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Oxygen Therapy in Patients with Acute Myocardial Infarction: A Systemic Review and Meta-Analysis

Published:January 17, 2018DOI:https://doi.org/10.1016/j.amjmed.2017.12.027

      Abstract

      Objective

      Oxygen therapy is frequently used for patients with acute myocardial infarction. The aim of this study is to perform a systematic review and meta-analysis to compare the outcomes of oxygen therapy versus no oxygen therapy in post–acute myocardial infarction settings.

      Methods

      A systematic search of electronic databases was conducted for randomized studies, which reported cardiovascular events in oxygen versus no oxygen therapy. The evaluated outcomes were all-cause mortality, recurrent coronary events (ischemia or myocardial infarction), heart failure, and arrhythmias. Summary-adjusted risk ratios (RRs) were calculated by the random effects DerSimonian and Laird model. The risk of bias of the included studies was assessed by Cochrane scale.

      Results

      Our meta-analysis included a total of 7 studies with 3842 patients who received oxygen therapy and 3860 patients without oxygen therapy. Oxygen therapy did not decrease the risk of all-cause mortality (pooled RR, 0.99; 95% confidence interval [CI], 0.81-1.21; P = .43), recurrent ischemia or myocardial infarction (pooled RR, 1.19; 95% CI, 0.95-1.48; P = .75), heart failure (pooled RR, 0.94; 95% CI, 0.61-1.45; P = .348), and occurrence of arrhythmia events (pooled RR, 1.01; 95% CI, 0.85-1.2; P = .233) compared with the no oxygen arm.

      Conclusions

      This meta-analysis confirms the lack of benefit of routine oxygen therapy in patients with acute myocardial infarction with normal oxygen saturation levels.

      Keywords

      Clinical Significance
      • Society guidelines endorse oxygen therapy for the management of patients with acute myocardial infarction in the context of hypoxemia.
      • The study revealed the lack of benefit of routine oxygen therapy in patients with acute myocardial infarction with normal oxygen saturation levels.
      • The value of the present study is to resolve the debate of routine oxygen use in the setting of acute myocardial infarction with no hypoxia with the most updated evidence, including randomized trials.

      Introduction

      Ischemic heart disease is the most common cause of death worldwide.
      • Ibanez B.
      • James S.
      • Agewall S.
      • et al.
      2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC).
      Furthermore, acute myocardial infarctions occur in approximately 790,000 Americans every year.
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics—2017 update: a report from the American Heart Association.
      Reperfusion therapy is the gold standard treatment strategy for patients who present with acute myocardial infarction.
      • Ibanez B.
      • James S.
      • Agewall S.
      • et al.
      2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC).
      Other treatment therapies, such as routine oxygen therapy, have been evaluated to determine their impact on cardiovascular outcomes. Oxygen therapy in ischemic heart disease was first reported in 1900 and since that time has been incorporated in the usual care during acute treatment for patients with acute myocardial infarction.
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics—2017 update: a report from the American Heart Association.
      Previous animal and clinical studies hypothesized that supplemental oxygen up to even hyperoxic levels in patients with acute myocardial infarction would reduce myocardial injury by increasing oxygen delivery to ischemic myocardium.
      • Chan A.W.
      • Kornder J.
      • Elliott H.
      • et al.
      Improved survival associated with pre-hospital triage strategy in a large regional ST-segment elevation myocardial infarction program.
      • Steele C.
      Severe angina pectoris relieved by oxygen inhalations.
      • Maroko P.R.
      • Radvany P.
      • Braunwald E.
      • et al.
      Reduction of infarct size by oxygen inhalation following acute coronary occlusion.
      Yet, those studies were not randomized or blinded. Conversely, it has since been reported that hyperoxia may precipitate an increase in myocardial injury due to coronary vasoconstriction and oxidative stress.
      • Kelly R.F.
      • Hursey T.L.
      • Parrillo J.E.
      • et al.
      Effect of 100% oxygen administration on infarct size and left ventricular function in a canine model of myocardial infarction and reperfusion.
      • Madias J.
      • Madias N.
      • Hood Jr, W.
      Precordial ST-segment mapping. 2. Effects of oxygen inhalation on ischemic injury in patients with acute myocardial infarction.
      Yet the use of supplemental oxygen continued to be a routine practice in patients with cardiac disease. More important, no randomized, blinded, and controlled studies have shown an advantage in normoxemic patients, with surging evidence proving the conceivable adverse effects of hyperoxia in acute myocardial infarction.
      • Kenmure A.C.F.
      • Murdoch W.R.
      • Beattie A.D.
      • et al.
      Circulatory and metabolic effects of oxygen in myocardial infarction.
      • Mak S.
      • Azevedo E.R.
      • Liu P.P.
      • et al.
      Effect of hyperoxia on left ventricular function and filling pressures in patients with and without congestive heart failure.
      A Cochrane report from 2016 did not show any benefit to using oxygen in patients with acute myocardial infarction.
      • Kenmure A.C.F.
      • Murdoch W.R.
      • Beattie A.D.
      • et al.
      Circulatory and metabolic effects of oxygen in myocardial infarction.
      Additionally, a recent meta-analysis reviewed 5 randomized controlled trials and concluded that oxygen supplementation did not benefit patients with baseline normal peripheral oxygen saturations ≥90%.
      • Mak S.
      • Azevedo E.R.
      • Liu P.P.
      • et al.
      Effect of hyperoxia on left ventricular function and filling pressures in patients with and without congestive heart failure.
      Most recently, a registry-based randomized clinical trial was performed to evaluate oxygen therapy on all-cause mortality at 1 year (The Determination of the Role of Oxygen in Suspected Acute Myocardial Infarction),
      • Cabello J.B.
      • Burls A.
      • Emparanza J.I.
      • et al.
      Oxygen therapy for acute myocardial infarction.
      which showed that routine supplemental oxygen in patients without hypoxemia at baseline undergoing hospitalization for acute myocardial infarction did not have a reduced 1-year all-cause mortality. This study provides definitive evidence that supplemental oxygen is not beneficial in patients who have normal baseline oxygen saturations with acute myocardial infarction.
      • Fu S.
      • Lv X.
      • Fang Q.
      • Liu Z.
      Oxygen therapy for acute myocardial infarction: a systematic review and meta-analysis.
      In this context, we performed an updated meta-analysis with the most updated evidence to evaluate the efficacy of routine oxygen supplementation in patients with acute myocardial infarction.

      Methods

      Data Sources

      An electronic search of the MEDLINE, Web of Science, and Cochrane Collaboration of Clinical Trials was performed from inception to November 2017 without language restriction, using the keywords “acute myocardial infarction,” “oxygen therapy,” “assessment,” and “outcomes,” as illustrated in Figure 1. Bibliographies of the included studies, relevant review articles, and meta-analyses were manually searched for any potential overlooked studies. The major cardiovascular conferences and proceedings, for example, American College of Cardiology and American Heart Association conferences, were screened for any abstracts addressing this topic.
      Figure 1
      Figure 1Summary of how the systematic search was conducted and eligible studies were identified (PRISMA flow diagram). NS-ACS = non ST elevation-Acute Coronary Syndrome.

      Selection Criteria and Data Extraction

      Randomized controlled studies and observational studies evaluating cardiovascular outcomes in adult subjects with acute myocardial infarction and oxygen therapy with no hypoxemia were included. We required that the studies had reported outcomes in both an oxygen therapy arm and no oxygen arm (control) to be included. If a studied population reported more than 1 publication, the outcomes were preferentially reported at the longest follow-up duration. Data were extracted by 2 independent groups and revised by AA and AE for accuracy. Any discrepancy was resolved by consensus among the authors.

      Outcomes and Definitions

      The outcomes assessed in this study included all-cause mortality (cardiac or noncardiac during longest follow-up period), recurrent ischemia or myocardial infarction (occurred after the index admission with recurrent angina or new ST-T segment changes, positive cardiac enzyme value >~99th percentile upper reference limit, or new angiographic findings), heart failure (defined as shortness of breath related due to fluid overload with signs and symptoms consistent with heart failure with or without decrease in ejection fraction, positive cardiac peptides), and arrhythmia (defined as sustained and nonsustained ventricular and atrial tachyarrhythmia or bradyarrhythmia requiring medical intervention or telemetry).

      Quality Assessment

      The quality of evidence was assessed at both the individual study level and the outcome level. The Cochrane tool was used for assessment of the individual studies.
      • Hofmann R.
      • James S.K.
      • Jernberg T.
      • et al.
      Oxygen therapy in suspected acute myocardial infarction.
      The Grades of Recommendation, Assessment, Development, and Evaluation tool
      • Loscalzo J.
      Is oxygen therapy beneficial in acute myocardial infarction? Simple question, complicated mechanism, simple answer.
      was used for assessment of the overall quality of evidence for each outcome. This tool specifies 4 levels of quality (high, moderate, low, and very low) depending on the design of the included studies, indirectness of evidence, unexplained heterogeneity or inconsistency of results, imprecision of the results, and high probability of the publication bias (Table 1, Table 2).
      Table 1Showing Risk of Bias of Randomized Trials by Cochrane Risk Assessment Tool
      Rawles et al
      • Rawles J.
      • Kenmure A.C.F.
      Controlled trial of oxygen in uncomplicated myocardial infarction.
      Wilson et al
      • Wilson A.T.
      • Channer K.S.
      Hypoxaemia and supplemental oxygen therapy in the first 24 hours after myocardial infarction: the role of pulse oximetry.
      Ukholkina et al
      • Ukholkina G.B.
      • Kostianov I.I.
      • Kuchkina N.V.
      • et al.
      Effect of oxygen therapy used in combination with reperfusion in patients with acute myocardial infarction.
      Ranchord et al
      • Ranchord A.M.
      • Argyle R.
      • Beynon R.
      • et al.
      High-concentration versus titrated oxygen therapy in ST-elevation myocardial infarction: a pilot randomized controlled trial.
      Stub et al
      • Stub D.
      • Smith K.
      • Bernard S.
      • et al.
      Air versus oxygen in ST-segment elevation myocardial infarction.
      Khoshnood et al
      • Khoshnood A.
      • Carlsson M.
      • Akbarzadeh M.
      • et al.
      Effect of oxygen therapy on myocardial salvage in ST elevation myocardial infarction: the randomized SOCCER trial.
      Hofmann et al
      • Hofmann R.
      • James S.K.
      • Jernberg T.
      • et al.
      Oxygen therapy in suspected acute myocardial infarction.
      Random sequence generation (selection bias)
      Allocation concealment (selection bias)
      Blinding of (performance bias and detection bias)
      Baseline characteristics
      Incomplete outcome data (attrition bias)
      Selective reporting (reporting bias)
      Other sources of bias
       = Low risk of bias;  = Risk of bias;  = Unclear.
      Table 2Showing Grades of Recommendation, Assessment, Development, and Evaluation Tool for Outcome Bias. Question: Routine Oxygen Therapy Compared with No Oxygen for Acute Myocardial Infarction
      Certainty Assessment№ of PatientsEffectCertaintyImportance
      № of StudiesStudy DesignRisk of BiasInconsistencyIndirectnessImprecisionOther ConsiderationsRoutine Oxygen therapyNo OxygenRelative

      (95% CI)
      Absolute

      (95% CI)
      All-Cause Mortality (Follow-up: Range, 1 wk to 12 mo)
      6Randomized trialsNot seriousNot seriousNot seriousNot seriousNone188/3820 (4.9%)189/3840 (4.9%)RR 0.99

      (0.81-1.21)
      0 fewer per 1000

      (from 9 fewer to 10 more)
      ⨁⨁⨁⨁

      High
      Critical
      Recurrent Ischemia or Myocardial Infarction (Follow-up: Range, 1 d to 12 mo)
      6Randomized trialsNot seriousNot seriousNot seriousNot seriousNone160/3723 (4.3%)138/3723 (3.7%)RR 1.19

      (0.95-1.48)
      7 more per 1000 (from 2 fewer to 18 more)⨁⨁⨁⨁

      High
      Critical
      Heart Failure (Follow-up: Range, 1-12 mo)
      3Randomized trialsNot seriousNot seriousNot seriousNot seriousNone49/3415 (1.4%)53/3446 (1.5%)RR 0.94

      (0.61-1.45)
      1 fewer per 1000

      (from 6 fewer to 7 more)
      ⨁⨁⨁⨁

      High
      Important
      Arrhythmia (Follow-up: Range, 1-12 Mo)
      5Randomized trialsNot seriousNot seriousNot seriousNot seriousNone322/3789 (8.5%)323/3793 (8.5%)RR 1.01

      (0.85-1.20)
      1 more per 1000

      (from 13 fewer to 17 more)
      ⨁⨁⨁⨁

      High
      Important
      CI = confidence interval; RR = risk ratio.

      Statistical Analysis

      Outcomes were assessed with an intention-to-treat analysis. Random effects summary risk ratios (RRs) were calculated with the DerSimonian and Laird model.
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      A fixed-effect model using the Mantel–Haenszel method was performed as a secondary analysis.
      • Mantel N.
      • Haenszel W.
      Statistical aspects of the analysis of data from retrospective studies of disease.
      Statistical heterogeneity was measured using the I2 statistic.
      • Higgins J.P.T.
      • Green S.
      Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011].
      Egger's method was used to assess publication bias.
      • Higgins J.P.
      • Green S.
      Cochrane Handbook for Systematic Reviews of Inverventions.
      All P values were 2 tailed, with statistical significance set at .05, and confidence intervals (CIs) were calculated at the 95% level for the overall estimates effect. All analyses were performed using STATA software version 14 (StataCorp LP, College Station, Tex).

      Results

      Patient Population

      A total of 8 studies
      • Higgins J.P.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in metaanalyses.
      • Egger M.
      • Davey Smith G.
      • Schneider M.
      • et al.
      Bias in meta-analysis detected by a simple, graphical test.
      • Rawles J.
      • Kenmure A.C.F.
      Controlled trial of oxygen in uncomplicated myocardial infarction.
      • Wilson A.T.
      • Channer K.S.
      Hypoxaemia and supplemental oxygen therapy in the first 24 hours after myocardial infarction: the role of pulse oximetry.
      • Ukholkina G.B.
      • Kostianov I.I.
      • Kuchkina N.V.
      • et al.
      Effect of oxygen therapy used in combination with reperfusion in patients with acute myocardial infarction.
      • Ranchord A.M.
      • Argyle R.
      • Beynon R.
      • et al.
      High-concentration versus titrated oxygen therapy in ST-elevation myocardial infarction: a pilot randomized controlled trial.
      • Stub D.
      • Smith K.
      • Bernard S.
      • et al.
      Air versus oxygen in ST-segment elevation myocardial infarction.
      • Khoshnood A.
      • Carlsson M.
      • Akbarzadeh M.
      • et al.
      Effect of oxygen therapy on myocardial salvage in ST elevation myocardial infarction: the randomized SOCCER trial.
      fulfilled our inclusion criteria. One study
      • Heidari F.
      • Rahzani K.
      • Iranpoor D.
      • Rezaee K.
      The effect of oxygen on the outcomes of non-ST-segment elevation acute coronary syndromes.
      did define the treatment oxygen group as non–ST-acute coronary syndrome with no data on the individual acute myocardial infarction group versus unstable angina. Thus, this study was excluded, and only 7 studies were included in the final analysis
      • Hofmann R.
      • James S.K.
      • Jernberg T.
      • et al.
      Oxygen therapy in suspected acute myocardial infarction.
      • Rawles J.
      • Kenmure A.C.F.
      Controlled trial of oxygen in uncomplicated myocardial infarction.
      • Wilson A.T.
      • Channer K.S.
      Hypoxaemia and supplemental oxygen therapy in the first 24 hours after myocardial infarction: the role of pulse oximetry.
      • Ukholkina G.B.
      • Kostianov I.I.
      • Kuchkina N.V.
      • et al.
      Effect of oxygen therapy used in combination with reperfusion in patients with acute myocardial infarction.
      • Ranchord A.M.
      • Argyle R.
      • Beynon R.
      • et al.
      High-concentration versus titrated oxygen therapy in ST-elevation myocardial infarction: a pilot randomized controlled trial.
      • Stub D.
      • Smith K.
      • Bernard S.
      • et al.
      Air versus oxygen in ST-segment elevation myocardial infarction.
      • Khoshnood A.
      • Carlsson M.
      • Akbarzadeh M.
      • et al.
      Effect of oxygen therapy on myocardial salvage in ST elevation myocardial infarction: the randomized SOCCER trial.
      (Figure 1). All studies were randomized controlled and retrieved from the MEDLINE search, whereas the other sources did not identify any additional studies. The follow-up period ranged between the index admissions up to 12 months (weighted mean, 2.1 months). A total of 3842 patients with a mean age of 62 years underwent routine oxygen therapy. The no oxygen therapy group included 3860 patients with a mean age of 63 years. The population in both groups was mainly male. The most common comorbidities reported in the studies were hypertension, diabetes, hyperlipidemia, and smoking. Table 3 summarizes the baseline characteristics of the included patients.
      Table 3Showing Patient Demographics
      StudyYearAge (O2)Age (RA)Male (O2)Male

      (RA)
      HTN

      (O2)
      HTN

      (RA)
      DM

      (O2)
      DM

      (RA)
      HLP

      (O2)
      HLP

      (RA)
      Smoking

      (O2)
      Smoking

      (RA)
      Stub et al
      • Stub D.
      • Smith K.
      • Bernard S.
      • et al.
      Air versus oxygen in ST-segment elevation myocardial infarction.
      20156362.679.8781301233741121118141165
      Hofmann et al
      • Hofmann R.
      • James S.K.
      • Jernberg T.
      • et al.
      Oxygen therapy in suspected acute myocardial infarction.
      2017686868.470.715751559589644N/AN/A704721
      Ranchord et al
      • Ranchord A.M.
      • Argyle R.
      • Beynon R.
      • et al.
      High-concentration versus titrated oxygen therapy in ST-elevation myocardial infarction: a pilot randomized controlled trial.
      20126062.177.970.623287819253221
      Rawles et al
      • Rawles J.
      • Kenmure A.C.F.
      Controlled trial of oxygen in uncomplicated myocardial infarction.
      197680776361N/AN/AN/AN/AN/AN/AN/AN/A
      Wilson et al
      • Wilson A.T.
      • Channer K.S.
      Hypoxaemia and supplemental oxygen therapy in the first 24 hours after myocardial infarction: the role of pulse oximetry.
      19976465N/AN/AN/AN/A22N/AN/A57
      Khoshnood et al25200663.765.52934112139N/AN/A3132
      Ukholkina et al
      • Ukholkina G.B.
      • Kostianov I.I.
      • Kuchkina N.V.
      • et al.
      Effect of oxygen therapy used in combination with reperfusion in patients with acute myocardial infarction.
      2005626066N/AN/AN/AN/AN/AN/AN/AN/AN/A
      DM = diabetes mellitus; HLP = hyperlipidemia; HTN = hypertension; N/A = not available; O2 = oxygen; RA = room air.

      Meta-Analysis

      Oxygen therapy did not decrease all-cause mortality in 6 studies
      • Hofmann R.
      • James S.K.
      • Jernberg T.
      • et al.
      Oxygen therapy in suspected acute myocardial infarction.
      • Rawles J.
      • Kenmure A.C.F.
      Controlled trial of oxygen in uncomplicated myocardial infarction.
      • Ukholkina G.B.
      • Kostianov I.I.
      • Kuchkina N.V.
      • et al.
      Effect of oxygen therapy used in combination with reperfusion in patients with acute myocardial infarction.
      • Ranchord A.M.
      • Argyle R.
      • Beynon R.
      • et al.
      High-concentration versus titrated oxygen therapy in ST-elevation myocardial infarction: a pilot randomized controlled trial.
      • Stub D.
      • Smith K.
      • Bernard S.
      • et al.
      Air versus oxygen in ST-segment elevation myocardial infarction.
      • Khoshnood A.
      • Carlsson M.
      • Akbarzadeh M.
      • et al.
      Effect of oxygen therapy on myocardial salvage in ST elevation myocardial infarction: the randomized SOCCER trial.
      (pooled RR, 0.99; 95% CI, 0.81-1.21; P = .429; I
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics—2017 update: a report from the American Heart Association.
       = 0.0%) (Figure 2). Six studies
      • Hofmann R.
      • James S.K.
      • Jernberg T.
      • et al.
      Oxygen therapy in suspected acute myocardial infarction.
      • Wilson A.T.
      • Channer K.S.
      Hypoxaemia and supplemental oxygen therapy in the first 24 hours after myocardial infarction: the role of pulse oximetry.
      • Ukholkina G.B.
      • Kostianov I.I.
      • Kuchkina N.V.
      • et al.
      Effect of oxygen therapy used in combination with reperfusion in patients with acute myocardial infarction.
      • Ranchord A.M.
      • Argyle R.
      • Beynon R.
      • et al.
      High-concentration versus titrated oxygen therapy in ST-elevation myocardial infarction: a pilot randomized controlled trial.
      • Stub D.
      • Smith K.
      • Bernard S.
      • et al.
      Air versus oxygen in ST-segment elevation myocardial infarction.
      • Khoshnood A.
      • Carlsson M.
      • Akbarzadeh M.
      • et al.
      Effect of oxygen therapy on myocardial salvage in ST elevation myocardial infarction: the randomized SOCCER trial.
      reported the effect of oxygen therapy on recurrent ischemia or myocardial infarction. Again, the oxygen arm did not show any benefit (pooled RR, 1.19; 95% CI, 0.95-1.48; P = .751; I2 = 0.0%) (Figure 3). Three studies
      • Hofmann R.
      • James S.K.
      • Jernberg T.
      • et al.
      Oxygen therapy in suspected acute myocardial infarction.
      • Ukholkina G.B.
      • Kostianov I.I.
      • Kuchkina N.V.
      • et al.
      Effect of oxygen therapy used in combination with reperfusion in patients with acute myocardial infarction.
      • Khoshnood A.
      • Carlsson M.
      • Akbarzadeh M.
      • et al.
      Effect of oxygen therapy on myocardial salvage in ST elevation myocardial infarction: the randomized SOCCER trial.
      described the occurrence of heart failure in both arms, and again oxygen therapy did not show an advantageous effect (pooled RR, 0.94; 95% CI, 0.61-1.45; P = .348; I2 = 5.3%) (Figure 4). The occurrence of arrhythmia events did not decrease with routine oxygen use (pooled RR, 1.01; 95% CI, 0.85-1.2; P = .233; I2 = 28.3%) (Figure 5) when compared with the no oxygen arm.
      Figure 2
      Figure 2Summary plot for all-cause mortality. CI = confidence interval; RR = risk ratio.
      Figure 3
      Figure 3Summary plot for recurrent ischemia or myocardial infarction. CI = confidence interval; RR = risk ratio.
      Figure 4
      Figure 4Summary plot for heart failure. CI = confidence interval; RR = risk ratio.
      Figure 5
      Figure 5Summary plot for arrhythmia. CI = confidence interval; RR = risk ratio.

      Discussion

      The results of this meta-analysis of 7 studies with 7702 patients indicate that routine supplemental oxygen does not reduce short-term mortality or incidents of arrhythmias, heart failure, and recurrent ischemic events in patients with acute myocardial infarction without hypoxemia.
      The utility of providing oxygen supplementation to patients who are not hypoxic with acute myocardial infarction has been controversial, with initial studies
      • Steele C.
      Severe angina pectoris relieved by oxygen inhalations.
      • Madias J.
      • Madias N.
      • Hood Jr, W.
      Precordial ST-segment mapping. 2. Effects of oxygen inhalation on ischemic injury in patients with acute myocardial infarction.
      favoring its use and later studies demonstrating potential harm.
      • Rawles J.
      • Kenmure A.C.F.
      Controlled trial of oxygen in uncomplicated myocardial infarction.
      • Wilson A.T.
      • Channer K.S.
      Hypoxaemia and supplemental oxygen therapy in the first 24 hours after myocardial infarction: the role of pulse oximetry.
      • Ukholkina G.B.
      • Kostianov I.I.
      • Kuchkina N.V.
      • et al.
      Effect of oxygen therapy used in combination with reperfusion in patients with acute myocardial infarction.
      • Ranchord A.M.
      • Argyle R.
      • Beynon R.
      • et al.
      High-concentration versus titrated oxygen therapy in ST-elevation myocardial infarction: a pilot randomized controlled trial.
      • Stub D.
      • Smith K.
      • Bernard S.
      • et al.
      Air versus oxygen in ST-segment elevation myocardial infarction.
      • Khoshnood A.
      • Carlsson M.
      • Akbarzadeh M.
      • et al.
      Effect of oxygen therapy on myocardial salvage in ST elevation myocardial infarction: the randomized SOCCER trial.
      Few meta-analyses have attempted to determine the utility of oxygen use in acute myocardial infarction; however, limitations have included small sample sizes and quality of the studies evaluated.
      • Cabello J.B.
      • Burls A.
      • Emparanza J.I.
      • et al.
      Oxygen therapy for acute myocardial infarction.
      • Fu S.
      • Lv X.
      • Fang Q.
      • Liu Z.
      Oxygen therapy for acute myocardial infarction: a systematic review and meta-analysis.
      Our study includes the most recent, high-quality randomized trials. In our meta-analysis, the lack of benefit of supplemental oxygen in acute myocardial infarction is consistent with previous meta-analysis.
      • Cabello J.B.
      • Burls A.
      • Emparanza J.I.
      • et al.
      Oxygen therapy for acute myocardial infarction.
      • Fu S.
      • Lv X.
      • Fang Q.
      • Liu Z.
      Oxygen therapy for acute myocardial infarction: a systematic review and meta-analysis.
      Distinctions between our study and previous meta-analysis should be noted. Primarily, our meta-analysis included 7702 participants, whereas the previous analysis was fairly small, consisting of only 1173
      • Cabello J.B.
      • Burls A.
      • Emparanza J.I.
      • et al.
      Oxygen therapy for acute myocardial infarction.
      and 921
      • Fu S.
      • Lv X.
      • Fang Q.
      • Liu Z.
      Oxygen therapy for acute myocardial infarction: a systematic review and meta-analysis.
      participants. Our study has a larger sample size and a longer follow-up (1-12 months) than previous meta-analyses. Moreover, the previous reports only found that oxygen therapy could not decrease the rate of postacute myocardial infarction sequelae, whereas our study found that oxygen therapy may hint toward more recurrent ischemia (mainly myocardial infarction), although this observation did not reach statistical significance (Figure 3).
      The findings in our meta-analysis are not surprising, and similar results were found in other populations. For instance, in patients with acute stroke who did not have hypoxemia at baseline, there was no difference in mortality comparing routine use of 2 to 3 liters of oxygen with usual care.
      • Hofmann R.
      • James S.K.
      • Jernberg T.
      • et al.
      Oxygen therapy in suspected acute myocardial infarction.
      In patients postcardiac arrest, hyperoxia was associated with increased mortality.
      • Heidari F.
      • Rahzani K.
      • Iranpoor D.
      • Rezaee K.
      The effect of oxygen on the outcomes of non-ST-segment elevation acute coronary syndromes.
      In critically ill patients, hyperoxia was associated with increased mortality in 2 recent meta-analyses.
      • Roffe C.
      • Nevatte T.
      • Sim J.
      • et al.
      Effect of routine low-dose oxygen supplementation on death and disability in adults with acute stroke: the stroke oxygen study randomized clinical trial.
      • Llitjos J.-F.
      • Mira J.-P.
      • Duranteau J.
      • Cariou A.
      Hyperoxia toxicity after cardiac arrest: what is the evidence?.
      In fact, delivering more than 50% fraction of inspired oxygen to critically ill patients with oxygen saturation >92% resulted in worse oxygenation index in 48 hours,
      • Helmerhorst H.J.
      • Roos-Blom M.J.
      • van Westerloo D.J.
      • de Jonge E.
      Association between arterial hyperoxia and outcome in subsets of critical illness: a systematic review, meta-analysis, and meta-regression of cohort studies.
      which can be explained by the occurrence of more atelectasis with higher oxygen levels.
      • Damiani E.
      • Adrario E.
      • Girardis M.
      • et al.
      Arterial hyperoxia and mortality in critically ill patients: a systematic review and meta-analysis.
      Although definition of hyperoxia in the literature is variable, the amount of oxygen given in the studies included in our meta-analysis was also variable. Thus, although our meta-analysis shows no benefit, we cannot exclude that a harmful effect of excessive oxygenation was diluted with studies that used less oxygen than others. The concern of harm with excessive oxygenation is raised on the basis of the proven deleterious effects of hyperoxia in other populations as aforementioned. Future studies should attempt to examine if harm exists in acute myocardial infarction with hyperoxygenation to predefined partial pressure arterial oxygen and fraction of inspired oxygen ratios.
      The 2004, the American College of Cardiology/American Heart Association guidelines for ST-segment elevation myocardial infarction reported a Class IIa, Level C evidence recommendation that oxygen administration to all patients with ST-segment elevation myocardial infarction in the first 6 hours was a reasonable management strategy; however, there was minimal evidence supporting its use.
      • Rachmale S.
      • Li G.
      • Wilson G.
      • Malinchoc M.
      • Gajic O.
      Practice of excessive F(IO(2)) and effect on pulmonary outcomes in mechanically ventilated patients with acute lung injury.
      Subsequent guidelines have reserved oxygen therapy for only those patients who have hypoxia (oxygen saturation <90%), respiratory distress, or risk factors for hypoxemia.
      • Ibanez B.
      • James S.
      • Agewall S.
      • et al.
      2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC).
      • Martin D.S.
      • Grocott M.P.W.
      Oxygen therapy and anaesthesia: too much of a good thing?.
      With the most recent randomized controlled trial compiled in our meta-analysis, it is important to conclude with sound evidence there is a lack of clinical benefit with routine oxygen administration, and the current guidelines reflect this by recommending against oxygen supplementation unless the patient is hypoxic.
      We postulate significant adverse hemodynamic effects, including a reduction in coronary blood flow; myocardial oxygen consumption and an increase in coronary vascular resistance
      • Antman E.M.
      • Anbe D.T.
      • Armstrong P.W.
      • et al.
      ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction–executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction).
      • Farquhar H.
      • Weatherall M.
      • Wijesinghe M.
      • et al.
      Systematic review of studies of the effect of hyperoxia on coronary blood flow.
      mediate the lack of benefit from routine supplemental oxygen in patients with acute myocardial infarction without hypoxia. The physiology behind these effects has been linked to the release of free oxygen radicals with subsequent endothelial dysfunction from nitric oxide attenuation.
      • Amsterdam E.A.
      • Wenger N.K.
      • Brindis R.G.
      • et al.
      2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      • McNulty P.H.
      • King N.
      • Scott S.
      • et al.
      Effects of supplemental oxygen administration on coronary blood flow in patients undergoing cardiac catheterization.
      Additionally, increased coronary vasoconstriction has been demonstrated to occur from endothelial dysfunction in the setting of hyperoxia mediated by closure of adenosine triphosphate–sensitive potassium channels and independent of free radicals, nitric oxide, or cyclooxygenase products.
      • Amsterdam E.A.
      • Wenger N.K.
      • Brindis R.G.
      • et al.
      2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      • Mouren S.
      • Souktani R.
      • Beaussier M.
      • et al.
      Mechanisms of coronary vasoconstriction induced by high arterial oxygen tension.
      These mechanisms negate the benefit of supplemental oxygen in normoxic patients with the potential for adverse effects. However, we did not identify any clinically significant adverse outcomes in our study.

      Study Limitations

      There are several noteworthy limitations to our meta-analysis involving the limitations of each individual study. First, the studies included vary in quality. Only 1 study was double-blinded,
      • Roffe C.
      • Nevatte T.
      • Sim J.
      • et al.
      Effect of routine low-dose oxygen supplementation on death and disability in adults with acute stroke: the stroke oxygen study randomized clinical trial.
      and several studies had incomplete follow-up, leaving a high potential for bias. None of the trials were powered to detect a difference in clinically significant adverse cardiac events. The majority of included studies consist of patients presenting with ST-segment elevation myocardial infarction, which may limit generalizability to patients with non–ST-segment elevation myocardial infarction and unstable angina. Finally, it is important to note that patients with hypoxia were excluded from trials; therefore, results only pertain to patients with normoxia, and this can inflate the possibility of publication bias.

      Conclusions

      Routine oxygen supplementation has been shown to be not only without benefit but also associated with possible harmful effects. With more conclusive evidence, this meta-analysis confirms prior studies and supports the changing trend in recommendations to avoid supplemental oxygen in patients with peripheral oxygen saturations ≥90%.

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