oxygen partial pressure, known as a [[Setpoint (control system)|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.<ref name="ap vision" />

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 [[Freediving blackout|loses consciousness]] before reaching the surface.<ref name="Pearn et al 2015"/><ref name="Lindholm 2006" />

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.<ref name="Milroy 2018" />

====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<ref name="Roueché 1953" />{{ums|date=June 2019}} as well as certain drugs and other chemicals.<ref name="BC DPIC" />

===Anemia===
{{Main|Anemia}}
Hemoglobin plays a substantial role in carrying oxygen throughout the body,<ref name=MARTIN1999 /> 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.<ref name=DAVIDSONS2010 />{{rp|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.<ref name=DAVIDSONS2010 />{{rp|997–99}}

===Histotoxic hypoxia===
{{Main|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.<ref name="KCUMB" /> Histotoxic hypoxia results from tissue poisoning, such as that caused by [[cyanide]] (which acts by inhibiting [[cytochrome oxidase]]) and certain other [[poison]]s like [[hydrogen sulfide]] (byproduct of sewage and used in leather tanning).<ref name="Pittman 2011" />

==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).<ref name="Lacroix et al" /> 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.<ref name="Kluckow and Seri 2012" /> Serum lactate levels have been correlated with illness severity and mortality in critically ill adults and in ventilated neonates with respiratory distress.<ref name="Kluckow and Seri 2012" />

===Physiological responses===
All vertebrates must maintain oxygen homeostasis to survive, and have evolved physiological systems to ensure adequate oxygenation 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.<ref name="Michiels 2004" />

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.<ref name="Michiels 2004" />
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.<ref name="Lumb 2017" />

Hypoxia-inducible factors (HIFs) are [[transcription factors]] that respond to decreases in available oxygen in the cellular environment, or hypoxia.<ref name="Smith et al 2008" /><ref name="Wilkins et al 2016" /> The HIF signaling cascade mediates the effects of hypoxia on the cell. Hypoxia often keeps cells from [[Cellular differentiation|differentiating]]. However, hypoxia promotes the [[angiogenesis|formation of blood vessels]], and is important for the formation of a [[vascular system]] in [[embryo]]s and tumors. The hypoxia in [[wound]]s also promotes the migration of [[keratinocyte]]s and the restoration of the [[epithelium]].<ref name="Benizri et al 2008" /> It is therefore not surprising that HIF-1 modulation was identified as a promising treatment paradigm in wound healing.<ref name="Duscher et al" />

Exposure of a tissue to repeated short periods of hypoxia, between periods of normal oxygen levels, influences the tissue's later response to prolonged ischaemic exposure. Thus is  known as [[ischaemic preconditioning]], and it is known to occur in many tissues.<ref name="Lumb 2017" />

===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.<ref name="Hobler and Carey 1973" /> If severe or prolonged it could lead to cell death.<ref name="Fulda et al 2010" />

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.<ref name="Arieff 2013" /> This response does not control ventilation rate at normal P<sub>O<sub>2</sub></sub>, 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 P<sub>O<sub>2</sub></sub> despite a falling P<sub>CO<sub>2</sub></sub>{{citation needed|date=September 2022}}

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 [[lung]]s, 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.<ref name="Michiels 2004" /> 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.<ref name="Gao et al 2021" />
Hypoxic ventilatory response (HVR) is the increase in [[ventilation (physiology)|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]].<ref name="Cymerman and Rock" /><ref name="Teppema and Dahan 2010" />

===Chronic===
{{see also|Hypoxic ventilatory response#Chronic hypoxic ventilatory response|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&nbsp;mm Hg have been measured without the development of lethal pulmonary edema.<ref name="Guytun and Hall" />

There are several potential physiologic mechanisms for hypoxemia, but in patients with chronic obstructive pulmonary disease ([[COPD]]), [[Ventilation/perfusion ratio|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.<ref name="Pierson 2000" />

===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 oxygen 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 oxygenation 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 Ca<sup>2+</sup> 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 (medicine)|penumbra]]'', which is reversible if the oxygen supply is resumed soon enough.<ref name="Michiels 2004" />

====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.<ref name="Michiels 2004" /> 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.<ref name="Michiels 2004" />

====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.<ref name="Michiels 2004" />

{{expand section|date=December 2022}}

==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.<ref name="Bhutta et al 2022" />

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.<ref name="Bhutta et al 2022" />

Lung [[auscultation]] can provide useful information.<ref name="Bhutta et al 2022" />

===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 (P<sub>a<sub>O<sub>2</sub></sub></sub>), partial pressure of carbon dioxide (P<sub>a<sub>CO<sub>2</sub></sub></sub>), blood pH level, and bicarbonate (HCO<sub>3</sub>)<ref name="Cleveland ABG" />
*An arterial oxygen tension (P<sub>a<sub>O<sub>2</sub></sub></sub>) less than 80&nbsp;mmHg is considered abnormal, but must be considered in context of the clinical situation.<ref name="Bhutta et al 2022" />
*In addition to diagnosis of hypoxemia, the ABG may provide additional information, such as P<sub>CO<sub>2</sub></sub>, which can help identify the etiology. The arterial partial pressure of carbon dioxide is an indirect measure of exchange of carbon dioxide with the air in the lungs, and is related to minute ventilation. P<sub>CO<sub>2</sub></sub> is raised in hypoventilation.<ref name="Bhutta et al 2022" />
*The normal range of P<sub>a<sub>O<sub>2</sub></sub></sub>:F<sub>i<sub>O<sub>2</sub></sub></sub> 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.<ref name="Bhutta et al 2022" />
*The [[alveolar–arterial gradient]] (A-a<sub>O<sub>2</sub></sub>,<ref name=loganabbrev /> or A–a gradient), is the difference between the [[Pulmonary alveolus|alveolar]] (A) [[concentration]] of [[oxygen]] and the [[artery|arterial]] (a) concentration of oxygen. It is a useful parameter for narrowing the differential diagnosis of [[hypoxemia]].<ref name="NBK545153" /> The A–a gradient helps to assess the integrity of the alveolar capillary unit. For example, at high altitude, the arterial oxygen P<sub>a<sub>O<sub>2</sub></sub></sub> is low, but only because the alveolar oxygen P<sub>A<sub>O<sub>2</sub></sub></sub> 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 [[Pulmonary alveolus|alveoli]] to the blood which results in an elevated A-a gradient. P<sub>a<sub>O<sub>2</sub></sub></sub> can be obtained from the arterial blood gas analysis and P<sub>A<sub>O<sub>2</sub></sub></sub> is calculated using the [[alveolar gas equation]].<ref name="Bhutta et al 2022" />
*An abnormally low [[hematocrit]] (volume percentage of red blood cells) may indicate anemia.

[[X-ray]]s or [[CT scan]]s of the chest and airways can reveal abnormalities that may affect ventilation or perfusion.<ref name="MNT diagnosis" />

A [[ventilation/perfusion scan]],<ref name="Cleveland diagnosis" /> also called a V/Q lung scan, is a type of [[medical imaging]] using [[scintigraphy]] and [[Nuclear medicine|medical isotopes]] to evaluate the circulation of air and blood within a patient's [[lungs]],<ref name="UMMC" /><ref name="seminars"/> 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]]<ref name="MNT diagnosis" /> may include:
* Tests that measure oxygen levels during the night<ref name="MNT diagnosis" />
* The [[Pulmonary function testing#Oxygen desaturation during exercise|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.<ref name="MNT diagnosis" />
* Diagnostic measurements that may be relevant include:<ref name="Temple" /> [[Lung volumes]], including lung capacity, [[airway resistance]], [[Muscles of respiration|respiratory muscle]] strength, [[diffusing capacity]] 
* Other pulmonary function tests which may be relevant include:<ref name="Temple" /> [[Spirometry]], [[body plethysmography]], forced oscillation technique for calculating the volume, pressure, and air flow in the lungs, [[Pulmonary function testing#Bronchodilator responsiveness|bronchodilator responsiveness]], [[Pulmonary function testing#Diffusing capacity|carbon monoxide diffusion test]] (DLCO), [[Oxygen therapy#Chronic conditions|oxygen titration studies]], [[cardiopulmonary stress test]], [[bronchoscopy]], and [[thoracentesis]]

===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 (P<sub>a<sub>O<sub>2</sub></sub></sub>) 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.<ref name="Bhutta et al 2022" /> Both acute and chronic hypoxia and hypercapnia caused by respiratory dysfunction can produce neurological symptoms such as encephalopathy, seizures, headache, [[papilledema]], and [[asterixis]].<ref name="Prasad et al 2021" /> Obstructive sleep apnea syndrome may cause morning headaches<ref name="Prasad et al 2021" />

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.<ref name="Bhutta et al 2022" />

Anemic Hypoxia is caused by a deficit in oxygen-carrying capacity, usually due to low hemoglobin levels, leading to generalised inadequate oxygen delivery.<ref name="Bhutta et al 2022" />

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.<ref name="Bhutta et al 2022" />

Critical illness [[polyneuropathy]] or [[myopathy]] should be considered in the intensive care unit when patients have difficulty coming off the ventilator.<ref name="Prasad et al 2021" />

{{expand section|date=December 2022}}

==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.
{{expand section|more detail|date=December 2022}}

===Prevention of altitude induced hypoxia===
To counter the effects of high-altitude diseases, the body must return arterial P<sub>a<sub>O<sub>2</sub></sub></sub> toward normal. [[Acclimatization]], the means by which the body adapts to higher altitudes, only partially restores P<sub>O<sub>2</sub></sub> to standard levels. [[Hyperventilation]], the body's most common response to high-altitude conditions, increases alveolar P<sub>O<sub>2</sub></sub> by raising the depth and rate of breathing. However, while P<sub>O<sub>2</sub></sub> does improve with hyperventilation, it does not return to normal. Studies of miners and astronomers working at 3000 meters and above show improved alveolar P<sub>O<sub>2</sub></sub> with full acclimatization, yet the P<sub>O<sub>2</sub></sub> level remains equal to or even below the threshold for continuous oxygen therapy for patients with [[chronic obstructive pulmonary disease]] (COPD).<ref name="West 2004 789–800" /> 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.<ref name="NHS" />

In high-altitude situations, only oxygen enrichment or compartment pressurisation can counteract the effects of hypoxia. Pressurisation is practicable in vehicles, and for emergencies in ground installations. By increasing the concentration of oxygen in the at ambient pressure, the effects of lower barometric pressure are countered and the level of arterial P<sub>O<sub>2</sub></sub> is restored toward normal capacity. A small amount of supplemental oxygen reduces the equivalent altitude in climate-controlled rooms. At 4000&nbsp;m, raising the oxygen concentration level by 5% via an oxygen concentrator and an existing ventilation system provides an altitude equivalent of 3000&nbsp;m, which is much more tolerable for the increasing number of low-landers who work in high altitude.<ref name="West 1995" /> In a study of astronomers working in Chile at 5050&nbsp;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.<ref name="West 2004 789–800"/>

[[Oxygen concentrator]]s 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|date=September 2022}}

==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.<ref name="Wagstaff 2014" />

===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.<ref name="Bhutta et al 2022" /> 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 F<sub>i<sub>O<sub>2</sub></sub></sub>, and positive end-expiratory pressure, and can be combined with anaesthetic gas delivery. In some cases a [[tracheotomy]] may be necessary.<ref name="Bhutta et al 2022" /> 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.<ref name="Bhutta et al 2022" /> 

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.<ref name="Bhutta et al 2022" />

[[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.<ref name="UHMS" /><ref name="Bouachour et al 1996" /> 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.<ref name="UHMS DCS" /><ref name="Brubakk et al 2003" /><ref name="Acott 1999" /> It is also effective in [[carbon monoxide poisoning]]<ref name="Piantadosi 2004" /> and [[diabetic foot]].<ref name="UHMS problem wounds" /><ref name="Zamboni et al 1997" />

A prescription renewal for home oxygen following hospitalization requires an assessment of the patient for ongoing hypoxemia.<ref name="ACCPandATSfive" />

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

Hypoxia leading to reduced capacity to respond appropriately, or to loss of consciousness, 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.<!-- Not sure which section to put this in - could also be seen as a complication. -->
{{expand section|date=November 2022}}

==Epidemiology==
Hypoxia is a common disorder but there are many possible causes.<ref name="Bhutta et al 2022" /> 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.<ref name="Bhutta et al 2022" />

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.<ref name="SRLE 2018" />

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.<ref name="CDC" />
{{expand section|date=December 2022}}

===Silent hypoxia===
{{main|Silent hypoxia}}

Silent hypoxia (also known as happy hypoxia)<ref name="Tobin et al 2020" /><ref name="LaMotte 2020" /> is generalised <!-- whole body --> hypoxia that does not coincide with [[shortness of breath]].<ref name="Pappas 2020" /><ref name="Science Daily" /><ref name="Emily 2020" /> This presentation is known to be a complication of [[COVID-19]],<ref name="Chandra et al 2020" /><ref name="NYT 2020" /> and is also known in [[atypical pneumonia]],<ref name="Bowden 2020" /> altitude sickness,<ref name="Ottested 2020" /><ref name="Gillespie" /><ref name="Blanchet and Graeme" /> and [[rebreather]] malfunction accidents.<ref name="apdiving" /><ref name="Sellers 2016" />

==History==
The 2019 [[Nobel Prize in Physiology or Medicine]] was awarded to [[William G. Kaelin Jr.]], [[Peter J. Ratcliffe|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.<ref name="Nobel prize" /><ref name="Genetex" />

The use of the term ''hypoxia'' appears to be relatively recent, with the first recorded use in scientific publication from 1945. Previous to this the term ''anoxia'' was extensively used for all levels of oxygen deprivation. Investigation into the effects of lack of oxygen date from the mid 19th century.
<ref name="Richalet" >{{cite journal |last1=Richalet |first1=J.P. |title=The invention of hypoxia. |journal=J Appl Physiol |date=1 May 2021 |volume=130 |issue=5 |pages=1573–1582 |doi=10.1152/japplphysiol.00936.2020 |pmid=33703942 |s2cid=232198196 }}</ref>

===Etymology===
Hypoxia is formed from the Greek roots υπo (hypo), meaning under, below, and less than, and oξυ (oxy), meaning acute or acid, which is the root for oxygen.<ref name="Richalet" />

==See also==
* {{annotated link|Asphyxia}}
* {{annotated link|Cerebral hypoxia}} 
* {{annotated link|Erotic asphyxiation}} 
* {{annotated link|Fink effect|aka=diffusion hypoxia}}
* {{annotated link|G-LOC}} 
* {{annotated link|Histotoxic hypoxia}}
* {{annotated link|Hyperoxia}}
* {{annotated link|Hypoventilation training}}
* {{annotated link|Hypoxemia}} 
* {{annotated link|Hypoxia in fish}}
* {{annotated link|Hypoxia-inducible factor}}
* {{annotated link|Hypoxic hypoxia}}, a result of insufficient oxygen available to the lungs
* {{annotated link|Hypoxic ventilatory response}}
* {{annotated link|Hypoxicator}} a device intended for hypoxia acclimatisation in a controlled manner
* {{annotated link|Intermittent hypoxic training}}
* {{annotated link|Intrauterine hypoxia}}, when a fetus is deprived of an adequate supply of oxygen
* {{annotated link|Latent hypoxia}} 
* {{annotated link|Pseudohypoxia}}, increased cytosolic ratio of free NADH to NAD<sup>+</sup> in cells
* {{annotated link|Rhinomanometry}}
* {{annotated link|Sleep apnea}}
* [[Solid stress]] &ndash; one of the physical hallmarks of cancer
* {{annotated link|Time of useful consciousness}}
* {{annotated link|Tumor hypoxia}}
* [[Vasculogenic mimicry|Vasculogenic Mimicry]]

== Notes ==
{{NoteFoot}}

== References ==
{{Reflist|refs=

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}}

{{Medical resources 
| DiseasesDB     = 6623
| ICD11          = {{ICD11|CB41}}
| ICD10          = {{ICD10|J96}}
| ICD9           = {{ICD9|799.02}}
| ICDO           =
| OMIM           =
| MedlinePlus    =
| eMedicineSubj  =
| eMedicineTopic =
| eMedicine_mult =
| MeshID         = D000860
}}
{{Respiratory physiology}}
{{Consequences of external causes}}
{{underwater diving|divmed}}
{{Authority control}}

{{DEFAULTSORT:Hypoxia (medicine)}}
[[Category:Aviation medicine]]
[[Category:Underwater diving medicine]]
[[Category:Mountaineering and health]]
[[Category:Oxygen]]
[[Category:Pulmonology]]