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Oxygen: Providing Too Much of a Good Thing?

Critical Care Medicine www.ccmjournal.org 641 Oxygen is a two-edged sword. On the one hand, adequate tissue oxygen pressures/content is essential for proper aerobic metabolism. On the other hand, excessive oxygen can cause severe cellular injury through alterations in regional blood flow and the production of free radicals. Tissue homeostasis requires a balance between these effects and depends on complex mechanisms that can both compensate for hypoxic conditions if they develop and regulate the overproduction of dangerous reactive oxygen species. Adequate tissue oxygenation depends on oxygen delivery (cardiac output times, oxygen content), the ability of the tissues to extract this oxygen, and the ability of the mitochondria to use this oxygen (1). Importantly, multiple compensatory mechanisms exist for hypoxia (2). Extreme examples can be found in high-altitude dwellers who can function atop Mount Everest with Po 2 values less than 25 mm Hg. Another example is that of the human fetus that thrives with Po 2 levels of less than 30 mm Hg at term. In the animal kingdom, hypoxia can be tolerated at quite low levels through the hibernation process. The mechanisms involved in these conditions are not entirely clear but involve changes in the hemoglobin molecule, regional distribution of blood flow, improved extraction and utilization capabilities, and the multiple effects of hypoxia inducible factors on cellular function (3). Tissue hyperoxia does not exist in nature. However, it is a common occurrence in hospitalized patients as clinicians often attempt to provide protection from hypoxia with a supplemental oxygen “buffer.” This practice occurs despite the fact that it has been known for over a century that excessive oxygen exposure in the lungs can be toxic (4). The mechanisms underlying this toxicity are complex but involve the overproduction of reactive oxygen species that overwhelm the antioxidant-modulating systems operative under normoxic conditions (and which may be compromised in systemic inflammatory states). The thresholds for this are unclear, are likely tissue specific, and, no doubt, have a time component as well. Most authorities in the ICU consider an Fio 2 less than 40% as being tolerable to lung tissue for several days. In contrast, Fio 2 s above 80% are generally thought harmful to lung tissue within a few hours or days. In the tissues, it has been speculated that even modest hyperoxia (perhaps as low as Po 2 values exceeding 120–150 mm Hg) may also be associated with harm (5). In this issue of Critical Care Medicine, Helmerhorst et al (6) who have been studying this for years have come forth with a study looking at how one might change practices to minimize tissue hyperoxia. This study builds on numerous previous observational studies that suggest a “u-shaped” curve exists—a plot of oxygen concentration on a horizontal axis versus injury on the vertical axis that rises both as the tissues become hypoxic on the left and also as it becomes hyperoxic on the right. A recent meta-analysis of many of these studies was quite informative in suggesting that, indeed, hyperoxia in a number of clinical situations may be associated with harm (7). The effect was clearly related to the level of tissue hyperoxia (Pao 2 values > 300 mm Hg, most harmful), was more evident in certain subgroups (e.g., cardiac arrest patients), was certainly impacted by comorbidities, and was likely tissue specific. An interesting sidebar to these concepts exists in the perinatal period as the mechanisms protecting the fetus from hypoxia in utero likely make the newborn exquisitely sensitive to hyperoxia during the transition to a higher oxygen environment (8). This article demonstrates that Po 2 values of more than 120 mm Hg occurred 15.3% of the time in over 15,000 patients in a large database in the Netherlands. The authors then go on to explain how management practices through education and protocol development can effectively change this practice to reduce this exposure by 50%. The authors make an attempt to link this reduction to a mortality benefit. However, because this is observational data and the protocol was linked to other new management strategies, it is a difficult point to prove. A randomized trial would be needed to really confirm this observation. Nevertheless, because there is no compelling reason to provide Po 2 values that are high and the risk may be real, it would seem prudent for clinicians to pay attention to hyperoxia just as they do to hypoxia.