Oxygen toxicity

Oxygen toxicity is a condition resulting from the harmful effects of breathing molecular oxygen (O2) at elevated partial pressures. It is also known as oxygen toxicity syndrome, oxygen intoxication, and oxygen poisoning. Historically, the central nervous system condition was called the Paul Bert effect, and the pulmonary condition the Lorrain Smith effect, after the researchers who pioneered its discovery and description in the late 19th century. Severe cases can result in cell damage and death, with effects most often seen in the central nervous system, lungs and eyes. Oxygen toxicity is a concern for scuba divers, those on high concentrations of supplemental oxygen (particularly premature babies), and those undergoing hyperbaric oxygen therapy.
The result of breathing elevated concentrations of oxygen is hyperoxia, an excess of oxygen in body tissues. The body is affected in different ways depending on the type of exposure. Central nervous system toxicity is caused by short exposure to high concentrations of oxygen at greater than atmospheric pressure. Pulmonary and ocular toxicity result from longer exposure to elevated oxygen levels at normal pressure. Symptoms may include disorientation, breathing problems, and vision changes such as myopia. Prolonged or very high oxygen concentrations can cause oxidative damage to cell membranes, the collapse of the alveoli in the lungs, retinal detachment, and seizures. Oxygen toxicity is managed by reducing the exposure to elevated oxygen levels. Studies show that, in the long term, a robust recovery from most types of oxygen toxicity is possible.
Protocols for avoidance of hyperoxia exist in fields where oxygen is breathed at higher-than-normal partial pressures, including scuba diving, hyperbaric medicine, neonatal care and human spaceflight. These protocols have resulted in the increasing rarity of seizures due to oxygen toxicity, with pulmonary and ocular damage being mainly confined to the problems of managing premature infants.
In recent years, oxygen has become available for recreational use in oxygen bars. The U.S. Food and Drug Administration has warned those suffering from problems such as heart or lung disease not to use oxygen bars. Scuba divers use breathing gases containing up to 100% oxygen, and should have specific training in using such gases.
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[edit] Classification

The effects of oxygen toxicity may be classified by the organs affected, producing three principal forms:[2][3][4]
• Central nervous system, characterised by convulsions followed by unconsciousness, occurring under hyperbaric conditions;
• Pulmonary (lungs), characterised by difficulty in breathing and pain within the chest, occurring when breathing elevated pressures of oxygen for extended periods;
• Ocular (retinopathic conditions), characterised by alterations to the eyes, occurring when breathing elevated pressures of oxygen for extended periods.
Central nervous system oxygen toxicity can cause a seizure, a brief period of rigidity followed by convulsions and unconsciousness, and is of concern to divers who encounter greater than atmospheric pressures. Pulmonary oxygen toxicity results in damage to the lungs, causing pain and difficulty in breathing. Oxidative damage to the eye may lead to myopia or partial detachment of the retina. Pulmonary and ocular damage are most likely to occur when supplemental oxygen is administered as part of a treatment, particularly to newborn infants, but are also a concern during hyperbaric oxygen therapy.
Oxidative damage may occur in any cell in the body but the effects on the three most susceptible organs will be the primary concern. It may also be implicated in red blood cell destruction (hemolysis),[5][6] damage to liver (hepatic),[7] heart (myocardial),[8] endocrine glands (adrenal, gonads, and thyroid),[9][10][11] or kidneys (renal),[12] and general damage to cells.[2][13]
In unusual circumstances, effects on other tissues may be observed: it is suspected that during spaceflight, high oxygen concentrations may contribute to bone damage.[14] Hyperoxia can also indirectly cause carbon dioxide narcosis in patients with lung ailments such as chronic obstructive pulmonary disease or with central respiratory depression.[14] Oxygen toxicity is not associated with hyperventilation, because breathing air at atmospheric pressure always has a partial pressure of oxygen (ppO2) of 0.21 bar (21 kPa) and the lower limit for toxicity is more than 0.3 bar (30 kPa).[15]
[edit] Signs and symptoms
Oxygen Poisoning at 90 ft (27 m) in the Dry in 36 Subjects in Order of Performance – K W Donald[1]

Exposure (mins.) Num. of Subjects Symptoms
96 1 Prolonged dazzle; severe spasmodic vomiting
60–69 3 Severe lip-twitching; Euphoria; Nausea and vertigo; arm twitch
50–55 4 Severe lip-twitching; Dazzle; Blubbering of lips; fell asleep; Dazed
31–35 4 Nausea, vertigo, lip-twitching; Convulsed
21–30 6 Convulsed; Drowsiness; Severe lip-twitching; epigastric aura; twitch L arm; amnesia
16–20 8 Convulsed; Vertigo and severe lip twitching; epigastric aura; spasmodic respiration;
11–15 4 Inspiratory predominance; lip-twitching and syncope; Nausea and confusion
6–10 6 Dazed and lip-twitching; paraesthesiae; vertigo; "Diaphragmatic spasm"; Severe nausea
[edit] Central nervous system
Central nervous system oxygen toxicity manifests as symptoms such as visual changes (especially tunnel vision), ringing in the ears (tinnitus), nausea, twitching (especially of the face), irritability (personality changes, anxiety, confusion, etc.), and dizziness. This may be followed by a tonic–clonic seizure consisting of two phases: intense muscle contraction occurs for several seconds (tonic); followed by rapid spasms of alternate muscle relaxation and contraction producing convulsive jerking (clonic). The seizure ends with a period of unconsciousness (the postictal state).[16][17] The onset of seizure depends upon the partial pressure of oxygen (ppO2) in the breathing gas and exposure duration. However, exposure time before onset is unpredictable, as tests have shown a wide variation, both amongst individuals, and in the same individual from day to day.[16][18][19] In addition, many external factors, such as underwater immersion, exposure to cold, and exercise will decrease the time to onset of central nervous system symptoms.[1] Decrease of tolerance is closely linked to retention of carbon dioxide.[20][21][22] Other factors, such as darkness and caffeine, increase tolerance in test animals, but these effects have not been proven in humans.[23][24]
[edit] Pulmonary
Pulmonary toxicity symptoms result from an inflammation that starts in the airways leading to the lungs and then spreads into the lungs (tracheobronchial tree). The symptoms appear in the upper chest region (substernal and carinal regions).[25][26][27] This begins as a mild tickle on inhalation and progresses to frequent coughing.[25] If breathing elevated partial pressures of oxygen is not discontinued, patients experience a mild burning on inhalation along with uncontrollable coughing and occasional shortness of breath (dyspnea).[25] Physical findings related to pulmonary toxicity have included bubbling sounds heard through a stethoscope (bubbling rales), fever, and increased blood flow to the lining of the nose (hyperemia of the nasal mucosa).[27] The radiological finding from the lungs shows inflammation and swelling (pulmonary edema).[25][26] Pulmonary function measurements are reduced, as noted by a reduction in the amount of air that the lungs can hold (vital capacity) and changes in expiratory function and lung elasticity.[27][28] Tests in animals have indicated a variation in tolerance similar to that found in central nervous system toxicity, as well as significant variations between species. When the exposure to oxygen above 0.5 bar (50 kPa) is intermittent, it permits the lungs to recover and delays the onset of toxicity.[29]
[edit] Ocular
In premature babies, signs of damage to the eye (retinopathy of prematurity, or ROP) are observed via an ophthalmoscope as a demarcation between the vascularized and non-vascularised regions of an infant's retina. The degree of this demarcation is used to designate four stages: (I) the demarcation is a line; (II) the demarcation becomes a ridge; (III) growth of new blood vessels occurs around the ridge; (IV) the retina begins to detach from the inner wall of the eye (choroid).[30]
[edit] Causes
Oxygen toxicity is caused by exposure to oxygen at partial pressures greater than those to which the body is normally exposed. This occurs in three principal settings: underwater diving, hyperbaric oxygen therapy and the provision of supplemental oxygen, particularly to premature infants. In each case, the risk factors are markedly different.
[edit] Central nervous system toxicity
See also: Technical diving
Exposures, from minutes to a few hours, to partial pressures of oxygen above 1.6 bars (160 kPa)—about eight times the atmospheric concentration—are usually associated with central nervous system oxygen toxicity and are most likely to occur among patients undergoing hyperbaric oxygen therapy and divers. Since atmospheric pressure is about 1 bar (100 kPa), central nervous system toxicity can only occur under hyperbaric conditions, where ambient pressure is above normal.[31][32] Divers breathing air at depths greater than 60 m (200 ft) face an increasing risk of an oxygen toxicity "hit" (seizure). Divers breathing a gas mixture enriched with oxygen, such as nitrox, can similarly suffer a seizure at shallower depths, should they descend below the maximum depth allowed for the mixture.[33]
[edit] Pulmonary toxicity
The lungs, as well as the remainder of the respiratory tract, are exposed to the highest concentration of oxygen in the human body and are therefore the first organs to show toxicity. Pulmonary toxicity occurs with exposure to concentrations of oxygen greater than 0.5 bar (50 kPa), corresponding to an oxygen fraction of 50% at normal atmospheric pressure. Signs of pulmonary toxicity begins with evidence of tracheobronchitis, or inflammation of the upper airways, after an asymptomatic period between 4 and 22 hours at greater than 95% oxygen,[34] with some studies suggesting symptoms usually begin after approximately 14 hours at this level of oxygen.[35]
At partial pressures of oxygen of 2 to 3 bar (200 to 300 kPa)—100% oxygen at 2 to 3 times atmospheric pressure—these symptoms may begin as early as 3 hours after exposure to oxygen.[34] Experiments on rats show pulmonary manifestations of oxygen toxicity are not the same for normobaric conditions as they are for hyperbaric conditions.[36] Evidence of decline in lung function as measured by pulmonary function testing can occur as quickly as 24 hours of continuous exposure to 100% oxygen,[35] with evidence of diffuse alveolar damage and the onset of acute respiratory distress syndrome usually occurring after 48 hours on 100% oxygen.[34] Breathing 100% oxygen also eventually leads to collapse of the alveoli (atelectasis), while—at the same partial pressure of oxygen—the presence of significant partial pressures of inert gases, typically nitrogen, will prevent this effect.[37]
Preterm newborns are known to be at higher risk for bronchopulmonary dysplasia with extended exposure to high concentrations of oxygen.[38] Other groups at higher risk for oxygen toxicity are patients on mechanical ventilation with exposure to levels of oxygen greater than 50%, and patients exposed to chemicals that increase risk for oxygen toxicity such the chemotherapeutic agent bleomycin.[35] Therefore, current guidelines for patients on mechanical ventilation in intensive care suggests keeping oxygen concentration less than 60%.[34] Likewise, divers who undergo treatment of decompression sickness are at increased risk of oxygen toxicity as treatment entails exposure to long periods of oxygen breathing under hyperbaric conditions, in addition to any oxygen exposure during the dive.[31]
[edit] Ocular toxicity
See also: Retinopathy of prematurity
Prolonged exposure to high inspired fractions of oxygen causes damage to the retina.[39][40][41] Damage to the developing eye of infants exposed to high oxygen fraction at normal pressure has a different mechanism and effect from the eye damage experienced by adult divers under hyperbaric conditions.[42][43] Hyperoxia may be a contributing factor for the disorder called retrolental fibroplasia or retinopathy of prematurity (ROP) in infants.[42][44] In preterm infants, the retina is often not fully vascularised. Retinopathy of prematurity occurs when the development of the retinal vasculature is arrested and then proceeds abnormally. Associated with the growth of these new vessels is fibrous tissue (scar tissue) that may contract to cause retinal detachment. Supplemental oxygen exposure, while a risk factor, is not the main risk factor for development of this disease. Restricting supplemental oxygen use does not necessarily reduce the rate of retinopathy of prematurity, and may raise the risk of hypoxia-related systemic complications.[42]
Hyperoxic myopia has occurred in closed circuit oxygen rebreather divers with prolonged exposures.[43][45][46] It also occurs frequently in those undergoing repeated hyperbaric oxygen therapy.[40][47] This is due to an increase in the refractive power of the lens, since axial length and keratometry readings do not reveal a corneal or length basis for a myopic shift.[47][48] It is usually reversible with time.[40][47]
[edit] Mechanism
Main articles: Reactive oxygen species and Oxidative stress


The lipid peroxidation mechanism shows a single radical initiating a chain reaction which converts unsaturated lipids to lipid peroxides,
The biochemical basis for the toxicity of oxygen is the partial reduction of oxygen by one or two electrons to form reactive oxygen species,[49] which are natural by-products of the normal metabolism of oxygen and have important roles in cell signalling.[50] One species produced by the body, the superoxide anion (O2–),[51] is possibly involved in iron acquisition.[52] Higher than normal concentrations of oxygen lead to increased levels of reactive oxygen species.[53] Oxygen is necessary for cell metabolism, and the blood supplies it to all parts of the body. When oxygen is breathed at high partial pressures, a hyperoxic condition will rapidly spread, with the most vascularised tissues being most vulnerable. During times of environmental stress, levels of reactive oxygen species can increase dramatically, which can damage cell structures and produce oxidative stress.[19][54]
While all the reaction mechanisms of these species within the body are not yet fully understood,[55] one of the most reactive products of oxidative stress is the hydroxyl radical (•OH), which can initiate a damaging chain reaction of lipid peroxidation in the unsaturated lipids within cell membranes.[56] High concentrations of oxygen also increase the formation of other free radicals, such as nitric oxide, peroxynitrite, and trioxidane, which harm DNA and other biomolecules.[19][57] Although the body has many antioxidant systems such as glutathione that guard against oxidative stress, these systems are eventually overwhelmed at very high concentrations of free oxygen, and the rate of cell damage exceeds the capacity of the systems that prevent or repair it.[58][59][60] Cell damage and cell death then result.[61]
[edit] Diagnosis
Diagnosis of central nervous system oxygen toxicity in divers prior to seizure is difficult as the symptoms of visual disturbance, ear problems, dizziness, confusion and nausea can be due to many factors common to the underwater environment such as narcosis, congestion and coldness. However, these symptoms may be helpful in diagnosing the first stages of oxygen toxicity in patients undergoing hyperbaric oxygen therapy. In either case, unless there is a prior history of epilepsy or tests indicate hypoglycemia, a seizure occurring in the setting of breathing oxygen at partial pressures greater than 1.4 bar (140 kPa) suggests a diagnosis of oxygen toxicity.[62]
Diagnosis of bronchopulmonary dysplasia in new-born infants with breathing difficulties is difficult in the first few weeks. However, if the infant's breathing does not improve during this time, blood tests and x-rays may be used to confirm bronchopulmonary dysplasia. In addition, an echocardiogram can help to eliminate other possible causes such as congenital heart defects or pulmonary arterial hypertension.[63]
The diagnosis of retinopathy of prematurity in infants is typically suggested by the clinical setting. Prematurity, low birth weight and a history of oxygen exposure are the principal indicators, while no hereditary factors have been shown to yield a pattern.[64]
[edit] Prevention


The label on the diving cylinder shows that it contains oxygen-rich gas (36%) and is boldly marked with a maximum operating depth of 28 metres.
The prevention of oxygen toxicity depends entirely on the setting. Both underwater and in space, proper precautions can eliminate the most pernicious effects. Premature infants commonly require supplemental oxygen to treat complications of preterm birth. In this case prevention of bronchopulmonary dysplasia and retinopathy of prematurity must be carried out without compr
oxygen toxicity
n.
A condition resulting from breathing high partial pressures of oxygen, characterized by visual and hearing abnormalities, unusual fatigue, muscular twitching, anxiety, confusion, incoordination, and convulsions.
The American Heritage® Medical Dictionary Copyright © 2007, 2004 by Houghton Mifflin Company. Published by Houghton Mifflin Company. All rights reserved.
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oxygen toxicity,
a condition of oxygen overdosage that can result in pathologic tissue changes, such as retinopathy of prematurity or bronchopulmonary dysplasia. It can also decrease CO2 drive to breathe.
Mosby's Medical Dictionary, 8th edition. © 2009, Elsevier.
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oxygen
a chemical element, atomic number 8, atomic weight 15.999, symbol O. See Table 6. It is a colorless and odorless gas that makes up about 20% of the atmosphere. In combination with hydrogen, it forms water; by weight, 90% of water is oxygen. It is the most abundant of all the elements of nature. Large quantities of it are distributed throughout the solid matter of the earth, because the gas combines readily with many other elements. With carbon and hydrogen, oxygen forms the chemical basis of much organic material. Oxygen is essential in sustaining all kinds of life.
omising a supply of oxygen adequate to preserve the infant's life.

Toxicity
See also: Carbon dioxide poisoning


Main symptoms of Carbon dioxide toxicity, by increasing volume percent in air.[2][42].
Carbon dioxide content in fresh air (averaged between sea-level and 10 hPa level, i.e. about 30 km altitude) varies between 0.036% (360 ppm) and 0.039% (390 ppm), depending on the location[43].
Prolonged exposure to moderate[clarification needed] concentrations can cause acidosis and adverse effects on calcium phosphorus metabolism resulting in increased calcium deposits in soft tissue. Carbon dioxide is toxic to the heart and causes diminished contractile force.[42]
Toxicity and its effects increase with the concentration of CO2, here given in volume percent of CO2 in the air:
• 1%, as can occur in a crowded auditorium with poor ventilation, can cause drowsiness with prolonged exposure.[2]
• At 2% it is mildly narcotic and causes increased blood pressure and pulse rate, and causes reduced hearing.[42]
• At about 5% it causes stimulation of the respiratory centre, dizziness, confusion and difficulty in breathing accompanied by headache and shortness of breath.[42]. In addition at this concentration panic attacks may occur.[44][45]
• At about 8% it causes headache, sweating, dim vision, tremor and loss of consciousness after exposure for between five and ten minutes.[42]
A natural disaster linked to CO2 intoxication occurred during the limnic eruptions in the CO2-rich lakes of Monoun and Nyos in the Okun range of North-West Cameroon: the gas was brutally expelled from the mountain lakes and leaked into the surrounding valleys, killing most animal forms. During the Lake Nyos tragedy of 1988, 1700 villagers and 3500 livestock died.
Due to the health risks associated with carbon dioxide exposure, the U.S. Occupational Safety and Health Administration says that average exposure for healthy adults during an eight-hour work day should not exceed 5,000 ppm (0.5%). The maximum safe level for infants, children, the elderly and individuals with cardio-pulmonary health issues is significantly less. For short-term (under ten minutes) exposure, the U.S. National Institute for Occupational Safety and Health (NIOSH) and American Conference of Government Industrial Hygienists (ACGIH) limit is 30,000 ppm (3%). NIOSH also states that carbon dioxide concentrations exceeding 4% are immediately dangerous to life and health[46] although physiological experiments show that such levels can be tolerated for some time [47].
Adaptation to increased levels of CO2 occurs in humans. Continuous inhalation of CO2 can be tolerated at three percent inspired concentrations for at least one month and four percent inspired concentrations for over a week. It was suggested that 2.0 percent inspired concentrations could be used for closed air spaces (e.g. a submarine) since the adaptation is physiological and reversible. Decrement in performance or in normal physical activity does not happen at this level.[47][48] However, it should be noted that submarines have carbon dioxide scrubbers which reduce a significant amount of the CO2 present.[49]
These figures are valid for pure carbon dioxide. In indoor spaces occupied by people the carbon dioxide concentration will reach higher levels than in pure outdoor air. Concentrations higher than 1,000 ppm will cause discomfort in more than 20% of occupants, and the discomfort will increase with increasing CO2 concentration. The discomfort will be caused by various gases coming from human respiration and perspiration, and not by CO2 itself. At 2,000 ppm the majority of occupants will feel a significant degree of discomfort, and many will develop nausea and headaches. The CO2 concentration between 300 and 2,500 ppm is used as an indicator of indoor air quality.
Acute carbon dioxide toxicity is sometimes known by the names given to it by miners: blackdamp (also called choke damp or stythe). Backdamp is primarily nitrogen and carbon dioxide and kills via suffocation (having displaced oxygen). Miners would try to alert themselves to dangerous levels of blackdamp and other gasses in a mine shaft by bringing a caged canary with them as they worked. The canary is more sensitive to environmental gasses than humans and as it became unconscious would stop singing and fall off its perch. The Davey lamp could also detect high levels of blackdamp (which collect near the floor) by burning less brightly, while methane, another suffocating gas and explosion risk would make the lamp burn more brightly).
Carbon dioxide ppm levels (CDPL) are a surrogate for measuring indoor pollutants that may cause occupants to grow drowsy, get headaches, or function at lower activity levels. To eliminate most indoor air quality complaints, total indoor CDPL must be reduced to below 600. NIOSH considers that indoor air concentrations that exceed 1,000 are a marker suggesting inadequate ventilation. ASHRAE recommends they not exceed 1,000 inside a space.