Oxygen Therapy in Critical Illness

Precise Control of Arterial Oxygenation and Permissive Hypoxemia

Daniel Stuart Martin, BSc, MBChB, PhD, FRCA, FFICM; Michael Patrick William Grocott, MBBS, MD, FRCA, FRCP, FFICM


Crit Care Med. 2013;41(2):423-432. 

In This Article


Hypoxemia is a common finding among critically ill patients irrespective of their underlying diagnosis.[3,6] It is defined as a PaO2 or SaO2 that falls below what is conventionally considered to be normal. Normal, while breathing air at sea level has been described as a PaO2 of between 80 and 100 mm Hg (10.7 and 13.3 kPa)[7] and SaO2 of greater than 94%;[8] however, considerable interindividual variability may exist with respect to these quoted values. For example, arterial oxygenation is inversely related to age[9] due to the decline in ventilation–perfusion matching that occurs over time.[10] The PaO2 at which clinicians choose to make a diagnosis of hypoxemia varies widely, but typically is in the range of 60 to 75 mm Hg (8–10 kPa).[11–13] In order to determine its cause, hypoxemia can also been described in relation to fractional inspired oxygen concentration (FIO2). In this instance the ratio of PaO2 to FIO2 (PaO2/FIO2 or P/F ratio) is used. A P/F ratio of less than 100 (when PaO2 is measured in mm Hg) or 13.3 (when PaO2 is measured in kPa) has been suggested for the diagnosis of "refractory hypoxemia"[14] (e.g., a PaO2 of 60 mm Hg [8 kPa] while receiving 60% oxygen). Perhaps it is the lack of evidence that maintaining normoxemia in critically ill patients is beneficial[15] that explains the wide variation in practice surrounding the management of hypoxemia in these patients.[16–18]

The Cause and Time-course of Hypoxemia

Potential mechanisms leading to hypoxemia should be kept in mind when considering treatment strategies as some causes may respond to specific therapies. Calculation of the alveolar-arterial oxygen partial pressure gradient (P(A-a)O2) may assist in elucidating the cause of hypoxemia; an example being that hypoventilation with open lungs and no elevation of FIO2 will result in a normal P(A-a)O2 that responds to simple oxygen therapy; whereas a right-to-left shunt will produce a raised P(A-a)O2 that will not respond to additional oxygen (Table 1).

Regardless of its etiology, hypoxemia may also be defined in terms of the duration of its evolution. However, the precise criteria defining specific categories are open to subjective interpretation. We, therefore, propose a structured approach to defining the time-course of hypoxemia based on the changing physiological responses and adaptations to declining arterial oxygenation that occur over time (Table 2). As an example, acute hypoxemia occurring as a consequence of abrupt upper airway obstruction or penetrating chest injury evokes physiological responses that are limited to the immediate augmentation of oxygen delivery through increases in minute volume and cardiac output. Persistence of sublethal hypoxemia results in alternative adaptive mechanisms, predominantly at a cellular level. Critically ill patients tend to fall within the subacute (6 hrs to 7 days) and sustained (7–90 days) categories (Table 2). Sustained cross-generational hypoxic stress occurring in high altitude native populations can lead to modification of the genome. The time-course of hypoxemia may influence decisions surrounding implementation of PCAO and PH for individual patients.

Clinical "Acclimatization" to Hypoxemia and Cellular Hypoxia

Exposure to subacute and sustained hypoxemia permits a coordinated process of adaptation, which outside of a clinical setting is commonly referred to as acclimatization. For example, at altitude the human response to hypobaric hypoxia is well described and characterized by the restoration of convective oxygen delivery through increases in alveolar ventilation, cardiac output, and red blood cell mass.[19,20] It is unlikely that critically ill patients mount such effective cardiorespiratory countermeasures to increase oxygen delivery as a result of their underlying pathology. However, there may be similarities in tissue and cellular responses to hypoxia between patients and healthy volunteers at altitude.[21] In skeletal muscle biopsies of healthy volunteers exposed to sustained hypoxia at high altitude, there is deactivation of mitochondrial biogenesis and down-regulation of mitochondrial uncoupling, possibly resulting in improved efficiency of ATP production.[22] Comparable changes in mitochondrial biogenesis also occur in critical ill patients and may reflect similar adaptive responses.[23,24] The difficulty that arises in comparing acclimatization to high altitude and the physiological changes that occur in the critically ill is that the degree of iatrogenic control over the latter group may prevent some aspects of adaptation. For example, patients in whom ventilation is controlled artificially by mechanical means will be unable to mount a hypoxic ventilator response. However, it is unlikely that cellular adaptation to hypoxia via hypoxia inducible factor will be inhibited by such interventions.

Severe and sustained tissue oxygen deprivation results in cellular hypoxia and a decline in ATP production that triggers apoptosis, a regulated energy-dependent process of programmed cell death. The level of cellular hypoxia at which apoptosis is initiated is unclear and almost certainly varies between organs and individuals. In isolated mitochondria, oxidative cellular metabolism fails when the PO2 falls less than 0.08 to 0.53 mm Hg (0.01–0.07 kPa),[25,26] while the corresponding values for cultured cells in vitro seem to be in the range of 3.00 to 5.25 mm Hg (0.40–0.70 kPa).[25] Cellular oxygen consumption (VO2) is governed by metabolic activity rather than oxygen supply,[27] but this relationship can be modified during conditions of limited oxygen availability. Following exposure to moderately prolonged hypoxia, cultured cells demonstrate a 40 to 60% reduction in VO2 secondary to the down-regulation of "non-essential" cellular processes.[28–30] This phenomenon is reversible on re-exposure to normoxia[29] and is not associated with demonstrable long-term cellular harm.[28] Termed "oxygen conformance," this reversible reduction in cellular metabolism and ATP production represents a chronic adaptive response to hypoxia not observed during acute hypoxic exposure. The coordinated reduction in VO2 demonstrated by oxygen conformance not only attenuates the depletion of scarce oxygen supplies, but may also render cells less susceptible to hypoxic injury if oxygen delivery continues to fall to a critical level. Strikingly similar mechanisms have been demonstrated during multiple organ failure in critically ill patients, and it has been proposed as an effective cellular survival strategy in this context.[31] These processes may be a manifestation of a more generalized adaptive response to hypoxia that facilitates cellular survival under conditions of extreme physiological stress.