The unknowns about oxygen therapy in critically ill patients

Oxygen is a commonly used drug in healthcare (1). Despite the widespread and age-old use of oxygen therapy in acutely ill patients, there are several unknowns when some of the basic questions pertaining to the use of any drug are asked. On one hand, supra-physiological oxygen levels are often targeted, and achieved, in conventional practice (2-4), despite the lack of high-quality evidence that using supplemental oxygen to achieve the conventional hyperoxic levels has any benefit. Additionally, recent studies have highlighted potential harms associated with hyperoxia (5-7). On the other hand, harms of poor oxygenation and tissue hypoxia are well established. However, the incidence and severity of such harmful effects, the upper and lower oxygenation thresholds at which these harmful effects begin to occur, the inter-individual variability in the physiological response to abnormal oxygen levels, the time-dependent and the dose-dependent characteristics of harmful effects, and their long term safety data remain unclear. Just as the threshold for permissive hypoxemia is not clearly defined (8), the threshold for hyperoxia or hyperoxemia remains unclear too (6,9). Further, not only the oxygenation-related thresholds for potential injury may be different for different patients (10), but they may vary with different stages of a disease in the same patient. It seems inaccurate to extrapolate these threshold levels from the observational studies, where outcomes could be influenced by many recognized or unrecognized confounders. The bottom line is that the current state of knowledge is inadequate to recommend optimal oxygen targets among acutely ill patients. Therefore, it is imperative for the critical care research groups to lay the ground work for conducting well designed trials that can address some of these basic questions about oxygen therapy.

Several strategies have been recently proposed for the management of hypoxemic ICU patients. A strategy of “precise control of arterial oxygenation” can avoid significant fluctuations beyond a narrowly defined normoxemic range, and thus avoid potential adverse effects of hyperoxia usually attained in conventional practice (9,10). A strategy of “conservative oxygenation therapy” aims to restrict use of supplemental oxygen for the purpose of avoiding hypoxemia (i.e., target SaO₂ ≥90%) (11). A conservative strategy often targets the lower end of the acceptable range for arterial oxygenation levels (i.e., target SaO₂ 88–92%) (12). A strategy of “permissive hypoxemia” aims to restrict use of supplemental oxygen to achieve even lower oxygenation levels than are currently acceptable (10,13), which may be suited for patients who either have had time to adapt to subacute or sustained hypoxemia or have such severe gas exchange abnormality that the risks of interventions needed to achieve the desired oxygenation level outweigh the benefits of achieving that goal. Last, the strategy of “individualized oxygen therapy” is also gaining traction in this era of personalized health care. This strategy likely encompasses the previous three strategies with an aim to manage hypoxemia guided by the clinical response, the best available evidence, anticipated duration that supplemental oxygen may be needed, and the current stage of the disease in a patient. All these strategies need careful and prudent ongoing investigations.

Some clinicians suggest that the conservative oxygen therapy or permissive hypoxemia should only be used in a select group of patients who are at a high risk of hyperoxia, but not for all patients (14). However, it might be premature to assume that hyperoxic injury is unlikely to happen in a particular group of patients before being tested in an experimental setting. A normal lung is certainly no guarantee against hyperoxic injury, which is demonstrated to be directly related to both inspired concentration of oxygen (FiO₂) and the duration of exposure to excessive FiO₂ (15-17). Progression of the initial lung insult is not uncommon in ICU (18). One-third of the patients developed acute lung injury or ARDS at a median of three days after the ICU admission in a large observational study (19). Existing evidence suggests that a subclinical or a preexisting insult to the lung may change the susceptibility to oxygen-induced lung damage, which may cause or augment the severity of the lung injury (20-24). For these reasons, a broad group of ICU patients who are exposed to supplemental oxygen on a routine basis, while on invasive mechanical ventilation, must be studied in future pragmatic RCTs on different strategies of oxygen therapy. Explanatory trials are also needed to study if different oxygenation strategies have different effects on the clinical outcomes in specific conditions such as elderly, ARDS, traumatic brain injury or stroke, post cardiac arrest syndrome or circulatory shock state.

A major concern often raised with restrictive oxygen therapy is its lowering effect on systemic oxygen delivery (14). However, physiological studies show this effect to be trivial. Given that the systemic oxygen delivery is the product of cardiac output and arterial blood oxygen content (CaO₂), the effect of liberal versus restrictive oxygen therapy on both these factors need to be considered. First, high FiO₂ therapy or hyperoxia is demonstrated to markedly reduce coronary blood flow due to coronary vasoconstriction (25) with variable hemodynamic effects. In awake patients, high FiO₂ therapy showed no significant effects on stroke volume index or cardiac index (26), whereas among anaesthetized patients, increasing FiO₂ reduced cardiac output, and vice versa reducing FiO₂ increased cardiac output (27). Second, the sigmoidal shape of the O₂-hemoglobin dissociation curve (28) implies that the likely effect on CaO₂, when PaO₂ is increased from 55 to 150 or 300 mmHg, is trivial. The reason is that beyond a threshold PaO₂ of 55–60 mmHg, large increments in PaO₂ result in little gains in SaO₂ (29), which is a far more important determinant of CaO₂. Indeed in a crossover clinical trial, when a higher SaO₂ target (mean SaO₂ 97%; CaO₂ 18 mL/dL) was compared to a lower SaO₂ target (mean SaO₂ 92%; CaO₂ 16.9 mL/dL), there was a difference of just 1.1 mL/dL in the CaO₂ with no significant effect on cardiac output or oxygen consumption (30). Therefore, the overall incremental effect of liberal versus conservative oxygenation on the systemic oxygen delivery is trivial. Nonetheless, interventions targeted at elevating systemic oxygen delivery have consistently failed to improve outcomes among critically ill patients (31,32).

Last, it is well acknowledged that the safety and feasibility of a conservative oxygenation strategy or permissive hypoxemia need careful evaluation (8,12). The notion that either of these strategies might improve clinical outcomes is not without merits. It is plausible that among mechanically ventilated patients, any supplemental FiO₂ over and above 0.21 (i.e., a supra-physiological FiO₂) can cause a local hyperoxic environment that might have a dose-dependent injurious effect on the lung alveoli and surrounding tissues. The injury in pulmonary tissues may evolve or progress with time in presence of ongoing hyperoxia. In addition, a supra-physiological FiO₂ that results in a supra-physiological PaO₂ for an individual patient might cause a dose-dependent and time-dependent hyperoxic tissue injury in other organs, which may result in either new organ dysfunction or delay in recovery. On the other hand, not using sufficient supplemental FiO₂ or targeting SaO₂ or PaO₂ that is lower than currently acceptable limit (permissive hypoxemia) might result in hypoxic tissue injury in other organs. Whether a conservative oxygenation strategy, where the SaO₂ or PaO₂ targets are within the lower end of the currently acceptable range, has better risk-benefit profile than a strategy of permissive hypoxemia remains unclear. We tested the former strategy in a feasibility trial to assess whether we can minimize the use of supplemental FiO₂ in presence of an acceptable SpO₂. The SpO₂ targets in the conservative arm were stratified based on the FiO₂ requirement for the patient. When FiO₂ requirement was <0.50, the SpO₂ targets were 90–92%, whereas when FiO₂ requirement was 0.50, SpO₂ targets were 88–90% (12). Clinicians were allowed to alter these targets if they were concerned about adequacy of systemic oxygen delivery or any hypoxic injury. Despite limitations, our study was the first RCT investigating two oxygenation targets among the mechanically ventilated adult ICU patients, and provides important data that may encourage further investigations on different oxygenation strategies.

Acknowledgements

None.

Footnote

Conflicts of Interest: The author has no conflicts of interest to declare.

Response to:He HW, Liu DW. Permissive hypoxemia/conservative oxygenation strategy: Dr. Jekyll or Mr. Hyde? J Thorac Dis 2016;8:748-50.

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