ARTICLE IN PRESS

CLINICAL RESEARCH STUDY

Oxygen Therapy in Patients with Acute Myocardial

Infarction: A Systemic Review and Meta-Analysis
Ahmed Abuzaid, MD,a Carly Fabrizio, DO,a Kevin Felpel, MD,a Haitham S. Al Ashry, MD,b Pragya Ranjan, MD,a
Ayman Elbadawi, MD,c Ahmed H. Mohamed, MD,c Kirolos Barssoum, MD,cIslam Y. Elgendy, MDd
a
Department of Cardiovascular Medicine, Sidney Kimmel Medical College at Thomas Jefferson University/Christiana Care Health System,
Newark, Del; bDivision of Pulmonary, Critical Care, Allergy and Sleep Medicine, Medical University of South Carolina, Charleston;
c
Department of Medicine, Rochester General Hospital, Rochester, NY; dDepartment of Medicine, Division of Cardiovascular Medicine,
University of Florida, Gainesville.

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 re-
ported 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 in-
farction (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.
© 2018 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2018) ■■, ■■–■■

KEYWORDS: Coronary artery disease; Myocardial infarction; Oxygen

INTRODUCTION therapy is the gold standard treatment strategy for patients

Ischemic heart disease is the most common cause of death
worldwide.1 Furthermore, acute myocardial infarctions occur
in approximately 790,000 Americans every year.2 Reperfusion
Funding: None.
Conflicts of Interest: None.
Authorship: All authors had access to the data and played a role in writing
this manuscript.
Requests for reprints should be addressed to Ahmed Abuzaid, MD, De-
partment of Cardiovascular Medicine, Sidney Kimmel Medical College at
Thomas Jefferson University/Christiana Care Health System, 4755 Ogletown-
Stanton Road, E Tower, Room 2875, Newark, DE 19718.
E-mail address: aabuzaidmd@gmail.com, ahmed.s.abuzaid@
christianacare.org
who present with acute myocardial infarction.1 Other treat-
ment therapies, such as routine oxygen therapy, have been
evaluated to determine their impact on cardiovascular out-
comes. 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.2 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 isch-
emic myocardium.3-5 Yet, those studies were not randomized
or blinded. Conversely, it has since been reported that
hyperoxia may precipitate an increase in myocardial injury

0002-9343/$ - see front matter © 2018 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.amjmed.2017.12.027
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2 The American Journal of Medicine, Vol ■■, No ■■, ■■ 2018

due to coronary vasoconstriction and oxidative stress.6,7 Yet METHODS

the use of supplemental oxygen continued to be a routine prac-
tice in patients with cardiac disease. More important, no Data Sources
randomized, blinded, and controlled studies have shown an An electronic search of the MEDLINE, Web of Science, and
advantage in normoxemic patients, with surging evidence Cochrane Collaboration of Clinical Trials was performed from
proving the conceivable adverse effects of hyperoxia in acute inception to November 2017 without language restriction, using
myocardial infarction.8,9 A Cochrane the keywords “acute myocardial in-
report from 2016 did not show any farction,” “oxygen therapy,”
benefit to using oxygen in patients CLINICAL SIGNIFICANCE “assessment,” and “outcomes,” as il-
with acute myocardial infarction.8 • Society guidelines endorse oxygen lustrated in Figure 1. Bibliographies
Additionally, a recent meta-analysis therapy for the management of pa- of the included studies, relevant
reviewed 5 randomized controlled review articles, and meta-analyses
tients with acute myocardial infarction
trials and concluded that oxygen were manually searched for any po-
in the context of hypoxemia. tential overlooked studies. The
supplementation did not benefit
patients with baseline normal pe- • The study revealed the lack of benefit major cardiovascular conferences
ripheral oxygen saturations ≥90%.9 of routine oxygen therapy in patients and proceedings, for example,
Most recently, a registry-based with acute myocardial infarction with American College of Cardiology
randomized clinical trial was per- normal oxygen saturation levels. and American Heart Association
formed to evaluate oxygen therapy conferences, were screened for any
on all-cause mortality at 1 year (The • The value of the present study is to abstracts addressing this topic.
Determination of the Role of resolve the debate of routine oxygen use
Oxygen in Suspected Acute Myo- in the setting of acute myocardial in- Selection Criteria and Data
cardial Infarction),10 which showed farction with no hypoxia with the most Extraction
that routine supplemental oxygen in updated evidence, including random- Randomized controlled studies and
patients without hypoxemia at base- ized trials. observational studies evaluating car-
line undergoing hospitalization for diovascular outcomes in adult
acute myocardial infarction did not subjects with acute myocardial in-
have a reduced 1-year all-cause mortality. This study pro- farction and oxygen therapy with no hypoxemia were included.
vides definitive evidence that supplemental oxygen is not We required that the studies had reported outcomes in both
beneficial in patients who have normal baseline oxygen satu- an oxygen therapy arm and no oxygen arm (control) to be
rations with acute myocardial infarction.11 In this context, we included. If a studied population reported more than 1 pub-
performed an updated meta-analysis with the most updated lication, the outcomes were preferentially reported at the
evidence to evaluate the efficacy of routine oxygen supple- longest follow-up duration. Data were extracted by 2 inde-
mentation in patients with acute myocardial infarction. pendent groups and revised by AA and AE for accuracy.

Figure 1 Summary of how the systematic search was conducted and eligible studies
were identified (PRISMA flow diagram). NS-ACS = non ST elevation-Acute Cor-
onary Syndrome.
 ARTICLE IN PRESS
Abuzaid et al Oxygen Therapy in Acute Coronary Syndrome
Table 1 Showing Risk of Bias of Randomized Trials by Cochrane Risk Assessment Tool
Rawles
et al20
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.
Any discrepancy was resolved by consensus among the
authors.
Outcomes and Definitions
The outcomes assessed in this study included all-cause mor-
tality (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 per-
centile 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.12 The Grades
of Recommendation, Assessment, Development, and Eval-
uation tool13 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, un-
explained heterogeneity or inconsistency of results, imprecision
of the results, and high probability of the publication bias
(Tables 1 and 2).
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.14 A fixed-effect model
using the Mantel–Haenszel method was performed as a sec-
ondary analysis.15 Statistical heterogeneity was measured using
the I2 statistic.16 Egger’s method was used to assess publi-
cation bias.17 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).
3
Wilson Ukholkina Ranchord Stub Khoshnood Hofmann
et al21 et al22 et al23 et al24 et al25 et al12
RESULTS
Patient Population
A total of 8 studies18-25 fulfilled our inclusion criteria. One
study26 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 analysis12,20-25 (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 pa-
tients with a mean age of 62 years underwent routine oxygen
therapy. The no oxygen therapy group included 3860 pa-
tients 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, hyper-
lipidemia, and smoking. Table 3 summarizes the baseline
characteristics of the included patients.
Meta-Analysis
Oxygen therapy did not decrease all-cause mortality in 6
studies12,20,22-25 (pooled RR, 0.99; 95% CI, 0.81-1.21; P = .429;
I2 = 0.0%) (Figure 2). Six studies12,21-25 reported the effect of
oxygen therapy on recurrent ischemia or myocardial infarc-
tion. 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 studies12,22,25 described the occurrence of heart failure
in both arms, and again oxygen therapy did not show an ad-
vantageous effect (pooled RR, 0.94; 95% CI, 0.61-1.45;
P = .348; I2 = 5.3%) (Figure 4). The occurrence of arrhyth-
mia 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.
DISCUSSION
The results of this meta-analysis of 7 studies with 7702 pa-
tients 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.
 4
Table 2 Showing 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 Patients Effect
Routine

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№ of Study Other Oxygen Relative Absolute
Studies Design Risk of Bias Inconsistency Indirectness Imprecision Considerations therapy No Oxygen (95% CI) (95% CI) Certainty Importance
All-Cause Mortality (Follow-up: Range, 1 wk to 12 mo)
6 Randomized Not serious Not serious Not serious Not serious None 188/3820 189/3840 RR 0.99 0 fewer ⨁⨁⨁⨁ Critical
trials (4.9%) (4.9%) (0.81-1.21) per 1000 High
(from 9 fewer
to 10 more)
Recurrent Ischemia or Myocardial Infarction (Follow-up: Range, 1 d to 12 mo)

The American Journal of Medicine, Vol ■■, No ■■, ■■ 2018

6 Randomized Not serious Not serious Not serious Not serious None 160/3723 138/3723 RR 1.19 7 more per 1000 ⨁⨁⨁⨁ Critical
trials (4.3%) (3.7%) (0.95-1.48) (from 2 fewer High
to 18 more)
Heart Failure (Follow-up: Range, 1-12 mo)
3 Randomized Not serious Not serious Not serious Not serious None 49/3415 53/3446 RR 0.94 1 fewer ⨁⨁⨁⨁ Important
trials (1.4%) (1.5%) (0.61-1.45) per 1000 High
(from 6 fewer
to 7 more)
Arrhythmia (Follow-up: Range, 1-12 Mo)
5 Randomized Not serious Not serious Not serious Not serious None 322/3789 323/3793 RR 1.01 1 more per 1000 ⨁⨁⨁⨁ Important
trials (8.5%) (8.5%) (0.85-1.20) (from 13 fewer High
to 17 more)
CI = confidence interval; RR = risk ratio.
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Abuzaid et al Oxygen Therapy in Acute Coronary Syndrome 5

Table 3 Showing Patient Demographics

Age Age Male Male HTN HTN DM DM HLP HLP Smoking Smoking
Study Year (O2) (RA) (O2) (RA) (O2) (RA) (O2) (RA) (O2) (RA) (O2) (RA)
Stub et al24 2015 63 62.6 79.8 78 130 123 37 41 121 118 141 165
Hofmann et al12 2017 68 68 68.4 70.7 1575 1559 589 644 N/A N/A 704 721
Ranchord et al23 2012 60 62.1 77.9 70.6 23 28 7 8 19 25 32 21
Rawles et al20 1976 80 77 63 61 N/A N/A N/A N/A N/A N/A N/A N/A
Wilson et al21 1997 64 65 N/A N/A N/A N/A 2 2 N/A N/A 5 7
Khoshnood et al25 2006 63.7 65.5 29 34 11 21 3 9 N/A N/A 31 32
Ukholkina et al22 2005 62 60 66 N/A N/A N/A N/A N/A N/A N/A N/A N/A
DM = diabetes mellitus; HLP = hyperlipidemia; HTN = hypertension; N/A = not available; O2 = oxygen; RA = room air.

The utility of providing oxygen supplementation to pa-
tients who are not hypoxic with acute myocardial infarction
has been controversial, with initial studies4,7 favoring its use
and later studies demonstrating potential harm.20-25 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.10,11 Our study includes the most recent, high-
quality randomized trials. In our meta-analysis, the lack of
benefit of supplemental oxygen in acute myocardial infarc-
tion is consistent with previous meta-analysis.10,11 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 117310 and 92111 participants. Our study has a larger
sample size and a longer follow-up (1-12 months) than pre-
vious 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 in-
stance, 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.12 In patients postcardiac arrest, hyperoxia was associ-
ated with increased mortality.26 In critically ill patients,
hyperoxia was associated with increased mortality in 2 recent
meta-analyses.27,28 In fact, delivering more than 50% frac-
tion of inspired oxygen to critically ill patients with oxygen

Figure 2 Summary plot for all-cause mortality. CI = confidence interval; RR = risk ratio.
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6 The American Journal of Medicine, Vol ■■, No ■■, ■■ 2018

Figure 3 Summary plot for recurrent ischemia or myocardial infarction. CI = confidence interval; RR = risk ratio.

Figure 4 Summary plot for heart failure. CI = confidence interval; RR = risk ratio.
 ARTICLE IN PRESS
Abuzaid et al Oxygen Therapy in Acute Coronary Syndrome
Figure 5 Summary plot for arrhythmia. CI = confidence interval; RR = risk ratio.
saturation >92% resulted in worse oxygenation index in 48
hours,29 which can be explained by the occurrence of more
atelectasis with higher oxygen levels.30 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 oxy-
genation 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 myo-
cardial 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 myo-
cardial 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.31 Subsequent guide-
lines have reserved oxygen therapy for only those patients
who have hypoxia (oxygen saturation <90%), respiratory dis-
tress, or risk factors for hypoxemia.1,32 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
7
the current guidelines reflect this by recommending against
oxygen supplementation unless the patient is hypoxic.
We postulate significant adverse hemodynamic effects, in-
cluding a reduction in coronary blood flow; myocardial oxygen
consumption and an increase in coronary vascular resistance33,34
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.35,36 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.35,37 These mecha-
nisms 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,27 and several studies had incomplete follow-
up, leaving a high potential for bias. None of the trials were
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8 The American Journal of Medicine, Vol ■■, No ■■, ■■ 2018
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 in-
farction, 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 con-
firms prior studies and supports the changing trend in
recommendations to avoid supplemental oxygen in patients
with peripheral oxygen saturations ≥90%.
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