Postoperative Troponin Elevation, Myocardial Injury, and Pulmonary Embolism

In this issue of Anesthesia & Analgesia, Grobben et al1 present the results of a pilot study of coronary computed tomography angiography (CCTA) in patients over 60 years of age without a history of coronary artery disease, who experienced a postoperative troponin elevation after intermediate and major noncardiac surgery. The unexpected finding that about 1/3 of these patients had evidence of postoperative pulmonary embolism is provocative. The ideal study to determine the etiology of troponin elevation after noncardiac surgery should include both preoperative and postoperative CCTA in the patient assessment. Unfortunately, the present study data only provide CCTA data in the postoperative period, and another influential study only provides data in the preoperative period.2 The study investigators are therefore left to surmise what happened during the uninvestigated time period, which obviously has fundamental weaknesses. The work by Grobben et al1 encourages us to reflect on our current understanding of postoperative troponin elevation. The most common cause of troponin elevation after adult noncardiac surgery is “myocardial injury after noncardiac surgery” (MINS).3 MINS is defined as myocardial injury caused by ischemia that occurs during or within 30 days after surgery and is independently associated with mortality.3 MINS is a diagnosis of exclusion. This means that other known causes of troponin elevation in the perioperative period, such as sepsis and pulmonary embolism, should be excluded before making the diagnosis of MINS. Patients excluded with the diagnosis of sepsis or pulmonary embolism represent a small fraction of all patients with postoperative troponin elevation (95/1295, 7.3%, 95% confidence interval, 5.9–8.8).3 However, these patients with sepsis and pulmonary embolism are symptomatic, and a clinical diagnosis is possible to exclude them before the diagnosis of MINS. In contrast, the presence of asymptomatic pulmonary embolism in the study by Grobben et al1 of patients who would traditionally fulfill a diagnosis of MINS raises the following question: “What proportion of patients that we would routinely make a diagnosis of MINS, do in fact have an alternate diagnosis?” This is an important question, as our subsequent management (and therefore the prognosis) of the patient may be dependent on the correct diagnosis and our subsequent care. It is therefore important to summarize our understanding of the etiology of postoperative troponin elevation associated with MINS. Coronary artery disease is the most common association with MINS, and the perioperative physiology is particularly primed for perioperative thrombus formation.4 Therefore, after a diagnosis of MINS, the primary management strategy should be to address coronary artery disease and myocardial supply–demand mismatch. Approximately, 3/4 of the patients who fulfilled the inclusion criteria for the Vascular events In noncardiac Surgery patIents cOhort evaluatioN2 and the Cardiac Health After Surgery studies1 had established coronary artery disease with >50% stenosis of at least 1 coronary artery. In the study by Grobben et al,1 approximately half the patients with troponin elevation had established coronary artery disease, and of the patients who did not have a history of coronary artery disease, the CCTA study confirmed that approximately half had undiagnosed coronary artery disease (23/46, 50%, 95% confidence interval, 35.6–64.4). It is possible that the CCTA may have missed small emboli. Therefore, approximately ¾ of all patients with troponin elevation after intermediate and major noncardiac surgery will have coronary artery disease with stenoses exceeding 50%, and therefore, management of myocardial ischemia must remain the primary focus. Furthermore, it is possible (and likely) that myocardial ischemia resulting in MINS does not require coronary stenosis of >50% as a prerequisite for a perioperative myocardial injury, and it is possible that myocardial injury in the perioperative period can occur without significant coronary stenoses.2,5 In addition, in the perioperative period, this is further supported by the fact that the degree of coronary stenosis appears to have no relationship with perioperative myocardial infarction.5 Thus, the group of patients in the article by Grobben et al,1 who were reported to have an absence of “coronary artery disease” and no “pulmonary embolism,” were MINS patients without coronary artery disease considered to be obstructive (ie, >50% stenosis), but the presence of atherosclerotic disease sufficient to result in myocardial ischemia in the postoperative environment, due the disadvantageous hemodynamics of the postoperative period.4 The pathophysiology of the perioperative myocardial injury is complex, but is certainly uniquely separate from the “nonsurgical” myocardial event, and highly likely that nonobstructive coronary lesions are sufficient to precipitate MINS in a surgical patient who is hypercoagulable and hypotensive.4 Therefore in summary, postoperative troponin elevation that fulfills the diagnostic criteria of MINS is certainly MINS secondary to myocardial ischemia in excess of 75% of the cases. The exact proportion of patients who fall into the remaining “gray diagnostic zone” of MINS remains uncertain. Unfortunately, the study by Grobben et al1 cannot inform this point, as it is a pilot study which underpowered to establish an independent association between troponin elevation and pulmonary embolism, and is subject to selection bias.1 Furthermore, traditional clinical examination does not allow us to accurately determine the proportion of patients in this gray diagnostic zone who have an alternate diagnosis to MINS, as these patients are essentially asymptomatic, or present with vague, nonspecific symptoms, as presented in this cohort.1 The gray diagnostic zone could range anywhere from 0% to 25% of patients with a MINS diagnosis, although it is impossible on the present data to determine if it is at the low or high end of this range. There are 2 possible etiologies for the troponin elevation in these patients; either the patient has an “alternate diagnosis” to MINS, such as pulmonary embolism that results in a secondary complication of myocardial ischemia, or the patient has separate 2 pathologies, for example, pulmonary embolism (which is too minor to result in myocardial supply–demand mismatch and troponin elevation) and MINS. Both these scenarios are possible. The risk factors for venous thromboembolism and atherosclerosis overlap,6 and it is therefore plausible that both pulmonary embolism and MINS may develop in patients in the postoperative period. Immaterial of which scenario exists, postoperative troponin elevation results in a poorer prognosis for noncardiac surgical patients. Postoperative troponin elevation is an independent predictor of mortality after noncardiac surgery,7 and increasing levels of troponins significantly increase mortality after MINS3,8 and short-term mortality after acute, nonmassive pulmonary embolism.9–11 What could we do to ensure that the correct diagnosis is made for these different etiologies of postoperative troponin elevation to ensure that the patient receives the appropriate therapy in the postoperative period? There are little data on how to identify patients in this proposed gray diagnostic zone of MINS and how to approach this problem clinically. Until such time, as we have substantially more evidence on how to identify these patients, a practical bedside management program could be advocated (Figure). Patients with a history of coronary artery disease should be treated as “genuine” MINS, based on the strong association between coronary artery disease and MINS,1,2 and the perioperative pathophysiology of ischemia.4 In patients in whom a history of coronary artery disease is absent, an approach to exclude pulmonary embolism can be adopted, before acceptance of the diagnosis of MINS. It is unlikely that CCTA would have a primary role in the postoperative period to distinguish between MINS and pulmonary embolism. It is an impractical screening test in the postoperative period, as demonstrated in this study, where 395/519 (76.1%) of patients presented difficulties to CCTA screening.1 A potential solution may lie in postoperative d-dimer screening, as a negative test is good at ruling out pulmonary embolism,12,13 with a low negative likelihood ratio,14 and one could then continue to manage the patient for MINS. A positive d-dimer in elderly patients (>65 years of age) has been associated with an increased false-positive rate for pulmonary embolism, based on d-dimer levels,12 and therefore a positive test is not necessary diagnostic of postoperative pulmonary embolism. If clinical reservations remain about the diagnosis of pulmonary embolism in the presence of elevated d-dimer levels, then transthoracic echocardiography would be appropriate test. Demonstration of right ventricular dysfunction, in an elderly postoperative patient with a positive d-dimer, would be a reasonable confirmation of pulmonary embolism. Although it is unclear of the extent of pulmonary embolism necessary to result in troponin elevation, troponin elevation after pulmonary embolism has been independently associated with right ventricular dysfunction.15 This approach would allow us to exclude pulmonary embolism in the MINS gray diagnostic zone and quickly institute therapies that have been associated with increased survival after MINS. These include aspirin and statin therapy16 and intensification of other cardiac medications.17 Furthermore, it would allow us to prospectively gather the data necessary to determine the incidence of pulmonary embolism in the gray diagnostic zone, allow for the institution of appropriate therapy, and determine the prognostic importance of asymptomatic pulmonary embolism in postoperative patients.Figure.: A proposed management algorithm for patients with a diagnosis of MINS. MINS indicates myocardial injury after noncardiac surgery.In conclusion, postoperative troponin elevation is associated with increased mortality, of which MINS remains the most common cause, and this should always be the first management consideration. However, in patients without a history of coronary artery disease, it is possible that there may be a gray diagnostic zone of MINS patients who may indeed have troponin elevation from an alternate etiology. This group remains a small proportion of the cases, but in patients without a history of coronary artery disease, it may be advisable to include d-dimers in the work up of these patients. Further work is needed to delineate the incidence, clinical characteristics, and prognosis of these patients. DISCLOSUREs Name: Bruce McClure Biccard, PhD. Contribution: This author generated the hypothesis, analyzed the data, and wrote the manuscript. Conflicts of Interest: B. M. Biccard was a Vascular events In noncardiac Surgery patIents cOhort evaluatioN (VISION) investigator, and part of the writing committee for the Myocardial Injury after Noncardiac Surgery (MINS) papers. This manuscript was handled by: W. Scott Beattie, PhD, MD, FRCPC.