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REVIEW

Oxygen Therapy for Acute Myocardial Infarction—Thenand Now. A Century of UncertaintyRichard Kones, MD, FAHA, FESC

Cardiometabolic Research Institute, Houston, Tex.

E-mail address

0002-9343/$ -see fdoi:10.1016/j.amjm

ABSTRACT

For about 100 years, inhaled oxygen has been administered to all patients suspected of having an acutemyocardial infarction. The basis for this practice was the belief that oxygen supplementation raisedoften-deficient arterial oxygen content to improve myocardial oxygenation, thereby reducing infarct size.This assumption is conditional and not evidence-based. While such physiological changes may pertain insome patients who are hypoxemic, considerable data suggest that oxygen therapy may be detrimental inothers. Acute oxygen therapy may raise blood pressure and lower cardiac index, heart rate, cardiac oxygenconsumption, and blood flow in the cerebral and renal beds. Oxygen also may lower capillary density andredistribute blood in the microcirculation. Several reports now confirm that these changes occur in humans.In patients with both acute coronary syndromes and stable coronary disease, oxygen administration mayconstrict the coronary vessels, lower myocardial oxygen delivery, and may actually worsen ischemia.There are no large, contemporary, randomized studies that examine clinical outcomes after this interven-tion. Hence, this long-accepted but potentially harmful tradition urgently needs reevaluation. Clinicalguidelines appear to be changing, favoring use of oxygen only in hypoxemic patients, and then cautiouslytitrating to individual oxygen tensions.© 2011 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2011) 124, 1000-1005

KEYWORDS: Acute coronary syndrome guidelines; Acute myocardial infarction; Coronary artery disease; Hyper-oxia; Hyperoxic vasoconstriction; Hypoxemia; Myocardial oxygenation; Oxygen inhalation; Oxygen toxicity

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In September 1955, President Eisenhower, who had been a4-pack/day smoker and followed an atherogenic diet, sus-tained an anterior myocardial infarction. He was placed inan oxygen tent, given anticoagulants despite a friction rub,and kept at strict bed rest for 4 weeks. Observers blamedchronic low intensity exercise—golf—as an etiological fac-tor in producing the episode. Dr Paul Dudley White was notonly criticized for mobilizing him “early,” allowing him tobegin walking at 6 weeks, but also for suggesting thatchronic exercise was cardioprotective.1 The President’s per-onal experience may have led him to establish, by Execu-ive Order, the President’s Council on Youth Fitness someonths later.

Funding: None.Conflict of Interest: None.Authorship: The author is solely responsible for the entire content of

this review.Requests for reprints should be addressed to Richard Kones, MD,

FAHA, FESC, Cardiometabolic Research Institute, 8181 Fannin St, U314,Houston, TX 77054.

h: drrkones@comcast.net

ront matter © 2011 Elsevier Inc. All rights reserved.ed.2011.04.034

The management of acute coronary syndromes hashanged markedly from the 1950s, when medicine wasrganized as a “cottage industry” and about to transitionrom a descriptive discipline. During the 61 years since,edicine has undergone a metamorphosis to an increasingly

uantitative science based upon the scientific method, physico-hemical principles, and “evidence-based medicine.” Onef the holdovers from that era, when patients with acuteyocardial infarction (AMI) were treated with bed rest for

-6 weeks and were relatively unmonitored, is the use ofxygen supplementation.

Because heart muscle death during AMI is associated withxygen and substrate deprivation caused by acutely diminishedoronary blood flow, and hypoxemia, frequently observed inuch patients, reduces the ability of the blood to carry oxygen,he belief evolved that oxygen inhalation raised oxygen deliv-ry to ischemic myocardium, leading to reduced infarct size.ased upon this assumption, it appeared reasonable to admin-

ster oxygen by nasal cannula, mask, or tent, and this practiceas continued rather routinely for all patients suspected of

aving an AMI for about 100 years. In 2011, however, with

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more sophisticated and rigorous criteria, advanced technology,and relying more upon demonstrable clinical outcomes thantranslating directly from the laboratory to the bedside, the useof inhaled oxygen in patients with uncomplicated acutecoronary syndromes is being questioned. Closer examinat-ion reveals that the long-standingassumption upon which oxygentherapy is based is conditional, andis not evidence-based. There is nobetter example of being misled byobservational reports than the past,overzealous use of prophylactic in-travenous lidocaine in such patients,only to discover that actual out-comes were convincingly detrimen-tal.2 Similarly, because evidence ofharm was not striking during tradi-tional oxygen use in AMI duringthese many years, a laissez-faireattitude prevailed. In hypoxemic pa-tients with complicated AMI, oxy-gen therapy was, and remains,clearly evidence-based.3

EARLY LABORATORY ANDCLINICAL TRIALSAfter Steele successfully used inhaled oxygen to relieveangina in 1900,4 the practice endured, based upon the pop-lar notion that administered oxygen increased oxygen de-ivery to the myocardium and reduced infarct size.5,6 Fiftyears later Russek et al7 found that 100% oxygen given by

mask not only failed to relieve or modify angina, but ac-centuated and prolonged some electrocardiographic changesof ischemia. They postulated that hyperoxic blood pre-vented reactive hyperemia in ischemic myocardium andmight be contraindicated during normoxemia but not duringhypoxia. Two decades later, when techniques capable ofdecreasing infarct size were being explored, Maroko et al8

showed that 40% oxygen administration reduced the extentof myocardial ischemic injury assessed by ST-segment andbiochemical marker elevations in a canine model. Madiasand Hood9 also reported reductions in ST-segment eleva-tions on precordial mapping in patients inhaling 16% oxy-gen through masks, which was again attributed to a decreasein the volume of ischemic myocardium. Both of these stud-ies, however, had significant methodological limitations. Atrial by Horvat et al10 in 11 patients with coronary heartisease (CHD) found that oxygen supplementation raisedhe threshold to pacing-induced angina, that is, at a greaterate-pressure product associated with a higher left ventric-lar oxygen consumption.

Rawles and Kenmure11 conducted a double-blind studyof the effects of oxygen in 200 consecutive patients withsuspected myocardial infarction who were randomized toreceive either oxygen 6 L/min by mask or compressed air

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during their first 24 hours in the hospital. After 43 patients i

were excluded who proved not to have a myocardial infarc-tion, both groups were comparable except for higher serumaspartate aminotransferase and PaO2 levels in the oxygengroup. The incidence of arrhythmias and mortality was nobetter in the oxygen group than in the nontreated subjects.

Although not statistically signifi-cant, 9 of 80 (11.25%) patients inthe oxygen group died, comparedwith 3 of 77 (3.8%) in the com-pressed air group.

Wilson and Channer12 sur-veyed coronary care units in Eng-land regarding use of pulse oxim-etry to guide oxygen therapy afterAMI. They randomized 50 pa-tients who presented within 24hours of AMI to either inhaled ox-ygen or room air. Among patientsbreathing room air, 70% had anoxygen saturation (SpO2) �90%,and 35% of them had an SpO2

�35%, compared with 27% and4%, respectively, among patientswho received oxygen. There wereno differences between groups inthe incidence of arrhythmias orST-segment changes. Oxygen

therapy was easily guided by pulse oximetry, although un-common at that time.

HEMODYNAMIC EFFECTS OF OXYGEN ANDMYOCARDIAL OXYGEN AVAILABILITYOxygen is a vasoactive substance, and the hemodynamiceffects upon healthy subjects and patients with AMI arefairly well known. Acute oxygen administration may raiseblood pressure13 and lower cardiac index, heart rate, andcardiac oxygen consumption.14,15 Coronary blood flow fallsn response to hyperoxia-induced vasoconstriction regard-ess of initial saturation.16 Oxygen-induced vasoconstrictionay similarly lower cerebral17 and renal blood flow.18

Thomas et al19 found that 40% oxygen given to patientsithin a few days of onset of AMI increased arterial bloodressure with a fall in cardiac output, later confirmed byenmure et al.20 Foster et al21 were able to document a

continuous increase in systemic vascular resistance and ar-terial pressure as arterial oxygen tension increased, but nota fall in cardiac output.

Preclinical studies show that hyperoxia may lower myo-cardial oxygen consumption for reasons unrelated to cardiacoutput or heart rate. Because high oxygen tensions lowercapillary density, thereby reducing oxygen transport intomuscle, hyperoxia may decrease myocardial oxygen con-sumption.22,23 In addition, high-flow oxygen administration

ay disturb blood distribution in the microcirculation, lead-

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oxygen consumption,24 perhaps teleologically to protect tis-ues from toxic effects of high oxygen tensions.

Indeed, Sukumalchantra et al25 reported that in AMIpatients whose arterial oxygen saturation was over 90%,oxygen administration did not produce a net increase inoxygen transport in the myocardium because the effects oflowered cardiac output, associated with decreases in coro-nary blood flow and higher coronary vascular resistance,26

overcame the increase in oxygen content. However, whenarterial oxygen saturation was �90%, the resulting increasen both cardiac output and oxygen content after oxygenupplementation increased net oxygen transport. By mea-uring lactate/pyruvate ratios in coronary venous blood,eill27 demonstrated that in patients with CHD, anaerobic

metabolism, reflecting ischemia, occurred when arterial ox-ygen saturation was between 70% and 85%, but in healthysubjects, hypoxia did not cause such changes until oxygensaturation was about 50%. Hyperoxia did not raise myocar-dial oxygen availability or reverse ischemia in patients withheart disease. Bourassa and associates28 noted further that inatients with advanced triple vessel disease, abnormal lac-ate values were associated with 100% oxygen therapy.hus, while high-flow oxygen may increase oxygen content,simultaneous fall in coronary blood flow may not only fail

o improve overall myocardial oxygenation, but actuallyorsen the effects of ischemia. Oxidant stress is also asso-

iated with endothelial dysfunction and a cascade of subse-uent deleterious molecular events.

More recently, McNulty et al26 measured the effects ofreathing 100% oxygen by face mask for 15 minutes onoronary blood flow (via coronary Doppler flow wire) in 18atients with stable CHD. Breathing 100% oxygenromptly decreased coronary blood flow by 29% and raisedoronary vascular resistance by 41% without changing theiameter of large-conduit coronary arteries, suggesting in-olvement of the microcirculation. Momen et al29 used

duplex ultrasound to measure coronary blood velocity, anindex of coronary blood flow, in 7 healthy volunteersbreathing room air and 100% oxygen for 5 minutes. Com-pared with room air, coronary blood velocity fell �15%while coronary vascular resistance rose by �20%. Becausesimilar changes also were observed in patients who receivedcardiac transplants several months before, hyperoxia appar-ently produced vasoconstriction of the coronary arteriesthrough a direct effect, rather than through autonomicnerves.

SYSTEMATIC REVIEWSSeveral systematic reviews of the effects of oxygen inpatients with CHD are available. In 2004, a review of 9trials failed to demonstrate effectiveness because of insuf-ficient evidence.30 In 2008, Wijesinghe et al31 identified 51tudies, but only 2 met inclusion criteria of substantivelinical outcomes. It was concluded that evidence was lim-ted, but primarily using the trial results of Rawles and

enmure,11 support for oxygen therapy in all patients with

uncomplicated AMI was lacking, and oxygen may in facthave resulted in a larger infarct size, as reflected by theincrease in aspartate aminotransferase levels observed.

A Cochrane study32 reviewed bibliographic databases forandomized controlled trials of patients with suspected orroven AMI in which oxygen was administered within 24ours after onset, and outcomes—particularly pain andeath—were compared with patients breathing room air. Of228 articles screened, only 3 trials qualified: Rawles andenmure,11 Wilson and Channer,12 both older studies con-

ducted in the UK, and a Russian study, Ukholkina et al.33,34

Caution was urged because of the differences in currentmanagement of AMI and, during the study periods, highrisk of bias for the main outcomes, and the curiously lowdeath rate among control participants, which averaged just1.7%. A total of 387 patients were included, with a total of14 deaths, about 3 times as many in patients randomized tooxygen treatment than room air, not statistically significant,and no benefit regarding pain relief, as assessed by analgesicuse. The pooled relative risk of death was 2.88 (95% con-fidence interval [CI], 0.88-9.39) in an intention-to-treatanalysis, and 3.03 (95% CI, 0.93-9.83) in patients withproven AMI. The pooled relative risk for analgesic use was0.97 (95% CI, 0.78-1.20). Noting the paucity and poorquality of the evidence, the authors concluded certainly nobenefit accrued from oxygen therapy in uncomplicated AMIpatients, but their analysis could not demonstrate any harm.A definitive randomized controlled trial was deemed ofurgent importance.

A commentary accompanying the Cochrane study35 la-mented the continuation of oxygen therapy in uncompli-cated AMI patients, including use of oxygen in ambulancesbefore evaluation. The expense and difficulty of organizingand performing a large randomized trial, especially withoutfunding and impetus of the pharmaceutical industry, werecited. Another obstacle noted was the entrenchment of apractice which was believed to be reasonable, simple, inex-pensive, convenient, and apparently innocuous, togetherwith the psychological benefit to the paramedic, patient, andphysician by “doing something.”

An editorial in the British Medical Journal surprisedmany readers by arguing in favor of routine use of supple-mental oxygen, given the “positive physiological reasons”and no trial evidence of harm.36 To be sure, the methodol-gy was poor in all 3 trials analyzed by Cochrane; 2 studiesere performed unblinded and the third was accessible only

n abstract form in English.33 The editorialist opined thatthese limitations, combined with absence of demonstrableharm, suggested the practice should continue. A flurry ofletters contesting this view followed.37

Of interest is the report by Kilgannon et al,38 who ana-lyzed data collected for the Project IMPACT database in-volving 6326 adults with nontraumatic cardiac arrest admit-ted to 120 US intensive care units after resuscitation.Hyperoxia was present in 18% of the patients, hypoxiapresent in 63%, and normoxia in 19%. The presence of

hyperoxia conferred an odds ratio for death of 1.8 (95% CI,

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1003Kones Oxygen Therapy for Acute Myocardial Infarction

1.5-2.2), indicating that arterial hyperoxia was indepen-dently associated with increased in-hospital mortality com-pared with either normoxia or hypoxia. Extension of thiswork suggested a dose-dependent, linear relationship be-tween supranormal oxygen tension and risk of in-hospitaldeath in postresuscitation patients.51

WHAT THE GUIDELINES SAYOf guidelines that no longer recommend oxygen for allAMI patients, one of the first was the British ThoracicSociety Guideline for Emergency Oxygen use, in whichoxygen was recommended only for hypoxemic patients.39

The National Institute for Health and Clinical Excellence(NICE) Guideline on the management of chest pain ofsuspected cardiac origin, the UK Ambulance Serviceoxygen guideline, and a number of other societies sub-sequently adopted similar advice.40-42 The NICE guide-ine specifies the level of hypoxia that needs attentionith lower levels for patients with chronic obstructiveulmonary disease (COPD).43 Specifically, recommenda-ions are:

● Do not routinely administer oxygen, but monitor oxygensaturation using pulse oximetry as soon as possible, ide-ally before hospital admission. Only offer supplementaloxygen to people with oxygen saturation (SaO2) of�94% who are not at risk of hypercapnic respiratoryfailure, aiming for SaO2 of 94%–98%.

● In patients with COPD who are at risk of hypercapnicrespiratory failure, try to achieve a target SpO2 of 88%–92% until blood gas analysis is available.40

The American College of Cardiology/American HeartAssociation (ACC/AHA) guideline on ST-elevation myo-cardial infarction (STEMI)43 assigned a class IIa, level ofvidence (LOE) C recommendation to the use of oxygen,onsidering it reasonable to give supplemental oxygen to allatients with uncomplicated STEMI during the first 6 hours.he ACC/AHA guidelines for unstable angina (UA)/non-TEMI (NSTEMI)44 gave a class I, LOE B recommenda-

tion for administration of oxygen to all patients with UA/NSTEMI with SaO2 �90%, respiratory distress, or otherisk-risk features for hypoxemia, also recommending con-inuous monitoring with pulse oximetry. They also assignedclass IIa, LOE C recommendation for supplemental oxy-

en to all patients with UA/NSTEMI during the first 6 hoursfter presentation.

The current European Society of Cardiology (ESC)uideline on STEMI advises that in patients presenting withhest pain, “oxygen 2-4 L/min by mask or nasal prongshould be administered to those who are breathless or whoave any features of heart failure or shock.”45 Members ofhe ESC AMI-STEMI task force are aware of the issue and

review is planned for the new ESC Clinical Practiceuidelines due in 2012.In addition to the variation in guidelines, there is some

urther evidence that oxygen is inconsistently and casually

rescribed.46-48 Garg and Lagan46 audited 20 patients onardiology wards with respect to oxygen indication, modef delivery, documentation, and prescriptions written over a-month period. Numerous defects and issues were identi-ed; prescriptions for oxygen were described as “veryoor,” resulting in significant potential for patient harm. Aall for greater quality and appropriateness in prescribingxygen was made. Most crucial was the need to improvessessment for oxygen therapy and adequate titration tondividual patient requirement.49

CONCLUSIONOxygen is a vasoactive drug and should be prescribedonly when indicated. The burden of proof properly fallson the intervention, and there is no large, contemporary,randomized study available. Evidence supporting use ofoxygen in patients suspected of having an AMI who arenormoxemic is of poor quality and now old, predatingmodern trial methods, reperfusion, and other advances inmanagement. Recent data suggest that physiological ev-idence of harm is strong, clinical evidence of harm isweak, and there is no evidence for benefit. A large ran-domized clinical trial is urgently needed. Currently, theAir Versus Oxygen in myocardial Infarction Study(AVOID) is in progress, a randomized trial with a pri-mary end-point of infarct size as assessed with cardiactroponin I and creatine kinase.50

In the interim, and consistent with the doctrine ofprimum non nocere, it is suggested that in patients withacute myocardial infarction who are hypoxemic, oxygenis indicated to maintain arterial oxygen saturation from94% to 96%. Sufficient evidence now exists that hyper-oxia has the potential to induce unfavorable hemody-namic and metabolic changes and should be avoided. Inpatients with comorbidities, adjustments may be pro-vided by proven therapies for those conditions. In pa-tients at risk of hypercapnic respiratory failure, for in-stance, a target oxygen saturation of 88% to 92% mightbe appropriate until arterial blood gas results are avail-able, with possible revision upward if PaCO2 is notelevated and there is no prior history of blunting hypox-emia-driven respiratory drive with oxygen.

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