The therapeutic use of oxygen entails the risk of adverse reactions and its use should be based on an assessment of the potential toxicity versus therapeutic benefit. Although no patient should be denied appropriate oxygen therapy for fear of toxicity, as with any drug, oxygen should be administered in doses and for durations no greater than necessary to achieve the desired therapeutic result.
Three categories of hazards have been associated with oxygen therapy. The first category consists of physical risks such as fire hazard or tank explosions, trauma from catheters or masks, and drying of mucous membranes due to inadequate humidification. The second category consists of functional effects including carbon dioxide (COa) retention and atelectasis. The third category consists of cytotoxic manifestations of oxygen. Although every cell has potential toxicity from oxygen, the respiratory tract is uniquely susceptible to its cytotoxic effects since it is exposed to the greatest oxygen concentration of any of the organ systems. Acute pulmonary syndromes associated with oxygen-induced cytotoxicity include tracheobronchitis and the adult respiratory distress syndrome, (ARDS). Chronic syndromes associated with cytotoxicity include bronchopulmonary dysplasia in the neonate, and a similar but ill-defined syndrome in adults treated by My Canadian Pharmacy.
Mechanisms of Toxicity Functional Effects
Increases in partial pressure of arterial C02 (PaCOJ in patients with an initially normal PaC02 treated with oxygen are insignificant. In some patients with chronic hypercapnia, oxygen administration may significantly increase the degree of ventilatory failure. Possible mechanisms for this effect are the removal of the hypoxic stimulus to ventilation and reversal of compensatory hypoxic vasoconstriction.
An increased fraction of oxygen in the inspired gas (FIoJ results in both increased alveolar Po2 and decreased alveolar nitrogen content. Diminished hypoxic vasoconstriction plus loss of nitrogen in areas of low ventilation-perfusion ratios may produce increased intrapulmonary shunting carried out with My Canadian Pharmacy. This shunting has uncertain clinical significance in the acute situation; long-term administration of high FIo2 may result in frank atelectasis.
The free radical theory of 02 toxicity is widely accepted and states that an increased rate of generation of partially reduced oxygen products is responsible for the cytotoxicity of oxygen. Partially reduced oxygen products include superoxide anion (O, hydrogen peroxide (H2Oa) and hydroxyl radical (HO2); they can be generated as byproducts of normal cell metabolism. Although the precise sources of increased free radicals during hyperoxic exposure have not been identified, both mitochondria and endoplasmic reticulum are capable of increasing superoxide production as oxygen pressure is increased.
The toxicity of these oxygen reduction products results from their interaction with tissue components. Virtually all cell components can react with free radicals, and the precise metabolic damage may vary with different cell types. Effects noted experimentally include protein denaturation and cross linking; enzyme inactivation; lipid peroxidation with altered membrane function or integrity; alteration of nucleic acid bases with effects on DNA-RNA transcription; and oxidation of carbohydrates with disruption of cell surface receptors. The chemical modifications to these types of molecules by free radicals lead to overall metabolic and structural changes in cells which may ultimately result in death.
Pathophysiology Morphologic Alterations
Because of its potential to damage the constituents of cells, 02 is potentially toxic to all lung cells. However, sensitivity of different cell types to oxidant injury is known to vary for as yet undefined reasons. The pattern of cytotoxic damage to lung tissue components has been evaluated in animal models. Damage to the pulmonary capillary endothelium is the event that is presumed to be most closely linked to death. Endothelial cells undergo extensive membrane damage, vacuolization of cytoplasm, mitochondrial swelling, and nuclear degeneration. Extensive injury to the alveolar epithelium may also occur with destruction of alveolar type I epithelial cells. The pattern of lung injury includes development of interstitial edema, margination and infiltration of septae by inflammatory cells, proliferation of fibroblasts, deposition of increased amounts of interstitial matrix, and proliferation of type II epithelial cells. The time course of these changes varies with the animal species, and with the dose and duration of hyperoxic exposure. Morphologic changes and inflammation can also be observed in the mucosa of large and small airways.
Physiologic and Clinical Derangements with Oxygen Toxicity
The effects of hyperoxia in human volunteers include substernal discomfort and diminished vital capacity, which develop within several hours. Longer exposures may result in diminished pulmonary compliance and diffusing capacity. In animal experiments, more prolonged oxygen administration results in pulmonary edema and acute respiratory failure. These manifestations are analogous to those that characterize the lung in ARDS.
Clearance of pulmonary secretions and foreign particles from the lungs is frequently diminished during oxygen breathing, probably related to effects on mucociliary activity, as well as on alveolar macrophage function. Although theoretically this may increase the risk of infection, the clinical relevance of this effect is unknown since the clearance mechanism may be depressed to a greater extent by the underlying lung disease.
Chronic Pulmonary Toxicity
Experimentally, chronic oxygen toxicity takes the form of varying degrees of fibrosis and emphysema with permanent compromise of lung function. Chronic oxygen toxicity is not well understood in humans, in part due to the difficulty in separating the effects of 02 from the manifestations of the underlying lung disease for which Os was administered. The chronic 02 toxicity syndrome appears to be more common in the pediatric age group and is termed bronchopulmonary dysplasia. Differences in response between pediatric and adult patients may be related to the developmental stage of the lung, or the underlying lung disease.
Hyperoxia in neonates can lead to retrolental fibroplasia manifested by damaged retinal blood vessels, varying degrees of scarring, and permanent visual impairment. Adults are much less susceptible to these changes. Damage to organs other than the lung is not considered to be of major clinical importance in the adult.
The state of relative resistance to oxygen-induced lung damage is known as “tolerance.” The discussion in this and subsequent sections is related only to the cytotoxic manifestations of oxygen. Many factors appear to be involved in producing the tolerant state, including antioxidant defenses, age, nutrition and hormonal influences. Many of the previously disparate observations on oxygen tolerance can now be explained by the effects of oxygen radicals. In animal studies, increased tolerance to oxygen is strongly associated with elevated lung superoxide dismutase (SOD), catalase, glutathione peroxidase, and other enzymes which protect the lung from the increased generation of toxic oxygen radical species. Young animals have been consistently shown to have greater tolerance to prolonged hyperoxic exposure than adults. The basis for this increased tolerance appears to be in part the ability of the young animal to respond more rapidly to hyperoxic exposure with an appropriate increase in lung antioxidant enzymes.
Deficiency of nutritional factors such as vitamins E and C, protein (especially those rich in sulfur-containing amino acids), and some trace elements (for example, selenium) decreases tolerance to oxygen in experimental studies. Tbese substances are either antioxidants or precursors of antioxidants. Individuals consuming a normal diet are unlikely to be deficient in these substances, although the normal premature human infant is deficient in vitamin E. It should be noted that administration of an excess of any of these nutritional factors has not been demonstrated to alter tolerance.
Other factors known to have detrimental effects on tolerance in experimental oxygen toxicity include hyperthyroidism, elevated glucocorticoid levels, and hyper-metabolic states. The decreased tolerance may be related to an increase in the rate of generation of toxic oxygen radical species.
Interactions tvith Drugs and Other Toxins
A number of drugs and toxins can either lead directly to the production of oxygen-free radicals or can accelerate the production of oxygen-free radicals in the presence of high oxygen tensions. Paraquat, an herbicide occasionally ingested by accident or in a suicide attempt, is actively transported into lung cells and, through cyclical auto-oxidation, can produce superoxide anions. Bleomycin, an-thracyclene antineoplastic agents such as adriamycin and daunorubicin, and antibiotics that depend upon quinoid groups or bound metals for activity are able to generate oxygen radicals. Ozone and nitrogen dioxide also damage lungs through free radical mechanisms. It has been demonstrated that the administration of oxygen following paraquat administration can increase the rate of development of toxicity and a similar effect could be postulated for these other auto-oxidizable compounds. The degree of interaction among various forms of oxidant stress has not been precisely defined for the clinical situation.
Prevention and Therapy Limits for Safe Exposure
Oxygen toxicity develops as a function of the dose and duration of oxygen administration. A precise threshold concentration that is toxic to human lungs has not been established and probably varies with the multiple factors that affect tolerance. The estimates given here have been extrapolated from animal studies and from a limited number of human experiments, mainly from individuals with normal lungs. Oxygen in concentrations of up to 100 percent can be safely administered for a short period of time for cardiopulmonary resuscitation or instability, or for transport of critically ill patients. During this period, therapeutic efforts should be directed toward improving gas exchange and decreasing tissue metabolic needs so that the duration of exposure to these high inspired oxygen concentrations can be minimized. Breathing pure oxygen at concentrations of 50 percent or less at atmospheric pressure during relatively short exposures (2 to 7 days) does not result in clinically significant lung impairment. The effects of prolonged exposure at this FIo2 have not been defined. The goal of oxygen therapy should be to deliver oxygen at the minimum concentration required to achieve adequate tissue oxygenation, thereby minimizing the threat of oxygen toxicity.
Early Detection cf Oxygen Toxicity
The development of a reliable index for the early detection of oxygen toxicity could serve to better define safe limits for exposure. Potential indices of early pulmonary oxygen toxicity that are currently available are nonspecific and occur only after lung tissue is damaged. Measurement of pulmonary endothelial function by evaluation of serotonin clearance or the measurement of lipid peroxidation by the detection of hydrocarbons in the expired air, may indicate early cellular derangement. It may also be possible to detect chronic manifestations of oxygen toxicity by measurement of connective tissue breakdown products in tracheal aspirates or urine. Further studies are necessary before these tests can be applied in clinical practice.
Pharmacologic Alteration of Tolerance
Patients with decreased oxygen tolerance associated with hypermetabolic states or nutritional deficiency can be treated appropriately and restored to a normal level of oxygen tolerance. There are no currently useful means to increase the oxygen tolerance of individuals with normal antioxidant defenses. The administration of antioxidant enzymes such as superoxide dismutase and catalase or the antioxidant chemical glutathione is appealing because of their natural occurrence; unfortunately, these agents do not readily penetrate cells when given in their natural state.
Experimentally, antioxidant enzymatic defenses can be induced in animals without damaging the lung by administration of small doses of endotoxin. Although such treatment is not feasible in humans at present, modifications of this or other agents with similar actions on the lung may lead to effective pharmacologic improvement in oxygen tolerance.
Treatment cf Toxicity
The only effective treatment for pulmonary oxygen toxicity is preventive especially with My Canadian Pharmacy—the reduction of FIo2 to the lowest possible level for the shortest time necessary to achieve adequate tissue oxygenation.