Continuing Education Activity

Oxygen is essential for aerobic metabolism, but exposure to partial pressures above physiological levels produces hyperoxia, resulting in oxygen toxicity. Two primary clinical scenarios exist: short-term exposure to very high oxygen concentrations, causing acute toxicity, and prolonged exposure to moderately elevated concentrations, causing chronic toxicity. Acute toxicity predominantly affects the central nervous system, presenting with seizures, visual disturbances, nausea, dizziness, and altered consciousness. Chronic toxicity primarily involves the lungs, manifesting as cough, dyspnea, chest discomfort, and impaired gas exchange. Reactive oxygen species generated during hyperoxia induce lipid peroxidation, protein oxidation, DNA damage, and inflammatory responses, culminating in cellular injury and apoptosis.

Diagnosis relies on exposure history, clinical presentation, and supportive investigations, including pulmonary function testing or neurophysiologic monitoring in high-risk settings. Management focuses on reducing inspired oxygen to the lowest effective concentration, discontinuing hyperbaric exposure, and providing supportive care. Complications include permanent pulmonary fibrosis or neurological sequelae following severe central nervous system pathology. Prognosis is generally favorable with early recognition and intervention, although prolonged or severe exposure can result in irreversible organ damage. Hyperbaric therapy recipients, premature infants, and divers are particularly vulnerable.

This activity for healthcare professionals is designed to sharpen learners' skills in evaluating and managing oxygen toxicity. Participants will deepen their understanding of the condition's etiology, risk factors, pathophysiology, clinical presentation, and evidence-based diagnostic and therapeutic recommendations. Improved proficiency will empower clinicians to collaborate successfully with interprofessional teams caring for affected individuals.

Objectives:

• Assess patients for oxygen toxicity based on clinical signs, symptoms, and diagnostic findings, enabling stratification for appropriate intervention.
• Implement evidence-based, personalized approaches for managing oxygen toxicity and mitigating its potential sequelae.
• Develop strategies for increasing awareness among vulnerable populations about oxygen toxicity, including risk factors, clinical manifestations, and measures to reduce exposure and prevent complications.
• Collaborate with the interprofessional team to educate, treat, and monitor patients who have an increased risk for or experience oxygen toxicity to improve overall health outcomes.

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Introduction

Oxygen is vital to sustain life. However, breathing this gas at higher-than-normal partial pressures produces hyperoxia and can cause toxicity or poisoning.[1] The clinical contexts of oxygen toxicity are chiefly classified into 2 types: short-duration exposure to hyperoxic levels and long-term exposure to sub-hyperoxic concentrations. These scenarios result in acute and chronic oxygen toxicity, respectively. Acute toxicity typically manifests with central nervous system (CNS) effects, whereas chronic toxicity primarily affects the lungs. Severe oxygen toxicity can lead to cellular injury and death. Populations at increased risk include patients undergoing hyperbaric oxygen therapy (HBOT), individuals exposed to prolonged high levels of oxygen, premature infants, and underwater divers.

Etiology

Extended exposure to elevated oxygen partial pressures—or shorter exposures to very high partial pressures— causes oxidative damage to cell membranes, leading to alveolar collapse in the lungs. Pulmonary effects can present as early as 24 hours of breathing pure oxygen. Symptoms include pleuritic chest pain, substernal heaviness, coughing, and dyspnea secondary to tracheobronchitis and absorptive atelectasis, which can progress to pulmonary edema. Pulmonary symptoms typically resolve within 4 hours of exposure cessation in most patients.

Meanwhile, oxygen-induced CNS toxicity manifests with a wide range of symptoms. Early signs are variable, but twitching of the perioral region and small muscles of the hand is relatively consistent. Sustained exposure to elevated oxygen pressures can lead to tinnitus, dysphoria, nausea, and generalized convulsions. CNS pathology is accelerated by factors such as elevated partial pressure of carbon dioxide (PCO2), stress, fatigue, and cold.[2]

Epidemiology

The "Bert effect" refers to the CNS manifestations of oxygen toxicity under hyperbaric conditions. This phenomenon occurs in a dose-dependent manner.[3] Overall risk ranges from 1 in 2,000 to 3,000 treatments. The risk rises to 1 in 200 at higher pressures of 2.8 to 3.0 ATA. At pressures of 2 ATA or less, the risk falls to 1 in 10,000. The incidence of CNS symptoms from oxygen toxicity is approximately 2%, with a seizure rate of 0.6%.

Pulmonary toxicity is commonly referred to as the "Smith effect," occurring after prolonged exposure to oxygen concentrations exceeding 0.5 ATA. The incidence of pulmonary symptoms in oxygen toxicity is approximately 5%. Preterm newborns face an elevated risk for bronchopulmonary dysplasia and retinopathy of prematurity (ROP; formerly retrolental fibroplasia) following prolonged exposure to high oxygen concentrations.

Exposure to certain chemicals elevates the risk of oxygen toxicity. Bleomycin, a chemotherapeutic agent, has been shown to contribute to this increased risk.[4]

Pathophysiology

Oxygen-derived free radicals have been proposed as the primary etiological factor in oxygen toxicity. Free radicals are generated by mitochondrial oxidoreductive processes and certain types of extramitochondrial enzymatic activity, such as that mediated by xanthine oxidase or urate oxidase. Auto-oxidative reactions and phagocyte activity during bacterial killing may also contribute to free radical formation in the body. These free radicals induce lipid peroxidation, particularly in cell membranes, impair nucleic acid and protein synthesis, and inactivate cellular enzymes. Continued exposure to high oxygen concentrations further increases free radical production. The resulting damage includes pulmonary epithelial injury, surfactant inactivation, intra-alveolar edema, interstitial thickening, and fibrosis, ultimately causing pulmonary atelectasis.[5]

Hyperoxia also destabilizes iron-containing proteins, impairing multiple pathways, particularly the electron transport chain. This disruption reduces mitochondrial oxygen consumption and contributes to lung injury.[6]

Histopathology

Oxygen toxicity induces pathological changes in the lung, including pulmonary edema, congestion, intra-alveolar hemorrhage, and tissue injury. Tissue examination demonstrates that surfactant disruption and epithelial damage trigger increased cytokine expression, which activates inflammatory cells. Elevated production of oxygen-free radicals alters normal endothelial function. Microscopic examination at high magnification reveals alveoli filled with smooth-to–slightly floccular pink material, characteristic of pulmonary edema and congestion. Alveolar wall capillaries are congested with numerous red blood cells.[7]

Toxicokinetics

Breathing 100% oxygen can be tolerated at sea level for approximately 24 to 48 hours without severe tissue damage. Prolonged exposure produces definitive tissue injury. Moderate carinal irritation occurs on deep inspiration after 3 to 6 hours of exposure at 2 ATA, progressing to extreme carinal irritation with uncontrolled coughing after 10 hours. Chest pain and dyspnea develop subsequently. These symptoms resolve within 4 hours after cessation of exposure in most patients.[8]

History and Physical

Symptoms of oxygen toxicity include disorientation, breathing difficulties, and visual changes, such as myopia and cataract formation. CNS manifestations encompass headache, irritability, anxiety, dizziness, disorientation, hyperventilation, hiccups, cold shivering, fatigue, tingling in the limbs, blurred or tunnel vision, tinnitus, hearing disturbances, nausea, muscle twitching, and tonic-clonic seizures. Pulmonary toxicity presents with a mild tickle or burning sensation on inhalation, uncontrollable coughing, hemoptysis, dyspnea, rales, fever, hyperemia of the nasal mucosa, and radiographic evidence of inflammation and pulmonary edema. Ocular effects in premature infants include ROP, retinal edema, and, following long-term exposure, cataract formation.

Evaluation

Patients at risk for pulmonary oxygen toxicity require monitoring of oxygen saturation and work of breathing. Evaluation may include pulmonary function testing and chest x-ray, which can reveal findings consistent with acute respiratory distress syndrome (ARDS). Eye examinations assessing visual acuity and lens opacification allow detection of early ocular oxygen toxicity. CNS toxicity presents as previously described, often accompanied by tachycardia and diaphoresis. Termination of hyperbaric exposure upon recognition of these signs can prevent seizure occurrence.[9]

Treatment / Management

Management of oxygen toxicity involves reducing exposure to elevated oxygen levels. The lowest oxygen concentration that alleviates tissue hypoxia is optimal in patients with ARDS and neonates with decompensation, who are at increased risk for ROP. Oxygen-induced seizures are generally self-limited and do not increase susceptibility to epilepsy. Although concern exists that such convulsive events could cause tissue damage, they are considered benign and analogous to febrile seizures in children, for which no specific treatment is indicated.

High-risk individuals receiving HBOT may benefit from antiepileptic therapy, prolonged air breaks, and limited treatment pressures. Protocols for avoiding hyperoxia exist in settings where oxygen is administered at elevated partial pressures. These settings include underwater diving using compressed breathing gases, neonatal care, hyperbaric medicine, and human spaceflight. Current protocols have reduced the incidence of seizures due to oxygen toxicity, with pulmonary and ocular damage primarily limited to complications in managing premature infants. Oxygen toxicity seizures during hyperbaric therapy have also declined following the introduction of air breaks, which involve intermittent breathing of air within the hyperbaric environment. This intervention can reduce seizure risk by a factor of 10.[10]

Deep divers operating below 185 feet require breathing mixtures containing less than 21% oxygen to reduce toxicity risk. Breathing mixtures transition from nitrogen to helium at these depths. Convulsions underwater necessitate immediate ascent, as the risk of pulmonary barotrauma and decompression illness is outweighed by the extremely high risk of fatal drowning.[11]

Differential Diagnosis

Diagnosis is typically made clinically, though several conditions can mimic oxygen toxicity. Differential diagnosis should include carbon dioxide narcosis, carbon monoxide poisoning, hyperventilation, envenomation or toxin ingestion, cerebrovascular events, migraine, seizure disorders, infection, multiple sclerosis, and hypoglycemia.[12] A recent review identified additional mimics of oxygen toxicity convulsions, including posterior reversible encephalopathy syndrome (PRES), pethidine toxicity, epilepsy secondary to prior CNS injury, such as subarachnoid hemorrhage, and severe hypoglycemia.[13]

Treatment Planning

Treatment of oxygen toxicity is purely symptomatic. Early recognition of this condition requires vigilant monitoring. Sudden discontinuation of oxygen at the onset of toxicity may, in some cases, exacerbate symptoms. The onset and rate of progression of oxygen toxicity are influenced by multiple conditions, procedures, and drugs. Induction of antioxidant enzymes, such as superoxide dismutase, by exposure to nonlethal levels of hyperoxia or hypoxia, alone or in combination, has been successfully demonstrated in animal models and is currently under evaluation in humans. This approach may promote the development of tolerance to subsequent hyperoxic exposure. Exogenous antioxidants, particularly vitamins E and C, have been shown to reduce the incidence of ROP in premature infants exposed to hyperoxia.[14]

Toxicity and Adverse Effect Management

Cerebral oxygen toxicity seizures are rarely fatal. However, at least 1 case report describes a death occurring during a hyperbaric chamber session. The patient had morbid obesity, and associated hypoventilation may have contributed to the event and complicated its consequences. Obesity and hypercapnia must be considered in prevention and management strategies. Immediate access to airway management is essential.

Prognosis

CNS oxygen toxicity may cause incidental injury in adults. However, studies indicate that removal of the inciting agent prevents long-term neurological damage.[15] Oxygen-induced pulmonary toxicity is reversible in most adults.

Infants who survive an episode of bronchopulmonary dysplasia typically achieve near-normal lung function, as lung growth continues during the first 5 to 7 years. Persistent vulnerability to respiratory infections remains, and subsequent infections are often more severe than in age-matched peers.[16]

ROP frequently resolves without intervention, with normal vision achievable in later years. Surgical intervention generally yields good outcomes for stage 3 ROP but is less favorable for advanced stages. Although surgery often restores ocular anatomy, nervous system damage from disease progression limits visual recovery. Coexisting conditions further reduce the likelihood of a favorable outcome.[17]

Complications

Oxygen toxicity can produce complications across multiple organ systems. CNS manifestations primarily include tonic-clonic convulsions and amnesia. Pulmonary sequelae range from mild tracheobronchitis and absorptive atelectasis to diffuse alveolar damage indistinguishable from ARDS. Ocular complications include reversible myopia, delayed cataract formation, and, in children, ROP. Serous otitis media and dysbaric osteonecrosis have also been reported. In patients with chronic obstructive pulmonary disease, status asthmaticus, respiratory muscle weakness (eg, from polyneuritis, poliomyelitis, or myasthenia gravis), or central respiratory depression due to narcotic poisoning, head injury, or elevated intracranial pressure, oxygen toxicity may induce carbon dioxide narcosis secondary to loss of hypoxemic drive and reduced ventilation.[18]

Deterrence and Patient Education

A major limitation to broader clinical use of hyperoxia is its potential toxicity and the narrow margin of safety between effective and toxic doses. Awareness of oxygen’s toxic effects and adherence to safe pressure and duration guidelines mitigate this risk. Careful dose management provides a rationale for expanding the list of clinical indications. The most prominent toxic effects involve the CNS and respiratory system.

Pulmonary oxygen toxicity is a concern in both compressed gas diving, particularly with closed-circuit rebreathers, and HBOT. Predictive calculations assist divers and physicians in preventing pulmonary oxygen toxicity. The Unit Pulmonary Toxic Dose calculation and the pulmonary oxygen toxicity index are both useful, with the latter demonstrating somewhat superior predictive value. The pulmonary oxygen toxicity index forecasts both pulmonary injury and reduction in vital capacity.[19]

Pearls and Other Issues

Susceptibility to oxygen toxicity varies widely. Factors that increase seizure risk include carbon dioxide retention, underwater immersion, cold exposure, and exercise. Scuba divers may use breathing gases containing up to 100% oxygen, such as enriched air nitrox or closed-circuit rebreathers, and require specialized training in safe use. In recent years, oxygen has become available for recreational use in oxygen bars. The US Food and Drug Administration advises individuals with cardiovascular or pulmonary conditions against the use of oxygen bars.[20]

Enhancing Healthcare Team Outcomes

Although the body of data on hyperoxia continues to grow, high-quality evidence regarding its clinical effects remains limited. Current evidence-based indications for hyperoxia cover a narrower range than the spectrum of clinical conditions, such as impaired oxygen delivery, cellular hypoxia, tissue edema, inflammation, and infection, that may potentially benefit from oxygen therapy.

The widespread availability of normobaric hyperoxia necessitates a more rigorous approach to evaluating its clinical efficacy. The broad beneficial actions of hyperoxia support the need for well-designed, prospective research to determine safe, nontoxic dose ranges and optimal treatment durations.

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References

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Disclosure: Jeffrey Cooper declares no relevant financial relationships with ineligible companies.

Disclosure: Marjorie Launico declares no relevant financial relationships with ineligible companies.