Editing Hypoxia (medicine) (section)

==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" />