NIHR DC Discover

NIHR Signal A reminder that too much oxygen increases mortality in acutely ill adults

Published on 24 July 2018

doi: 10.3310/signal-000627

In acutely ill adults, liberal use of oxygen supplementation is found to increase the risk of death compared with more conservative oxygen strategies. More liberal oxygen therapy increases patient mortality in hospital by about 11 deaths amongst every 1,000 people exposed. Deaths also increase after 30 days follow-up, without improving other important health outcomes, such as disability, infection or length of hospital stay.

Oxygen is routinely used for acutely ill patients and is widely considered by healthcare professionals to be beneficial, or at worst, a completely harmless therapy. Indeed, adequate oxygen therapy is essential if oxygen levels are low. However, concerns are increasing about over-use of oxygen or liberal use (when the saturation of peripheral blood with oxygen reaches more than 96%) and its potentially harmful adverse effects. 

This systematic review and meta-analysis represents high-quality evidence combining international data from 25 randomised controlled trials. The findings support conservative use of oxygen therapy, to raise blood levels no higher than needed, and will inform guidelines to sufficiently outline the risks, alongside the benefits, of supplemental oxygen use in the acutely ill.  

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Why was this study needed?

In the UK, approximately one-third of patients in ambulances and a quarter of patients in emergency rooms are treated with supplemental oxygen. However, oxygen therapy is not always beneficial. Hyperoxaemia, a state of abnormally high blood oxygen levels, has been associated with adverse clinical outcomes in people with respiratory failure, stroke, and heart attack.

Current guidelines recommend oxygen to treat only low blood oxygen and to raise oxygen no higher than a narrow therapeutic range. However, in clinical practice, between 50-73% of critically ill patients in intensive care are given excess oxygen therapy and become hyperoxaemic.

Disparity in practice may be because of uncertainty concerning the benefit and harms of oxygen therapy in acutely ill patients. A number of randomised controlled trials exist that compare different oxygen strategies in various acute illnesses; however, this is the first review to synthesise this information.

What did this study do?

The IOTA systematic review and meta-analysis pooled the results of 25 randomised controlled trials. The 16,037 participants required non-elective hospital admission for acute illnesses including sepsis, critical illness, stroke, trauma, myocardial infarction, and cardiac arrest. The average age was 64 years. Six studies were conducted in the UK.

The studies compared liberal and conservative oxygenation strategies. In each study, the treatment group with higher oxygen supplementation was categorised as liberal (median baseline oxygen saturation of peripheral blood across trials, 96%, range 94-99%), and the group with lower oxygen supplementation achieving saturation less than this was conservative. The trials in this study were generally high quality.

On average, supplementation of oxygen was substantially higher in the liberal treatment group. However, this varied greatly across studies. Such variation may underestimate true differences between groups. Importantly, this review excluded studies focused on chronic respiratory disease.

What did it find?

  • Liberal oxygen therapy was associated with increased mortality in hospital compared with conservative oxygen therapy, (relative risk [RR] 1.21, 95% confidence interval [CI] 1.03 to 1.43; 11 more deaths per 1,000 treated; 19 trials, 15,071 participants).
  • Mortality at 30 days after admission was also increased (RR 1.41, 95% CI 1.01 to 1.29; 14 more deaths per 1,000 treated; 14 trials, 15,053 participants).
  • There was no difference in disability following a stroke or traumatic brain injury between liberal and conservative oxygen therapy (RR 0.94, 95% CI 0.62 to 1.41; 5 trials, 5,523 participants).
  • There was no difference between treatment groups for hospital-acquired pneumonia (RR 1.00, 95% CI 0.74 to 1.35; 4 trials, 1,785 participants).
  • There was no difference between treatment groups for length of hospital stay (mean difference 0.25 fewer days, 95% CI 0.68 fewer to 0.18 more days in hospital; 12 trials, 2,448 participants).

What does current guidance say on this issue?

The British Thoracic Society 2017 guideline for oxygen use in adults in healthcare and emergency settings states that oxygen should be used as a treatment for low blood oxygen, not breathlessness.  

The guideline recommends immediate high-concentration oxygen for critically ill patients, but that this should be prescribed to achieve target oxygen saturations of between 94 to 98% for most acutely ill patients, and 88 to 92% for those at risk of hypercapnic (high blood carbon dioxide) respiratory failure. Those administering oxygen should monitor the patient to keep within target range.  

What are the implications?

The increased mortality observed in this study makes it clear that excessive treatment with oxygen should be avoided. 

This evidence points to a slightly lower upper threshold for safe oxygen supplementation. This could, therefore, offer an improvement on existing guideline advice. Healthcare professionals should take care not to exceed such recommended boundaries amongst the acutely ill.

This review did not include evidence from those being treated for chronic respiratory diseases, and these patients will require modified targets.

Bibliography

Hale KE, Gavin C, O’Driscoll BR. Audit of oxygen use in emergency ambulances and in a hospital emergency department. Emerg Med J. 2008;25(11):773-6.

Helmerhorst HJ, Schultz MJ, van der Voort PH, et al. Self-reported attitudes versus actual practice of oxygen therapy by ICU physicians and nurses. Ann Intensive Care. 2014;4(1):23.

Kelly CA, Lynes D, O'Brien MR, Shaw B. A wolf in sheep's clothing? Patients’ and healthcare professionals’ perceptions of oxygen therapy: An interpretative phenomenological analysis. Clin Respir J. 2018;12(2):616-32.

O'Driscoll BR, Howard LS, Earis J, Mak V. BTS guideline for oxygen use in adults in healthcare and emergency settings. Thorax. 2017;72(Suppl 1):ii1-90.

Suzuki S, Eastwood GM, Peck L, Glassford NJ, Bellomo R. Current oxygen management in mechanically ventilated patients: a prospective observational cohort study. J Crit Care. 2013;28(5):647-54.

Why was this study needed?

In the UK, approximately one-third of patients in ambulances and a quarter of patients in emergency rooms are treated with supplemental oxygen. However, oxygen therapy is not always beneficial. Hyperoxaemia, a state of abnormally high blood oxygen levels, has been associated with adverse clinical outcomes in people with respiratory failure, stroke, and heart attack.

Current guidelines recommend oxygen to treat only low blood oxygen and to raise oxygen no higher than a narrow therapeutic range. However, in clinical practice, between 50-73% of critically ill patients in intensive care are given excess oxygen therapy and become hyperoxaemic.

Disparity in practice may be because of uncertainty concerning the benefit and harms of oxygen therapy in acutely ill patients. A number of randomised controlled trials exist that compare different oxygen strategies in various acute illnesses; however, this is the first review to synthesise this information.

What did this study do?

The IOTA systematic review and meta-analysis pooled the results of 25 randomised controlled trials. The 16,037 participants required non-elective hospital admission for acute illnesses including sepsis, critical illness, stroke, trauma, myocardial infarction, and cardiac arrest. The average age was 64 years. Six studies were conducted in the UK.

The studies compared liberal and conservative oxygenation strategies. In each study, the treatment group with higher oxygen supplementation was categorised as liberal (median baseline oxygen saturation of peripheral blood across trials, 96%, range 94-99%), and the group with lower oxygen supplementation achieving saturation less than this was conservative. The trials in this study were generally high quality.

On average, supplementation of oxygen was substantially higher in the liberal treatment group. However, this varied greatly across studies. Such variation may underestimate true differences between groups. Importantly, this review excluded studies focused on chronic respiratory disease.

What did it find?

  • Liberal oxygen therapy was associated with increased mortality in hospital compared with conservative oxygen therapy, (relative risk [RR] 1.21, 95% confidence interval [CI] 1.03 to 1.43; 11 more deaths per 1,000 treated; 19 trials, 15,071 participants).
  • Mortality at 30 days after admission was also increased (RR 1.41, 95% CI 1.01 to 1.29; 14 more deaths per 1,000 treated; 14 trials, 15,053 participants).
  • There was no difference in disability following a stroke or traumatic brain injury between liberal and conservative oxygen therapy (RR 0.94, 95% CI 0.62 to 1.41; 5 trials, 5,523 participants).
  • There was no difference between treatment groups for hospital-acquired pneumonia (RR 1.00, 95% CI 0.74 to 1.35; 4 trials, 1,785 participants).
  • There was no difference between treatment groups for length of hospital stay (mean difference 0.25 fewer days, 95% CI 0.68 fewer to 0.18 more days in hospital; 12 trials, 2,448 participants).

What does current guidance say on this issue?

The British Thoracic Society 2017 guideline for oxygen use in adults in healthcare and emergency settings states that oxygen should be used as a treatment for low blood oxygen, not breathlessness.  

The guideline recommends immediate high-concentration oxygen for critically ill patients, but that this should be prescribed to achieve target oxygen saturations of between 94 to 98% for most acutely ill patients, and 88 to 92% for those at risk of hypercapnic (high blood carbon dioxide) respiratory failure. Those administering oxygen should monitor the patient to keep within target range.  

What are the implications?

The increased mortality observed in this study makes it clear that excessive treatment with oxygen should be avoided. 

This evidence points to a slightly lower upper threshold for safe oxygen supplementation. This could, therefore, offer an improvement on existing guideline advice. Healthcare professionals should take care not to exceed such recommended boundaries amongst the acutely ill.

This review did not include evidence from those being treated for chronic respiratory diseases, and these patients will require modified targets.

Bibliography

Hale KE, Gavin C, O’Driscoll BR. Audit of oxygen use in emergency ambulances and in a hospital emergency department. Emerg Med J. 2008;25(11):773-6.

Helmerhorst HJ, Schultz MJ, van der Voort PH, et al. Self-reported attitudes versus actual practice of oxygen therapy by ICU physicians and nurses. Ann Intensive Care. 2014;4(1):23.

Kelly CA, Lynes D, O'Brien MR, Shaw B. A wolf in sheep's clothing? Patients’ and healthcare professionals’ perceptions of oxygen therapy: An interpretative phenomenological analysis. Clin Respir J. 2018;12(2):616-32.

O'Driscoll BR, Howard LS, Earis J, Mak V. BTS guideline for oxygen use in adults in healthcare and emergency settings. Thorax. 2017;72(Suppl 1):ii1-90.

Suzuki S, Eastwood GM, Peck L, Glassford NJ, Bellomo R. Current oxygen management in mechanically ventilated patients: a prospective observational cohort study. J Crit Care. 2013;28(5):647-54.

Mortality and morbidity in acutely ill adults treated with liberal versus conservative oxygen therapy (IOTA): a systematic review and meta-analysis

Published on 5 May 2018

Chu, D. K.,Kim, L. H.,Young, P. J.,Zamiri, N.,Almenawer, S. A.,Jaeschke, R.,Szczeklik, W.,Schunemann, H. J.,Neary, J. D.,Alhazzani, W.

Lancet Volume 391 Issue 10131 , 2018

BACKGROUND: Supplemental oxygen is often administered liberally to acutely ill adults, but the credibility of the evidence for this practice is unclear. We systematically reviewed the efficacy and safety of liberal versus conservative oxygen therapy in acutely ill adults. METHODS: In the Improving Oxygen Therapy in Acute-illness (IOTA) systematic review and meta-analysis, we searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, HealthSTAR, LILACS, PapersFirst, and the WHO International Clinical Trials Registry from inception to Oct 25, 2017, for randomised controlled trials comparing liberal and conservative oxygen therapy in acutely ill adults (aged >/=18 years). Studies limited to patients with chronic respiratory diseases or psychiatric disease, patients on extracorporeal life support, or patients treated with hyperbaric oxygen therapy or elective surgery were excluded. We screened studies and extracted summary estimates independently and in duplicate. We also extracted individual patient-level data from survival curves. The main outcomes were mortality (in-hospital, at 30 days, and at longest follow-up) and morbidity (disability at longest follow-up, risk of hospital-acquired pneumonia, any hospital-acquired infection, and length of hospital stay) assessed by random-effects meta-analyses. We assessed quality of evidence using the grading of recommendations assessment, development, and evaluation approach. This study is registered with PROSPERO, number CRD42017065697. FINDINGS: 25 randomised controlled trials enrolled 16 037 patients with sepsis, critical illness, stroke, trauma, myocardial infarction, or cardiac arrest, and patients who had emergency surgery. Compared with a conservative oxygen strategy, a liberal oxygen strategy (median baseline saturation of peripheral oxygen [SpO2] across trials, 96% [range 94-99%, IQR 96-98]) increased mortality in-hospital (relative risk [RR] 1.21, 95% CI 1.03-1.43, I(2)=0%, high quality), at 30 days (RR 1.14, 95% CI 1.01-1.29, I(2)=0%, high quality), and at longest follow-up (RR 1.10, 95% CI 1.00-1.20, I(2)=0%, high quality). Morbidity outcomes were similar between groups. Findings were robust to trial sequential, subgroup, and sensitivity analyses. INTERPRETATION: In acutely ill adults, high-quality evidence shows that liberal oxygen therapy increases mortality without improving other patient-important outcomes. Supplemental oxygen might become unfavourable above an SpO2 range of 94-96%. These results support the conservative administration of oxygen therapy. FUNDING: None.

Expert commentary

"First do no harm" is a principle which should guide healthcare professionals. This thorough study clearly indicates that the widespread practice of routinely putting an oxygen mask on all acutely ill/emergency patients is unsafe.  

Supplemental oxygen is necessary if the patient is cyanosed (blue inner surface of the lips or underside of the tongue) or in the absence of cyanosis, when oxygen saturation of the blood is less than 94%, aiming to achieve 94-96% saturation.  

Higher saturations are unnecessary physiologically and can endanger survival.  In most acutely ill adults with less than 94% saturation, 24% oxygen should be enough.

Dr Ian Campbell, Honorary Consultant Physician, Cardiff & Vale UHB

Expert commentary

This large systematic review raises significant concerns about the consequences of unrestricted oxygen therapy in acutely ill adults. The results are limited by the large variety of illnesses studied and the many different approaches to oxygen treatment. Patients having elective surgery were excluded.

These results should encourage practitioners to think carefully about the dose each time they take responsibility for administering oxygen. Oxygen is a drug that should be prescribed with care and monitored where possible: both excess and inadequate therapy may cause harm. Definitive clinical trials are needed to define the safest doses for oxygen therapy in specific patient groups.

Mike Grocott, Professor of Critical Care, University of Southampton