Sideeffects

Symptoms and physiological manifestations

Four normal men remained in 98 per cent oxygen for periods ranging from 30 to 74 h. During this time oxygen toxicity became clinically evident as symptoms affecting both the respiratory and nervous systems. Cough and chest pain occurred in all four, and paresthesias and anorexia occurred in three. There was a progressive statistically significant fall in vital capacity in all subjects. In all but one, vital capacity returned to normal quickly; however, the remaining subject had a delayed recovery lasting for several weeks. Diffusing capacity decreased during the oxygen exposure, but returned to normal in the follow-up period.

The volume-pressure curves of oxygen-breathing subjects were altered in the direction of decreased volume for a given pressure (i.e. less compliant) compared with control subjects breathing air. Some subjects could not inhale to total lung capacity and seemed unable to generate maximal transpulmonary pressure. Non-uniform behavior of the lung after atelectasis led to disproportionate receptor firing and an early inhibition of inflation.

Clinical manifestations

Five hospitalized patients with irreversible brain damage who were ventilated with pure oxygen developed significantly worse lung function. Gas exchange worsened

and a decrease in arterial oxygen tension occurred. Both intrapulmonary shunt and the ratio of dead-space to tidal volume (reflecting abnormalities in V/Q ratio) increased significantly in the group exposed to pure oxygen. Their lungs showed radiographic evidence of edema and were heavier at autopsy.

Patients who had undergone cardiac surgery were randomized to receive either pure oxygen or a gas mixture sufficient to maintain an arterial PO2 between 80 and 120 mmHg (10.7 and 16 kPa) for 24 to 48 h. During this time, no difference in intrapulmonary shunt, lung or respiratory system compliance, or the ratio of dead-space to tidal volume could be detected.

Detection of pulmonary oxygen toxicity by traditional physiological testing is insensitive. Decreased tracheal mucous velocity, which can be assessed by direct observation through a fiber-optic bronchoscope, is a very early manifestation of oxygen toxicity. Investigators have detected changes in bronchoalveolar lavage constituents in normal subjects who were exposed to oxygen for approximately 17 h. Albumin and transferrin concentrations increased in lavage fluid from these subjects. Cultured alveolar macrophages from subjects exposed to oxygen released increased amounts of fibronectin and alveolar macrophage-derived growth factor for fibroblasts. The changes disappeared when the subjects were studied 2 weeks later, but they suggested that functional abnormalities may occur very early in oxygen exposure that later initiate fibrosis of the alveolar wall. T§b,[e..2. summarizes the approximate time course of oxygen toxicity in humans.

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Table 2 Time course of pulmonary oxygen toxicity in humans

Human studies

The pulmonary function of many patients supported by early mechanical ventilators underwent gradual deterioration. Most patients were ventilated with pressure-limited oxygen-driven ventilators, which resulted in a mean oxygen concentration of over 90 per cent. Patients exposed to the highest concentrations of oxygen for long periods had heavier and more consolidated lungs. Microscopic studies showed an early exudative phase characterized by congestion, alveolar edema, intra-alveolar hemorrhage, and a fibrin exudate together with prominent alveolar membranes. Later, a proliferative phase characterized by alveolar and septal edema and fibroblast proliferation occurred, together with fibrosis and hyperplasia of alveolar lining cells.

Patients exposed to 40 to 100 per cent oxygen for periods of up to 30 days have undergone autopsy. The earliest pathological changes involved alveolar type I cells and endothelial cells. Septal edema was noted, and endothelial sloughing followed by fibrin thrombus formation occurred. Hyaline membranes were found after exposure for about 7 days, and re-epithelialization of the alveoli occurred by proliferation of granular pneumocytes. Septal proliferation and deposition of interstitial collagen, elastin, and fibrosis occurred after 10 days.

More recently, detailed studies of the morphology and time course of oxygen toxicity in baboons have clarified the time course of injury in primates ( Fig 1). The earliest detectable injury includes endothelial injury followed by neutrophil aggregation and thickening of the alveolar interstitium. Later phases of the injury are characterized by loss of alveolar type I cells, denudation of basement membranes, and proliferation of alveolar type II cells.

Fig. 1 Pathogenesis of pulmonary oxygen toxicity. Oxygen toxicity is initiated by reactive oxygen metabolites and inflammatory mediators derived from granulocytes and platelets. Initially detectable as impaired cellular metabolism, oxygen toxicity evolves through stages in which physiological or pathological manifestations predominate. The lung injury may resolve or be perpetuated as fibrosis.

Similar acute changes that progress to fibrosis occur after cutaneous burns and following smoke inhalation, influenza pneumonia, thoracic irradiation, and ingestion of toxins such as paraquat. The histological resemblance of pulmonary oxygen toxicity to diffuse alveolar damage from other causes (like sepsis and trauma) has led some investigators to propose that oxygen toxicity is a major cause of the acute respiratory distress syndrome. However, near uniformity of oxygen administration to patients with respiratory failure of diverse etiologies makes isolation of oxygen as the primary cause of acute respiratory distress syndrome problematic.

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