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

Carbon monoxide 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.

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). A carbon monoxide level of 40 ppm is equivalent to a reduction in hemoglobin levels of 10 g/L.

CO 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. In so doing, the hemoglobin is less likely to release its oxygens at the peripheral tissues. Certain abnormal hemoglobin variants also have higher than normal affinity for oxygen, and so are also poor at delivering oxygen to the periphery.

Shunting refers to blood that bypasses the pulmonary circulation, meaning that the blood does not receive oxygen from the alveoli. In general, a shunt may be within the heart or lungs, and cannot be corrected by administering oxygen alone. Shunting may occur in normal states:

- Anatomic shunting, occurring via the bronchial circulation, which provides blood to the tissues of the lung. Shunting also occurs by the smallest cardiac veins, which empty directly into the left ventricle.

- Physiological shunts, occur due to the effect of gravity. The highest concentration of blood in the pulmonary circulation occurs in the bases of the pulmonary tree compared to the highest pressure of gas in the apexes of the lungs. Alveoli may not be ventilated in shallow breathing.

Shunting may also occur in disease states:

- Acute lung injury and adult respiratory distress syndrome, which may cause alveolar collapse. This will increase the amount of physiological shunting, and unlike many forms of shunting, can be managed by administering 100% Oxygen.

- Pathological shunts such as patent ductus arteriosus, patent foramen ovale, and atrial septal defects or ventricular septal defects. These states are when blood from the right side of the heart moves straight to the left side, without first passing through the lungs. This is known as a right-to-left shunt, which is often congenital in origin.

This refers to a disruption in the ventilation/perfusion equilibrium. Oxygen entering the lungs typically diffuses across the alveolar-capillary membrane into blood. However this equilibration does not occur when the alveolus is insufficiently ventilated, and as a consequence the blood exiting that alveolus is relatively hypoxemic. When such blood is added to blood from well ventilated alveoli, the mix has a lower oxygen partial pressure than the alveolar air, and so the A-a difference develops. Examples of states that can cause a ventilation-perfusion mismatch include:

- Exercise. Whilst modest activity and exercise improves ventilation-perfusion matching, hypoxemia may develop during intense exercise as a result of preexisting lung diseases. During exercise, almost half of the hypoxemia is due to diffusion limitations (again, on average).

- Aging. An increasingly poor match between ventilation and perfusion is seen with age, as well as a decreased ability to compensate for hypoxic states.

- Disease that affect the pulmonary interstitum can also result in hypoxia, by affecting the ability of oxygen to diffuse into arteries. An example of these diseases is pulmonary fibrosis, where even at rest a fifth of the hypoxemia is due to diffusion limitations (on average).

- Diseases that result in acute or chronic respiratory distress can result in hypoxia. These diseases can be acute in onset (such as obstruction by inhaling something or a pulmonary embolus) or chronic (such as chronic obstructive pulmonary disease).

- Cirrhosis can be complicated by refractory hypoxemia due to high rates of blood flow through the lung, resulting in ventilation-perfusion mismatch.

In the United States, intrauterine hypoxia and birth asphyxia were listed together as the tenth leading cause of neonatal death.

Apnea of prematurity occurs in at least 85 percent of infants who are born at less than 34 weeks of gestation. The incidence is inversely related to the gestational maturity of the infant, but has considerable individual variability.

Since AOP is fundamentally a problem of the immaturity of the physiological systems of the premature infant, it is a self-limited condition that will resolve when these systems mature. It is unusual for an infant to continue to have significant problems with AOP beyond 42 weeks post-conceptual age.

Infants who have had AOP are at increased risk of recurrence of apnea in response to exposure to anesthetic agents, at least until around 52 weeks post-conceptual age.

There is no evidence that a history of AOP places an infant at increased risk for SIDS. However, any premature infant (regardless of whether they have had AOP) is at increased risk of SIDS. It is important that other factors related to SIDS risk be avoided (exposure to smoking, prone sleeping, excess bedding materials, etc.)

Treatment of infants suffering birth asphyxia by lowering the core body temperature is now known to be an effective therapy to reduce mortality and improve neurological outcome in survivors, and hypothermia therapy for neonatal encephalopathy begun within 6 hours of birth significantly increases the chance of normal survival in affected infants.

There has long been a debate over whether newborn infants with birth asphyxia should be resuscitated with 100% oxygen or normal air. It has been demonstrated that high concentrations of oxygen lead to generation of oxygen free radicals, which have a role in reperfusion injury after asphyxia. Research by Ola Didrik Saugstad and others led to new international guidelines on newborn resuscitation in 2010, recommending the use of normal air instead of 100% oxygen.

Disorders like congenital central hypoventilation syndrome (CCHS) and ROHHAD (rapid-onset obesity, hypothalamic dysfunction, hypoventilation, with autonomic dysregulation) are recognized as conditions that are associated with hypoventilation. CCHS may be a significant factor in some cases of sudden infant death syndrome (SIDS), often termed "cot death" or "crib death".

The opposite condition is hyperventilation (too much ventilation), resulting in low carbon dioxide levels (hypocapnia), rather than hypercapnia.

When humans breathe in an asphyxiant gas, such as pure nitrogen, helium, neon, argon, sulfur hexafluoride, methane, or any other physiologically inert gas(es), they exhale carbon dioxide without re-supplying oxygen. Physiologically inert gases (those that have no toxic effect, but merely dilute oxygen) are generally free of odor and taste. As such, the human subject detects little abnormal sensation as the oxygen level falls. This leads to asphyxiation (death from lack of oxygen) without the painful and traumatic feeling of suffocation (the hypercapnic alarm response, which in humans arises mostly from carbon dioxide levels rising), or the side effects of poisoning. In scuba diving rebreather accidents, there is often little sensation but euphoria—however, a slow decrease in oxygen breathing gas content has effects which are quite variable. By contrast, suddenly breathing pure inert gas causes oxygen levels in the blood to fall precipitously, and may lead to unconsciousness in only a few breaths, with no symptoms at all.

Some animal species are better equipped than humans to detect hypoxia, and these species are more uncomfortable in low-oxygen environments that result from inert gas exposure.

Respiratory stimulants such as nikethamide were traditionally used to counteract respiratory depression from CNS depressant overdose, but offered limited effectiveness. A new respiratory stimulant drug called BIMU8 is being investigated which seems to be significantly more effective and may be useful for counteracting the respiratory depression produced by opiates and similar drugs without offsetting their therapeutic effects.

If the respiratory depression occurs from opioid overdose, usually an opioid antagonist, most likely naloxone, will be administered. This will rapidly reverse the respiratory depression unless complicated by other depressants. However an opioid antagonist may also precipitate an opioid withdrawal syndrome in chronic users.

Hypoxic hypoxia is a result of insufficient oxygen available to the lungs. A blocked airway, a drowning or a reduction in partial pressure (high altitude above 10,000 feet) are examples of how lungs can be deprived of oxygen. Some medical examples are abnormal pulmonary function or respiratory obstruction. Hypoxic hypoxia is seen in patients suffering from chronic obstructive pulmonary diseases (COPD), neuromuscular diseases or interstitial lung disease.

Central cyanosis is often due to a circulatory or ventilatory problem that leads to poor blood oxygenation in the lungs. It develops when arterial oxygen saturation drops to ≤85% or ≤75%.

Acute cyanosis can be as a result of asphyxiation or choking, and is one of the definite signs that respiration is being blocked.

Central cyanosis may be due to the following causes:

1. Central nervous system (impairing normal ventilation):

- Intracranial hemorrhage

- Drug overdose (e.g. heroin)

- Tonic–clonic seizure (e.g. grand mal seizure)

2. Respiratory system:

- Pneumonia

- Bronchiolitis

- Bronchospasm (e.g. asthma)

- Pulmonary hypertension

- Pulmonary embolism

- Hypoventilation

- Chronic obstructive pulmonary disease, or COPD (emphysema)

3. Cardiovascular diseases:

- Congenital heart disease (e.g. Tetralogy of Fallot, right to left shunts in heart or great vessels)

- Heart failure

- Valvular heart disease

- Myocardial infarction

4. Blood:

- Methemoglobinemia * Note this causes "spurious" cyanosis, in that, since methemoglobin appears blue, the patient can appear cyanosed even in the presence of a normal arterial oxygen level.

- Polycythaemia

- Congenital cyanosis (HbM Boston) arises from a mutation in the α-codon which results in a change of primary sequence, H → Y. Tyrosine stabilises the Fe(III) form (oxyhaemoglobin) creating a permanent T-state of Hb.

5. Others:

- High altitude, cyanosis may develop in ascents to altitudes >2400 m.

- Hypothermia

- Obstructive sleep apnea

Carbon monoxide poisoning in pregnant women may cause severe adverse fetal effects. Poisoning causes fetal tissue hypoxia by decreasing the release of maternal oxygen to the fetus. Carbon monoxide also crosses the placenta and combines with fetal hemoglobin, causing more direct fetal tissue hypoxia. Additionally, fetal hemoglobin has a 10 to 15% higher affinity for carbon monoxide than adult hemoglobin, causing more severe poisoning in the fetus than in the adult. Elimination of carbon monoxide is slower in the fetus, leading to an accumulation of the toxic chemical. The level of fetal morbidity and mortality in acute carbon monoxide poisoning is significant, so despite mild maternal poisoning or following maternal recovery, severe fetal poisoning or death may still occur.

A typical human breathes between 12 and 20 times per minute at a rate primarily influenced by carbon dioxide concentration, and thus pH, in the blood. With each breath, a volume of about 0.6 litres is exchanged from an active lung volume (tidal volume + functional residual capacity) of about 3 litres. Normal Earth atmosphere is about 78% nitrogen, 21% oxygen, and 1% argon, carbon dioxide, and other gases. After just two or three breaths of nitrogen, the oxygen concentration in the lungs would be low enough for some oxygen already in the bloodstream to exchange back to the lungs and be eliminated by exhalation.

Unconsciousness in cases of accidental asphyxia can occur within 1 minute. Loss of consciousness results from critical hypoxia, when arterial oxygen saturation is less than 60%. "At oxygen concentrations [in air] of 4 to 6%, there is loss of consciousness in 40 seconds and death within a few minutes". At an altitude over , where the ambient oxygen concentration is equivalent to 3.6% at sea level, an average individual can perform flying duties efficiently for only 9 to 12 seconds without oxygen supplementation. The US Air Force trains air crews to recognize their individual subjective signs of approaching hypoxia. Some individuals experience headache, dizziness, fatigue, nausea, euphoria and some become unconscious without warning.

Loss of consciousness may be accompanied by convulsions and is followed by cyanosis and cardiac arrest. About 7 minutes of oxygen deprivation causes death of the brainstem.

Mild and moderate cerebral hypoxia generally has no impact beyond the episode of hypoxia; on the other hand, the outcome of severe cerebral hypoxia will depend on the success of damage control, amount of brain tissue deprived of oxygen, and the speed with which oxygen was restored.

If cerebral hypoxia was localized to a specific part of the brain, brain damage will be localized to that region. A general consequence may be epilepsy. The long-term effects will depend on the purpose of that portion of the brain. Damage to the Broca's area and the Wernicke's area of the brain (left side) typically causes problems with speech and language. Damage to the right side of the brain may interfere with the ability to express emotions or interpret what one sees. Damage on either side can cause paralysis of the opposite side of the body.

The effects of certain kinds of severe generalized hypoxias may take time to develop. For example, the long-term effects of serious carbon monoxide poisoning usually may take several weeks to appear. Recent research suggests this may be due to an autoimmune response caused by carbon monoxide-induced changes in the myelin sheath surrounding neurons.

If hypoxia results in coma, the length of unconsciousness is often indicative of long-term damage. In some cases coma can give the brain an opportunity to heal and regenerate, but, in general, the longer a coma, the greater the likelihood that the person will remain in a vegetative state until death. Even if the patient wakes up, brain damage is likely to be significant enough to prevent a return to normal functioning.

Long-term comas can have a significant impact on a patient's families. Families of coma victims often have idealized images of the outcome based on Hollywood movie depictions of coma. Adjusting to the realities of ventilators, feeding tubes, bedsores, and muscle wasting may be difficult. Treatment decision often involve complex ethical choices and can strain family dynamics.

Peripheral cyanosis is the blue tint in fingers or extremities, due to an inadequate or obstructed circulation. The blood reaching the extremities is not oxygen-rich and when viewed through the skin a combination of factors can lead to the appearance of a blue color. All factors contributing to central cyanosis can also cause peripheral symptoms to appear but peripheral cyanosis can be observed in the absence of heart or lung failures. Small blood vessels may be restricted and can be treated by increasing the normal oxygenation level of the blood.

Peripheral cyanosis may be due to the following causes:

- All common causes of central cyanosis

- Reduced cardiac output (e.g. heart failure or hypovolaemia)

- Cold exposure

- Chronic obstructive pulmonary disease (COPD)

- Arterial obstruction (e.g. peripheral vascular disease, Raynaud phenomenon)

- Venous obstruction (e.g. deep vein thrombosis)

Carbon monoxide is a product of combustion of organic matter under conditions of restricted oxygen supply, which prevents complete oxidation to carbon dioxide (CO). Sources of carbon monoxide include cigarette smoke, house fires, faulty furnaces, heaters, wood-burning stoves, internal combustion vehicle exhaust, electrical generators, propane-fueled equipment such as portable stoves, and gasoline-powered tools such as leaf blowers, lawn mowers, high-pressure washers, concrete cutting saws, power trowels, and welders. Exposure typically occurs when equipment is used in buildings or semi-enclosed spaces.

Riding in the back of pickup trucks has led to poisoning in children. Idling automobiles with the exhaust pipe blocked by snow has led to the poisoning of car occupants. Any perforation between the exhaust manifold and shroud can result in exhaust gases reaching the cabin. Generators and propulsion engines on boats, especially houseboats, has resulted in fatal carbon monoxide exposures.

Poisoning may also occur following the use of a self-contained underwater breathing apparatus (SCUBA) due to faulty diving air compressors.

In caves carbon monoxide can build up in enclosed chambers due to the presence of decomposing organic matter. In coal mines incomplete combustion may occur during explosions resulting in the production of afterdamp. The gas is up to 3% CO and may be fatal after just a single breath. Following an explosion in a colliery, adjacent interconnected mines may become dangerous due to the afterdamp leaking from mine to mine. Such an incident followed the Trimdon Grange explosion which killed men in the Kelloe mine.

Another source of poisoning is exposure to the organic solvent dichloromethane, found in some paint strippers, as the metabolism of dichloromethane produces carbon monoxide.

Ascending slowly is the best way to avoid altitude sickness. Avoiding strenuous activity such as skiing, hiking, etc. in the first 24 hours at high altitude reduces the symptoms of AMS. Alcohol and sleeping pills are respiratory depressants, and thus slow down the acclimatization process and should be avoided. Alcohol also tends to cause dehydration and exacerbates AMS. Thus, avoiding alcohol consumption in the first 24–48 hours at a higher altitude is optimal.

Individual susceptibility to HAPE is difficult to predict. The most reliable risk factor is previous susceptibility to HAPE, and there is likely to be a genetic basis to this condition, perhaps involving the gene for angiotensin converting enzyme (ACE). Recently, scientists have found the similarities between low amounts of 2,3-BPG (also known as 2,3-DPG) with the occurrence of HAPE at high altitudes. Persons with sleep apnea are susceptible due to irregular breathing patterns while sleeping at high altitudes.

Pre-acclimatization is when the body develops tolerance to low oxygen concentrations before ascending to an altitude. It significantly reduces risk because less time has to be spent at altitude to acclimatize in the traditional way. Additionally, because less time has to be spent on the mountain, less food and supplies have to be taken up. Several commercial systems exist that use altitude tents, so called because they mimic altitude by reducing the percentage of oxygen in the air while keeping air pressure constant to the surroundings.

For newborn infants starved of oxygen during birth there is now evidence that hypothermia therapy for neonatal encephalopathy applied within 6 hours of cerebral hypoxia effectively improves survival and neurological outcome. In adults, however, the evidence is less convincing and the first goal of treatment is to restore oxygen to the brain. The method of restoration depends on the cause of the hypoxia. For mild-to-moderate cases of hypoxia, removal of the cause of hypoxia may be sufficient. Inhaled oxygen may also be provided. In severe cases treatment may also involve life support and damage control measures.

A deep coma will interfere with body's breathing reflexes even after the initial cause of hypoxia has been dealt with; mechanical ventilation may be required. Additionally, severe cerebral hypoxia causes an elevated heart rate, and in extreme cases the heart may tire and stop pumping. CPR, defibrilation, epinephrine, and atropine may all be tried in an effort to get the heart to resume pumping. Severe cerebral hypoxia can also cause seizures, which put the patient at risk of self-injury, and various anti-convulsant drugs may need to be administered before treatment.

There has long been a debate over whether newborn infants with cerebral hypoxia should be resuscitated with 100% oxygen or normal air. It has been demonstrated that high concentrations of oxygen lead to generation of oxygen free radicals, which have a role in reperfusion injury after asphyxia. Research by Ola Didrik Saugstad and others led to new international guidelines on newborn resuscitation in 2010, recommending the use of normal air instead of 100% oxygen.

Brain damage can occur both during and after oxygen deprivation. During oxygen deprivation, cells die due to an increasing acidity in the brain tissue (acidosis). Additionally, during the period of oxygen deprivation, materials that can easily create free radicals build up. When oxygen enters the tissue these materials interact with oxygen to create high levels of oxidants. Oxidants interfere with the normal brain chemistry and cause further damage (this is known as "reperfusion injury").

Techniques for preventing damage to brain cells are an area of ongoing research. Hypothermia therapy for neonatal encephalopathy is the only evidence-supported therapy, but antioxidant drugs, control of blood glucose levels, and hemodilution (thinning of the blood) coupled with drug-induced hypertension are some treatment techniques currently under investigation. Hyperbaric oxygen therapy is being evaluated with the reduction in total and myocardial creatine phosphokinase levels showing a possible reduction in the overall systemic inflammatory process.

In severe cases it is extremely important to act quickly. Brain cells are very sensitive to reduced oxygen levels. Once deprived of oxygen they will begin to die off within five minutes.

HACE occurs in 0.5% to 1% of people who climb or trek between and . In some unusual cases, up to 30% of members of expeditions have suffered from the condition. The condition is seldom seen below , but in some rare cases it has developed as low as . The condition generally does not occur until an individual has spent 48 hours at an altitude of .

Patients with HACE should be brought to lower altitudes and provided supplemental oxygen, and rapid descent is sometimes needed to prevent mortality. Early recognition is important because as the condition progresses patients are unable to descend without assistance. Dexamethasone should also be administered, although it fails to ameliorate some symptoms that can be cured by descending to a lower altitude. It can also mask symptoms, and they sometimes resume upon discontinuation. Dexamethasone's prevention of angiogenesis may explain why it treats HACE well. Three studies that examined how mice and rat brains react to hypoxia gave some credence to this idea.

If available, supplemental oxygen can be used as an adjunctive therapy, or when descent is not possible. FiO2 should be titrated to maintain arterial oxygen saturation of greater than 90%, bearing in mind that oxygen supply is often limited in high altitude clinics/environments.

In addition to oxygen therapy, a portable hyperbaric chamber (Gamow bag) can by used as a temporary measure in the treatment of HACE. These devices simulate a decrease in altitude of up to 7000 ft, but they are resource intensive and symptoms will often return after discontinuation of the device. Portable hyperbaric chambers should not be used in place of descent or evacuation to definitive care.

Diuretics may be helpful, but pose risks outside of a hospital environment. Sildenafil and tadalafil may help HACE, but there is little evidence of their efficacy. Theophylline is also theorized to help the condition.

Although AMS is not life-threatening, HACE is usually fatal within 24 hours if untreated. Without treatment, the patient will enter a coma and then die. In some cases, patients have died within a few hours, and a few have survived for two days. Descriptions of fatal cases often involve climbers who continue ascending while suffering from the condition's symptoms.

Recovery varies between days and weeks, but most recover in a few days. After the condition is successfully treated, it is possible for climbers to reascend. Dexamethesone should be discontinued, but continual acetazolamide is recommended. In one study, it took patients between one week and one month to display a normal CT scan after suffering from HACE.

The incidence of clinical HAPE in unacclimatized travelers exposed to high altitude (~) appears to be less than 1%. The U.S. Army Pike's Peak Research Laboratory has exposed sea-level-resident volunteers rapidly and directly to high altitude; during 30 years of research involving about 300 volunteers (and over 100 staff members), only three have been evacuated with suspected HAPE.