Supplemental oxygen for adults admitted to the intensive care unit

Review question

We set out to assess whether more supplemental oxygen is better than less supplemental oxygen for adults admitted to the intensive care unit (ICU).

Background

Adults admitted to the ICU are critically ill and are at high risk of dying. Oxygen supplementation, or therapy, is given to most adults admitted to ICU, and many are mechanically ventilated. Severe illness can result in a lack of oxygen in the blood, known as hypoxaemia, which puts patients at risk of low tissue levels of oxygen (hypoxia) and organ failure. The use of sedatives and strong pain relief medications can also depress breathing and therefore oxygen levels.

The practice of supplemental oxygen administration has been liberal, possibly resulting in too much oxygen, known as hyperoxia. Despite a lack of robust evidence of effectiveness, supplemental oxygen administration has been widely recommended in international clinical practice guidelines. However, a new guideline recommends against high oxygen levels as some, but not all, clinical studies have indicated a link between hyperoxaemia and an increased risk of dying. The potential benefit of supplemental oxygen must be weighed against the potentially harmful effects of hyperoxaemia.

Study characteristics

We identified 10 randomized controlled trials (studies where participants are randomly allocated to either an experimental or a control group) involving 1458 participants up to December 2018. Seven of the trials (1285 participants) provided findings on the number of deaths, serious adverse events, and lung injuries in the three months following oxygen therapy in the ICU. Lung injury was measured according to participants developing acute respiratory distress syndrome or pneumonia. Five trials included adults admitted to an ICU caring for patients with a range of serious health conditions and one to a surgical ICU. Two trials involved adults with traumatic brain injury; one trial adults after cardiac arrest and resuscitation; and one trial adults with stroke. All participants in six trials received invasive mechanical ventilation directly through a tube into the main airway. In one trial some of the participants were on mechanical ventilation, whilst others received non-invasive oxygen administration. Three trials involved adults receiving non-invasive oxygen. All trials compared more with less oxygen, however using very different levels of oxygen supplementation. Oxygen therapy was given for timeframes ranging from one hour to the length of hospital admission.

Key results

We are uncertain about the effects of higher levels of oxygen as our findings are based on very low-certainty evidence. We found no evidence for a beneficial effect of higher compared with lower supplemental oxygen levels for adults admitted to ICU. Higher levels of oxygen may have increased the risk of death (4 trials; 1135 participants) and serious adverse events (6 trials; 1234 participants). There was no evidence of a difference in lung injuries with the use of higher supplemental oxygen compared with lower supplemental oxygen, but the evidence is very uncertain (5 trials; 1167 participants). None of the included trials reported on quality of life at any time point, acute myocardial infarction, and stroke. Only one trial reported on sepsis.

Certainty of the evidence

The numbers of participants enrolled in the trials were too small to permit a definitive judgement about the review findings. The trials varied in the types of illness of the participants, their associated clinical care, disease severity, the targets for how much oxygen was given, and for how long. Two of the trials had a low risk of bias other than for lack of blinding of participants and personnel. Overall all included trials had a high risk of bias.

Authors' conclusions: 

We are very uncertain about the effects of higher versus lower fraction of inspired oxygen or targets of arterial oxygenation for adults admitted to the ICU on all-cause mortality, serious adverse events, and lung injuries at the time point closest to three months due to very low-certainty evidence. Our results indicate that oxygen supplementation with higher versus lower fractions or oxygenation targets may increase mortality. None of the trials reported the proportion of participants with one or more serious adverse events according to the ICH-GCP criteria, however we found that the trials reported an increase in the number of serious adverse events with higher fractions or oxygenation targets. The effects on quality of life, acute myocardial infarction, stroke, and sepsis are unknown due to insufficient data.

Read the full abstract...
Background: 

The mainstay treatment for hypoxaemia is oxygen therapy, which is given to the vast majority of adults admitted to the intensive care unit (ICU). The practice of oxygen administration has been liberal, which may result in hyperoxaemia. Some studies have indicated an association between hyperoxaemia and mortality, whilst other studies have not. The ideal target for supplemental oxygen for adults admitted to the ICU is uncertain. Despite a lack of robust evidence of effectiveness, oxygen administration is widely recommended in international clinical practice guidelines. The potential benefit of supplemental oxygen must be weighed against the potentially harmful effects of hyperoxaemia.

Objectives: 

To assess the benefits and harms of higher versus lower fraction of inspired oxygen or targets of arterial oxygenation for adults admitted to the ICU.

Search strategy: 

We identified trials through electronic searches of CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, BIOSIS Previews, CINAHL, and LILACS. We searched for ongoing or unpublished trials in clinical trials registers. We also scanned the reference lists of included studies. We ran the searches in December 2018.

Selection criteria: 

We included randomized controlled trials (RCTs) that compared higher versus lower fraction of inspired oxygen or targets of arterial oxygenation for adults admitted to the ICU. We included trials irrespective of publication type, publication status, and language.

We included trials with a difference between the intervention and control groups of a minimum 1 kPa in partial pressure of arterial oxygen (PaO2), minimum 10% in fraction of inspired oxygen (FiO2), or minimum 2% in arterial oxygen saturation of haemoglobin/non-invasive peripheral oxygen saturation (SaO2/SpO2).

We excluded trials randomizing participants to hypoxaemia (FiO2 below 0.21, SaO2/SpO2 below 80%, and PaO2 below 6 kPa) and to hyperbaric oxygen.

Data collection and analysis: 

Three review authors independently, and in pairs, screened the references retrieved in the literature searches and extracted data. Our primary outcomes were all-cause mortality, the proportion of participants with one or more serious adverse events, and quality of life. None of the trials reported the proportion of participants with one or more serious adverse events according to the International Conference on Harmonisation Good Clinical Practice (ICH-GCP) criteria. Nonetheless, most trials reported several serious adverse events. We therefore included an analysis of the effect of higher versus lower fraction of inspired oxygen, or targets using the highest reported proportion of participants with a serious adverse event in each trial. Our secondary outcomes were lung injury, acute myocardial infarction, stroke, and sepsis.

None of the trials reported on lung injury as a composite outcome, however some trials reported on acute respiratory distress syndrome (ARDS) and pneumonia. We included an analysis of the effect of higher versus lower fraction of inspired oxygen or targets using the highest reported proportion of participants with ARDS or pneumonia in each trial. To assess the risk of systematic errors, we evaluated the risk of bias of the included trials. We used GRADE to assess the overall certainty of the evidence.

Main results: 

We included 10 RCTs (1458 participants), seven of which reported relevant outcomes for this review (1285 participants). All included trials had an overall high risk of bias, whilst two trials had a low risk of bias for all domains except blinding of participants and personnel.

Meta-analysis indicated harm from higher fraction of inspired oxygen or targets as compared with lower fraction or targets of arterial oxygenation regarding mortality at the time point closest to three months (risk ratio (RR) 1.18, 95% confidence interval (CI) 1.01 to 1.37; I2 = 0%; 4 trials; 1135 participants; very low-certainty evidence). Meta-analysis indicated harm from higher fraction of inspired oxygen or targets as compared with lower fraction or targets of arterial oxygenation regarding serious adverse events at the time point closest to three months (estimated highest proportion of specific serious adverse events in each trial RR 1.13, 95% CI 1.04 to 1.23; I2 = 0%; 1234 participants; 6 trials; very low-certainty evidence). These findings should be interpreted with caution given that they are based on very low-certainty evidence.

None of the included trials reported any data on quality of life at any time point.

Meta-analysis indicated no evidence of a difference between higher fraction of inspired oxygen or targets as compared with lower fraction or targets of arterial oxygenation on lung injury at the time point closest to three months (estimated highest reported proportion of lung injury RR 1.03, 95% CI 0.78 to 1.36; I2 = 0%; 1167 participants; 5 trials; very low-certainty evidence).

None of the included trials reported any data on acute myocardial infarction or stroke, and only one trial reported data on the effects on sepsis.

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