Oxygen Toxicity

Etiology

Extended exposure to above-normal oxygen partial pressures or shorter exposures to very high partial pressures can cause oxidative damage to cell membranes leading to the collapse of the alveoli in the lungs.  Pulmonary effects can present as early as within 24 hours of breathing pure oxygen.  Symptoms include pleuritic chest pain, substernal heaviness, coughing, and dyspnea secondary to tracheobronchitis and absorptive atelectasis, which can lead to pulmonary edema.  Pulmonary symptoms typically abate 4 hours after cessation of exposure in the majority of patients.  CNS effects manifest with a multitude of potential symptoms.  Early symptoms and signs are quite variable, but the twitching of the perioral and small muscles of the hand is a fairly consistent feature.  If exposure to oxygen pressures is sustained, tinnitus, dysphoria, nausea, and generalized convulsions can develop. CNS toxicity is expedited by factors such as raised PCO₂, stress, fatigue, and cold [2].

Epidemiology

The CNS effects secondary to oxygen toxicity are known as the Bert effect. This can occur with hyperbaric oxygen therapy in a dose-dependent corelation[3].  The overall risk may be as frequent as 1 in 2000 to 3000 treatments. However, this risk may be as high as 1 in 200 at higher pressures (2.8 to 3.0 times normal atmospheric pressure or one atmosphere absolute (ATA)) and as low as 1 in 10,000 for treatment at 2 ATA (atmosphere absolute air) or less.  The incidence of displaying CNS symptoms secondary to oxygen toxicity is 2%, with a seizure rate of 0.6%.

The phenomenon of pulmonary toxicity is commonly referred to as the Smith effect.  This can occur after prolonged exposure to oxygen greater than 0.5 ATA.  The incidence of displaying pulmonary symptoms with oxygen toxicity is 5%.  Preterm newborns are at distinct risk for bronchopulmonary dysplasia and retrolental fibroplasia with prolonged exposure to high concentrations of oxygen.

Some chemicals, such as the chemotherapeutic agent bleomycin, also increase the risk of oxygen toxicity [4].

Pathophysiology

Oxygen-derived free radicals have been proposed as being the probable etiological cause in the development of oxygen toxicity. Free radicals are generated due to the mitochondrial oxidoreductive processes and also induced by the function of enzymes such as xanthine/urate oxidase at extra-mitochondrial sites, from auto-oxidative reactions, and by phagocytes during the bacterial killing. These free radicals create lipid peroxidations, especially in the cell membranes, subdue nucleic acids and protein synthesis, and mollify cellular enzymes. Continued exposure to high concentrations of oxygen results in heightened free radical production.  This may damage the pulmonary epithelium, inactivate the surfactant, form intra-alveolar edema, interstitial thickening, fibrosis, and ultimately lead to pulmonary atelectasis.[5] 

Histopathology

Oxygen toxicity stimulates the development of histological changes in the lung. This consists of pulmonary edema, congestion, intra-alveolar hemorrhage, and pulmonary injury.  Tissue examination reveals that surfactant interruption and epithelial injury initiate the expanded expression of cytokines that activate inflammatory cells. The heightened release of oxygen free radicals modifies normal endothelial function. Microscopic examination at high magnification display the alveoli in the lung filled with smooth to slight floccular pink material characteristic of pulmonary edema and congestion. The capillaries in the alveolar walls are congested with many red blood cells.[6]

Toxicokinetics

100% oxygen can be tolerated at sea level for about 24-48 hours without any severe tissue damage.  Lengthy exposures produce definite tissue injury.  There is moderate carinal irritation on deep inspiration after 3 to 6 hours of exposure of 2 ATA, extreme carinal irritation with uncontrolled coughing after 10 hours, and finally, chest pain and dyspnea ensue.  In a majority of patients, these symptoms subside 4 hours after cessation of exposure.[7]

History and Physical

Symptoms may include disorientation, breathing problems, and visual changes such as myopia and cataract formation. System-based signs and symptoms include the following.

Central Nervous System 

• Headache
• Irritability and anxiety
• Dizziness
• Disorientation
• Hyperventilation
• Hiccups
• Cold shivering
• Fatigue
• Tingling in the limbs
• Visual changes such as blurring and tunnel vision 
• Tinnitus and Hearing disturbances
• Nausea
• Twitching  
• Tonic-clonic seizure 

Pulmonary Toxicity

• Mild tickle sensation on inhalation 
• Mild burning on inhalation 
• Uncontrollable coughing 
• Hemoptysis
• Dyspnea
• Rales 
• Fever
• Hyperemia of the nasal mucosa
• CXR shows inflammation and pulmonary edema

Eyes  

• In premature babies, retinopathy of prematurity and retrolental fibroplasia
• retinal edema
• Cataract formation (long-term exposure) [8]

Evaluation

Patients at risk for pulmonary oxygen toxicity should be monitored for oxygen saturation and elevated work of breathing. They can be evaluated by pulmonary function testing and chest x-ray, which can show signs of acute respiratory distress syndrome (ARDS). Similarly, eye exams assessing acuity and looking for lens opacification can be done to detect early ocular oxygen toxicity. CNS toxicity manifests as described above and will often have associated tachycardia and diaphoresis. Aborting a hyperbaric exposure when these signs are present can prevent seizure occurrence [8].

Treatment / Management

Oxygen toxicity is managed by reducing the exposure to increased oxygen levels. The lowest possible concentration of oxygen that alleviates tissue hypoxia is optimal in patients with ARDS and decompensated neonates who are at particular risk for retrolental fibroplasia. Oxygen-induced seizures are self-limited and do not increase susceptibility to epilepsy. There is concern that oxygen-induced seizures could lead to damage but are felt to be benign and similar to febrile seizures in children, where no particular treatment is available [8].

For hyperbaric oxygen treatments, those at high risk may benefit from anti-epileptic therapy, prolonged air breaks, and limited treatment pressure. Protocols for the avoidance of hyperoxia exist in fields where oxygen is breathed at higher-than-normal partial pressures.  This comprises underwater diving using compressed breathing gases, neonatal care, hyperbaric medicine, and human spaceflight. The present protocols have diminished the incidence of seizures due to oxygen toxicity, with pulmonary and ocular damage being mainly confined to the problems of managing premature infants. Oxygen toxicity seizures during hyperbaric therapy have also been curtailed by the introduction of "air breaks" (intermittent air breathing while in the hyperbaric environment). This intervention may lower risk by a factor of 10. [9](B3)

Deep divers (diving below 185 feet) require breathing mixtures that contain less than 21% oxygen to reduce toxicity risk. At these depths, the mixture is changed from nitrogen to helium as well.  Underwater seizures require immediate ascent as the risk of pulmonary barotrauma and decompression illness is offset by the extraordinarily high risk of fatal drowning [10].(B3)

Differential Diagnosis

Several conditions can be mistaken for oxygen toxicity.  Typically diagnosis is made clinically and can be confirmed with PaO₂ (arterial oxygen levels).  The following conditions must be ruled out when clinically evaluating for oxygen toxicity [11]:

• Carbon dioxide narcosis
• Carbon monoxide poisoning
• Hyperventilation
• Envenomation or toxin ingestion
• Cerebrovascular event
• Migraine
• Seizure disorder
• Infection
• Multiple sclerosis
• Hypoglycemia

Treatment Planning

Treatment for oxygen toxicity is purely symptomatic. Therefore, it is imperative to monitor for early recognition of toxicity. It should be remembered that the sudden stoppage of oxygen at the onset of toxicity may, at times, aggravate symptoms. The onset and rate of progression of oxygen toxicity can be influenced by a variety of conditions, procedures, and drugs. Induction of antioxidant enzymes, such as superoxide dismutase, by exposure to non-lethal levels of hyperoxia/hypoxia isolated or conjointly has been tried successfully in animals and is in the process of being evaluated in man [12]. It is thought that this may lead to the progression of tolerance to subsequent hyperoxic exposure.  Exogenous antioxidants, notably vitamins E and C, have been found to lower the prevalence of retrolental fibroplasia in premature infants on hyperoxic therapy [13].

Prognosis

For adults, although central nervous system oxygen toxicity may lead to incidental injury, studies show that with the removal of the inciting agent, no long-term neurological damage occurs [14].  Damage due to oxygen-induced pulmonary toxicity is reversible in most adults.

For infants, those who have survived following an incidence of bronchopulmonary dysplasia will ultimately recover near-normal lung function since lungs continue to grow during the first 5 to 7 years.  Nevertheless, they are likely to be more vulnerable to respiratory infections for the rest of their lives, and the harshness of later infections is often greater than that of their peers [15].

Retinopathy of prematurity (ROP) in infants frequently reverses without intervention, and eyesight may be normal in later years. When the disease has advanced to the stages requiring surgery, the results 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 favorable outcome [16].

Complications

Oxygen toxicity can cause a variety of complications affecting multiple organ systems.  CNS complications primarily include tonic-clonic convulsions and amnesia.  Pulmonary sequelae range from mild tracheobronchitis and absorptive atelectasis to diffuse alveolar damage that is indistinguishable from ARDS.  Ocular complications consist of reversible myopia, delayed cataract formation, and in children, retrolental fibroplasia.  Serous otitis media and dysbaric osteonecrosis have also been observed.  In patients with chronic obstructive pulmonary disease (COPD), status asthmaticus, weakness of the respiratory muscles (e.g., from polyneuritis, poliomyelitis, or myasthenia gravis), and in those with central respiratory depression from narcotic poisoning, head injury, or raised intracranial tension, oxygen toxicity can cause carbon dioxide narcosis secondary to a loss in the hypoxemic drive and decrease in ventilation [17].