Determination of the role of oxygen in acute myocardial infarction

Abstract

Background: Oxygen therapy has been used routinely in patients with suspected acute myocardial infarction (AMI) for more than a hundred years. Even today, supplemental oxygen is widely recommended in guidelines and implemented in clinical practice, despite limited data supporting a beneficial clinical effect. The overall objective of the present thesis was to clarify the role of routine oxygen therapy in AMI. After testing logistics, feasibility and safety in a pilot study, a nationwide registry-based randomized clinical trial (RRCT) concept was used to evaluate hard clinical endpoints. In a subgroup of patients, biomarkers were used to get insights on aspects of underlying pathophysiology.

Methods and results: Study I was a pilot study at Södersjukhuset. One hundred twenty-nine normoxemic patients with suspected AMI were randomized 1:1 to either oxygen therapy at 6 L/min delivered by open face mask for 12 hours or ambient air. A total of 81 (63%) patients were diagnosed with AMI. No unexpected logistical or notable medical problems occurred. Oxygen therapy for 12 hours was well tolerated. Study II was a nationwide, multicenter, prospective, registry-based randomized clinical trial (RRCT) using a public quality registry for coronary care (SWEDEHEART) for trial procedures and evaluating the primary outcome – all-cause mortality at one year – through national health registries. Patients with suspected AMI and oxygen saturation of 90% or above were randomly assigned to either supplemental oxygen at 6 L/min for 6-12 hours delivered by open face mask or ambient air. A total of 6,629 patients were enrolled from April 2013 through December 2015. No patients were lost to follow-up. The primary endpoint death from any cause at 1-year occurred in 5.0% (166 of 3,311) of patients in the oxygen group compared to 5.1% (168 of 3,318) in the ambient-air group (hazard ratio 0.97; 95% confidence interval, 0.79 – 1.21; p=0.8). The results were consistent across all predefined subgroups. Study III was a prespecified two-center substudy to study II. One hundred forty-four patients were consecutively recruited after randomization and blood samples were secured at randomization and 5-7 hours after. Ninety-two inflammatory biomarkers, using proximity extension assay technology, were analyzed to evaluate the effect of oxygen on the systemic inflammatory response to AMI. The inflammatory response did not differ between the two treatment groups, neither did plasma troponin T levels. After adjustment for increase in troponin T over time, age, and sex, the release of inflammation-related biomarkers was still similar in the groups.

Summary and conclusions: In summary, study I found the design of the DETO2X-AMI-trial to be robust and feasible. Implemented inclusion criteria identified patients with acute cardiac disease with a high proportion of acute myocardial infarctions among the study population. Study II demonstrated that the routine use of supplemental oxygen in patients with suspected AMI without hypoxemia at presentation did not reduce 1-year all-cause mortality. Neither did it affect the incidence of rehospitalization with myocardial infarction or the size of myocardial injury as assessed by highly sensitive cardiac troponin T. Study III showed that the use of supplemental oxygen did not have any impact on the early release of systemic inflammatory markers.

In conclusion, we were able to build up a study system and nationwide network based on the SWEDEHEART registry. Thereby, we managed to recruit many eligible patients within a short time frame, delivering high quality data at relatively low cost. Normoxemic patients with suspected AMI did not benefit from routine oxygen therapy when assessing 1-year all-cause mortality. Although our findings do not support the general use of oxygen in the normoxemic patient with suspected AMI, there nevertheless remains the risk to develop hypoxemia which must be detected and treated immediately. Furthermore, even though we could not demonstrate deleterious effects of routine oxygen treatment, there might be a dose-dependent relationship and inadvertent hyperoxemia should be avoided.