Hypoxia Part I

 Hypoxia is a condition in which the body or a region of the body is deprived of adequate oxygen supply at the tissue level. Hypoxia may be classified as either generalized, affecting the whole body, or local, affecting a region of the body. Although hypoxia is often a pathological condition, variations in arterial oxygen concentrations can be part of 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 in the blood. 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). Hypoxia also occurs in healthy individuals when breathing inappropriate mixtures of gases with a low oxygen content, e.g., while diving underwater, especially when using malfunctioning closed-circuit 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 levels.

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

Classification

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. 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 generalized hypoxia, may be caused by:

Hypoventilation, is insufficient ventilation of the lungs due to any cause (fatigue, excessive work of breathing, 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, breathing hypoxic breathing gas at an unsuitable depth, breathing inadequately, re-oxygenated recycled breathing gas from a rebreather, life support system, or anesthetic machine.

Chronic obstructive pulmonary disease (COPD)

Neuromuscular diseases or interstitial lung disease

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. This definition overlaps considerably with that of hypoxic hypoxia.

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:

Ventilation-perfusion mismatch (V/Q mismatch), which can be either low or high. 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 ventilation. In this situation, there is not enough oxygen in the alveolar gas to fully oxygenate the blood volume passing through, and PaO2 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, PaO2 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.

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 intracardiac shunts, pulmonary arteriovenous malformations, fistulas, and hepatopulmonary syndrome, or physiological shunting, in which blood passes through non-ventilated alveoli.

Impaired diffusion, is 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 diseases such as pulmonary fibrosis, sarcoidosis, hypersensitivity pneumonitis, and connective tissue disorders.

Circulatory hypoxia, also known as ischemic hypoxia or stagnant hypoxia, is caused by abnormally low blood flow to the lungs, which can occur during 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 oxygenated in the lungs, and the tissues can accept the oxygen available, but the flow rate to the tissues is insufficient. Venous oxygenation is particularly low.

Anemic hypoxia or hypemic hypoxia is the lack of capacity of the blood to carry the normal level of oxygen. It can be caused by anemia or:

Carbon monoxide poisoning, in which carbon monoxide combines with the hemoglobin, to form carboxyhemoglobin (HbCO) preventing it from transporting oxygen.

Methemoglobinemia, is a change in the hemoglobin molecule from a ferrous ion (Fe2+) to a ferric ion (Fe3+), which has a lesser capacity to bind free oxygen molecules, and a greater affinity for bound oxygen. This causes a left shift in the O2–Hb curve. It can be congenital or caused by medications, food additives, or toxins, including chloroquine, benzene, nitrites, and benzocaine.

Histotoxic hypoxia (Dysoxia) or Cellular hypoxia occurs when the cells of the affected tissues are unable to use oxygen provided by normally oxygenated hemoglobin. 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.

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. 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.

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 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, 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, numbness/tingling of extremities, nausea, and cerebral hypoxia. These symptoms are often difficult to identify, but early detection of symptoms can be critical.

In severe hypoxia, or hypoxia of very rapid onset, ataxia, confusion, disorientation, hallucinations, behavioral change, severe headaches, reduced level of consciousness, papilloedema, breathlessness, pallor, tachycardia, and pulmonary hypertension eventually lead to late signs of cyanosis, slow heart rate, cor pulmonale, and low blood pressure followed by heart failure eventually leading to shock and death.

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. In cases where the oxygen is displaced by another molecule, such as carbon monoxide, the skin may appear 'cherry red' instead of cyanotic. Hypoxia can cause premature birth, and injure the liver, among other deleterious effects.

Localized hypoxia

Hypoxia 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. Ischemia is generally caused by problems with blood vessels, with resultant damage to or dysfunction of tissue i.e. hypoxia and microvascular dysfunction. 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 nutrients and inadequate removal of metabolic wastes. 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 anatomical compartments results in insufficient blood supply to tissue within that space. There are two main types: acute and chronic. Compartments of the leg or arm are most commonly involved.

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

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 neuronal cell death via apoptosis, resulting in a hypoxic brain injury.

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 birth asphyxia, it can occur in all age groups and is often a complication of cardiac arrest.

Corneal hypoxia

Although corneal hypoxia can arise from any of several causes, it is primarily attributable to the prolonged use of contact lenses. 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.

Intrauterine hypoxia

Intrauterine hypoxia, also known as fetal hypoxia, occurs when the fetus is deprived of an adequate supply of oxygen. It may be due to a variety of reasons such as prolapse or occlusion of the umbilical cord, placental infarction, maternal diabetes (pre-pregnancy or gestational diabetes) and 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 has been implicated as either a primary or a contributing risk factor in numerous neurological and neuropsychiatric disorders such as epilepsy, attention deficit hyperactivity disorder, eating disorders, and cerebral palsy.

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 micro-environements in solid tumors are a result of available oxygen being consumed within 70 to 150 μm of tumor 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 in normal tissues and it is reported somewhere between 1%–2% O2. 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. Tumor hypoxia is usually associated with highly malignant tumors, 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

Increased 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 12,000 feet (3,700 m).

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 significantly 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 vapor, 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 the blood, oxygen is bound to hemoglobin, a protein in red blood cells. The binding capacity of hemoglobin is influenced by the 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.

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. 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. Experimentally, oxygen diffusion becomes rate-limiting when arterial oxygen partial pressure falls to 60 mmHg (5.3 kPa) or below.

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, 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.

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 embolism, a heart attack that decreases overall blood flow, trauma to a tissue that results in damage reducing perfusion, and a variety of other causes. A consequence of insufficient blood flow causing local hypoxia is gangrene which occurs in diabetes.

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.

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 the 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.

Hypoxemic hypoxia

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.

Common disorders that can cause respiratory dysfunction include trauma to the head and spinal cord, non-traumatic 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.

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.  Carbon monoxide poisoning can occur acutely, as with smoke intoxication, or over some 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.

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. In so doing, the hemoglobin is less likely to release its oxygen 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.

Altitude

Atmospheric pressure reduces with altitude and proportionally, so does the oxygen content of the air. The reduction in the partial pressure of inspired oxygen at higher altitudes lowers the oxygen saturation of the blood, ultimately leading to hypoxia. The clinical features of altitude sickness include sleep problems, dizziness, headache, and edema.

Hypoxic breathing 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 that will not reliably maintain consciousness at sea-level pressure.

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.

Gases with as little as 2% oxygen by volume in a helium diluent are used for deep diving operations. The ambient pressure at 190 msw is sufficient to provide a partial pressure of about 0.4 bar, which is suitable for saturation diving. As the divers are decompressed, the breathing gas must be oxygenated to maintain a breathable atmosphere.

It is also possible for the breathing gas for diving to have a dynamically controlled oxygen partial pressure, known as a 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.

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 loses consciousness before reaching the surface.

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 recognizable by smell, others are odorless.

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.

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 as well as certain drugs and other chemicals.

Anemia

Hemoglobin plays a substantial role in carrying oxygen throughout the body, and when it is deficient, anemia can result, causing 'anemic 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 synthesized 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 anemia.

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 (anemic hypoxia), low cardiac output (stagnant hypoxia) or low haemoglobin saturation (hypoxic hypoxia). 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. Serum lactate levels have been correlated with illness severity and mortality in critically ill adults and in ventilated neonates with respiratory distress.