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substernal

Oxygen toxicity

Oxygen toxicity or oxygen toxicity syndrome (also known as the "Paul Bert effect" or the "Lorrain Smith effect") describes harmful effects caused by breathing oxygen at elevated partial pressures. The condition of an excess of oxygen in body tissues is known as hyperoxia. Such above-normal concentrations of oxygen within the body can cause cell damage and death. Oxidative damage is most often reported in the central nervous system (CNS), lungs (pulmonary) and eye (retinopathic conditions). It may also be implicated in red blood cell destruction (erythrocyte hemolysis), liver (hepatic) effects, heart (myocardial) damage, endocrine effects (adrenal, gonads, and thyroid), kidney (renal) damage, and general damage to cells.

The damage is caused by long exposure (days) to lower concentrations of oxygen or by shorter exposure (minutes or hours) to high concentrations. Short exposures to partial pressure of oxygen above are usually associated with CNS oxygen toxicity and are most likely to occur among patients undergoing hyperbaric oxygen therapy and divers. Long exposures to partial pressures of oxygen above can result in pulmonary oxygen toxicity and are a concern for patients breathing pure oxygen for extended periods.

The serious effect of CNS oxygen toxicity is a seizure, consisting of a brief period of rigidity followed by convulsions and unconsciousness, which is of concern to divers who breathe gases at much greater than atmospheric pressure. Pulmonary oxygen toxicity results in damage to the lungs causing pain and difficulty in breathing, while oxidative damage to the eye may lead to myopia or partial detachment of the retina. These occur when supplemental oxygen is administered as part of a treatment, particularly to newborn infants.

Prevention of oxygen toxicity is an important precaution whenever oxygen is breathed at greater than normal partial pressures and has led to use of protocols for avoidance of hyperoxia in such fields as diving, hyperbaric therapy, neonatal care and human spaceflight. This has lead to oxygen toxicity seizures becoming increasingly rare, with pulmonary and ocular damage being mainly confined to the problems of managing premature infants.

Classification

In humans, a convenient classification is by organ affected. There are three principal types of oxygen toxicity:

  • Central nervous system (CNS), characterised by convulsions followed by unconsciousness, occurring under hyperbaric conditions
  • Pulmonary, characterised by difficulty in breathing and pain within the chest, occurring when breathing elevated pressures of oxygen for extended periods
  • Ocular, characterised by alterations to the eye, occurring when breathing elevated pressures of oxygen for extended periods

Oxidative damage may occur in any cell in the body but the effects on the most susceptible organs will be the primary concern. In unusual circumstances, effects on other tissues may be observed: it is suspected that during spaceflight, high oxygen concentrations may contribute to bone damage. Hyperoxia can also indirectly cause carbon dioxide narcosis in patients with chronic obstructive pulmonary disease (COPD). Oxygen toxicity is not associated with hyperventilation, because it never results from breathing air at atmospheric pressure.

Signs and symptoms

CNS oxygen toxicity manifests as symptoms such as visual changes, ringing in the ears, nausea, twitching (especially on the face), irritability (personality changes, anxiety, confusion, etc.), and dizziness. This may be followed by a tonic-clonic seizure where intense muscle contraction occurs for several seconds followed by rapid spasms of alternate muscle relaxation and contraction producing convulsive jerking, which is followed by a period of unconsciousness (the postictal state). The onset depends upon partial pressure of oxygen (ppO2) in the breathing gas and exposure duration but experiments have shown that there is a wide variation in exposure time before onset amongst individuals and in the same individual from day to day. In addition, many external factors, such as underwater immersion, exposure to cold, and exercise will decrease the time to onset of CNS symptoms. Decrease of tolerance has been shown to be closely linked to retention of carbon dioxide. Other factors, such as darkness and caffeine increase tolerance in test animals, but these effects have not been proven in humans.

Pulmonary toxicity symptoms result from tracheobronchitis of the substernal and carinal area that spreads to the remaining tracheobronchial tree. This begins as a mild tickle on inspiration and progresses into frequent coughing. If oxygen breathing is not discontinued, patients will have a mild burning on inspiration along with uncontrollable coughing and occasionally dyspnea. Physical findings related to pulmonary toxicity have included bubbling rales, fever, and hyperemia in the nasal mucosa. The radiological finding from the lungs show inflammation and swelling (pulmonary edema). Pulmonary function measurements are reduced as noted by the reduction in vital capacity and change in expiratory function and lung elasticity. Tests in animals have indicated a similar variation in tolerance as found in CNS toxicity as well as significant variations between species. When the exposure to oxygen above is intermittent, it permits the lungs to recover and delays the onset of toxicity.

Causes

CNS toxicity

As CNS toxicity is caused by breathing oxygen at elevated ambient pressures, patients undergoing hyperbaric oxygen therapy are at risk of suffering hyperoxic seizures following short exposures to the high pressure oxygen. For the same reason, divers breathing air at depths greater than face a risk of an oxygen toxicity "hit" (seizure) as do divers breathing a gas mixture enriched with oxygen (Enriched Air Nitrox).

Pulmonary toxicity

The lungs have a very large area in contact with the breathing gas and contain thin membranes with limited antioxidant defenses, making them particularly susceptible to damage by oxygen. Pulmonary toxicity occurs with prolonged exposure to elevated concentrations of oxygen. Pulmonary manifestations of oxygen toxicity are not the same for normobaric conditions as they are for hyperbaric conditions.

The risk of bronchopulmonary dysplasia ("BPD") in infants, or adult respiratory distress syndrome (ARDS) in adults, begins to increase with exposure for over 16 hours to oxygen partial pressures of or more. At sea-level, is exceeded by gas mixtures having oxygen fractions greater than 50%, while the rate of damage rises non-linearly between the 50% threshold of toxicity and the rate at 100% oxygen. Partial pressures between (normal at sea level) and are considered non-toxic but intensive care patients breathing more than 60% oxygen, and especially patients at fractions near 100% oxygen, are considered to be at particularly high risk. If the treatment continues for a lengthy period, it may begin to cause lung damage which exacerbates the original problem requiring the high-oxygen mixture. Oxygen toxicity is also a potential complication of mechanical ventilation with pure oxygen, where it is called respiratory lung syndrome.

Breathing 100% oxygen eventually leads to collapse of the alveoli (atelectasis), while — at same partial pressure of oxygen — the presence of significant partial pressures of inert gases will prevent this effect. In the treatment of decompression sickness, divers are exposed to long periods of oxygen breathing under hyperbaric conditions. This exposure, coupled with that from the dive preceding the symptoms, can be a significant cumulative oxygen exposure and pulmonary toxicity may occur.

Ocular toxicity

Prolonged exposure to high inspired fractions of oxygen causes damage to the retina. 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. Hyperoxia may be a contributing factor for the disorder called retrolental fibroplasia or retinopathy of prematurity (ROP) in infants. In preterm infants, the retina is often not fully vascularised. ROP 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 ROP, and may raise the risk of other hypoxia-related systemic complications.

Hyperoxic myopia has occurred in closed circuit oxygen rebreather divers with prolonged exposures. This must be 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.

Mechanism

A high concentration of oxygen damages cells. Not all mechanisms of damage caused by reactive oxygen species (ROS) are known, but the process of lipid peroxidation causes damage to cell membranes. ROS form as a natural byproduct of the normal metabolism of oxygen and have important roles in cell signaling. However, during times of environmental stress ROS levels can increase dramatically, which can result in significant damage to cell structures. This cumulates into a situation known as oxidative stress. One example is that oxygen has a propensity to react with certain metals to form the ROS superoxide, which attacks double bonds in many organic molecules, including the unsaturated fatty acid residues in cells. High concentrations of oxygen are also known to increase the formation of free radicals which harm DNA and other structures (see nitric oxide, peroxynitrite, and trioxidane). Normally the body has many defense systems against such injury, such as glutathione, catalase, and superoxide dismutase, but at higher concentrations of free oxygen, these systems are eventually overwhelmed, and the rate of damage to cell membranes exceeds the capacity of the systems which control or repair it. Cell damage and cell death then result.

Diagnosis

Diagnosis of CNS 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, a seizure occurring while breathing oxygen at partial pressures of or greater will be diagnosed as oxygen toxicity.

Diagnosis of BPD 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 BPD. In addition, an echocardiogram can help to eliminate other possible causes such as congenital heart defects or pulmonary arterial hypertension.

The diagnosis of ROP 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.

Prevention

A seizure caused by CNS oxygen toxicity is a deadly but entirely avoidable event while diving. The diver may experience no warning symptoms. The effects are sudden convulsions and unconsciousness, during which victims can lose their regulator and drown. There is an increased risk of CNS oxygen toxicity on deep dives, long dives and dives where oxygen-rich breathing gases are used. Divers are taught to calculate a maximum operating depth for oxygen-rich breathing gases. Cylinders containing such mixtures must be clearly marked with that depth.

In some diver training courses for these types of diving, divers are taught to plan and monitor what is called the "oxygen clock" of their dives. This is a notional alarm clock, which "ticks" more quickly at increased ppO2 and is set to activate at the maximum single exposure limit recommended in the National Oceanic and Atmospheric Administration (NOAA) Diving Manual. For the following partial pressures of oxygen the limit is: 45 minutes at , 120 minutes at , 150 minutes at , 180 minutes at and 210 minutes at , but is impossible to predict with any reliability whether or when CNS symptoms will occur. Many Nitrox-capable dive computers calculate an "oxygen loading" and can track it across multiple dives. The aim is to avoid activating the alarm by reducing the ppO2 of the breathing gas or the length of time breathing gas of higher ppO2. As the ppO2 depends on the fraction of oxygen in the breathing gas and the depth of the dive, the diver obtains more time on the oxygen clock by diving at a shallower depth, by breathing a less oxygen-rich gas or by shortening the duration of exposure to oxygen-rich gases.

BPD is reversible in the early stages by use of "break periods" on lower oxygen pressures, but it may eventually result in irreversible lung injury if allowed to progress to severe damage. Usually several days of exposure without "oxygen breaks" are needed to cause such damage.

Pulmonary oxygen toxicity is an entirely avoidable event while diving. The limited duration and naturally intermittent nature of most diving makes this a relatively rare (and even then, reversible) complication for divers. Guidelines have been established that allow divers to calculate when they are at risk of pulmonary toxicity.

In low-pressure environments oxygen toxicity may be avoided since the toxicity is caused by high oxygen partial pressure, not merely by high oxygen fraction. This is illustrated by modern pure oxygen use in spacesuits, which must operate at low pressure (also historically, very high percentage oxygen and lower than normal atmospheric pressure was used in early spacecraft, for example, the Gemini and Apollo spacecraft). In such applications high-fraction oxygen is non-toxic, even at breathing mixture fractions approaching 100%, because the oxygen partial pressure is not allowed to chronically exceed .

Vitamin E and selenium were proposed and later rejected as a potential method of protection against pulmonary oxygen toxicity. There is however some experimental evidence in rats that vitamin E and selenium aid in preventing in vivo lipid peroxidation and free radical damage, and therefore prevent retinal changes following repetitive hyperbaric oxygen exposures.

Management

Treatment of seizures during oxygen therapy consists of removing the patient from oxygen, thereby dropping the partial pressure of oxygen delivered. A seizure underwater requires that the diver is brought to the surface as soon as practicable. The buddy will ensure that the victim's air supply is established and maintained, then carry out a controlled buoyant lift. The buddy will need to ensure their own safety is not compromised during the convulsive phase, but lifting an unconscious body is taught by most diver training agencies. Upon reaching the surface, emergency services should be contacted as there is a possibility of further complications requiring medical attention.

The occurrence of symptoms of BPD or ARDS is treated by lowering the fraction of oxygen administered, along with a reduction in the periods of exposure and an increase in the break periods where normal air is supplied. Where supplemental oxygen is required for treatment of another disease (particularly in infants), a ventilator may be needed to ensure that the lung tissue remains inflated. Reductions in pressure and exposure will be made progressively and medications such as bronchodilators and pulmonary surfactants may be used.

ROP may regress spontaneously, but should the disease progress beyond a threshold (defined as five contiguous or eight cumulative hours of stage 3 ROP), both cryosurgery and laser surgery have been shown to reduce the risk of blindness as an outcome. Where the disease has progressed further, techniques such as scleral buckling and vitrectomy surgery may assist in re-attaching the retina.

Prognosis

Although the convulsions caused by CNS oxygen toxicity may lead to incidental injury to the victim, it remained uncertain for many years whether damage to the nervous system following the seizure could occur and several studies searched for evidence of such damage. An overview of these studies by Bitterman in 2004 concluded that following removal of breathing gas containing high fractions of oxygen, no long-term neurological damage from the seizure remains.

The majority of infants who have survived following an incidence of BPD will eventually recover near-normal lung function, since lungs continue to grow during the first 5–7 years and the damage caused by BPD is to some extent reversible (even in adults). However, they are likely be more susceptible to respiratory infections for the rest of their lives and the severity of later infections is often greater than that in their peers.

ROP in infants frequently regresses without intervention and eyesight may be normal in later years. Where the disease has progressed to the stages requiring surgery, the outcomes are generally good for the treatment of stage 3 ROP, but are much worse for the later stages. Although surgery is usually successful in restoring the anatomy of the eye, damage to the nervous system by the progression of the disease leads to comparatively poorer results in restoring vision. The presence of other complicating diseases also reduces the likelihood of a favourable outcome.

Epidemiology

The incidence of CNS toxicity among divers has decreased since the Second World War, as protocols have developed to limit exposure and partial pressure of oxygen inspired. In 1947, Donald recommended limiting the depth breathing pure oxygen to , or a ppO2 of . This limit has been reduced until today a limit of during a dive and during shallow decompression stops is accepted: oxygen toxicity has become a rare occurrence other than when caused by equipment malfunction and human error. Historically, the U.S. Navy has refined its Navy Diving Manual Tables to reduce oxygen toxicity incidents. Between 1995 and 1999, reports showed 405 surface-supported dives using the helium-oxygen tables; of these, oxygen toxicity symptoms were observed on 6 dives (1.5%). As a result, the U.S. Navy in 2000 modified the schedules and conducted field tests of 150 dives, none of which produced symptoms of oxygen toxicity. Revised tables were published in 2001.

The variability in tolerance and other variable factors such as workload have resulted in the U.S. Navy abandoning screening for oxygen tolerance. Of the 6,250 oxygen-tolerance tests performed between 1976 and 1997, only 6 episodes of oxygen toxicity were observed (0.1%).

The incidence of CNS oxygen toxicity among patients undergoing hyperbaric oxygen therapy is rare and influenced by a number of a factors: individual sensitivity and treatment protocol; and probably therapy indication and equipment used. A study by Welslau in 1996 reported 16 incidents out of a population of 107,264 patients (0.015%), while Hampson and Atik in 2003 found a rate of 0.03%. Yildiz, Ay and Qyrdedi, in a summary of 36,500 patient treatments between 1996 and 2003, reported only 3 oxygen toxicity incidents, giving a rate of 0.008%.

BPD is among the most common complications of prematurely born infants and its incidence has grown as the survival of extremely premature infants has increased. Nevertheless, the severity has decreased as better management of supplemental oxygen has resulted in the disease now being related mainly to factors other than hyperoxia.

In 1997 a summary of studies of neonatal intensive care units in industrialised countries showed that up to 60% of low birth weight babies develop ROP, which rises to 72% in extremely low birth weight babies, i.e. less than at birth. However, severe outcomes are much less frequent: for very low birth weight babies (defined as less than at birth), the incidence of blindness was found to be no more than 8%.

History

CNS toxicity was first described by Paul Bert in 1878. He showed that oxygen was toxic to insects, arachnids, myriapods, molluscs, earthworms, fungi, germinating seeds, birds, and other animals. Pulmonary oxygen toxicity was first described by Lorrain Smith in 1899 when he noted CNS toxicity and discovered in experiments in mice and birds that had no effect but of oxygen was a pulmonary irritant. The first recorded human exposure was undertaken in 1910 by Bornstein when two men breathed oxygen at for 30 minutes while he went on to 48 minutes with no symptoms. In 1912, Bornstein developed cramps in his hands and legs while breathing oxygen at for 51 minutes. Smith then went on to show that intermittent exposure to a breathing gas with less oxygen permitted the lungs to recover and delayed the onset of pulmonary toxicity.

Behnke et al. in 1935 were the first to observe visual field contraction (tunnel vision) on dives between and . During World War II, Donald and Yarbrough et al. performed over 2,000 experiments on oxygen toxicity to support the initial use of closed circuit oxygen rebreathers. Naval divers in the early years of oxygen rebreather diving developed a mythology about a monster called "Oxygen Pete", who lurked in the bottom of the Admiralty Experimental Diving Unit "wet pot" (a water-filled hyperbaric chamber) to catch unwary divers. They called having an oxygen toxicity attack "getting a Pete".

In the decade following World War II, Lambertsen et al. made further discoveries on the effects of oxygen at pressure as well as methods of prevention. Their work on intermittent exposures for extension of oxygen tolerance and on a model for prediction of pulmonary oxygen toxicity based on pulmonary function are key documents in the development of operational oxygen procedures. Lambertsen's work showing the effect of carbon dioxide in decreasing time to onset of CNS symptoms has influenced work from current exposure guidelines to future breathing apparatus design.

ROP was not observed prior to World War II, but with the availability of supplemental oxygen in the decade following, it rapidly became one of the principal causes of infant blindness in developed countries. By 1960 the use of oxygen had become identified as a risk factor and its administration restricted. The resulting fall in ROP was accompanied by a rise in infant mortality and hypoxia-related complications. Since then, more sophisticated monitoring and diagnosis has established protocols for oxygen use which aim to balance between hypoxic conditions and problems of ROP.

Bitterman et al. in 1986 and 1995 showed that darkness and caffeine will delay the onset of changes to brain electrical activity in rats. In the years since, research on CNS toxicity has centered around methods of prevention and safe extension of tolerance. These include topics such as circadian rhythm, drugs, age, and gender that have been shown to contribute to CNS oxygen toxicity sensitivity. In 1988, Hamilton et al. wrote procedures for NOAA to establish oxygen exposure limits for habitat operations. Even today, models for the prediction of pulmonary oxygen toxicity do not explain all the results of exposure to high partial pressures of oxygen.

References

Bibliography

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