Oxygen therapy in acute myocardial infarctions: do we need to re-evaluate its necessity?

KEYWORDS:

• Oxygen
• acute myocardial infarction

Oxygen was used for over a century in the acute management of patients with chest pain and suspected acute myocardial infarction (AMI). This practice was mostly based on biological plausibility with the assumption that administering oxygen to a patient with disrupted myocardial perfusion will increase the delivery of oxygen to the at-risk myocardium and will minimize the related cardiac damage. The few studies that backed this hypothesis suffered from the lack of randomization and biased unblinded ascertainments of endpoints [1,2].

Although there exists a broad consensus in favor of using oxygen in cases of AMI with hypoxemia (i.e. low oxygen saturation levels), no evidence is there to support its use in patients presenting with normal oxygen saturation levels (a.k.a. normoxemia). To evaluate and monitor blood oxygen levels in clinical practice, clinicians usually use either the partial pressure of oxygen (PaO₂), arterial oxygen saturation (SaO₂), or peripheral oxygen saturation (SpO₂) indices. While PaO₂ and SaO₂ are evaluated through arterial blood gas analysis, SpO₂ is an estimate of SaO₂ measured by pulse oximetry and it refers to the amount of oxygenated hemoglobin in the blood. Several small physiologic studies suggested that excessive oxygen use might have deleterious effects [3–5]. Joseph Priestley, who was one of three scientists known for the discovery of oxygen also identified that risk by observing candles burn faster in the oxygen-enriched air as compared to the room air, stating that ‘we might live out too fast and the animal powers be too soon exhausted in this pure kind of air’, and concluding that ‘the air which nature has provided for us is as good as we deserve’ [6].

The main mechanisms to explain the potential deleterious effects of excessive O₂ therapy are the endothelial production of reactive oxygen species (ROS) and hyperoxia-induced vasoconstriction in the coronary, cerebral, and systemic vasculature. These two are interrelated, as the ROS production can increase the endothelin-1 level and decrease the nitric oxide and prostaglandin I₂ levels, which itself can lead to vasoconstriction. Additionally, ROS-independent pathways (e.g. hyperoxia- and hyperventilation-induced hypocapnia and decreased PaCO₂ as a potent vasoactive agent) also link hyperoxia to vasoconstriction [7].

Oxygen tends to have vasoconstrictive properties at high concentrations. Several studies have shown that hyperoxia markedly reduces the coronary blood flow (10–30%) through an increase in coronary vascular resistance, which occurs predominantly at the microvasculature. Ganz and colleagues demonstrated increased coronary resistance and reduction in the cardiac index with high concentrations of oxygen [5]. For example, a short (15 min) exposure to 100% oxygen was associated with a 40% increase in coronary vascular resistance and 30% decrease in coronary blood flow [3], leading to an effective decrease in oxygen delivery to the myocardium, which is the opposite of the intention of oxygen therapy. In a systematic review, Farquhar et al. reported the high-concentration oxygen therapy and its related hyperoxia to be associated with significant reduction in coronary blood flow and myocardial oxygen consumption in a heterogeneous cohort of subjects from healthy volunteers to patients with coronary artery disease and congestive heart failure [4].

Despite its clinical use over an extended period, adequately designed clinical trials did not appear until 2015. The Air Versus Oxygen In myocardial infarction trial showed no additional clinical benefit, but higher rates of recurrent MI and arrhythmia, and numerically higher inhospital mortality with supplemental oxygen therapy (8 L/min O₂ via face mask) in 441 normoxemic patients with confirmed uncomplicated ST-elevation Myocardial Infarction (STEMI) [8]. Furthermore, a 17–21% increase in the biochemical markers of myocardial necrosis (creatine kinase and cardiac troponin) was seen with exposure to high concentrations of oxygen via face mask [9].

In the DETermination of the role of OXygen in suspected AMI (DETO2X-AMI) trial, which enrolled 6,629 patients with suspected AMI into a registry-based RCT, supplemental O₂ therapy, delivered at 6 L/min for 6–12 h through an open face mask, was not associated with reduced (or increased) mortality or re-hospitalization within one year after randomization [10]. The peak troponin levels were not different between those who received supplemental O₂ therapy or room air. Recently, a meta-analysis including all RCTs that investigated O₂ therapy in AMI (8 RCTs, n = 7,998) and the results showed no clinical benefits such as reduced mortality with supplemental O₂ therapy [11].

The totality of evidence from clinical trials weighs in favor of not giving supplemental oxygen in normoxemic patients. Although the evidence points to the lack of benefit so far, it cannot rule out the possibility of harm, considering that both DETO2X-AMI trial and the meta-analysis were underpowered for the safety end point outcome of mortality [11]. Based on data derived from the DETO2X-AMI trial, the 2017 European Society of Cardiology guideline for the acute management of patients presenting with STEMI recommended not to administer oxygen routinely when SaO₂ is ≥ 90% (Class III, Level of Evidence B) [12].

According to a recent meta-analysis, oxygen therapy reduces the rate of hypoxemia in normoxemic patients with AMI [11], but that reduction in hypoxemia did not translate to improved clinical outcomes. How much oxygen should be given to patients with hypoxemia to prevent hyperoxemia and potentially-related adverse effects such as coronary vasoconstriction, and ROS production? What is the maximum safe dose of oxygen or the optimal target SpO₂ level? Those are questions that remain to be answered. Even in cases of patients with hypoxemia at presentation, taking a personalized approach toward the oxygen therapy management would be more reasonable [13].

It’s noteworthy that the effect of supplemental oxygen therapy in other cardiovascular conditions such as atrial fibrillation or acute heart failure is still unclear and needs to be explored in well-designed randomized controlled trials. A recent trial (n = 65) showed no difference in the level of myocardial injury in patients undergoing cardioversion for atrial fibrillation/flutter with high-flow oxygen (10–15 L/min) as compared to room air [14]. Another trial (NCT02518828) is underway that explores the effects of titration of oxygen delivery to high versus low O₂ saturation levels in patients with acute heart failure. The results are expected to be available by late 2018.

In conclusion, oxygen therapy has no benefit in normoxemic patients with AMI and may be harmful. We should not let historic practices continue without revision once new data is available. The daily practice needs to be sculpted to conform with the emerging evidence in this field.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was supported by the Alberta Innovates-Health Solution.