See Articles, p 170 and p 187
Anesthesia-related intraoperative mortality is now so rare that it is difficult to quantify.1,2 In contrast, almost 1% of surgical patients in the United States die within a month of noncardiac surgery. Among inpatients, mortality is about 2%.3,4 If the 30 days after noncardiac surgery were considered a disease, it would be the third-leading cause of death in the United States.5 About two-thirds of deaths occur during the initial hospitalization, that is, under physician care in high-level health care facilities. Deaths are most strongly associated with major bleeding or myocardial injury.6
The goal of this narrative review is to offer an updated clinical perspective on myocardial injury after noncardiac surgery (MINS) during the perioperative period. We summarize pertinent terminology, pathophysiology, and the role of troponin monitoring. We discuss the epidemiology of MINS in the postoperative period. We also explore the potential role of conventional preoperative cardiac risk stratification tools and cardiac biomarkers in predicting MINS, prevention and management strategies for MINS, and finally, the association between perioperative hypotension and myocardial injury.
MYOCARDIAL INFARCTION VERSUS MYOCARDIAL INJURY
According to the Fourth Universal Definition of Myocardial Infarction, myocardial injury is defined as troponin elevation thought to be of ischemic origin, with or without clinical signs.7 Postoperative myocardial infarction (MI) requires myocardial injury and at least one of the following: symptoms of acute myocardial ischemia, new ischemic electrocardiogram (ECG) changes, development of pathological Q waves, imaging evidence of a new regional wall motion abnormality in the pattern consistent with an ischemic etiology, or identification of a coronary thrombus on angiography including intracoronary imaging or by autopsy.7
The Fourth Universal Definition of Myocardial Infarction categorizes MI into 5 different types (Table 1).7 Acute MI types 1–3 are defined as acute myocardial injury with clinical evidence of acute myocardial ischemia and with detection of an increase in troponin concentrations with at least 1 value exceeding the 99th percentile. Types 4 and 5 MIs must meet the criteria for a >5 (type 4) or >10-fold (type 5) increase of cardiac biomarkers (in patients with normal baseline concentrations) and manifest a change from baseline value >20% (in patients with an elevated baseline).
Table 1. -
Types of Myocardial Infarction
||Caused by atherothrombotic coronary artery disease and usually precipitated by atherosclerotic plaque disruption (rupture or erosion)
||Based on a mismatch between oxygen supply and demand, such as coronary spasm, coronary embolism, arrhythmia, anemia, or hypotension
||Sudden cardiac death, having typical signs and symptoms of myocardial infarction, but patient may succumb soon. Death may occur before elevation in serum biomarkers
||Related to coronary revascularization procedures, whether percutaneous coronary intervention or coronary artery bypass grafting, may be temporally related to the procedure itself, reflecting periprocedural issues, or may occur later reflecting complications of a device, like early or late stent thrombosis or in-stent restenosis for PCI, or graft occlusion or stenosis with CABG
||Myocardial infarction that occurs during coronary artery bypass grafting, and is mostly related to the details of cardiac preservation, the extent of the direct traumatic injury to the myocardium, as well as any potential ischemic injury
Source: American Heart Association, Inc.7
Abbreviations: CABG, coronary artery bypass surgery; PCI, percutaneous coronary intervention.
In the nonsurgical setting, myocardial injury typically presents as acute coronary syndrome, which is manifested as MI or unstable angina, and is typically accompanied by chest pain and or shortness of breath.8 The etiology is usually either thrombotic (type I) or demand ischemia (type II).8–11
Perioperative MIs after noncardiac surgery are apparently largely caused by supply-demand mismatch and are considered type II infarctions.8,11 Perioperative infarctions are usually clinically silent, with symptoms such as chest pain and shortness of breath being rare.9 In fact, most present as isolated troponin elevation after surgery that is typically accompanied by neither symptoms nor signs.12,13
Myocardial Injury After Noncardiac Surgery
Because isolated troponin elevations are associated with death, a new syndrome was defined by the Vascular Events In Noncardiac Surgery Patients Cohort Evaluation (VISION) investigators: MINS.12 MINS is a myocardial injury that occurs postoperatively. It differs from MI, in being defined by troponin elevation apparently from cardiac ischemia with or without signs and symptoms. It does not include perioperative myocardial injury due to nonischemic causes such as sepsis, rapid atrial fibrillation, pulmonary embolism, or renal failure; nor does it include chronically elevated troponin concentrations. MINS occurs in about 8 million patients worldwide yearly and is independently associated with risk of death and cardiovascular complications over the initial postoperative year.14 Throughout this review, we will focus on MINS and distinguish MINS from MI, which will be restricted to events that are accompanied by myocardial symptoms or signs, thus meeting the Fourth Universal Definition of Myocardial Infarction.
Troponins are a family of proteins found in skeletal and cardiac muscle fibers that contribute to contraction. There are 3 subgroups of troponin: C, T, and I. Troponin T and troponin I are both integral parts of the cardiac muscle infrastructure and each contributes to excitation-contraction coupling.15 The skeletal and cardiac versions of these proteins differ, which led to the development of assays specific to cardiac troponin, although even cardiac-specific assays can rarely cross-react with skeletal muscle proteins released after major muscle injury.16,17
Normally, cardiac-specific troponin is undetectable or only barely detectable in blood. But after cardiomyocyte necrosis, troponin is released and can be detected in circulating blood, typically after 3–4 hours. Blood concentrations typically remain elevated for 10–14 days.18 In the setting of acute coronary syndrome, even slight troponin elevations are strongly associated with mortality.19
Types of Cardiac Troponin and Thresholds
Troponin I tests are generic and vary depending on the test in use. The harm thresholds must therefore be determined in consultation with local laboratories. In contrast, troponin T is a branded product (Roche Diagnostics, Basel, Switzerland), and the assay is the same worldwide.
There are 2 versions of troponin T in current use: fourth- and fifth-generation high-sensitivity troponin. Most of the world now use high-sensitivity troponin, but the test was only recently approved in the United States. Consequently, many centers in the United States still use the fourth-generation test. Changes in fourth troponin T were most comprehensively evaluated in the initial VISION cohort.12 A peak postoperative concentration ≥0.03 ng/mL predicted a nearly 4-fold increase in 30-day mortality and is therefore now considered the harm threshold.
Because many patients have detectable troponin concentrations preoperatively, the harm threshold for high-sensitivity troponin depends on the baseline concentration. Specifically, high-sensitivity troponin T is considered to be elevated when the peak postoperative concentration increases by at least 5 ng/L from the preoperative concentration to at least 20 ng/L, or when the concentration exceeds 65 ng/L irrespective of baseline concentration.13 An important proviso and clinical corollary is that it is difficult to reliably assess MINS without a baseline troponin concentration.
Elevated Baseline Troponin
High-sensitivity troponin T concentrations are elevated preoperatively (>14 ng/L) in 2% of patients aged 50 years and almost 40% of patients >70 years of age.20,21 Elevated baseline high-sensitivity troponin is common in patients with end-stage renal disease, which is consistent with renal excretion of the protein—although chronic kidney disease per se has remarkably little effect on serum troponin concentration.22,23 Instead, it is likely that many of these patients have concurrent myocardial dysfunction.
Other nonischemic etiologies for high-sensitivity elevations include chronic elevation (64%), sepsis (11%), atrial fibrillation (9%), pulmonary embolus (3%), and cardioversion (1%).13 But whatever the etiology, preoperative troponin elevation is a poor prognostic sign and is associated with substantially increased mortality over at least 3 postoperative years.24 For example, noncardiac surgical patients with baseline troponin elevations have an adjusted hazard ratio (HR) for 1-year mortality of 2.5 (95% confidence interval [CI], 2.0–3.2; P < .001).25 Preoperative troponin elevation thus identifies patients who are at high risk of both short-term and long-term mortality.
Routine Troponin Monitoring
It is now clear that without routine troponin screening, most MINS is undetected because nearly all such patients are asymptomatic.12,13 Consequently, the 2017 Canadian Cardiovascular Society guidelines recommend “daily troponin measurements for 2–3 days in patients with moderate cardiovascular risk.”26 The recent Fourth Universal Definition of Myocardial Infarction international consensus statement, which included the European Society of Cardiology, American College of Cardiology, American Heart Association, and World Heart Federation, recommends “postoperative troponin surveillance in high-risk surgical patients.”7 A useful empirical and practical approach is to monitor troponin in noncardiac surgical inpatients who are 45–64 years old and have at least 1 cardiovascular risk factor, and in all surgical inpatients ≥65 years old. An alternative approach is to restrict troponin monitoring to surgical inpatients who have preoperative N-terminal pro b-type natriuretic peptide (NT-proBNP) concentrations exceeding 300 ng/mL.27
Generally, troponin screening should start preoperatively and continue for the first 2 days after surgery—an approach that will identify <95% of MINS.28 Meta-analysis also suggests that routine troponin measurement is cost-effective, although cost varies considerably from country to country and depends on the specific troponin assay used.29 Currently, there is no reliable way besides troponin screening to detect either MINS or postoperative MI.
EPIDEMIOLOGY OF MINS
Incidence and Etiology
The incidence of perioperative MI ranges from 3% to 6%, and these events are fatal at least as often as nonoperative MIs.30,31 The etiology and pathophysiology of MINS is incompletely understood and it remains unclear whether thrombosis or demand ischemia dominants8—although most occur in patients who have underlying atheroma. Much postoperative myocardial ischemia is nonetheless probably consequent to supply-demand mismatch.32,33
In the nonsurgical setting, approximately 38% of patients who present to the hospital with acute coronary syndrome have an ST-elevation MI.34 More than 90% of patients with MINS do not display ST segment elevation or any other ischemic symptom.13 Some patients with perioperative infarctions have angiographic evidence of coronary plaque rupture consistent with type 1 MI. However, few patients with MINS have coronary angiography, and those with ST segment elevation and regional wall motion abnormalities are probably overrepresented.35,36 The difficulty is that only about 20% of cases of MINS meet the Fourth Universal Definition criteria for MI—although mortality with MINS is nearly as high as it is for MI.13
Table 2. -
Perioperative Myocardial Injury Is Common, Silent, and Deadly
|4% of inpatients >45 y have a postoperative MI
| 8 million adults/y worldwide
| 93% without symptoms
| 80% do not meet third universal definition of MI
| Typically type-2 events (supply-demand mismatch)
| Mortality is 4% at 30 d
|It is not just “troponitis”
| 8.5% have an MI, cardiac arrest, or death in 30 d
| 1 in 7 has a major vascular event within 16 mo
Data primary from the Vascular Events In Noncardiac Surgery Patients Cohort Evaluation Trial cohort study. MINS is defined by postoperative troponin elevation apparently due to myocardial ischemia. The threshold depends on the type and generation of troponin.13
Abbreviations: MI, myocardial infarction; MINS, myocardial injury after noncardiac surgery.
Approximately 40% of MINS occurs on the day of surgery, 40% on the first postoperative day, and 15% on the second postoperative day. Thus, while some perioperative myocardial injury presumably occurs during surgery, most apparently develops postoperatively. Only about 14% of patients who experience perioperative MIs report chest pain and 65% of these events are entirely clinically silent. Consequently, 93% of MINS and 68% of MIs are typically unrecognized without troponin screening.13,14 Postoperative analgesics might explain why some patients with troponin elevation do not experience chest or arm pain, but a more likely explanation is that the etiology and pathology of postoperative myocardial injury differs from conventional infarctions.28,37 Key features of MINS are listed in Table 2.
VISION, a prospective cohort study, initially evaluated fourth-generation troponin T at 6–12 hours after surgery and on the first 3 postoperative days while patients remained hospitalized.38 The initial VISION cohort, published in 2012, included 15,133 patients of whom 8% experienced MINS. Overall mortality in patients experiencing MINS was 9.8% compared to 1.1% patients without MINS.38 Patients with MINS were also at increased risk of 30-day mortality (adjusted HR, 3.3 [95% CI, 2.3–4.8]), and the population-attributable risk was 34% (95% CI, 27–42).12
Importantly, the vast majority (84%) of patients remained asymptomatic, and only 42% of the patients fulfilled the formal criteria for MI. Fourth-generation troponin T concentrations that even only slightly exceeded 0.03 ng/mL were prognostic. But the prognosis for cardiac death depended on the magnitude of the perioperative troponin rise, with higher concentrations also corresponding to a shorter median time to death—most of which occurred during the initial hospitalization.
The second phase of the VISION cohort study prospectively enrolled 21,842 patients >45 years of age who were scheduled for noncardiac surgery. Troponin T was again measured 6–12 hours after surgery and on the first 3 postoperative days while patients remained hospitalized. Most patients also had troponin measured preoperatively. The critical distinction from the initial VISION cohort is that high-sensitivity troponin T (hsTnT) was measured, rather than fourth-generation troponin.13
Among 21,842 enrolled patients, 266 died within 30 days after surgery (1.2%; 95% CI, 1.1%–1.4%). Mortality increased markedly from 0.1% at a troponin T concentration <5 ng/L to 30% when troponin T exceeded 1000 ng/L (Figure 1). Any change in hsTnT of 5 ng/L or more in absolute terms was associated with an increased risk of 30-day mortality (adjusted HR 4.7, 95% CI, 3.5–6.2). A total of 3633 of 3904 patients with MINS (93.1%, 95% CI, 92.2%–93.8%) did not experience an ischemic symptom. Nevertheless, even in these patients, an elevated postoperative hsTnT (ie, 20–<65 ng/L with an absolute change ≥5 ng/L or hsTnT ≥65 ng/L) was associated with 30-day mortality (adjusted HR 3.2, 95% CI, 2.37–4.32).
Use of high-sensitivity troponin T resulted in several important distinctions from the initial VISION cohort. About 18% of the enrolled surgical patients had at least slightly elevated preoperative troponin concentrations. Consequently, preoperative values need to be considered in defining MINS (see proceeding section for details). Ninety-three percent of MINS was asymptomatic, and 94% occurred within the initial 2 postoperative days. The risk of cardiac death at 1 year in patients having MINS was 4.1% compared to 0.6% in patients without MINS. The adjusted HR for 30-day mortality was 55% greater in patients having ischemic symptoms than those without, a difference that is small compared with the 8.5 increase in odds between patients without and with MINS.
CARDIAC RISK STRATIFICATION FOR MINS
Postoperative myocardial injury does not occur randomly; it is most likely in patients who have preexisting cardiovascular disease. While type, duration, and extent of surgery contribute, baseline risk is a far stronger determinant of both myocardial risk and mortality.39–41 Perioperative cardiac risk prediction may help guide patient choices, treatment decisions (eg, open versus endoscopic procedure), and intensity and duration of postoperative monitoring. Risk prediction generally uses a combination of clinical risk tools, noninvasive cardiac testing, and, more recently and seemingly most promising, cardiac biomarkers. Table 3 summarizes the advantages, disadvantages, and evidence supporting various risk assessment tools.
Table 3. -
Advantages, Disadvantages, and Evidence Supporting Each Risk Assessment Tool for Cardiac Outcomes After Noncardiac Surgery
||Ease of use
||May not predict risk as well in nonvascular, nonorthopedic and nonthoracic surgery.
Assigns most patients to intermediate risk—offers minimal guidance to clinicians
Uses only electrocardiographic changes to diagnose myocardial infarction—under estimates risk
|Single-center with 4315 patients; last patient enrolled in 1994; 92 events43
||More accurate than RCRI
||Needs online calculator
Uses electrocardiographic changes to diagnose myocardial infarction—under estimates risk
|400 hospitals with 1414,006 patients covering 1557 unique CPT codes45
||More accurate than RCRI
||Needs online calculator
Uses electrocardiographic changes to diagnose myocardial infarction—under estimates risk
|>250 centers, with 468,795 patients; last patient enrolled in 2008; 2772 events90
||Useful in patients who are immobile for reasons other than cardiovascular insufficiency
||A third of cardiovascular complications occur with normal preoperative stress tests.
Prophylactic preoperative revascularization in addition to recommended medical therapy does not improve outcomes in patients with positive stress tests
|1179 patients with 82 cardiac events with semiquantitative dipyridamole myocardial perfusion scintigraphy91
||Noninvasive evaluation of coronary vasculature
Risk reclassification worsens predictions compared to RCRI/NSQIP
|955 at risk patients who had noncardiac surgery. Composite of cardiovascular death and nonfatal myocardial infarction occurred in 7492
|No evidence to suggest improvement in clinical outcomes
||100 moderate-to-high-risk patients in a preoperative clinic93–95
|BNP and NT-proBNP
||May also be elevated in inflammatory states and certain neuroendocrine disorders
||2179 patients; preoperative BNP (and NT-proBNP) correctly reclassified 16% more high-risk patients and 15% more low-risk patients than a model based on preoperative baseline risk factors alone50
Abbreviations: ACS NSQIP, American College of Surgeons National Surgical Quality Improvement Program Surgical Risk Calculator; BNP, B-type natriuretic peptides; CCTA, coronary computed tomography angiography; CPT, current procedural terminology; NSQIP MICA, National Surgical Quality Improvement Program for Myocardial Infarction and Cardiac Arrest risk index; NT-proBNP, N-terminal pro b-type natriuretic peptide; RCRI, revised cardiac risk index.
Anesthesiologists frequently use patient-reported exercise tolerance as a rough index of fitness. But patients generally have a poor ability to estimate their exercise tolerance, and perhaps consequently, physicians also poorly estimate patient's exercise tolerance. Poor estimates of exercise tolerance probably do not much matter though because even formal cardiopulmonary testing poorly predicts perioperative cardiovascular risk.42
Clinical Cardiac Risk Assessment Tools
Many tools for predicting cardiac risk and outcomes after noncardiac surgery have been proposed over the past 40 years, often for specific populations or procedures. The 3 best-validated and most widely used tools are the Revised Cardiac Risk Index (RCRI), the American College of Surgeons National Surgical Quality Improvement Program Surgical Risk Calculator (ACS NSQIP), and the National Surgical Quality Improvement Program for Myocardial Infarction and Cardiac Arrest (NSQIP MICA) risk index.
The RCRI is a well-validated cardiovascular risk prediction model based on a combination of the risk of surgery, preexisting medical disease, and laboratory values.43,44 The original derivation and test datasets included many patients who had thoracic, vascular, and orthopedic surgery. Unsurprisingly, subsequent validation in broader surgical populations found that the RCRI does not predict cardiac events as well in patients having other types of noncardiac surgery.44
The ACS NSQIP surgical risk calculator was first reported in 2013, based on standardized clinical data from nearly 400 hospitals.45 The model included >1,400,000 patients who had procedures represented by 1557 unique current procedural terminology codes. The web-based calculator requires users to enter 21 preoperative factors, including demographic characteristics, comorbidities, and procedure details.
The NSQIP MICA risk index, also known as Gupta’s index, is a risk prediction model that uses patient age, American Society of Anesthesiologist’s physical status, preoperative creatinine, functional status, and procedure type.46 Currently, none of these 3 best-validated and widely used tools for predicting cardiac risk and outcomes after noncardiac surgery has been shown to have adequate predictive strength and applicability for MINS.
B-type natriuretic peptides (BNPs) are biomarkers that are released into the systemic circulation in response to left atrial myocardial stretching. They are also released in response to ischemia, inflammation, and neuroendocrine stimuli.47,48 Point-of-care tests are available for natriuretic proteins. Preoperative BNP concentrations are strong predictors of perioperative cardiac events, including mortality, MI, and heart failure.49,50 In patients having vascular surgery, preoperative BNP risk assessment substantially improves predictions based on the RCRI.51
Rodseth et al27 performed a systematic review of 2179 patients and individual-patient meta-analysis. Elevated preoperative BNP at concentrations >92 ng/L or preoperative NT-proBNP concentrations >300 ng/L were strong predictors of death or nonfatal MI at 180 days or more after surgery (odds ratio [OR], 2.6 [95% CI, 2.0–3.4; P < .001]) and within 30 days of surgery (OR, 3.4 [95% CI, 2.6–4.5; P < .001]). A model using preoperative BNP correctly reclassified 16% more high-risk patients and 15% more low-risk patients than a model based on preoperative baseline risk factors alone.27,50 Adding postoperative BNP and N-terminal fragment of proBNP (NT-proBNP) concentrations to preoperative concentrations increases the predictive ability for a composite of death and nonfatal MI at 30 days (adjusted OR, 3.7 [95% CI, 2.2–6.2]) and 180 days (adjusted OR, 2.2 [95% CI, 1.9–2.7]) after noncardiac surgery.27
The European Society of Anesthesiology guidelines for preoperative risk assessment for noncardiac surgery recommend preoperative measurement of natriuretic peptides in high-risk patients scheduled for major general or orthopedic surgery (level of evidence 2C) and in intermediate- and high-risk patients scheduled for vascular or major thoracic surgery (level of evidence 1C).52 The Canadian Cardiovascular Society Guidelines for noncardiac surgery recommend measuring brain natriuretic peptide or NT-proBNP before surgery to enhance perioperative cardiac risk estimation in patients who are 65 years of age or older, are 45–64 years of age with significant cardiovascular disease, or have a RCRI score ≥1. In addition, patients who have elevated biomarker concentrations should have troponin measured on the first 2 postoperative days.26
POSSIBLE ASSOCIATION BETWEEN HYPOTENSION AND TACHYCARDIA AND MINS
Intraoperative Hypotension and Tachycardia
Even brief periods of intraoperative hypotension, at thresholds that until recently were considered acceptable by many anesthesiologists, are associated with myocardial injury, renal injury, and mortality.53–55
Absolute mean arterial pressure (MAP) <65 mm Hg and a relative decrease of about 30% from baseline are both comparably associated with myocardial injury (Figure 2).56 Severity and duration of hypotension are key determinants of cardiac injury and mortality. For example, once mean pressure decreases to 55 mm Hg, a duration of only a few minutes is associated with increased mortality.54,57 A systematic review of reported associations of relative and absolute blood pressure values concluded that the first indication of organ injury occurs when mean arterial pressure decreases <80 mm Hg for ≥10 minutes and that risk increases at progressively lower blood pressures.58
We note that adjusted associations between intraoperative hypotension and myocardial injury are considerably weaker than those with many baseline clinical factors. As noted earlier, perioperative myocardial injury does not occur randomly; it is largely restricted to patients with preexisting cardiovascular risk. Baseline risk is thus a far stronger predictor of cardiovascular outcomes than intraoperative hypotension.59,60 But the possible association between hypotension and MINS is nonetheless important because, unlike baseline patient characteristics, blood pressure can largely be controlled. For example, about a third of all hypotension occurs between anesthetic induction and incision and is independently associated with acute kidney injury.61 Hypotension during and shortly after induction results from anesthetic drugs and is presumably largely preventable. Continuous intraoperative monitoring (including the use of arterial catheters) reduces episodes of hypotension.62,63
Futier et al64 performed an elegant parallel-group randomized trial that compared tight intraoperative blood pressure control (norepinephrine infusion to maintain systolic pressure within 10% of baseline) versus minimal control (ephedrine for systolic pressure <80 mm Hg or <40% below baseline) in 298 high-risk surgical patients.64 The primary outcome, a collapsed composite of systemic inflammatory response syndrome and/or at least 1 organ failure, occurred in 56/147 patients in the norepinephrine group versus 75/145 patients in the minimal control group: relative risk 0.73 (95% CI, 0.56–0.94).
The intervention threshold in the minimal control group was a systolic pressure of just 80 mm Hg. Presumably, a higher intervention pressure would reduce the observed 25% benefit. Curiously, only 1 MI was reported, which is many times fewer than would be expected in a high-risk population.13 Futier et al64 also report a very small actual difference in mean pressure (6.5 mm Hg) and have not reported the amount of hypotension below critical thresholds where most myocardial injury presumably occurs. An additional limitation is that the protocol focused on vasopressor infusions rather than fluid administration. Nonetheless, this is an important study because it suggests that at least some of the observed association between intraoperative hypotension and organ injury is causal and therefore amenable to intervention. Larger robust trials are clearly needed to establish causality.
Tachycardia increases myocardial oxygen demand and impairs diastolic filling time. Chronic tachycardia, including paroxysms of tachycardia with superimposed rhythm disturbances, may contribute to nonoperative MI.33,65 Given the contribution of tachycardia to nonoperative MIs, clinicians might reasonably assume that intraoperative tachycardia would similarly contribute to MINS, which is thought to be largely consequent to supply-demand mismatch.32 Consistent with this theory, there is an association between preoperative ambulatory tachycardia and postoperative MINS.66 Such a relationship has been reported in small cohorts having noncardiac surgery.67 But interestingly, in nearly 3000 noncardiac surgical patients at Cleveland Clinic, various degrees of tachycardia including the highest individual rate and rates exceeding 100 beats/min were not associated with myocardial injury.68 Similarly, Abbott et al69 report that although myocardial injury was associated with tachycardia, harm was most apparent when heart rate exceeded 100 beats/min for prolonged periods.
While there are surely degrees and durations of tachycardia that promote MINS, tachycardia appears to contribute considerably less than hypotension. Available data suggest that heart rates up to 100 beats/min rarely require treatment. Sustained higher rates probably should be treated, but cautiously avoid consequent hypotension. Causing hypotension in an effort to treat tachycardia will likely worsen overall cardiac risk.
Postoperative Hypotension and Tachycardia
Most postoperative MIs and MINS occur postoperatively, nearly all within 48 hours. There is thus considerable reason to be concerned about hemodynamic control in patients recovering from surgery. Nonetheless, vital signs are infrequently measured on surgical wards, typically only at 4- to 8-hour intervals. Consequently, ward hypotension can be sustained for hours without recognition.
A recent analysis of continuous untethered blinded hypotension monitoring on surgical wards at the Cleveland Clinic showed that 24% of all patients had continuous episodes of mean arterial pressure <70 mm Hg for at least 30 minutes, and 14% had continuous pressures <65 mm Hg for at least 15 minutes. Seventy percent of these patients, all of whom had vital signs measured at 4-hour intervals, had no mention of hypotension in their electronic records (Figure 3).70
The current approach to ward monitoring was developed decades ago when surgery was largely restricted to relatively healthy patients who all stayed at least a night before surgery and then remained hospitalized long after surgery. Now, we operate on remarkably fragile patients, never even admit 60% in the United States, and send others home early. A consequence is that hospitalized surgical patients are now much sicker than in past decades. To the extent that postoperative hypotension (and perhaps tachycardia) contributes to myocardial injury, current sparse ward monitoring probably misses many potentially important hemodynamic events. The obvious solution is continuous hemodynamic monitoring, which seems likely to reduce the amount of hypotension and may improve outcomes71—although this theory remains speculative pending larger randomized trials.
As on surgical wards, hypotension in critical care units is often marked and more sustained than during surgery. Furthermore, intensive care unit (ICU) patients are inherently unstable and have ongoing organ system injury, which may be worsened by hypotension. A strong association of MINS with hypotension at pressures previously regarded as normal and higher than the traditional threshold mean pressure of 65 mm Hg has been seen in large cohorts of medical and surgical ICU patients.72,73 An important caveat is that this relationship is also complicated by several known and presumably some unknown confounders, which may be difficult to adjust for. Therefore, it currently remains difficult to precisely define thresholds of hypotension associated with myocardial damage in critically ill patients. Further defining blood pressure harm thresholds in critical care patients remains a priority.
PREVENTION OF MINS
Published data are currently lacking on how to safely and effectively prevent MINS. Yet some inferences can perhaps be drawn from 3 large trials that have evaluated potential ways of preventing perioperative myocardial events. PeriOperative ISchemic Evaluation trial (POISE)-I,74 POISE-2,75,76 and Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia (ENIGMA-2)77 each included MI as defined by the Third Universal Definition of Myocardial Infarction as their primary outcomes. They thus required an elevated cardiac biomarker and 1 or more ischemic symptoms including pathological Q waves, electrocardiographic changes indicative of ischemia, coronary artery intervention, or new wall motion abnormality on echocardiography or scanning, or autopsy finding of MI.
The POISE trial randomized 8351 patients with known or suspected atherosclerotic disease to receive extended-release metoprolol or placebo for inpatient noncardiac surgery. Perioperative β blockers prevented nonfatal MIs. However, extended-release metoprolol increased the risk of stroke; the strokes were devastating and increased overall mortality. Metoprolol therefore worsened overall perioperative outcomes.74 Patients who routinely take β blockers should be restarted by the first postoperative day to reduce the risk of atrial fibrillation,78 but β blockers should not be started de novo in the hopes of preventing postoperative myocardial ischemia and infarction.
The ENIGMA-2 trial also enrolled surgical inpatients with known or suspected cardiovascular disease (n = 7112), who were randomized to either nitrous oxide or nitrogen during anesthesia. The primary outcome was cardiac morbidity defined as a composite of death and cardiovascular complications (nonfatal MI, stroke, pulmonary embolism, or cardiac arrest) within 30 days of surgery. Nitrous oxide had neither beneficial nor substantive harmful effects (Figure 4).79
Death or nonfatal MI was also the primary outcome of the POISE-2 trial (n = 10,010). The study population also had known or suspected cardiovascular disease, were scheduled for noncardiac surgery, and were factorially randomized to receive aspirin or placebo and simultaneously to clonidine or placebo. Neither aspirin nor clonidine reduced the incidence of MI and death. However, clonidine was associated with bradycardia and hypotension, and aspirin with increased bleeding.75,76 A caveat is that few patients in the trial had coronary artery stents; the results of POISE-2 should therefore not be considered an indication for stopping aspirin in patients who have stents or other indications for platelet inhibition. But it does indicate that aspirin or clonidine should not be started de novo in the hopes of reducing perioperative cardiovascular risk.
MANAGEMENT OF MINS
Some believe that there is no need for troponin screening because nothing can be done for patients with elevated levels. Actually, there is much that can be done (Table 4). Failing to screen and to act on screening results is a missed opportunity to treat patients—and for anesthesiologists to act as perioperative physicians.
Table 4. -
Clinical Considerations When Patients Have Elevated Postoperative Troponin Concentrations
| Occasional patients need catheterization and angioplasty
| Patients will benefit from long-term care and monitoring
|Aspirin reduces secondary infarctions by 23%
|Consider statins and angiotensin-converting enzyme inhibitors
|Heart rate and hypertension control
|Lifestyle interventions (teachable moment)
| Smoking cessation
| Healthful diet
|Anticoagulation: 28% hazard reduction
Patients with MINS have at least a 3% chance of dying within 30 days,13 and increased mortality risk continues for at least 1 year.80 An anesthesiologist, intensivist, or hospitalist serving as the perioperative physician thus ideally engages with MINS patients and explains what has happened, the prognostic implications, and therapeutic options. Cardiologists may be best suited for these discussions; furthermore, patients with MINS need long-term follow-up that few anesthesiologists can provide. A cardiology consult is therefore probably the best initial response to postoperative troponin elevations. But that said, there are cardiologists who remain unfamiliar with MINS and inappropriately dismiss asymptomatic troponin elevations as unimportant “troponitis.” Perioperative physicians may thus need to guide cardiologists to the relevant literature.12,13,81
Aspirin is not helpful for primary prevention of perioperative infarctions,75 although it should usually be continued in patients who had previous percutaneous coronary interventions.81 But at least for nonoperative MIs, there is strong evidence that low-dose aspirin reduces the risk of secondary infarctions by 23%.82 Angiotensin-converting enzyme inhibitors,83 angiotensin receptor blockers,80 and statins84,85 also reduce secondary vascular complications. In an observational subanalysis of POISE patients, those who were started on aspirin and/or statins had markedly lower risk of 30-day mortality.74 Clinicians should at least consider these treatments in patients who experience MINS.
It is already well established that the perioperative period constitutes a “teachable moment” during which patients are especially receptive to lifestyle advice.86 Presumably, patients are even more receptive than usual after an operation complicated by a cardiovascular event. It is therefore an unfortunate missed opportunity when clinicians fail to use MINS as an opportunity to discuss smoking cessation, healthful eating, and exercise.
And finally, there is a specific treatment that has been shown to benefit MINS patients. Prolonged anticoagulation is a well-established treatment for nonoperative MIs.87,88 The Management of Myocardial Injury After Noncardiac Surgery (MANAGE) trial randomized patients who had MINS to dabigatran or placebo for up to 2 years. The primary outcome was a composite of vascular complications, primarily reinfarction. Dabigatran reduced the HR 28%, with a number-needed-to-treat of 24 (Figure 5).81 Dabigatran increased minor bleeding, but not major bleeding, which was comparable in the treatment and placebo groups. This is consistent with a previous study showing that the drug is safer than warfarin.89
Perioperative MIs are usually clinically silent, with symptoms such as chest pain and shortness of breath being rare. Troponin elevation after surgery—an indication of myocardial injury—is typically accompanied by neither symptoms nor signs—but the association between troponin elevation and mortality is nearly as strong without as with symptoms and signs. MINS differs from MI in being defined by troponin elevation apparently from cardiac ischemia, with or without signs and symptoms.
Perioperative myocardial injury (distinct from MI) is common, typically silent, and strongly associated with mortality. Myocardial injury is usually asymptomatic and only detected by routine troponin monitoring. A reasonable strategy is to determine serum troponin concentrations preoperatively and on the first 2 postoperative mornings in surgical inpatients >45 years old who have at least 1 cardiovascular risk factor, and in all surgical inpatients over the age of 65 years.
There is currently no known safe prophylaxis for perioperative MI and injury. Beta blockers significantly reduce MI risk, but with a concomitant increase in stroke and mortality. Avoiding nitrous oxide does not reduce cardiovascular risk. Clonidine and aspirin do not reduce risk and both cause complications.
Intraoperative and postoperative hypotension is associated with MINS, acute kidney injury, and death. In contrast, tachycardia appears to be considerably less important. Limited randomized data suggest that preventing hypotension reduces a composite of serious complications by about 25%. Large trials of hypotension prevention are clearly needed. But meanwhile, it seems prudent to avoid intraoperative and postoperative hypotension when practical.
Name: Kurt Ruetzler, MD.
Contribution: This author helped to conduct the literature search, write the manuscript, and approved the final version of the manuscript.
Conflicts of Interest: None.
Name: Ashish K. Khanna, MD, FCCP, FCCM.
Contribution: This author helped to conduct the literature search, write the manuscript, and approved the final version of the manuscript.
Conflicts of Interest: A. K. Khanna is a consultant for Edwards Lifesciences.
Name: Daniel I. Sessler, MD.
Contribution: This author helped to conduct the literature search, write the manuscript, and approved the final version of the manuscript.
Conflicts of Interest: D. I. Sessler is a consultant for Edwards Lifesciences. D. I. Sessler also participated in the development of the 2017 Canadian Cardiovascular Society guidelines.
This manuscript was handled by: Richard C. Prielipp, MD, MBA.
1. Lienhart A, Auroy Y, Péquignot F, et al. Survey of anesthesia-related mortality in France. Anesthesiology. 2006;105:1087–1097.
2. Li G, Warner M, Lang BH, Huang L, Sun LS. Epidemiology of anesthesia-related mortality in the United States, 1999-2005. Anesthesiology. 2009;110:759–765.
3. Fecho K, Lunney AT, Boysen PG, Rock P, Norfleet EA. Postoperative mortality after inpatient surgery: incidence and risk factors. Ther Clin Risk Manag. 2008;4:681–688.
4. Pearse RM, Moreno RP, Bauer P, et al.; European Surgical Outcomes Study (EuSOS) group for the Trials groups of the European Society of Intensive Care Medicine and the European Society of Anaesthesiology. Mortality after surgery in Europe: a 7 day cohort study. Lancet. 2012;380:1059–1065.
5. Bartels K, Karhausen J, Clambey ET, Grenz A, Eltzschig HK. Perioperative organ injury. Anesthesiology. 2013;119:1474–1489.
6. Kristensen SD, Knuuti J, Saraste A, et al.; Authors/Task Force Members. 2014 ESC/ESA Guidelines on non-cardiac surgery: cardiovascular assessment and management: The joint task force on non-cardiac surgery: cardiovascular assessment and management of the European Society of Cardiology (ESC) and the European Society of Anaesthesiology (ESA). Eur Heart J. 2014;35:2383–2431.
7. Thygesen K, Alpert JS, Jaffe AS, et al.; Executive Group on behalf of the Joint European Society of Cardiology (ESC)/American College of Cardiology (ACC)/American Heart Association (AHA)/World Heart Federation (WHF) Task Force for the Universal Definition of Myocardial Infarction. Fourth universal definition of myocardial infarction (2018). Circulation. 2018;138:e618–e651.
8. Helwani MA, Amin A, Lavigne P, et al. Etiology of acute coronary syndrome after noncardiac surgery. Anesthesiology. 2018;128:1084–1091.
9. Libby P. Mechanisms of acute coronary syndromes and their implications for therapy. N Engl J Med. 2013;368:2004–2013.
10. Pagidipati NJ, Peterson ED. Acute coronary syndromes in women and men. Nat Rev Cardiol. 2016;13:471–480.
11. Sheth T, Natarajan MK, Hsieh V, et al. Incidence of thrombosis in perioperative and non-operative myocardial infarction. Br J Anaesth. 2018;120:725–733.
12. Botto F, Alonso-Coello P, Chan MT, et al.; Vascular events In noncardiac Surgery patIents cOhort evaluatioN (VISION) Writing Group, on behalf of the VISION Investigators; Appendix 1. The VISION Study Investigators Writing Group; Appendix 2. The VISION Operations Committee; VISION Study Investigators. Myocardial injury after noncardiac surgery: a large, international, prospective cohort study establishing diagnostic criteria, characteristics, predictors, and 30-day outcomes. Anesthesiology. 2014;120:564–578.
13. Devereaux PJ, Biccard BM, et al.; Writing Committee for the Vision Study Investigators, Association of postoperative high-sensitivity troponin levels with myocardial injury and 30-day mortality among patients undergoing noncardiac surgery. JAMA. 2017;317:1642–1651.
14. Devereaux PJ, Xavier D, Pogue J, et al.; POISE (PeriOperative ISchemic Evaluation) Investigators. Characteristics and short-term prognosis of perioperative myocardial infarction in patients undergoing noncardiac surgery: a cohort study. Ann Intern Med. 2011;154:523–528.
15. Antman EM. Decision making with cardiac troponin tests. N Engl J Med. 2002;346:2079–2082.
16. Mair J, Lindahl B, Hammarsten O, et al. How is cardiac troponin released from injured myocardium? Eur Heart J Acute Cardiovasc Care. 2018;7:553–560.
17. Schmid J, Liesinger L, Birner-Gruenberger R, et al. Elevated cardiac troponin T in patients with skeletal myopathies. J Am Coll Cardiol. 2018;71:1540–1549.
18. Braunwald E, Antman EM, Beasley JW, et al.; American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). ACC/AHA guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction–2002: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (committee on the management of patients with unstable angina). Circulation. 2002;106:1893–1900.
19. Aviles RJ, Askari AT, Lindahl B, et al. Troponin T levels in patients with acute coronary syndromes, with or without renal dysfunction. N Engl J Med. 2002;346:2047–2052.
20. Webb IG, Yam ST, Cooke R, Aitken A, Larsen PD, Harding SA. Elevated baseline cardiac troponin levels in the elderly - another variable to consider? Heart Lung Circ. 2015;24:142–148.
21. Kavsak PA, Walsh M, Srinathan S, et al. High sensitivity troponin T concentrations in patients undergoing noncardiac surgery: a prospective cohort study. Clin Biochem. 2011;44:1021–1024.
22. Jacobs LH, van de Kerkhof J, Mingels AM, et al. Haemodialysis patients longitudinally assessed by highly sensitive cardiac troponin T and commercial cardiac troponin T and cardiac troponin I assays. Ann Clin Biochem. 2009;46:283–290.
23. Twerenbold R, Wildi K, Jaeger C, et al. Optimal cutoff levels of more sensitive cardiac troponin assays for the early diagnosis of myocardial infarction in patients with renal dysfunction. Circulation. 2015;131:2041–2050.
24. Nagele P, Brown F, Gage BF, et al. High-sensitivity cardiac troponin T in prediction and diagnosis of myocardial infarction and long-term mortality after noncardiac surgery. Am Heart J. 2013;166:325–332.e1.
25. Melki D, Lugnegård J, Alfredsson J, et al. Implications of introducing high-sensitivity cardiac troponin T into clinical practice: data from the SWEDEHEART Registry. J Am Coll Cardiol. 2015;65:1655–1664.
26. Duceppe E, Parlow J, MacDonald P, et al. Canadian Cardiovascular Society Guidelines on perioperative cardiac risk assessment and management for patients who undergo noncardiac surgery. Can J Cardiol. 2017;33:17–32.
27. Rodseth RN, Biccard BM, Le Manach Y, et al. The prognostic value of pre-operative and post-operative B-type natriuretic peptides in patients undergoing noncardiac surgery: B-type natriuretic peptide and N-terminal fragment of pro-B-type natriuretic peptide: a systematic review and individual patient data meta-analysis. J Am Coll Cardiol. 2014;63:170–180.
28. Sessler DI, Devereaux PJ. Perioperative troponin screening. Anesth Analg. 2016;123:359–360.
29. Torborg A, Ryan L, Kantor G, Biccard BM. The pharmacoeconomics of routine postoperative troponin surveillance to prevent and treat myocardial infarction after non-cardiac surgery. S Afr Med J. 2014;104:619–623.
30. Ghaferi AA, Birkmeyer JD, Dimick JB. Variation in hospital mortality associated with inpatient surgery. N Engl J Med. 2009;361:1368–1375.
31. Smilowitz NR, Gupta N, Ramakrishna H, Guo Y, Berger JS, Bangalore S. Perioperative major adverse cardiovascular and cerebrovascular events associated with noncardiac surgery. JAMA Cardiol. 2017;2:181–187.
32. Duvall WL, Sealove B, Pungoti C, Katz D, Moreno P, Kim M. Angiographic investigation of the pathophysiology of perioperative myocardial infarction. Catheter Cardiovasc Interv. 2012;80:768–776.
33. Landesberg G, Beattie WS, Mosseri M, Jaffe AS, Alpert JS. Perioperative myocardial infarction. Circulation. 2009;119:2936–2944.
34. Mozaffarian D, Benjamin EJ, et al.; Writing Group members, Heart disease and stroke statistics-2016 update: a report from the American Heart Association. Circulation. 2016;133:e38–360.
35. Hanson I, Kahn J, Dixon S, Goldstein J. Angiographic and clinical characteristics of type 1 versus type 2 perioperative myocardial infarction. Catheter Cardiovasc Interv. 2013;82:622–628.
36. Gualandro DM, Campos CA, Calderaro D, et al. Coronary plaque rupture in patients with myocardial infarction after noncardiac surgery: frequent and dangerous. Atherosclerosis. 2012;222:191–195.
37. Devereaux PJ, Sessler DI. Cardiac complications in patients undergoing major noncardiac surgery. N Engl J Med. 2015;373:2258–2269.
38. Devereaux PJ, Chan MT, et al.; Vascular Events In Noncardiac Surgery Patients Cohort Evaluation Study I, Association between postoperative troponin levels and 30-day mortality among patients undergoing noncardiac surgery. JAMA. 2012;307:2295–2304.
39. Chamoun GF, Li L, Chamoun NG, Saini V, Sessler DI. Comparison of an updated risk stratification index to hierarchical condition categories. Anesthesiology. 2018;128:109–116.
40. Criqui MH, Langer RD, Fronek A, et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med. 1992;326:381–386.
41. Kelly R, Staines A, MacWalter R, Stonebridge P, Tunstall-Pedoe H, Struthers AD. The prevalence of treatable left ventricular systolic dysfunction in patients who present with noncardiac vascular episodes: a case-control study. J Am Coll Cardiol. 2002;39:219–224.
42. Wijeysundera DN, Pearse RM, Shulman MA, et al.; METS study investigators. Assessment of functional capacity before major non-cardiac surgery: an international, prospective cohort study. Lancet. 2018;391:2631–2640.
43. Lee TH, Marcantonio ER, Mangione CM, et al. Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation. 1999;100:1043–1049.
44. Ford MK, Beattie WS, Wijeysundera DN. Systematic review: prediction of perioperative cardiac complications and mortality by the revised cardiac risk index. Ann Intern Med. 2010;152:26–35.
45. Bilimoria KY, Liu Y, Paruch JL, et al. Development and evaluation of the universal ACS NSQIP surgical risk calculator: a decision aid and informed consent tool for patients and surgeons. J Am Coll Surg. 2013;217:833–42.e1.
46. Gupta H, Gupta PK, Fang X, et al. Development and validation of a risk calculator predicting postoperative respiratory failure. Chest. 2011;140:1207–1215.
47. Struthers A, Lang C. The potential to improve primary prevention in the future by using BNP/N-BNP as an indicator of silent ‘pancardiac’ target organ damage: BNP/N-BNP could become for the heart what microalbuminuria is for the kidney. Eur Heart J. 2007;28:1678–1682.
48. Clerico A, Giannoni A, Vittorini S, Passino C. Thirty years of the heart as an endocrine organ: physiological role and clinical utility of cardiac natriuretic hormones. Am J Physiol Heart Circ Physiol. 2011;301:H12–H20.
49. Karthikeyan G, Moncur RA, Levine O, et al. Is a pre-operative brain natriuretic peptide or N-terminal pro-B-type natriuretic peptide measurement an independent predictor of adverse cardiovascular outcomes within 30 days of noncardiac surgery? A systematic review and meta-analysis of observational studies. J Am Coll Cardiol. 2009;54:1599–1606.
50. Rodseth RN, Lurati Buse GA, Bolliger D, et al. The predictive ability of pre-operative B-type natriuretic peptide in vascular patients for major adverse cardiac events: an individual patient data meta-analysis. J Am Coll Cardiol. 2011;58:522–529.
51. Biccard BM, Lurati Buse GA, Burkhart C, et al. The influence of clinical risk factors on pre-operative B-type natriuretic peptide risk stratification of vascular surgical patients. Anaesthesia. 2012;67:55–59.
52. De Hert S, Staender S, Fritsch G, et al. Pre-operative evaluation of adults undergoing elective noncardiac surgery: updated guideline from the European Society of Anaesthesiology. Eur J Anaesthesiol. 2018;35:407–465.
53. van Waes JA, van Klei WA, Wijeysundera DN, van Wolfswinkel L, Lindsay TF, Beattie WS. Association between intraoperative hypotension and myocardial injury after vascular surgery. Anesthesiology. 2016;124:35–44.
54. Walsh M, Devereaux PJ, Garg AX, et al. Relationship between intraoperative mean arterial pressure and clinical outcomes after noncardiac surgery: toward an empirical definition of hypotension. Anesthesiology. 2013;119:507–515.
55. Sun LY, Wijeysundera DN, Tait GA, Beattie WS. Association of intraoperative hypotension with acute kidney injury after elective noncardiac surgery. Anesthesiology. 2015;123:515–523.
56. Salmasi V, Maheshwari K, Yang D, et al. Relationship between intraoperative hypotension, defined by either reduction from baseline or absolute thresholds, and acute kidney and myocardial injury after noncardiac surgery: a retrospective cohort analysis. Anesthesiology. 2017;126:47–65.
57. Mascha EJ, Yang D, Weiss S, Sessler DI. Intraoperative mean arterial pressure variability and 30-day mortality in patients having noncardiac surgery. Anesthesiology. 2015;123:79–91.
58. Wesselink EM, Kappen TH, Torn HM, Slooter AJC, van Klei WA. Intraoperative hypotension and the risk of postoperative adverse outcomes: a systematic review. Br J Anaesth. 2018;121:706–721.
59. Sessler DI, Imrey PB. Clinical research methodology 1: study designs and methodologic sources of error. Anesth Analg. 2015;121:1034–1042.
60. Sessler DI, Imrey PB. Clinical research methodology 2: observational clinical research. Anesth Analg. 2015;121:1043–1051.
61. Maheshwari K, Turan A, Mao G, et al. The association of hypotension during non-cardiac surgery, before and after skin incision, with postoperative acute kidney injury: a retrospective cohort analysis. Anaesthesia. 2018;73:1223–1228.
62. Maheshwari K, Khanna S, Bajracharya GR, et al. A randomized trial of continuous noninvasive blood pressure monitoring during noncardiac surgery. Anesth Analg. 2018;127:424–431.
63. Meidert AS, Nold JS, Hornung R, Paulus AC, Zwißler B, Czerner S. The impact of continuous non-invasive arterial blood pressure monitoring on blood pressure stability during general anaesthesia in orthopaedic patients: a randomised trial. Eur J Anaesthesiol. 2017;34:716–722.
64. Futier E, Lefrant JY, Guinot PG, et al.; INPRESS Study Group. Effect of individualized vs standard blood pressure management strategies on postoperative organ dysfunction among high-risk patients undergoing major surgery: a randomized clinical trial. JAMA. 2017;318:1346–1357.
65. Androulakis A, Aznaouridis KA, Aggeli CJ, et al. Transient ST-segment depression during paroxysms of atrial fibrillation in otherwise normal individuals: relation with underlying coronary artery disease. J Am Coll Cardiol. 2007;50:1909–1911.
66. Ladha KS, Beattie WS, Tait G, Wijeysundera DN. Association between preoperative ambulatory heart rate and postoperative myocardial injury: a retrospective cohort study. Br J Anaesth. 2018;121:722–729.
67. Reich DL, Bennett-Guerrero E, Bodian CA, Hossain S, Winfree W, Krol M. Intraoperative tachycardia and hypertension are independently associated with adverse outcome in noncardiac surgery of long duration. Anesth Analg. 2002;95:273–277.
68. Ruetzler K, Yilmaz HO, Turan A, et al. Intra-operative tachycardia is not associated with a composite of myocardial injury and mortality after noncardiac surgery: a retrospective cohort analysis. Eur J Anaesthesiol. 2019;36:105–113.
69. Abbott TEF, Pearse RM, Archbold RA, et al. A Prospective International Multicentre Cohort Study of intraoperative heart rate and systolic blood pressure and myocardial injury after noncardiac surgery: results of the VISION Study. Anesth Analg. 2018;126:1936–1945.
70. Turan A, Chang C, Cohen B, et al. Incidence, severity, and detection of blood pressure perturbations after abdominal surgery: a Prospective Blinded Observational Study. Anesthesiology. 2019;130:550–559.
71. Sessler DI, Saugel B. Beyond ‘failure to rescue’: the time has come for continuous ward monitoring. Br J Anaesth. 2019;122:304–306.
72. Khanna AK, Maheshwari K, Mao G, et al. Association between mean arterial pressure and acute kidney injury and a composite of myocardial injury and mortality in postoperative critically ill patients: a retrospective cohort analysis. Crit Care Med. 2019 [Epub ahead of print].
73. Maheshwari K, Nathanson BH, Munson SH, et al. The relationship between ICU hypotension and in-hospital mortality and morbidity in septic patients. Intensive Care Med. 2018;44:857–867.
74. Devereaux PJ, Yang H, Yusuf S, et al.; POISE Study Group. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet. 2008;371:1839–1847.
75. Devereaux PJ, Mrkobrada M, Sessler DI, et al.; POISE-2 Investigators. Aspirin in patients undergoing noncardiac surgery. N Engl J Med. 2014;370:1494–1503.
76. Devereaux PJ, Sessler DI, Leslie K, et al.; POISE-2 Investigators. Clonidine in patients undergoing noncardiac surgery. N Engl J Med. 2014;370:1504–1513.
77. Myles PS, Leslie K, Peyton P, et al.; ANZCA Trials Group. Nitrous oxide and perioperative cardiac morbidity (ENIGMA-II) Trial: rationale and design. Am Heart J. 2009;157:488–494.e1.
78. Khanna AK, Naylor DF Jr, Naylor AJ, et al. Early resumption of β blockers is associated with decreased atrial fibrillation after noncardiothoracic and nonvascular surgery: a cohort analysis. Anesthesiology. 2018;129:1101–1110.
79. Myles PS, Leslie K, Chan MT, et al. The safety of addition of nitrous oxide to general anaesthesia in at-risk patients having major non-cardiac surgery (ENIGMA-II): a randomised, single-blind trial. Lancet. 2014;384:1446–1454.
80. Beattie WS, Wijeysundera DN, Chan MTV, et al.; ANZCA Clinical Trials Network and the ENIGMA-II Investigators. Survival after isolated post-operative troponin elevation. J Am Coll Cardiol. 2017;70:907–908.
81. Graham MM, Sessler DI, Parlow JL, et al. Aspirin in patients with previous percutaneous coronary intervention undergoing noncardiac surgery. Ann Intern Med. 2018;168:237–244.
82. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet. 1988;2:349–360.
83. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G; Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:145–153.
84. Auer J, Weber T, Eber B. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;351:714–717.
85. Pedersen TR, Kjekshus J, Berg K, et al.; Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). 1994. Atheroscler Suppl. 2004;5:81–87.
86. Warner DO, Klesges RC, Dale LC, et al. Clinician-delivered intervention to facilitate tobacco quitline use by surgical patients. Anesthesiology. 2011;114:847–855.
87. Mega JL, Braunwald E, Wiviott SD, et al.; ATLAS ACS 2–TIMI 51 Investigators. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012;366:9–19.
88. Eikelboom JW, Connolly SJ, Bosch J, et al.; COMPASS Investigators. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med. 2017;377:1319–1330.
89. Connolly SJ, Ezekowitz MD, Yusuf S, et al.; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–1151.
90. Etchells E, Meade M, Tomlinson G, et al. Semiquantitative dipyridamole myocardial stress perfusion imaging for cardiac risk assessment before noncardiac vascular surgery: a meta-analysis. J Vasc Surg. 2002;36:534–540.
91. Sheth T, Chan M, Butler C, et al. Prognostic capabilities of coronary computed tomographic angiography before non-cardiac surgery: prospective cohort study. BMJ. 2015;350:h1907.
92. Canty DJ, Royse CF, Kilpatrick D, et al.; The impact of focused transthoracic echocardiography in the pre-operative clinic. Anaesthesia. 2012;67:618–625.
93. Canty DJ, Royse CF, Kilpatrick D, et al.; The impact on cardiac diagnosis and mortality of focused transthoracic echocardiography in hip fracture surgery patients with increased risk of cardiac disease: a retrospective cohort study. Anaesthesia. 2012;67:1202–1209.
94. Canty DJ, Royse CF, Kilpatrick D, et al.; The impact of pre-operative focused transthoracic echocardiography in emergency non-cardiac surgery patients with known or risk of cardiac disease. Anaesthesia. 2012;67:714–720.
95. Devereaux PJ, Duceppe E, Guyatt G, et al. Dabigatran in patients with myocardial injury after noncardiac surgery (MANAGE): an international, randomized, placebo-controlled trial. Lancet. 2018;391:2325–2334.