The mortality of critically ill patients rises steadily as the partial pressure of arterial oxygen falls below about 11 kPa (80 mm Hg). A new animal study in the May 2005 issue of PLoS Biology showing a potential benefit for hypoxia is thus a challenge to current thinking

Bellingan, G

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Geoff Bellingan

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Hooray for Hypoxia?

Bellingan Geoff

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Hooray for hypoxia?

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PLoS Medicine  |  www.plosmedicine.org 0480The Risks of Hypoxia and HyperoxiaHypoxaemia kills. Recently we have shown, in a study of over 50 000 critically ill patients, that mortality rises steadily as the partial pressure of arterial oxygen (PaO2) falls below about 11 kPa (80 mm Hg) (Figure 1) [1]. Rats exposed to hypoxic conditions develop a mild inﬂ  ammatory response with increased capillary leak and pro-inﬂ  ammatory cytokine release [2]. Hypoxia increases leukocyte adhesion, prolongs neutrophil survival, enhances pro-inﬂ  ammatory responses (in particular, increasing leukocyte IL-8 expression), and reduces lung ﬂ  uid transport [3,4]. A new study by Thiel et al. in PLoS Biology that shows a potential beneﬁ  t for hypoxia is therefore a challenge to current thinking [5].To put this ﬁ  nding into context we must acknowledge the equally accepted fact that hyperoxia is toxic. Experiments in primates show that 100% oxygen results in progressive damage to the pulmonary endothelium and epithelium. It causes free radical release, capillary leak, and impaired surfactant function in addition to arteriolar vasoconstriction and maldistribution of microcirculatory perfusion [6,7]. What, then, is the clinical balance we should strike between these extremes? Oxygenation of patients with acutely impaired lung function saves lives, but what is the right amount of oxygen? Many clinicians use the oxygen dissociation curve, aiming for saturations of above 92%. Others highlight the fact that patients with severe respiratory failure can survive despite being mechanically ventilated for days on 100% oxygen. In other words, a high percentage of inspired oxygen itself may not be harmful. (In animal studies showing harm from giving 100% oxygen, the lungs are usually normal at the beginning of the study, so the arterial oxygen is correspondingly high—typically a PaO2 of 40 kPa (300 mm Hg); thus, it may be the high PaO2 rather than the high percentage of inspired oxygen that causes lung damage.) Some researchers question the importance of oxygen toxicity at all—for example, Meier et al., using a haemorrhagic shock model, found a signiﬁ  cant improvement in outcome from the addition of 100% oxygen to the resuscitation [8].The New Study in Mice: Hyperoxia May Enhance Tissue DamageIt is against this background that the study by Thiel et al. is so interesting. Two of the study’s authors, Ohta and Sitkovsky, showed recently that adenosine receptors are important in down-regulating inﬂ  ammation [9]. They argued that a negative feedback loop operates: inﬂ  ammation causes tissue damage, leading to adenosine release, which acts on G-protein-coupled adenosine A2A receptors (A2ARs) to increase intracellular cyclic AMP, which in turn reduces the activity of NFκB and down-regulates the inﬂ  ammatory response (Figure 2). Indeed, inﬂ  ammation was dramatically enhanced in A2AR-deﬁ  cient mice compared with wild-type controls. Importantly, no signiﬁ  cant compensatory changes in the expression of other adenosine receptors have been demonstrated in these A2AR-deﬁ  cient mice. Sitkovsky and colleagues went on to propose that tissue inﬂ  ammation induced local hypoxia and that this hypoxia was important in regulating the adenosine-driven protective response. As a corollary they postulated that hyperoxia interrupts the hypoxia adenosine A2AR lung protection pathway and hence could enhance tissue damage (Figure 2). The current paper by Sitovsky’s group in PLoS Biology examines this hypothesis [5].At the outset, using an inﬂ  ammatory challenge that signiﬁ  cantly impaired gas exchange, the authors conﬁ  rmed PerspectivesOpen access, freely available onlineJune 2005  |  Volume 2  |  Issue 6  |  e130The Perspectives section is for experts to discuss the clinical practice or public health implications of a published article that is freely available online.Hooray for Hypoxia?A new study comes to a counter-intuitive conclusion: hypoxia may have its beneﬁ  ts for patients with lung injuryGeoff BellinganCitation: Bellingan G (2005) Hooray for hypoxia? PLoS Med 2(6): e130.Copyright: © 2005 Geoff Bellingan. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abbreviations: A2AR, adenosine A2A receptor; PaO2, partial pressure of arterial oxygenGeoff Bellingan is Clinical Director, Department of Critical Care, University College Hospitals London and Senior Lecturer in Intensive Care Medicine, Centre for Respiratory Research, Rayne Institute, University College London, United Kingdom. E-mail: geoff.bellingan@uclh.nhs.ukCompeting Interests: The author declares that he has no competing interests.DOI: 10.1371/journal.pmed.0020130DOI: 10.1371/journal.pmed.0020130.g001Figure 1. Mortality Rises Steadily as PaO2 FallsPLoS Medicine  |  www.plosmedicine.org 0481that when mice were additionally exposed to 100% oxygen, the toxicity of the challenge was dramatically increased compared to the inﬂ  ammatory challenge in normoxic conditions (21% oxygen). (Over the time frame of the experiments high concentrations of oxygen alone were found to be only mildly inﬂ  ammatory.) Inﬂ  ammatory neutrophils from the challenged mice expressed the A2AR, and exposure to high concentrations of oxygen reduced this expression. Moreover, an adenosine agonist could block pro-inﬂ  ammatory responses. Mice lacking the A2AR had increased neutrophil inﬁ  ltration in the lungs after endotoxin challenge and poorer gas exchange. The same was seen in wild-type mice treated with an A2AR blocker. Endotoxin-challenged mice breathing 10% oxygen (hypoxia) had a low mortality and, in the survivors, lung inﬂ  ammation was less severe than in mice breathing room air. Hypoxia also signiﬁ  cantly reduced pulmonary neutrophil accumulation and improved gas exchange compared with normoxia, suggesting that hypoxia acted to protect the lung from additional inﬂ  ammatory damage. Importantly, hypoxia was also associated with elevated adenosine concentrations. In contrast to the 20% mortality of hypoxic, endotoxin-challenged wild-type mice, hypoxic, endotoxin-challenged A2AR-deﬁ  cient mice had elevated local and systemic accumulation of pro-inﬂ  ammatory cytokines, and all died. As hypoxia per se did not affect the A2AR-deﬁ  cient mice, this suggests that both hypoxia and A2AR functionality are required to induce the anti-inﬂ  ammatory response. Finally, the authors showed that an adenosine agonist also inhibited lung injury in endotoxin-treated mice, reducing leukocyte inﬂ  ux and capillary leak. Importantly, this agonist could dramatically improve mortality even with a severe two-hit inﬂ  ammatory challenge under hyperoxic conditions. Implications of the StudyThese are exciting and provocative results. They are, however, hard to reconcile with many studies showing pro-inﬂ  ammatory effects from hypoxia. Sitkovsky and colleagues attempt to reconcile this difference by saying that their study had a long time course (over 48 hours), whereas studies showing that hypoxia is harmful usually had much shorter study periods. The authors’ explanation is probably too simplistic, and many issues and questions remain. (1) Different challenges—for example, pulmonary versus extrapulmonary—might give different results. (2) There is emerging evidence that more prolonged hypoxia can affect many processes, for example, mitochondrial function, and such complicated metabolic changes may be important and need to be examined [10]. (3) We don’t know the mechanism of increased extracellular adenosine. (4) Lung injury may relate to tachypnoea and tidal volume, and these have not been measured. (5) In sampling arterial oxygen 15 minutes after removal from the hyperoxia, we do not know whether the animals were exposed to excessive PaO2 levels or whether the degree of lung injury prevented the animals from having excessive PaO2 levels. In other words, although the animals were given 100% oxygen, they may not have had an elevated PaO2 (the lung injury may have prevented oxygenation of the blood). This issue is critically important, as the use of high-percentage inspired oxygen simply to achieve a normal PaO2 is much more akin to clinical practice. Refreshingly, though, this is a study that invites us to re-evaluate our perspectives. We know hypoxia can be bad, but is it as bad as hyperoxia? The scenario is all too familiar—the patient’s lung injury has rendered the patient hypoxaemic, and the paramedics have started high-ﬂ  ow oxygen. In the emergency room the team are heartened to see the patient “pink up” and to hear the ominous sound of the saturation monitor abate. But, beware, is the team really in a comfort zone? Is the saturation monitor really now chirping happily with 100% oxygen saturations, or is this the harbinger of future problems as the PaO2 increases unnoticed? Should we have an additional set of alarm limits, hitherto unrecognised: those of high oxygen tensions? Should the monitors be alarming not only when arterial saturation is below 90% but also when it’s above 98%? The study by Thiel et al. suggests that we urgently need to ﬁ  nd out.  References1.  Bellingan G, Wunsch H, Young D, Rowan K (2004) Is there a difference in mortality between patients admitted to ICU/HDU with acute hypoxaemic respiratory failure from pulmonary and extra-pulmonary causes: A study of 57706 patients [abstract]? Am J Respir Crit Care Med 169: A17. 2.  Madjdpour C, Jewell UR, Kneller S, Zeigler U, Schwendener R, et al. (2003) Decreased alveolar oxygen induces lung inﬂ  ammation. Am J Physiol Lung Cell Mol Physiol 284: L360–L367.3.  Hirani N, Antonicelli F, Streiter RM, Weisner MS, Ratcliffe PJ, et al. (2001) The regulation of interleukin 8 by hypoxaemia in human macrophages—A potential role in the pathogenesis of the acute respiratory distress syndrome (ARDS). Mol Med 7: 685–697.4.  Hannah S, Mecklenburgh K, Rahman I, Bellingan GJ, Greening A, et al. (1995) Hypoxia prolongs neutrophil survival in vitro. FEBS Lett 372: 233–237.5.  Thiel M, Chouker A, Ohta A, Jackson E, Caldwell C, et al. (2005) Oxygenation inhibits the physiological tissue-protecting mechanism and thereby exacerbates acute inﬂ  ammatory lung injury. PLoS Biol 2: e174. DOI: 10.1371/journal.pbio.0030174June 2005  |  Volume 2  |  Issue 6  |  e130DOI: 10.1371/journal.pmed.0020130.g002Figure 2. Adenosine Receptors Down-Regulate Inﬂ  ammation through a Negative Feedback Loop Sitkovsky and colleagues postulate that inﬂ  ammation causes tissue damage leading to adenosine release, which acts on adenosine A2ARs to increase intracellular cyclic AMP. The rise in cyclic AMP down-regulates the inﬂ  ammatory response. Tissue inﬂ  ammation induces local hypoxia, which regulates the adenosine-driven protective response. The ﬁ  gure shows the steps in the pathway where hyperoxia might act (having an inhibitory effect). (Illustration: Giovanni Maki)PLoS Medicine  |  www.plosmedicine.org 0482 June 2005  |  Volume 2  |  Issue 6  |  e1306.  Welty-Wolf KE, Simonson SG, Huang YC, Kantrow SP, Carraway MS, et al. (1997) Aerosolized manganese SOD decreases hyperoxic pulmonary injury in primates. II. Morphometric analysis. J Appl Physiol 83: 559–568.7.  Tsai AG, Cabrales P, Winslow RM, Intaglietta M (2003) Microvascular oxygen distribution in awake hamster window chamber model during hyperoxia. Am J Physiol Heart Circ Physiol 285: H1537–H1545. 8.  Meier J, Kemming GI, Kisch-Wedel H, Blum J, Pape A, et al. (2004) Hyperoxic ventilation reduces six hour mortality after partial ﬂ  uid resuscitation from hemorrhagic shock. Shock 22: 240–247. 9.  Ohta A, Sitkovsky M (2001) Role of G-protein-coupled adenosine receptors in down regulation of inﬂ  ammation and protection from tissue damage. Nature 414: 916–920.10. Frost MT, Wang Q, Moncada S, Singer M (2004) Hypoxia accelerates nitric oxide-dependent inhibition of mitochondrial complex I in activated macrophages. Am J Physiol Regul Integr Comp Physiol 288: R394–R400.

Decreased alveolar oxygen induces lung inﬂ ammation.

Hypoxia prolongs neutrophil survival in vitro.

Is there a difference in mortality between patients admitted to ICU/HDU with acute hypoxaemic respiratory failure from pulmonary and extra-pulmonary causes: A study of 57706 patients [abstract]?

Oxygenation inhibits the physiological tissue-protecting mechanism and thereby exacerbates acute inﬂ ammatory lung injury.

The regulation of interleukin 8 by hypoxaemia in human macrophages—A potential role in the pathogenesis of the acute respiratory distress syndrome (ARDS).

Hooray for Hypoxia?

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