Hyperoxia-induced tissue injury

Under normobaric circumstances, the side effects of oxygen are initially restricted to the lungs. However, when hyperoxia manifests for prolonged periods or under hyperbaric conditions, other organs are concurrently at risk as more oxygen is dissolved in plasma [6]. The amount of dissolved oxygen will readily increase at partial pressures of arterial oxygen (PaO 2 ) exceeding 100 mm Hg. Oxyhemoglobin saturation is nearly complete when PaO 2 approaches this level and the carrying capacity of hemoglobin is therefore quickly overcharged with increasing fractions of inspired oxygen (FiO 2 ).

The harmful effects depend on underlying conditions, duration, and degree of the hyperoxic exposure. Rigid thresholds where harm exceeds the perceived benefits are not exactly known and may vary between subgroups [39]. Most pathophysiological changes originate rapidly and are rather universal effects, but the effects of hyperoxia are assumed to be time—and dose-dependent [40]. In general, excessive oxygen supply causes absorptive atelectasis by displacement of alveolar nitrogen. The progressive washout of nitrogen coincides with the abundant presence of oxygen in the alveoli which, driven by a steep pressure gradient, rapidly diffuses into the mixed venous blood. As a result, the alveolar volume is markedly reduced and leads to increased ventilation/perfusion mismatch by (partial) alveolar collapse and impaired gas exchange, which can be attenuated by applying positive end-expiratory pressure [41]. Impaired mucociliary clearance by hyperoxia contributes to obstructive atelectasis, and altered surfactant metabolism facilitates adhesive atelectasis through alveolar instability and collapse. Several lines of evidence indicate further effects of breathing high oxygen levels in animals and healthy subjects [1, 42], but evidence of pulmonary toxicity in a clinical scenario is limited [43]. The pathological features of this condition are commonly referred to as the Lorrain Smith effect [44] and are characterized by tracheobronchitis, which can be accompanied by pleuritic pain, bronchial irritation, cough, and sore throat. Symptoms may spread from the upper airways into the lungs, where diffuse alveolar damage manifests and contributes to edema, vascular leakage, arteriolar thickening, pulmonary fibrosis, and emphysema, reflected by progressive paradoxical hypoxia, dyspnea, and tachypnea. Additionally, prolonged hyperoxic exposure alters the microbial flora in the upper airways and further increases the risk of secondary infections and lethality. Notably, these pulmonary effects are often in addition to the primary (e.g., pneumonia) and secondary (e.g., ventilator-induced lung injury) lung injury, which are accompanied by inflammatory responses.

The central nervous system is typically the first to suffer from the effects of excessive ROS formation. The spectrum of neurological symptoms is referred to as the Paul Bert effect and ranges from nausea, dizziness, and headache to vision disturbances (retinal damage), neuropathies, paralysis, and convulsions [1].

Vascular effects of hyperoxia have been well documented and may have both harmful and beneficial effects. Arterial hyperoxia increases the systemic vascular resistance and induces vasoconstriction, which may impair organ perfusion, especially in the cerebral and coronary region [45–47]. Accompanying cardiovascular alterations result from even short-term exposure and include a decrease in heart rate, stroke volume, and cardiac output [48]. However, hyperoxia is not a universal vasoconstrictor in all vascular regions, and blood flow may be redistributed to the hepatosplanchnic circulation in septic shock [1, 49]. Alternatively, the administration of oxygen promotes hemodynamic stabilization during vasodilatory shock, decreases intracranial pressure by cerebral vasoconstriction, and preserves tissue oxygenation during hemodilution [2, 50].

Clinical studies

Critical care

Recent studies assessing the clinical effects of arterial hyperoxia or normobaric supplemental oxygen in critical care are listed in Table 1. As highlighted in recent meta-analyses [51, 52], the effects on major clinical endpoints are conflicting and may be partially explained by heterogeneous methodology and subgroup differences in critically ill patients. Pooled effect estimates favoring normoxia are quite consistent, but the harmful effects were previously shown to be impacted by the definition of hyperoxia and may be more pertinent to specific subgroups and at specific moments of admission.

Table 1 Studies assessing the clinical effects of arterial hyperoxia or supplemental oxygen in subgroups of critically ill patients Full size table

It is well established that the use of higher FiO 2 can lead to progressive hypercapnia during a state of chronic compensated respiratory acidosis, and serious adverse outcomes have been shown in acute exacerbations of chronic obstructive pulmonary disease or asthma [53–55]. Likewise, high fractions of oxygen in the inspired air and arterial blood have been associated with increased mortality in mechanically ventilated patients [56].

Owing to a striking lack of robust clinical trials, a causal relationship is still uncertain and both the magnitude and direction of the associations depend on the adjustment for illness severity scores, FiO 2 , and other confounders [56, 57]. Future randomized controlled studies are urgently needed to definitively elucidate the causal effects of oxygenation targets and derangements on clinical outcomes of critically ill patients.

Excessive oxygenation may be most intensively studied after resuscitation from cardiac arrest as both the vascular alterations and the ischemia and reperfusion injury are hypothesized to be hazardous [58]. In a dose-dependent manner, hyperoxia has been linked to worse outcome in these patients [59–62]. The adverse association was not systematically reproduced and this was possibly due to heterogeneity in study methods [63–68]. The only randomized controlled trial in the post-resuscitation period found that 30 % oxygen ventilation was not worse in comparison with 100 % oxygen, but the study was underpowered to detect significant differences [69]. In view of all recent data, supplemental oxygen administration during resuscitation still appears desirable, but hyperoxia should be avoided in the post-resuscitation phase and saturation should be targeted at 94–96 % [58, 70].

A large number of both experimental and clinical studies have primed pediatricians with great awareness of the risks of hyperoxia. For neonatal resuscitation, the routine use of 100 % oxygen has been abandoned after numerous associations with myocardial, neurological, and kidney injury and retinopathy, inflammation, and increased mortality [71, 72]. However, strict adherence to lower target ranges of oxygen saturation among preterm infants did not significantly reduce disability or deaths [73]. Results from a prospective large-scale meta-analysis investigating the most appropriate level of oxygenation for extremely preterm neonates suggested that functional oxyhemoglobin saturation be targeted at 90–95 % in the post-natal period [74].

Hyperoxia-induced vasoconstriction poses a major concern in the management of acute coronary syndromes, and guidelines increasingly suggest a restriction of supplementary oxygen to only those at increased risk for hypoxia [75]. Indeed, oxygen therapy has not been shown to be beneficial after acute myocardial infarction and may even be harmful, causing a marked reduction in coronary blood flow and myocardial oxygen consumption [76, 77]. The vasoconstriction caused by hyperoxia may be of special concern in the acute setting before reperfusion. The AVOID (Air Verses Oxygen In myocarDial infarction) trial aimed to definitively qualify the role of supplemental oxygen in acute myocardial infarction [78] and found increased myocardial injury, recurrent myocardial infarction, cardiac arrhythmia, and infarct size at 6 months [79]. In contrast, a smaller trial observed a beneficial effect of 30–40 % oxygen inhalation over controls during both occlusion and reperfusion [80]. Hemodynamic effects may also be pertinent to acute ischemic stroke patients, who do not appear to benefit from increased survival after prolonged treatment with oxygen [81, 82].

Despite the theoretical benefit of decreasing intracranial pressure through cerebral vasoconstriction, hyperoxia has repeatedly been associated with delayed cerebral ischemia and increased cerebral excitotoxicity after cerebrovascular incidents [83–85]. Interestingly, the synergistic combination of hyperbaric and normobaric hyperoxia was recently found to have potential therapeutic efficacy in severe traumatic brain injury [86]. However, observational data in patients with traumatic brain injury, ischemic stroke, subarachnoid, or intracerebral hemorrhage remain equivocal [87–92].

Perioperative care

Liberal oxygen supply is usually accepted in perioperative care in order to avoid potentially life-threatening consequences of hypoxia during surgery. Further effects of perioperative hyperoxia have been comprehensively summarized in meta-analyses enrolling over 7000 patients and generally showed a reduced risk of surgical site infections and postoperative nausea without luxation of postoperative atelectasis [93, 94]. However, risks may outweigh benefits in specific age groups [39] and different subsets. This was recently highlighted in patients undergoing cancer surgery in whom 80 % oxygen supply in the perioperative setting showed a significantly increased long-term all-cause mortality compared with those randomly assigned to 30 % [95].

Implications for therapy

Several therapeutic options that limit the harmful effects of hyperoxia can be contemplated, but prevention of excessive oxygenation is likely to be the most effective strategy. A rational approach may be a more conservative administration strategy in which oxygen is titrated to a lower tolerable level in order to prevent iatrogenic harm while preserving adequate tissue oxygenation. Recently, a pilot interventional study showed that conservative oxygen therapy in mechanically ventilated patients in the ICU can be feasible and free of adverse outcomes while decreasing excess oxygen exposure [96]. Importantly, when the risks for severe tissue hypoxia are pronounced, ample oxygen supply remains vital and should be started immediately to increase oxygen delivery and preserve tissue oxygenation. Also, oxygen may aid hemodynamic stabilization and decrease intracranial pressure and can be used to stimulate erythropoietin and increase hemoglobin when intermittent hyperoxia is used as a paradoxical trigger for HIF expression.

Experimental interventions to decrease harm from hyperoxia are targeted at numerous steps in the pathway of ROS-induced damage. The primary source for intervention in the oxidative cycle is inhibition of oxidant generation, either quantitatively or qualitatively. Bleomycin and amiodarone are well-known originators of drug-induced pulmonary disease and should be avoided to minimize preventable ROS formation [97, 98]. Limiting the exposure to other exogenous stimuli or preventing electron leakage in the electron transport chain may protect the mitochondria, but this strategy proves cumbersome in actual practice. Although the clinical applicability has been questioned because of little or no preventative or therapeutic effect, the supply of antioxidant enzymes may be a feasible approach to facilitate the conversion, avoid the intermediate formation, and reduce the concentration of strongly reactive oxidants. However, some of these antioxidants may actually have pro-oxidant properties, depending on their concentration and interaction with other molecules. The neutralizing effect of antioxidants may not be sufficient to secure metabolic stability, even when secondary inflammation is mitigated. Finally, oxidant scavenging can shift the balance toward harm when the role of oxidants in cell signaling pathways is suppressed [99].

As an alternative, pathways of cell integrity, cell death, and inflammation may be targeted to reduce further damage and enhance the defense against oxygen radicals. Experimental research suggests protective effects through modulation of protein kinases [100, 101] and transcription factors [102–105]. Moreover, numerous preclinical studies have demonstrated that manipulation of chemokines, cytokines [13, 106], growth factors [107], receptors [108–110], and DAMPs [11, 12, 111] may limit hyperoxia-induced injury, but these targets all remain to be evaluated at the bedside.