Is enough oxygen too much?

Human cells require O2 for their energy supply, and critical illness can threaten the efficient delivery of O2 in accordance with tissue metabolic needs. In the accompanying article, Martin and colleagues point out that hypoxia is a normal and well-tolerated stress during embryonic development. A better understanding of how fetal cells survive these conditions and how adult cells adapt to high altitude exposure may provide insight into how these mechanisms might be engaged in the treatment of hypoxemic patients. They suggest that 'permissive hypoxia' represents a therapeutic possibility. But before we turn down the inspired O2 levels we should consider the broader effects of hypoxia on tissue repair in critical illness.

Intensivists direct much eff ort toward maintaining tissue oxygenation in critically ill patients. While the consequences of oxygen deprivation are well known, we also know that excessive oxygenation creates new problems because hyperoxia exacerbates lung injury. So like many things in life, 'too much' is not the solution to 'not enough' .
Assessments of tissue oxygenation have taught us that 'normoxia' diff ers among organs, and that tissue oxygenation can decrease when the environment or activity levels change. For example, lung alveolar cells normally reside under 14% O 2 , while oxygenation in intestinal epithelium can be less than 2%. Severe exercise decreases myocardial oxygenation from 4% to less than 1% O 2 , while high altitude induces systemic hypoxemia. During embryonic development, systemic oxygenation in the fetus is severely hypoxic by comparison to the adult.
While severe hypoxia can threaten survival at any stage of life, it is interesting that our cells often experience signifi cant hypoxia without sustaining injury. Moreover, we have learned that both cells and organisms quickly acclimate to lower oxygen environments. Th is is evidenced by altitude-acclimated climbers near the summit of Mt Everest who were alert with arterial PO 2 less than 25 mmHg! A similar level in a critically ill patient would be ominous. So why is hypoxia tolerated well in some circumstances but not in others?
In this issue of Critical Care, Dr Martin and colleagues consider the eff ects of hypoxia on physiology, and they review mechanisms allowing cells and organisms to tolerate oxygen deprivation without sustaining injury [1]. One mechanism involves the up-regulation of protective genes by hypoxia-inducible factor (HIF) transcription factors [2]. Th e cadre of genes controlled by HIF varies among cell types, but generally includes the expression of glycolytic enzymes, glucose transporters, vascular growth factors, and genes regulating vascular tone and systemic oxygen transport [3]. HIF also contributes to the downregulation of mitochondrial respiration, which lessens tissue need for oxygen. Loss of HIF is lethal during embryonic development, largely because hypoxia acts as a morphogen controlling migration and diff erentiation of cells in the embryo and placenta [4].
Other systems engaged by hypoxia include AMPdepen dent protein kinase (AMPK), which responds to increases in cellular [AMP] and is also activated by hypoxia. AMPK preserves energy substrate supply by upregulating glycolysis and fatty acid oxidation [5]. AMPK also regulates other biological processes.
Interestingly, O 2 acts as a signal in triggering the activation of both HIF and AMPK during hypoxia by releasing low levels of reactive oxygen species (ROS) from the electron transport chain [6]. Th ese ROS migrate to the inter-membrane space where they can escape to the cytosol and trigger the activation of HIF and AMPK [7]. Th us, O 2 acts in a paradoxical manner as a signaling molecule activating protective mechanisms during hypoxia.
Martin and colleagues raise the provocative concept of 'permissive hypoxia' in critical illness. To be sure, the degree to which hypoxemia should be corrected is incompletely understood. A reduction in cellular energy

Abstract
Human cells require O 2 for their energy supply, and critical illness can threaten the effi cient delivery of O 2 in accordance with tissue metabolic needs. In the accompanying article, Martin and colleagues point out that hypoxia is a normal and welltolerated stress during embryonic development. A better understanding of how fetal cells survive these conditions and how adult cells adapt to high altitude exposure may provide insight into how these mechanisms might be engaged in the treatment of hypoxemic patients. They suggest that 'permissive hypoxia' represents a therapeutic possibility. But before we turn down the inspired O 2 levels we should consider the broader eff ects of hypoxia on tissue repair in critical illness. demand during hypoxia, a form of adaptive hibernation, could lessen the consequences of oxygen deprivation. But before we reach for the FIO 2 control on the ventilator, we should consider other arguments. First, organ failure is essentially a situation where cells fail to perform their normal tissue function. In heart failure, cardiomyocytes are alive yet they fail to contract normally. In hypoxic tissues, adaptive responses might foster survival, but the consequences for organ function can be catastrophic. For example, in hypoxic lungs ROS signals activate AMPK, which triggers internalization of the epithelial Na,K-ATPase, an enzyme essential for alveolar edema re absor ption [8]. Hence, responses triggered by hypoxia may not optimize tissue repair and survival in the critically ill. Finally, intensivists need to know whether all cells in a tissue are oxygenated. Microvascular heterogeneity in the patient can create local hypoxic areas within excessively perfused regions. At the tissue level perfusion seems adequate, yet some cells are struggling in 'hypoxic islands' . A parallel situation occurs in solid tumors, where local cellular anoxia occurs despite high blood fl ows and excessive (albeit abnormally structured) capillary density [9]. So high overall blood fl ow does not guarantee uniform oxygenation.
In summary, hypoxia triggers protective responses, but not all of these are adaptive at the tissue level. A better understanding of the heterogeneity of microvascular oxygen supply in the critically ill patient would help us begin to understand the situation before we turn down the oxygen.

Competing interests
The author declares that he has no competing interests.