Original Article
Oxygen in the Setting of Acute Myocardial Infarction: Is It Really a Breath of Fresh Air?
Journal of Cardiovascular Pharmacology and Therapeutics 1-7 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1074248415598004 cpt.sagepub.com
Rohit S. Loomba, MD1, Karan Nijhawan, BS2, Saurabh Aggarwal, MD3, and Rohit R. Arora, MD4
Abstract Introduction: Supplemental oxygen has been used in the setting of acute myocardial infarction (AMI). Once an official recommendation in the guidelines for the management of acute ST-segment elevation myocardial infarction, it is now mentioned as an intervention to be considered. Data for the use of supplemental oxygen or AMI are limited, and some data have suggested associated harm. Methods: We performed a systematic review of the literature and a subsequent meta-analysis of the data to determine the effect of high concentration oxygen versus titrated oxygen or room air in the setting of AMI. The following end points were studied: in-hospital mortality, opiate use, percentage of infarcted myocardium by magnetic resonance imaging (MRI), and mass of infarcted myocardium by MRI. Results: No significant difference was noted with end points when comparing those randomized to high-concentration oxygen versus those randomized to titrated oxygen or room air in the setting of AMI. No significant publication bias was identified although this could not be assessed for all end points. Conclusion: High-concentration oxygen may not offer any benefit when compared to titrated oxygen or room air. A large, randomized trial is warranted to further delineate these differences with respect to multiple end points. Keywords myocardial infarction, heart attack, oxygen, hyperoxia, oxygen tension, oxygen saturation
Introduction Supplemental oxygen has been a part of the routine management for acute myocardial infarction (AMI). The 2004 American College of Cardiology/American Heart Association guidelines for the management of patients with ST-segment elevation myocardial infarction included administration of supplemental oxygen for patients with arterial saturations of less than 90% as a class I recommendation and included administration of supplemental oxygen for all patients with AMI during the first 6 hours as a class IIa recommendation.1 The 2013 guidelines no longer recommend oxygen therapy and rather simply state that supplemental oxygen be given consideration in light of limited data regarding its use.2 Data for oxygen therapy come from 2 studies done in dogs and only a handful of human studies, with much of these data being from an era in which thrombolytic therapy was not available. Newer studies have even demonstrated an association of liberal oxygen supplemental use in the setting of AMI with harm.3-6 Decrease in coronary blood flow, decrease in myocardial oxygen consumption, decrease in cardiac output, increase in systemic vascular resistance, and increase in reperfusion injury in patients with cardiac disease when exposed to hyperoxia may all be possible mechanisms.7-10 We conducted a systematic review of the literature with a meta-analysis of available data to compare the use of high
concentration oxygen versus titrated oxygen or room air in the setting of AMI.
Methods Identified Outcomes The aim of the study was to determine the effect of high concentration oxygen versus titrated oxygen or room air in the setting of AMI. Preliminary review of studies identified the following end points for comparison: in-hospital mortality, opiate use as a surrogate for pain, infarction percentage by magnetic resonance imaging (MRI), and infarction mass by MRI. 1
Children’s Hospital of Wisconsin/Medical College of Wisconsin, Department of Cardiology, Milwaukee, WI, USA 2 Rush University Medical Center, Department of Cardiology, Chicago, IL, USA 3 Creighton University Medical Center, Department of Cardiology, Omaha, NE, USA 4 Chicago Medical School, Chicago, Department of Cardiology, IL, USA Manuscript submitted: March 24, 2015; accepted: June 27, 2015. Corresponding Author: Rohit S. Loomba, Children’s Hospital of Wisconsin/Medical College of Wisconsin, 9000 Wisconsin Avenue, Milwaukee, WI 53226, USA. Email: [email protected]
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Search Methodology and Study Identification Electronic databases PubMed, EMBASE, Medline, and the Cochrane central register of clinical trials were searched for pertinent studies. Each database was queried using the following search terms: ‘‘acute myocardial infarction,’’ ‘‘coronary thrombosis,’’ and ‘‘heart attack’’ in isolation or in combination with one of the following search terms: ‘‘supplemental oxygen,’’ ‘‘oxygen,’’ ‘‘room air,’’ ‘‘hypoxemia,’’ ‘‘normobaric,’’ and ‘‘hyperbaric.’’ There were no restrictions placed on date or language of publication. Resulting manuscripts were reviewed by title and abstract with pertinent manuscripts being selected for full-text review. Full-text review was then conducted with additional studies being excluded if felt to not be pertinent to the study question. References of manuscripts undergoing full-text review were also reviewed to identify additional manuscripts. Cited Web sites were also visited for additional data. This search methodology was carried out by 2 authors (RL and KN) independently with subsequent comparison and reconciliation of any differences.
confidence intervals were also calculated for each. Forest plots were generated for each end point. This analysis was done using Comprehensive Meta-Analysis version 3.0 (Englewood, New Jersey). Meta-regression was conducted for in-hospital mortality using year of publication, age, and gender as variables in the regression model.
Results Study Identification A total of 4371 studies were identified with 2508 remaining after duplicates were removed (Figure 1). Of these studies, 162 were identified for review of the full text. Ultimately, 5 studies were included in the final analysis.11-15 One of these studies was not published in a journal but had data available online with its methods previously published.11,16 There were a total of 446 patients in the high concentration oxygen and 467 patients in the titrated oxygen or room air group. Patient characteristics for included studies are provided in Table 1.
In-Hospital Mortality
Bias Assessment The Cochrane Collaboration’s tool for assessing risk of bias was utilized for the assessment. This tool assesses for adequate sequence generation, allocation concealment, blinding, incomplete reporting of outcome data, selective reporting of outcome data, and other potential areas of bias. Bias assessment of studies identified for inclusion in the study was done by 2 authors independently (KN and SA) with subsequent comparison and reconciliation of any differences. Publication bias was assessed by both a qualitative and quantitative method. Funnel plots were created for visual assessment of publication bias, and an Egger test was conducted to quantify publication bias.
A total of 4 studies with 425 patients in the high-concentration oxygen and 447 patients in the titrated oxygen or room air group (Figure 2). A fixed-effects model was used as significant heterogeneity was not present (Q ¼ 6.123, P ¼ .106, I2 ¼ 51%). The in-hospital mortality rate was 4% among those receiving high-concentration oxygen and 3% among those receiving room air. No significant difference was noted between the 2 groups (odds ratio 0.981, 95% confidence interval 0.439-2.195).
Opiate Use
Data abstraction was done for previously identified end points using a data collection tool. Data abstraction was done by 2 authors independently (RL and SA) with subsequent comparison and reconciliation of any differences. Authors of included studies were not contacted for additional data.
Data for opiate use were extracted from 2 studies with 102 patients in the high concentration oxygen group and 97 in the titrated oxygen or room air group (Figure 3). A fixed-effects model was used as significant heterogeneity was not present (Q ¼ 2.140, P ¼ .144, I2 ¼ 53%). Opiate use was needed in 72% of those receiving high-concentration oxygen and 72% of those receiving room air. No significant difference was noted between the 2 groups (odds ratio 0.990, 95% confidence interval 0.526-1.865).
Data Analysis
Infarction Percentage by MRI
Continuous data are presented as means. Categorical data are presented as frequencies with absolute numbers as well as percentages. P values of .05 were considered statistically significant. Pooled analysis was conducted using a Haenszel-Mantel fixed-effects model when significant heterogeneity was not present and using DerSimonian and Laird random-effects model when significant heterogeneity was present. Heterogeneity was assessed using both chi-square and I2 tests. The odds ratio was calculated for categorical variables while mean difference was calculated for continuous variables. The 95%
Two studies were pooled with 286 patients in the highconcentration oxygen group and 291 patients in the titrated oxygen or room air group (Figure 4). A fixed-effects model and random-effects model were used due to ambiguity in the heterogeneity analysis (Q ¼ 2.976, P ¼ .085, I2 ¼ 66%). Chisquare analysis did not demonstrate significant heterogeneity although the I2 test did. A significant difference was noted between the 2 groups (mean difference 2.224%, 95% confidence interval 0.906-3.541). When the analysis was repeated with a random-effects model this became insignificant.
Data Abstraction
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Figure 1. Study methodology.
Table 1. Patient Characteristics in Included Studies. Number of Patients Rawles and Kenmure15 Room air or titrated oxygen High-concentration oxygen Ranchord et al12 Room air or titrated oxygen High concentration oxygen Ukholkina et al14 Room air or titrated oxygen High concentration oxygen Stub et al11,16 Room air or titrated oxygen High concentration oxygen Wilson and Channer13 Room air or titrated oxygen High concentration oxygen
Gender (Males)
Age, Years
Intervention
56.4 + 0.8 55.1 + 0.9
21% oxygen by mask at 6 L/min 100% oxygen by mask at 6 L/min
48 (71%) 53 (78%)
62.1 + 12.5 60.0 + 12.8
Oxygen by nasal cannula to maintain saturations 93% to 96% 100% oxygen by mask at 6 L/min
79 58
– –
– –
Room air 40% oxygen by mask at 3-6 L/min
223 218
174 (80%) 174 (78%)
62.6 + 13.0 63.0 + 11.9
Room air 100% oxygen by mask at 8 L/min
105 93
– –
– –
77 80
61 (79) 63 (79)
68 68
Infarction Mass by MRI Two studies were pooled with 286 patients in the high concentration oxygen group and 291 patients in the titrated oxygen or room air group (Figure 5). A random-effects model
Room air 100% oxygen by mask 4 L/min
was used as significant heterogeneity was present (Q ¼ 4.552, P ¼ .033, I2 ¼ 78%). A significant difference was not noted between the 2 groups (mean difference 2.418 g, 95% confidence interval 1.960-6.797).
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Figure 2. Forest plot comparing in-hospital mortality.
Figure 3. Forest plot comparing opiate use.
Figure 4. Forest plot comparing percentage of infarcted myocardium by magnetic resonance imaging.
Bias Assessment No studies were excluded from the analysis due to bias as evaluated using the Cochrane Collaboration’s tool for assessing risk of bias (Table 2). Ranchord et al was found to have a high
risk of selective reporting as MRI was only performed in a subgroup of patients.12 This also added to the risk of other bias. Ukholkina et al was found to have a high risk of incomplete outcome data, as there were some significant differences in
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Figure 5. Forest plot comparing mass of infarcted myocardium by magnetic resonance imaging. Table 2. Bias Assessment. Study
Random Sequence Generation (Bias Risk)
Allocation Concealment (Bias Risk)
Incomplete Outcome Data (Bias Risk)
Selective Reporting (Bias Risk)
Other Bias (Bias Risk)
Rawles and Kenmure15 Ranchord et al12 Stub et al11,16 Ukholkina et al14 Wilson and Channer13
Unclear Low Low Unclear Unclear
Low Low Low Unclear Low
Low Low Low Low Low
Low High Low Low High
Low High Low High Low
baseline characteristics.14 Wilson and Channer were found to have a high risk of selective reporting, as no mortality data were reported.13 Publication bias was assessed only for in-hospital mortality as the remainder of end points had too few studies. Visual inspection of the funnel plot did not demonstrate significant publication bias, which was confirmed by an Egger test which demonstrated a 95% confidence interval of 9.124 to 10.979 with a P value of .729 (Figure 6).
Meta-Regression A meta-regression was conducted for in-hospital mortality (Table 3). This could not be done for other end points, as there were not an adequate number of studies included. While there was not significant heterogeneity present, age accounted for a majority of the heterogeneity that was present.
Discussion This analysis of 5 studies demonstrated no difference in inhospital mortality, opiate use, infarction percentage by MRI, and infarction mass by MRI between those receiving high concentration oxygen and those who received titrated oxygen or room air in the setting of AMI.11-15 A significant difference was initially noted in infarction percentage by MRI with a fixed-effects model and when repeated with a random-effects model significance was lost. Thus, there was a trend in greater infarct percentage, but this was found to be statistically insignificant. Such statistically insignificant trends were also found
in relation to in-hospital mortality and infarction mass by MRI. These findings are similar to that of a meta-analysis published by Cabello et al in 2013 which had similar findings. We now include recent data, including the largest randomized study to date, to the previous study with similar results.17 The use of oxygen for a cardiac indication was initially described by Steele in 1900 in the setting of severe angina.18 In 1930, Levy published a 4 patient case series demonstrating relief of clinical symptoms associated with supplemental oxygen in the setting of AMI, thus introducing the routine recommendation of supplemental oxygen in the setting of AMI.19 Based on data from animal models, it was hypothesized that supplemental oxygen would help reduce the area of infarction and the risk of arrhythmias, further propagating the use of oxygen in AMI.20 It was as early as 1950 that studies began to demonstrate that supplemental oxygen may not be beneficial and, in fact, may be associated with some harm. Supplemental oxygen was found to be associated with longer duration of electrocardiographic changes consistent with ischemia and did not have any effect on pain, thought to be secondary to hyperoxia interfering with AMI-induced hyperemia.21 Subsequent studies demonstrated the hemodynamic effects of supplemental oxygen including a decrease in cardiac output, decrease in cerebral perfusion, decrease in renal perfusion, and increase in systemic vascular resistance.9,22-26 Despite these findings, high-concentration oxygen supplementation for AMI continued. Using the in-hospital mortality from this analysis, a total of 3050 patients with 1525 in each group would be necessary to detect a statistically significant difference of 2% in mortality
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Figure 6. Funnel plot for in-hospital mortality. Table 3. Summary Results of Meta-Analysis. End Point In-hospital mortality Opiate use Infarction percentage by MRI Infarction mass by MRI
Odds Ratio or Mean Difference Group and 95% Confidence Interval Favored 0.981 (0.439-2.195) 0.990 (0.526-1.865) 2.224% (0.410-3.521)
Neither Neither Neither
2.148 g (1.960-6.797)
Neither
Abbreviation: MRI, magnetic resonance imaging.
between the 2 groups with 90% power and an alpha of 0.05. The largest study included in this analysis consisted of 218 patients in the high-concentration oxygen group and 223 patients in the titrated or room air group.11 This highlights the need for a large randomized effort to evaluate supplemental oxygen in patients with AMI. Such an effort would ideally compare serial electrocardiographic, troponin, and brain natriuretic peptide (BNP) data in addition to the prevalence of arrhythmia and mortality between the 2 groups. The percentage and mass of infarcted myocardium by MRI assessment would also be of great value. There are limitations of this analysis. Limited number of similar end points for abstraction across included studies limited the number of end points. The BNP levels and troponin levels would have been of interest to assess but these were not available in all studies. Additionally, some of these studies included patients who may have received supplemental oxygen upon initial triage by out-of-hospital responders and while in the ambulance en route to the hospital. They were then subsequently randomized to 1 of the 2 oxygen groups upon hospital arrival. More detailed meta-regression and assessment of publication bias could not be conducted due to the small number of studies for most end points. This analysis is also underpowered. In regard to bias, it is also hard to
entirely rule out the possibility of publication analysis, despite the statistical analysis run and thus it can only be said that our analysis implies but does not prove the absence of publication bias.
Conclusion There were no statistically significant differences noted between those with AMI randomized to high-concentration oxygen or titrated oxygen or room air in respect to inhospital mortality, opiate use, percentage of infarcted myocardium, or mass of infarcted myocardium. Author Contribution R. Loomba and S. Aggarwal contributed to conception and design; acquisition, analysis, and interpretation; drafted the article; critically revised the article; gave final approval; and agreed to be accountable for all aspects of work ensuring integrity and accuracy. K. Nijhawan contributed to design, acquisition, and analysis; drafted the article; critically revised the article; gave final approval; and agreed to be accountable for all aspects of work ensuring integrity and accuracy. R. Arora contributed to design; acquisition, analysis, and interpretation; drafted the article; critically revised the article; gave final approval, and agreed to be accountable for all aspects of work ensuring integrity and accuracy.
Authors’ Note This article has not been submitted elsewhere for simultaneous consideration of publication and has not been previously published. All the authors have been involved in the conception, execution, and preparation of this article and are aware of its submission.
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
13.
References 1. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction). Circulation. 2004;110(9):e82-e292. 2. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127(4):e362-e425. 3. Madias JE, Madias NE, Hood WB Jr. Precordial ST-segment mapping. 2. Effects of oxygen inhalation on ischemic injury in patients with acute myocardial infarction. Circulation. 1976; 53(3):411-417. 4. Wijesinghe M, Perrin K, Ranchord A, Simmonds M, Weatherall M, Beasley R. Routine use of oxygen in the treatment of myocardial infarction: systematic review. Heart. 2009;95(3):198-202. 5. Moradkhan R, Sinoway LI. Revisiting the role of oxygen therapy in cardiac patients. J Am Coll Cardiol. 2010;56(13):1013-1016. 6. Maroko PR, Radvany P, Braunwald E, Hale SL. Reduction of infarct size by oxygen inhalation following acute coronary occlusion. Circulation. 1975;52(3):360-368. 7. Bodetoft S, Carlsson M, Arheden H, Ekelund U. Effects of oxygen inhalation on cardiac output, coronary blood flow and oxygen delivery in healthy individuals, assessed with MRI. Eur J Emerg Med. 2011;18(1):25-30. 8. Farquhar H, Weatherall M, Wijesinghe M, et al. Systematic review of studies of the effect of hyperoxia on coronary blood flow. Am Heart J. 2009;158(3):371-377. 9. Thomas M, Malmcrona R, Shillingford J. Haemodynamic effects of oxygen in patients with acute myocardial infarction. Br Heart J. 1965;27(3):401-407. 10. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med. 2007;357(11):1121-1135. 11. Stub D, Smith K, Bernard S, et al. Air versus oxygen in ST-elevation myocardial infarction; 2014. Web site. clinicaltrialre sults.org/Slides/AHA2014/Stub_AVOID.ppt,2015. Published July 2014. Updated January 2015. Accessed February 4, 2015. 12. Ranchord AM, Argyle R, Beynon R, et al. High-concentration versus titrated oxygen therapy in ST-elevation myocardial
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infarction: a pilot randomized controlled trial. Am Heart J. 2012;163(2):168-175. Wilson AT, Channer KS. Hypoxaemia and supplemental oxygen therapy in the first 24 hours after myocardial infarction: the role of pulse oximetry. J R Coll Physicians Lond. 1997;31(6): 657-661. Ukholkina GB, Kostianov I, Kuchkina NV, Grendo EP, Gofman Ia B. Effect of oxygenotherapy used in combination with reperfusion in patients with acute myocardial infarction [in Russian]. Kardiologiia. 2005;45(5):59. Rawles JM, Kenmure AC. Controlled trial of oxygen in uncomplicated myocardial infarction. Br Med J. 1976;1(6018): 1121-1123. Stub D, Smith K, Bernard S, et al. A randomized controlled trial of oxygen therapy in acute myocardial infarction Air Verses Oxygen In myocarDial infarction study (AVOID Study). Am Heart J. 2012;163(3):339-345. e331. Cabello JB, Burls A, Emparanza JI, Bayliss S, Quinn T. Oxygen therapy for acute myocardial infarction. Cochrane Database Syst Rev. 2013;8:CD007160. Steele C. Severe angina pectoris relieved by oxygen inhalations. BMJ. 1900;2:1568. Levy H. Normal coordinates in the geometry of paths. Proc Natl Acad Sci USA. 1930;16(7):492-496. Smith G, Lawson DA. Experimental coronary arterial occlusion: effects of the administration of oxygen under pressure. Scottish Med J. 1958;3(8):346-350. Russek HI, Regan FD, Naegele CF. One hundred percent oxygen in the treatment of acute myocardial infarction and severe angina pectoris. JAMA. 1950;144(5):373-375. Kenmure AC, Murdoch WR, Beattie AD, Marshall JC, Cameron AJ. Circulatory and metabolic effects of oxygen in myocardial infarction. BMJ. 1968;4(5627):360-364. Daly WJ, Behnke RH. Hemodynamic consequences of oxygen breathing in left ventricular failure. Circulation. 1963;27: 252-256. Dollery CT, Hill DW, Mailer CM, Ramalho PS. High oxygen pressure and the retinal blood-vessels. Lancet. 1964;2(7354): 291-292. Kety SS, Schmidt CF. The effects of altered arterial tensions of carbon dioxide and oxygen on cerebral blood flow and cerebral oxygen consumption of normal young men. J Clin Invest. 1948; 27(4):484-492. Aber GM, Harris AM, Bishop JM. The effect of acute changes in inspired oxygen concentration on cardiac, respiratory and renal function in patients with chronic obstructive airways disease. Clin Sci. 1964;26:133-143.
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Oxygen in the Setting of Acute Myocardial Infarction: Is It Really a Breath of Fresh Air?
Journal of Cardiovascular Pharmacology and Therapeutics 1-7 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1074248415598004 cpt.sagepub.com
Rohit S. Loomba, MD1, Karan Nijhawan, BS2, Saurabh Aggarwal, MD3, and Rohit R. Arora, MD4
Abstract Introduction: Supplemental oxygen has been used in the setting of acute myocardial infarction (AMI). Once an official recommendation in the guidelines for the management of acute ST-segment elevation myocardial infarction, it is now mentioned as an intervention to be considered. Data for the use of supplemental oxygen or AMI are limited, and some data have suggested associated harm. Methods: We performed a systematic review of the literature and a subsequent meta-analysis of the data to determine the effect of high concentration oxygen versus titrated oxygen or room air in the setting of AMI. The following end points were studied: in-hospital mortality, opiate use, percentage of infarcted myocardium by magnetic resonance imaging (MRI), and mass of infarcted myocardium by MRI. Results: No significant difference was noted with end points when comparing those randomized to high-concentration oxygen versus those randomized to titrated oxygen or room air in the setting of AMI. No significant publication bias was identified although this could not be assessed for all end points. Conclusion: High-concentration oxygen may not offer any benefit when compared to titrated oxygen or room air. A large, randomized trial is warranted to further delineate these differences with respect to multiple end points. Keywords myocardial infarction, heart attack, oxygen, hyperoxia, oxygen tension, oxygen saturation
Introduction Supplemental oxygen has been a part of the routine management for acute myocardial infarction (AMI). The 2004 American College of Cardiology/American Heart Association guidelines for the management of patients with ST-segment elevation myocardial infarction included administration of supplemental oxygen for patients with arterial saturations of less than 90% as a class I recommendation and included administration of supplemental oxygen for all patients with AMI during the first 6 hours as a class IIa recommendation.1 The 2013 guidelines no longer recommend oxygen therapy and rather simply state that supplemental oxygen be given consideration in light of limited data regarding its use.2 Data for oxygen therapy come from 2 studies done in dogs and only a handful of human studies, with much of these data being from an era in which thrombolytic therapy was not available. Newer studies have even demonstrated an association of liberal oxygen supplemental use in the setting of AMI with harm.3-6 Decrease in coronary blood flow, decrease in myocardial oxygen consumption, decrease in cardiac output, increase in systemic vascular resistance, and increase in reperfusion injury in patients with cardiac disease when exposed to hyperoxia may all be possible mechanisms.7-10 We conducted a systematic review of the literature with a meta-analysis of available data to compare the use of high
concentration oxygen versus titrated oxygen or room air in the setting of AMI.
Methods Identified Outcomes The aim of the study was to determine the effect of high concentration oxygen versus titrated oxygen or room air in the setting of AMI. Preliminary review of studies identified the following end points for comparison: in-hospital mortality, opiate use as a surrogate for pain, infarction percentage by magnetic resonance imaging (MRI), and infarction mass by MRI. 1
Children’s Hospital of Wisconsin/Medical College of Wisconsin, Department of Cardiology, Milwaukee, WI, USA 2 Rush University Medical Center, Department of Cardiology, Chicago, IL, USA 3 Creighton University Medical Center, Department of Cardiology, Omaha, NE, USA 4 Chicago Medical School, Chicago, Department of Cardiology, IL, USA Manuscript submitted: March 24, 2015; accepted: June 27, 2015. Corresponding Author: Rohit S. Loomba, Children’s Hospital of Wisconsin/Medical College of Wisconsin, 9000 Wisconsin Avenue, Milwaukee, WI 53226, USA. Email: [email protected]
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Search Methodology and Study Identification Electronic databases PubMed, EMBASE, Medline, and the Cochrane central register of clinical trials were searched for pertinent studies. Each database was queried using the following search terms: ‘‘acute myocardial infarction,’’ ‘‘coronary thrombosis,’’ and ‘‘heart attack’’ in isolation or in combination with one of the following search terms: ‘‘supplemental oxygen,’’ ‘‘oxygen,’’ ‘‘room air,’’ ‘‘hypoxemia,’’ ‘‘normobaric,’’ and ‘‘hyperbaric.’’ There were no restrictions placed on date or language of publication. Resulting manuscripts were reviewed by title and abstract with pertinent manuscripts being selected for full-text review. Full-text review was then conducted with additional studies being excluded if felt to not be pertinent to the study question. References of manuscripts undergoing full-text review were also reviewed to identify additional manuscripts. Cited Web sites were also visited for additional data. This search methodology was carried out by 2 authors (RL and KN) independently with subsequent comparison and reconciliation of any differences.
confidence intervals were also calculated for each. Forest plots were generated for each end point. This analysis was done using Comprehensive Meta-Analysis version 3.0 (Englewood, New Jersey). Meta-regression was conducted for in-hospital mortality using year of publication, age, and gender as variables in the regression model.
Results Study Identification A total of 4371 studies were identified with 2508 remaining after duplicates were removed (Figure 1). Of these studies, 162 were identified for review of the full text. Ultimately, 5 studies were included in the final analysis.11-15 One of these studies was not published in a journal but had data available online with its methods previously published.11,16 There were a total of 446 patients in the high concentration oxygen and 467 patients in the titrated oxygen or room air group. Patient characteristics for included studies are provided in Table 1.
In-Hospital Mortality
Bias Assessment The Cochrane Collaboration’s tool for assessing risk of bias was utilized for the assessment. This tool assesses for adequate sequence generation, allocation concealment, blinding, incomplete reporting of outcome data, selective reporting of outcome data, and other potential areas of bias. Bias assessment of studies identified for inclusion in the study was done by 2 authors independently (KN and SA) with subsequent comparison and reconciliation of any differences. Publication bias was assessed by both a qualitative and quantitative method. Funnel plots were created for visual assessment of publication bias, and an Egger test was conducted to quantify publication bias.
A total of 4 studies with 425 patients in the high-concentration oxygen and 447 patients in the titrated oxygen or room air group (Figure 2). A fixed-effects model was used as significant heterogeneity was not present (Q ¼ 6.123, P ¼ .106, I2 ¼ 51%). The in-hospital mortality rate was 4% among those receiving high-concentration oxygen and 3% among those receiving room air. No significant difference was noted between the 2 groups (odds ratio 0.981, 95% confidence interval 0.439-2.195).
Opiate Use
Data abstraction was done for previously identified end points using a data collection tool. Data abstraction was done by 2 authors independently (RL and SA) with subsequent comparison and reconciliation of any differences. Authors of included studies were not contacted for additional data.
Data for opiate use were extracted from 2 studies with 102 patients in the high concentration oxygen group and 97 in the titrated oxygen or room air group (Figure 3). A fixed-effects model was used as significant heterogeneity was not present (Q ¼ 2.140, P ¼ .144, I2 ¼ 53%). Opiate use was needed in 72% of those receiving high-concentration oxygen and 72% of those receiving room air. No significant difference was noted between the 2 groups (odds ratio 0.990, 95% confidence interval 0.526-1.865).
Data Analysis
Infarction Percentage by MRI
Continuous data are presented as means. Categorical data are presented as frequencies with absolute numbers as well as percentages. P values of .05 were considered statistically significant. Pooled analysis was conducted using a Haenszel-Mantel fixed-effects model when significant heterogeneity was not present and using DerSimonian and Laird random-effects model when significant heterogeneity was present. Heterogeneity was assessed using both chi-square and I2 tests. The odds ratio was calculated for categorical variables while mean difference was calculated for continuous variables. The 95%
Two studies were pooled with 286 patients in the highconcentration oxygen group and 291 patients in the titrated oxygen or room air group (Figure 4). A fixed-effects model and random-effects model were used due to ambiguity in the heterogeneity analysis (Q ¼ 2.976, P ¼ .085, I2 ¼ 66%). Chisquare analysis did not demonstrate significant heterogeneity although the I2 test did. A significant difference was noted between the 2 groups (mean difference 2.224%, 95% confidence interval 0.906-3.541). When the analysis was repeated with a random-effects model this became insignificant.
Data Abstraction
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Figure 1. Study methodology.
Table 1. Patient Characteristics in Included Studies. Number of Patients Rawles and Kenmure15 Room air or titrated oxygen High-concentration oxygen Ranchord et al12 Room air or titrated oxygen High concentration oxygen Ukholkina et al14 Room air or titrated oxygen High concentration oxygen Stub et al11,16 Room air or titrated oxygen High concentration oxygen Wilson and Channer13 Room air or titrated oxygen High concentration oxygen
Gender (Males)
Age, Years
Intervention
56.4 + 0.8 55.1 + 0.9
21% oxygen by mask at 6 L/min 100% oxygen by mask at 6 L/min
48 (71%) 53 (78%)
62.1 + 12.5 60.0 + 12.8
Oxygen by nasal cannula to maintain saturations 93% to 96% 100% oxygen by mask at 6 L/min
79 58
– –
– –
Room air 40% oxygen by mask at 3-6 L/min
223 218
174 (80%) 174 (78%)
62.6 + 13.0 63.0 + 11.9
Room air 100% oxygen by mask at 8 L/min
105 93
– –
– –
77 80
61 (79) 63 (79)
68 68
Infarction Mass by MRI Two studies were pooled with 286 patients in the high concentration oxygen group and 291 patients in the titrated oxygen or room air group (Figure 5). A random-effects model
Room air 100% oxygen by mask 4 L/min
was used as significant heterogeneity was present (Q ¼ 4.552, P ¼ .033, I2 ¼ 78%). A significant difference was not noted between the 2 groups (mean difference 2.418 g, 95% confidence interval 1.960-6.797).
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Figure 2. Forest plot comparing in-hospital mortality.
Figure 3. Forest plot comparing opiate use.
Figure 4. Forest plot comparing percentage of infarcted myocardium by magnetic resonance imaging.
Bias Assessment No studies were excluded from the analysis due to bias as evaluated using the Cochrane Collaboration’s tool for assessing risk of bias (Table 2). Ranchord et al was found to have a high
risk of selective reporting as MRI was only performed in a subgroup of patients.12 This also added to the risk of other bias. Ukholkina et al was found to have a high risk of incomplete outcome data, as there were some significant differences in
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Figure 5. Forest plot comparing mass of infarcted myocardium by magnetic resonance imaging. Table 2. Bias Assessment. Study
Random Sequence Generation (Bias Risk)
Allocation Concealment (Bias Risk)
Incomplete Outcome Data (Bias Risk)
Selective Reporting (Bias Risk)
Other Bias (Bias Risk)
Rawles and Kenmure15 Ranchord et al12 Stub et al11,16 Ukholkina et al14 Wilson and Channer13
Unclear Low Low Unclear Unclear
Low Low Low Unclear Low
Low Low Low Low Low
Low High Low Low High
Low High Low High Low
baseline characteristics.14 Wilson and Channer were found to have a high risk of selective reporting, as no mortality data were reported.13 Publication bias was assessed only for in-hospital mortality as the remainder of end points had too few studies. Visual inspection of the funnel plot did not demonstrate significant publication bias, which was confirmed by an Egger test which demonstrated a 95% confidence interval of 9.124 to 10.979 with a P value of .729 (Figure 6).
Meta-Regression A meta-regression was conducted for in-hospital mortality (Table 3). This could not be done for other end points, as there were not an adequate number of studies included. While there was not significant heterogeneity present, age accounted for a majority of the heterogeneity that was present.
Discussion This analysis of 5 studies demonstrated no difference in inhospital mortality, opiate use, infarction percentage by MRI, and infarction mass by MRI between those receiving high concentration oxygen and those who received titrated oxygen or room air in the setting of AMI.11-15 A significant difference was initially noted in infarction percentage by MRI with a fixed-effects model and when repeated with a random-effects model significance was lost. Thus, there was a trend in greater infarct percentage, but this was found to be statistically insignificant. Such statistically insignificant trends were also found
in relation to in-hospital mortality and infarction mass by MRI. These findings are similar to that of a meta-analysis published by Cabello et al in 2013 which had similar findings. We now include recent data, including the largest randomized study to date, to the previous study with similar results.17 The use of oxygen for a cardiac indication was initially described by Steele in 1900 in the setting of severe angina.18 In 1930, Levy published a 4 patient case series demonstrating relief of clinical symptoms associated with supplemental oxygen in the setting of AMI, thus introducing the routine recommendation of supplemental oxygen in the setting of AMI.19 Based on data from animal models, it was hypothesized that supplemental oxygen would help reduce the area of infarction and the risk of arrhythmias, further propagating the use of oxygen in AMI.20 It was as early as 1950 that studies began to demonstrate that supplemental oxygen may not be beneficial and, in fact, may be associated with some harm. Supplemental oxygen was found to be associated with longer duration of electrocardiographic changes consistent with ischemia and did not have any effect on pain, thought to be secondary to hyperoxia interfering with AMI-induced hyperemia.21 Subsequent studies demonstrated the hemodynamic effects of supplemental oxygen including a decrease in cardiac output, decrease in cerebral perfusion, decrease in renal perfusion, and increase in systemic vascular resistance.9,22-26 Despite these findings, high-concentration oxygen supplementation for AMI continued. Using the in-hospital mortality from this analysis, a total of 3050 patients with 1525 in each group would be necessary to detect a statistically significant difference of 2% in mortality
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Figure 6. Funnel plot for in-hospital mortality. Table 3. Summary Results of Meta-Analysis. End Point In-hospital mortality Opiate use Infarction percentage by MRI Infarction mass by MRI
Odds Ratio or Mean Difference Group and 95% Confidence Interval Favored 0.981 (0.439-2.195) 0.990 (0.526-1.865) 2.224% (0.410-3.521)
Neither Neither Neither
2.148 g (1.960-6.797)
Neither
Abbreviation: MRI, magnetic resonance imaging.
between the 2 groups with 90% power and an alpha of 0.05. The largest study included in this analysis consisted of 218 patients in the high-concentration oxygen group and 223 patients in the titrated or room air group.11 This highlights the need for a large randomized effort to evaluate supplemental oxygen in patients with AMI. Such an effort would ideally compare serial electrocardiographic, troponin, and brain natriuretic peptide (BNP) data in addition to the prevalence of arrhythmia and mortality between the 2 groups. The percentage and mass of infarcted myocardium by MRI assessment would also be of great value. There are limitations of this analysis. Limited number of similar end points for abstraction across included studies limited the number of end points. The BNP levels and troponin levels would have been of interest to assess but these were not available in all studies. Additionally, some of these studies included patients who may have received supplemental oxygen upon initial triage by out-of-hospital responders and while in the ambulance en route to the hospital. They were then subsequently randomized to 1 of the 2 oxygen groups upon hospital arrival. More detailed meta-regression and assessment of publication bias could not be conducted due to the small number of studies for most end points. This analysis is also underpowered. In regard to bias, it is also hard to
entirely rule out the possibility of publication analysis, despite the statistical analysis run and thus it can only be said that our analysis implies but does not prove the absence of publication bias.
Conclusion There were no statistically significant differences noted between those with AMI randomized to high-concentration oxygen or titrated oxygen or room air in respect to inhospital mortality, opiate use, percentage of infarcted myocardium, or mass of infarcted myocardium. Author Contribution R. Loomba and S. Aggarwal contributed to conception and design; acquisition, analysis, and interpretation; drafted the article; critically revised the article; gave final approval; and agreed to be accountable for all aspects of work ensuring integrity and accuracy. K. Nijhawan contributed to design, acquisition, and analysis; drafted the article; critically revised the article; gave final approval; and agreed to be accountable for all aspects of work ensuring integrity and accuracy. R. Arora contributed to design; acquisition, analysis, and interpretation; drafted the article; critically revised the article; gave final approval, and agreed to be accountable for all aspects of work ensuring integrity and accuracy.
Authors’ Note This article has not been submitted elsewhere for simultaneous consideration of publication and has not been previously published. All the authors have been involved in the conception, execution, and preparation of this article and are aware of its submission.
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
13.
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