Editing Hypoxia (medicine) (section)

==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" />