Hypoxia (medicine)

Hypoxia exists when there is a reduced amount of oxygen in the tissues of the body. Hypoxemia refers to a reduction in arterial oxygenation below the normal range, regardless of whether gas exchange is impaired in the lung, arterial oxygen content (CaO2 – which represents the amount of oxygen delivered to the tissues) is adequate, or tissue hypoxia exists. 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, Localized hypoxia 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. 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. 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. Tumour hypoxia is usually associated with highly malignant tumours, which frequently do not respond well to treatment. 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. ==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 • Headache • Decreased reaction time, disorientation, and uncoordinated movement. • Impaired judgment, confusion, memory loss and cognitive problems. • Euphoria or dissociation • Visual impairment 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 . • Lightheaded or dizzy sensation, vertigo • Fatigue, drowsiness, or tiredness • Shortness of breath • Palpitations may occur in the initial phases. Later, the heart rate may reduce to a significant degree. In severe cases, abnormal heart rhythms may develop. • Nausea and vomiting • Initially raised blood pressure followed by lowered blood pressure as the condition progresses. • 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. • Tingling in fingers and toes • Numbness 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. • Obstructive sleep apnea syndrome is a risk factor for cerebrovascular disease and cognitive dysfunction. ==Causes==

Oxygen passively diffuses in the lung alveoli according to a concentration gradient, also referred to as a partial pressure gradient. Inhaled air rapidly reaches saturation with water vapour, which slightly reduces the partial pressures of the other components. Oxygen diffuses from the inhaled air to arterial blood, where its partial pressure is around 100 mmHg (13.3 kPa). In systemic tissues, oxygen again diffuses down a concentration gradient into cells and their mitochondria, where it is used to produce energy in conjunction with the breakdown of glucose, fats, and some amino acids. Altitude Atmospheric pressure reduces with altitude and proportionally, so does the oxygen content of the air. Anemia Hemoglobin plays a substantial role in carrying oxygen throughout the body, 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. 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. 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. Histotoxic hypoxia results from tissue poisoning, such as that caused by cyanide (which acts by inhibiting cytochrome oxidase) and certain other poisons like hydrogen sulfide (byproduct of sewage and used in leather tanning). ==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). In most tissues of the body, the response to hypoxia is vasodilation. By widening the blood vessels, the tissue allows greater perfusion. By contrast, in the lungs, the response to hypoxia is vasoconstriction. This is known as hypoxic pulmonary vasoconstriction, or "HPV", and has the effect of redirecting blood away from poorly ventilated regions, which helps match perfusion to ventilation, giving a more even oxygenation of blood from different parts of the lungs. The resulting tumor vasculature is often abnormal in structure and function — characterized by irregular vessel diameters, increased permeability, and poor perfusion — which further perpetuates local hypoxia and genomic instability. This feedback loop enhances the tumor’s adaptive potential and resistance to therapies such as radiotherapy and chemotherapy, both of which rely on adequate oxygenation to maximize cytotoxic effects. In addition to promoting angiogenesis, HIF signaling also supports metabolic reprogramming toward anaerobic glycolysis, enhances the expression of matrix metalloproteinases (MMPs) that degrade extracellular matrix components, and increases the expression of adhesion molecules that facilitate tumor invasion and metastatic dissemination. Together, these mechanisms make hypoxia-induced angiogenesis a central hallmark of malignant progression and a major therapeutic target in oncology. Agents that block VEGF signaling (such as bevacizumab) or inhibit HIF-1α activity are currently used or under investigation to counteract tumor angiogenesis and improve treatment outcomes. ==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. 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. Lung auscultation can provide useful information. Tests An arterial blood gas test (ABG) may be done, which usually includes measurements of oxygen content, hemoglobin, oxygen saturation (how much of the hemoglobin is carrying oxygen), arterial partial pressure of oxygen (PaO2), partial pressure of carbon dioxide (PaCO2), blood pH level, and bicarbonate (HCO3) • An arterial oxygen tension (PaO2) less than 80 mmHg is considered abnormal, but must be considered in context of the clinical situation. • In addition to diagnosis of hypoxemia, the ABG may provide additional information, such as PCO2, which can help identify the etiology. The arterial partial pressure of carbon dioxide is an indirect measure of exchange of carbon dioxide with the air in the lungs, and is related to minute ventilation. PCO2 is raised in hypoventilation. • The normal range of PaO2:FiO2 ratio is 300 to 500 mmHg, if this ratio is lower than 300 it may indicate a deficit in gas exchange, which is particularly relevant for identifying acute respiratory distress syndrome (ARDS). A ratio of less than 200 indicates severe hypoxemia. • The alveolar–arterial gradient (A-aO2, or A–a gradient), is the difference between the alveolar (A) concentration of oxygen and the arterial (a) concentration of oxygen. It is a useful parameter for narrowing the differential diagnosis of hypoxemia. The A–a gradient helps to assess the integrity of the alveolar capillary unit. For example, at high altitude, the arterial oxygen PaO2 is low, but only because the alveolar oxygen PAO2 is also low. However, in states of ventilation perfusion mismatch, such as pulmonary embolism or right-to-left shunt, oxygen is not effectively transferred from the alveoli to the blood which results in an elevated A-a gradient. PaO2 can be obtained from the arterial blood gas analysis and PAO2 is calculated using the alveolar gas equation. • An abnormally low hematocrit (volume percentage of red blood cells) may indicate anemia. X-rays or CT scans of the chest and airways can reveal abnormalities that may affect ventilation or perfusion. A ventilation/perfusion scan, also called a V/Q lung scan, is a type of medical imaging using scintigraphy and medical isotopes to evaluate the circulation of air and blood within a patient's lungs, 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 may include: • Tests that measure oxygen levels during the night • The six-minute walk test, which measures how far a person can walk on a flat surface in six minutes to test exercise capacity by measuring oxygen levels in response to exercise. • Diagnostic measurements that may be relevant include: Lung volumes, including lung capacity, airway resistance, respiratory muscle strength, diffusing capacity • Other pulmonary function tests which may be relevant include: Spirometry, body plethysmography, forced oscillation technique for calculating the volume, pressure, and air flow in the lungs, bronchodilator responsiveness, carbon monoxide diffusion test (DLCO), oxygen titration studies, cardiopulmonary stress test, bronchoscopy, and 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 (PaO2) is generally an indication of inability of the lungs to oxygenate the blood properly. 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. Both acute and chronic hypoxia and hypercapnia caused by respiratory dysfunction can produce neurological symptoms such as encephalopathy, seizures, headache, papilledema, and asterixis. Obstructive sleep apnea syndrome may cause morning headaches • Circulatory hypoxia is 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. • Anemic hypoxia is caused by a deficit in oxygen-carrying capacity, usually due to low hemoglobin levels, leading to generalised inadequate oxygen delivery. • 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. Critical illness polyneuropathy or myopathy should be considered in the intensive care unit when patients have difficulty coming off the ventilator. ==Prevention==

Prevention can be as simple as risk management of occupational exposure to hypoxic environments, and commonly involves the use of environmental monitoring and personal protective equipment. Prevention of hypoxia as a predictable consequence of medical conditions requires prevention of those conditions. Screening of demographics known to be at risk for specific disorders may be useful. Prevention of altitude-induced hypoxia To counter the effects of high-altitude diseases, the body must return arterial PaO2 toward normal. Acclimatization, the means by which the body adapts to higher altitudes, only partially restores PO2 to standard levels. Hyperventilation, the body's most common response to high-altitude conditions, increases alveolar PO2 by raising the depth and rate of breathing. However, while PO2 does improve with hyperventilation, it does not return to normal. Studies of miners and astronomers working at 3000 meters and above show improved alveolar PO2 with full acclimatization, yet the PO2 level remains equal to or even below the threshold for continuous oxygen therapy for patients with chronic obstructive pulmonary disease (COPD). ==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. 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. In some cases treatment may extend to improving oxygen capacity of the blood, which may include volumetric and circulatory intervention and support, hyperbaric oxygen therapy and treatment of intoxication. Invasive ventilation may be necessary or an elective option in surgery. This generally involves a positive pressure ventilator connected to an endotracheal tube, and allows precise delivery of ventilation, accurate monitoring of FiO2, and positive end-expiratory pressure, and can be combined with anaesthetic gas delivery. In some cases a tracheotomy may be necessary. 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. 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. 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. 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. It is also effective in carbon monoxide poisoning and diabetic foot. A prescription renewal for home oxygen following hospitalization requires an assessment of the patient for ongoing hypoxemia. ==Outcomes==

Prognosis in cases of hypoxia depends strongly on the underlying cause, the severity and duration of oxygen deprivation, the effectiveness and timeliness of treatment, and any pre-existing medical conditions that impair oxygen delivery or utilization, such as anemia, COPD, or cardiovascular disease. Mild, short-term hypoxia is often reversible with prompt oxygen therapy and correction of the underlying cause, whereas prolonged or severe hypoxia can result in irreversible cellular injury, hypoxic brain injury, or multi-organ failure. Hypoxia that leads to impaired judgment, delayed reactions, or loss of consciousness can indirectly contribute to fatal outcomes in situations where the immediate cause of death is secondary. This has been documented in underwater diving accidents, where hypoxia can cause confusion or unconsciousness before drowning occurs; in high-altitude mountaineering, where it contributes to exposure, hypothermia, and falls; and in aviation, where pilots of unpressurized aircraft or performers in aerobatic maneuvers may lose control of the aircraft following hypoxic incapacitation. ==Epidemiology==

Hypoxia is a common disorder but there are many possible causes. Potentially life-threatening hypoxemia is common in critically ill patients. Hypoxia related to underdeveloped lung function is also a frequent complication of premature birth. In preterm infants, incomplete maturation of the alveoli and insufficient production of surfactant can lead to respiratory distress syndrome, resulting in systemic oxygen deprivation. In the United States, intrauterine hypoxia and birth asphyxia together were ranked as the tenth leading cause of infant mortality in recent national statistics. Silent hypoxia Silent hypoxia (also known as happy hypoxia) is generalised hypoxia that does not coincide with shortness of breath. This presentation is known to be a complication of COVID-19, and is also known in atypical pneumonia, altitude sickness, and rebreather malfunction accidents. ==History==

The 2019 Nobel Prize in Physiology or Medicine was awarded to William G. Kaelin Jr., Sir Peter J. Ratcliffe, and Gregg L. Semenza in recognition of their discovery of cellular mechanisms to sense and adapt to different oxygen concentrations, establishing a basis for how oxygen levels affect physiological function. 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. ==See also==