Air Verses Oxygen In myocarDial Infarction Study
Air Verses Oxygen In myocarDial Infarction Study
- Aim

 The AVOID (Air Verses Oxygen In myocardial infarction) trial is designed to determine if the
 withholding of routine oxygen therapy in patients with acute heart attack leads to reduced
 heart damage compared to the current practice of routine inhaled oxygen for all patients.

 - Background

 There is evidence supporting and refuting the current practice of providing oxygen to all
 patients with acute heart attack. A recent summary of clinical trials suggested that oxygen
 may increase the degree of heart damage during heart attack. It also highlighted that the few
 trials into oxygen therapy were performed before the use of modern medications and procedures
 to treat heart attack and that further studies were urgently needed, using contemporary
 practices.

 - Design

 A total of 334 patients will participate in this randomized controlled trial. Patients in
 this study will receive the best current management and care for their condition. Patients
 will be randomized to routine pre-hospital care with oxygen therapy vs pre-hospital care
 without oxygen therapy. Patients will then receive standard hospital care, aside from
 allocated oxygen or no oxygen therapy. The primary outcome measure of heart damage will be
 investigated using routine blood tests. With additional information gathered from other
 aspects of routine heart care including coronary angiogram, electrocardiograms and
 complications of hospital stay. Patients will be followed up at 6 months to determine any
 longer term effects of treatment.
Coronary artery disease (CAD) is a leading cause of morbidity and mortality in Australia[1].
 In particular, many patients with CAD present with ST-elevation myocardial infarction (STEMI)
 as a result of acute thrombotic coronary artery occlusion. The optimal treatment for patients
 presenting with STEMI is reperfusion therapy either with primary percutaneous coronary
 intervention (PCI) or administration of a thrombolytic drug[2, 3].

 Current guidelines recommend additional treatments for patients with STEMI prior to
 reperfusion therapy, such as oxygen, aspirin and nitrates[4]. Whilst there is supportive
 evidence from clinical trials for the administration of aspirin[5] and nitrates[6], there is
 no data from prospective, randomised, controlled clinical trials to support the use of
 routine supplemental oxygen.

 For many years, the administration of supplemental oxygen has been considered beneficial for
 the treatment of patients with acute myocardial infarction largely based on experimental
 laboratory data. For example, in a laboratory study, anaesthetised dogs underwent coronary
 artery occlusion and were then administered either 21% oxygen, 40% oxygen or 100% oxygen. In
 the 40% oxygen group, there was decreased myocardial injury and infarct size compared with
 the air or 100% oxygen groups[7].

 In another laboratory study, two groups of dogs underwent 90 minutes of coronary occlusion
 followed by 72 hours of reperfusion[8]. One group received 100% inspired oxygen from 20
 minutes before reperfusion and three hours after reperfusion whereas the air group received
 room air. The infarct size in the oxygen group was reduced by 38% and left ventricular
 ejection fraction was improved compared with the dogs receiving room air. This data suggests
 that high concentrations of inspired oxygen may be of benefit in acute myocardial infarction
 followed by reperfusion therapy.

 However, there is increasing clinical data that suggests that oxygen administration before
 and during reperfusion in patients with STEMI may be harmful.

 For example, the hemodynamic effects of inhalation of oxygen in high concentration has been
 investigated in 50 patients with acute myocardial infarction[9]. This resulted in adverse
 effects including a fall in cardiac output, a rise in blood pressure and an increase systemic
 vascular resistance. The latter would be expected to increase myocardial work and increase
 myocardial ischaemia.

 There have been three prospective, controlled trials of supplemental oxygen compared with no
 supplemental oxygen in patients with myocardial infarction.

 In a double-blind, randomised in-hospital study, two-hundred patients with myocardial
 infarction were allocated to receive supplemental oxygen or air administered by face mask for
 the initial 24 hours in hospital[10]. The two groups were comparable at baseline. There was
 no significant difference in mortality, incidence of arrhythmias or use of analgesics between
 the groups. There was a higher incidence of sinus tachycardia in the patients given oxygen.
 This study suggested that there was no benefit from the routine administration of oxygen in
 uncomplicated myocardial infarction.

 In a second study, 50 patients were allocated to either supplemental oxygen or room air[11].
 The main outcome measure was the requirement for analgesia with 16 of 22 patients (72.7%) in
 the oxygen group using opiates for pain relief compared with 18 of 20 patients (90%) in the
 air group. This study did not report mortality rate.

 In a third study conducted in Russia, 137 patients were allocated to either supplemental
 oxygen (4-6L/Min) or air[12]. Complications including heart failure, pericarditis and rhythm
 disorders occurred less frequently in the air group (Risk ratio 0.45: 95% CI 0.22 to 0.94).
 One patient out of 58 died in the oxygen group and none out of 79 participants in the air
 group.

 A meta-analysis analysed the outcomes in the 387 patients included in these three
 studies[13]. The pooled risk ratio of death for patients allocated to oxygen administration
 was 2.88 (95% CI 0.88 to 9.39) in an intention-to-treat analysis and 3.03 (95% CI 0.93 to
 9.83) in patients with confirmed myocardial infarction. While suggestive of harm, the small
 number of deaths recorded meant that this finding did not reach statistical significance.
 Pain was measured by analgesic use and the pooled risk ratio for decreased use of analgesics
 in the oxygen group was 0.97 (95% CI 0.78 to 1.20).

 In addition to the above studies, other clinical studies have examined the use of novel
 techniques for additional oxygen delivery to the ischemic myocardium during reperfusion. In a
 clinical trial testing the role of hyperbaric oxygen (HBO) in myocardial infarction, 112
 patients with STEMI were allocated to either HBO or usual supplemental oxygen (40% by mask or
 6L/min by nasal prongs) during thrombolysis[14]. There was no significant difference between
 the groups in creatinine kinase levels at 24 hours or left ventricle ejection fraction (LVEF)
 on discharge. Overall, there was no overall benefit with this approach found in this study.

 In a clinical trial testing coronary artery reperfusion with hyperoxic blood during
 reperfusion, 269 patients with acute AMI undergoing PCI were randomly assigned to receive
 hyperoxemic blood reperfusion or normoxemic blood reperfusion by catheter into the area of
 reperfused myocardium[15]. At 30 days, there was no significant difference in the infarct
 size, ST-segment resolution, or regional wall motion score. Although improvement in cardiac
 function was seen in patients with anterior MI who were reperfused within 6 hours, this
 finding was a post-hoc analysis.

 A meta-analysis of all studies of hyperoxic myocardial reperfusion found that this treatment
 caused a significant reduction in coronary blood flow, an increase in coronary vascular
 resistance and a significant reduction in myocardial oxygen consumption[16]. This data
 appears to confirm that supplemental oxygen may be harmful.

 Given the lack of clinical data of the efficacy of oxygen administration, European guidelines
 for the management of acute coronary syndromes do not now include a recommendation for
 supplemental oxygen[17]. Whilst the recent American Heart Association guideline for the
 management of acute coronary syndromes does recommend oxygen, they note that there is no
 clinical trial evidence to support this recommendation[4]. The most recent addendum to the
 2006 Australian National Heart Foundation Guidelines does not recommend the routine use of
 supplemental oxygen[18].

 In summary, whilst there is some laboratory evidence of benefit for supplemental oxygen
 during STEMI and reperfusion, the available clinical data suggests that oxygen may be of no
 use or even harmful. Since oxygen is currently used routinely in many ambulance services and
 hospitals in the treatment of acute coronary syndromes, prospective clinical trials comparing
 supplemental oxygen with no supplemental oxygen in this condition are required[19, 20].

 Ambulance Victoria is uniquely placed to undertake this research. The Mobile Intensive Care
 Ambulances (MICA) of Ambulance Victoria are equipped with 12 lead ECG capability and
 pulse-oximetry monitors. In Melbourne, MICA attends approximately 400 STEMI patients per
 year.

 We therefore propose to undertake a randomised, controlled trial comparing supplemental
 oxygen therapy with air in patients without hypoxia who present with STEMI to determine the
 effect on the size of the myocardial infarct at hospital discharge.

 - References

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 2. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA Guidelines for the Management of
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 5. Freimark D, Matetzky S, Leor J, et al. Timing of aspirin administration as a determinant
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 6. Charvat J, Kuruvilla T, al Amad H. Beneficial effect of intravenous nitroglycerin in
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 7. Maroko PR, Radvany P, Braunwald E, Hale SL. Reduction of infarct size by oxygen
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Inclusion Criteria:

 -  Adults ≥ 18 years of age.

 -  Chest pain for < 12 hours

 -  ST-elevation Myocardial Infarction including either: 1) Persistent ST-segment
 elevation of ≥1mm in two contiguous limb leads; 2) ST-segment elevation of ≥ 2mm in
 two contiguous chest leads, or; 3) New left bundle branch block (LBBB) pattern.

 -  Able to be transported to a participating hospital

 Exclusion Criteria:

 -  Hypoxia with oxygen saturation measured on pulse oximeter < 94% with the patient
 breathing air

 -  Bronchospasm requiring nebulised salbutamol therapy using oxygen

 -  Altered conscious state