Is oxygen more toxic than currently believed?

Scheele and Priestly discovered oxygen independently of each other in 1772 and 1774, respectively. It was quickly realized that this gas is not only life-giving but might be poisonous as well. However, what man has known for only 2 centuries nature itself has known for some 700 million years. One of the biggest leaps forward in evolution occurred when blue–green-like algae developed enzymes that scavenge the superoxide radical enabling them to live in an oxygen-rich atmosphere.1 Shortly after its discovery, oxygen was used for medical purposes. In 1780 France’s Chaussier experimented giving oxygen to newborn infants who failed to establish normal breathing.2 In 1928 Flagg described a detailed procedure for intubation and intermittent positive pressure insufflation using a mixture of oxygen and carbon dioxide for resuscitation of asphyxiated newborns.2 Oxygen therapy for newborn infants was introduced in the United States in the 1930s and 1940s although the Finnish pediatrician Ylppo in 1917 had already recommended intragastric administration of oxygen, a practice that continued a surprisingly long time, into the mid1950s.2 Not before the discovery of its relation to retrolental fibroplasia (retinopathy of prematurity [ROP]) were questions raised concerning the use of oxygen.3 The rest of the story is well-known: in the 1950s and 1960s the oxygen concentration was turned down in many incubators apparently resulting in a reduction in ROP but probably increased mortality.4 In the 1970s the transcutaneous electrodes were introduced—first the oxygen and subsequently the carbon dioxide electrode. Such electrodes should be a means to strict control of the oxygenation of the neonate, and it was thought that the problem related to ROP was solved. Or perhaps it was not? One problem was that the skin of the most immature infants often could not tolerate the heated electrodes. Further, it became clear that these electrodes, however accurate and sensitive they are, in many cases give values that are too high or too low.5 During the 1980s many centers reported an increasing incidence of ROP, mainly attributable to the fact that more immature infants survived. However, it became clear that ROP is not only attributable to exposure of oxygen. Oxidative stress per se because of oxygen exposure and high oxygen content in the blood, increased oxidative stress mediated through inflammations, or reduced antioxidant defense might be important contributing factors.6 In the 1980s pulse oximeters were introduced in neonatal intensive care units. Now arterial oxygen saturation could be followed continuously without any dermal harm even in the tiniest infants. These devices are noninvasive, easy to use, do not require calibration or heating of the skin, and give almost immediate information regarding changes in arterial oxygenation. Several problems related to the use of pulse oximeters were, however, revealed. They have a relatively high rate of false alarms, often caused by motion artifacts. They are also light-sensitive. Different models use different techniques. For instance, oximeters that display functional oxygen saturation show a somewhat (1.5%–3%) higher saturation than those recording so-called fractional saturations.7 But perhaps more importantly, if the saturations are too high, for instance 95%, the pulse oximeters do not give sufficient information about the oxygen tension, which could be very high. Bronchopulmonary dysplasia or chronic lung disease (CLD) has also been recognized as a disease related to oxidative stress. A high oxygen concentration in inspired air therefore might be detrimental. Today we know that the truth is more complicated and that both barotrauma and volutrauma play roles. Still, oxidative stress seems to be an important factor triggering this condition.8 The other side of the coin is that too low saturations increase pulmonary resistance, increase airway resistance, limit somatic growth, and perhaps also increase the risks of sudden death in infants with CLD.9,10 Very recently at least 2 reports have explored whether a high saturation of oxygen may elevate the risks of lung and/or ophtalmologic injuries. The STOP-ROP trial tested whether a regime aiming at a high arterial oxygen saturation (96%–99% vs 89%– 94%) for at least 2 weeks reduced further development of ROP once pretreshold retinopathy had been detected. No reduction in progression of ROP in the high-saturation group was found but there was a tendency for pneumonia and/or exacerbation of CLD to occur in more infants in the highrather than in the low-saturation group (13% vs 8%). The need for supplemental oxygen at 50 weeks postmenstrual age was also lower in the low-saturation group (37% vs 47%; P .02).11 In another study by Van Marter et Received for publication Jul 12, 2001; accepted Jul 12, 2001. Reprint requests to (O.D.S.) Department of Pediatric Research, Rikshospitalet 0027, Oslo, Norway. E-mail: [email protected] PEDIATRICS (ISSN 0031 4005). Copyright © 2001 by the American Academy of Pediatrics.