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Perioperative myocardial infarction or injury after noncardiac surgery

Author: PJ Devereaux, MD, PhD

Section Editors: Jeroen J Bax, MD, PhD, Allan S Jaffe, MD
Deputy Editor: Gordon M Saperia, MD, FACC

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: May 2018. | This topic last updated: Feb 14, 2018.

INTRODUCTION — Among patients 45 years of age or older undergoing in-hospital noncardiac surgery,
complications of cardiac death, nonfatal myocardial infarction (MI), heart failure, or ventricular tachycardia
occur in up to 5 percent. Of these, perioperative MI is the most common.

In addition, there is a larger group of patients who have a rise in troponin, a biomarker of cardiac injury, but no
symptoms and no evidence of myocardial ischemia on an electrocardiogram. They are labelled as having
myocardial injury after noncardiac surgery when there is no evidence of a nonischemic etiology (eg, sepsis,
pulmonary embolism, rapid atrial fibrillation, chronic troponin elevation).

This topic will focus on the identification and management of patients with perioperative MI or MINS. Related
topics include:

● (See "Early cardiac complications of coronary artery bypass graft surgery", section on 'Perioperative MI'.)

● (See "Evaluation of cardiac risk prior to noncardiac surgery".)

● (See "Management of cardiac risk for noncardiac surgery".)

● (See "Perioperative management of heart failure in patients undergoing noncardiac surgery".)

DEFINITIONS OF MYOCARDIAL INFARCTION AND MYOCARDIAL INJURY — The terms myocardial

infarction (MI) and myocardial injury after noncardiac surgery (MINS) need to be defined. The 2007 Joint Task
Force of the European Society of Cardiology, American College of Cardiology Foundation, the American
Heart Association, and the World Health Federation (ESC/ACCF/AHA/WHF) defined acute MI as a clinical
event that results in the death of cardiac myocytes (myocardial necrosis) and is caused by ischemia (but not
other etiologies such as myocarditis or trauma) [1]. This definition was not fundamentally changed in the third
universal definition of MI released in 2012 by the ESC/ACCF/AHA/WHF [2]. The definition requires a rise
and/or fall of cardiac biomarker values. (See "Criteria for the diagnosis of acute myocardial infarction", section
on 'Third universal definition of MI'.)

MINS is a broader term than MI (after noncardiac surgery) and is defined as myocardial cell injury during the
first 30 days after noncardiac surgery due to an ischemic etiology (ie, no evidence of a nonischemic etiology
like sepsis, pulmonary embolism, cardioversion, chronically elevated troponin, etc) and is independently
associated with mortality. MINS includes MI (both symptomatic and non-symptomatic) and patients with
postoperative elevations in troponin but who do not have symptoms, electrocardiographic abnormalities, or

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other criteria that meet the universal definition described above, and have no evidence of a nonischemic
etiology for their troponin elevation [3].

MECHANISM — The pathophysiology of perioperative myocardial infarction (MI) is debated. Although supply-
demand mismatch (eg, hypertension, hypotension, or tachycardia in the setting of a fixed coronary artery
stenosis) has long been thought to explain many perioperative MIs, the evidence to support this explanation
is limited. However, plaque rupture may play a central role in some cases. In one angiographic study, nearly
50 percent of patients with perioperative acute coronary syndrome had evidence of plaque rupture [4].

In patients with myocardial injury after noncardiac surgery (MINS), the most common pathologies are either
underlying obstructive coronary artery disease, which can cause elevations of cardiac troponin due to a
supply-demand mismatch, or an acute thrombus [5-7]. Those who propose use of the term MINS do not apply
it to patients in whom myocardial injury is likely due to a nonischemic etiology such as pulmonary embolism,
sepsis, or cardioversion.

Two large prospective cohort studies in which adjudicators attempted to evaluate each case of an elevated
troponin for evidence of a nonischemic etiology found that over 85 percent of troponin elevations after surgery
were likely due to myocardial ischemia [3,8]. Regardless of the etiology, these elevations have important
prognostic relevance. (See 'Prognosis' below.)

INCIDENCE — Studies that have evaluated the incidence of perioperative cardiac troponin (cTn) elevation
attempt to report whether the elevation is a myocardial infarction (MI) or myocardial injury after noncardiac
surgery (MINS) (see 'Definitions of myocardial infarction and myocardial injury' above). In these studies, the
incidence of MINS ranges between 8 and 19 percent. MI accounts for about 40 percent of MINS when a non-
high sensitivity cTn is evaluated, and about 20 to 30 percent of these events when a high sensitivity cTn (hs-
cTn) assay is used.

Factors that explain between-study differences in the incidence of MINS and the percent of MINS that are
labelled as MI include:

● Most patients are receiving analgesic medication that can mask cardiac ischemic symptoms during the
first 48 hours after surgery when MI occurs (see 'Clinical presentation' below). Had patients been
symptomatic, they would likely have been classified as MI. Also, electrocardiograms (ECGs) are mainly
ordered after the detection of an elevated troponin, which may be 12 to 24 hours after the event, and
ECG changes may have resolved by the time the ECG is obtained [9].

● The incidence of MINS is influenced by the sensitivity of the biomarker used. As demonstrated across the
VISION cohort studies discussed later in this section, as the sensitivity of cTn assays improved (ie, from
a non-high sensitivity to an hs-cTn assay), the frequency of identifying perioperative troponin elevations
increased.

● The characteristics of the study population, such as severity of patient risk and the risk of surgery, will
influence incidence.

● A baseline troponin is necessary to determine if a postoperative troponin elevation represents an acute

or chronic event. Some studies have not rigorously compared postoperative with preoperative troponin
values.

Five large studies have evaluated the incidence of troponin elevations after noncardiac surgery [3,10-13]. The
best data on incidence of MINS and MI come from the following two studies:

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● The VISION Study was a prospective cohort study that included a representative sample of patients ≥45
years of age undergoing in-hospital noncardiac surgery, and all of the participants had troponin
measurements after surgery. Two cohorts have been reported:

• In the first VISION cohort of 15,065 patients, a non-high sensitivity fourth generation cTn assay was
measured during the first three postoperative days [3]. Among the patients with an elevated troponin,
all were assessed for ischemic symptoms, had ≥1 ECG obtained, and had two independent
adjudicators to determine if there was evidence of a non-ischemic cause (eg, pulmonary embolism,
sepsis) of the troponin elevation. Baseline cTnT values were not available. Study adjudicators
determined that 93 percent of patients with a troponin elevation had an ischemic etiology for their
troponin elevation and that 1200 (8 percent) patients suffered MINS. Among the MINS patients, 41.8
percent fulfilled the universal definition of MI. A limitation of this study is that troponin measurements
were not obtained systematically in patients before surgery.

• In the second VISION cohort of 21,842 patients, which followed the same procedures as the first
cohort, an hs-cTn assay was measured during the first three postoperative days; 40.4 percent of the
participants had a preoperative troponin measurement [8]. Study adjudicators determined that 11
percent had evidence of a non-ischemic etiology for their elevated troponin, and among the patients
who had an elevated perioperative troponin measurement, 13.8 percent had a preoperative high-
sensitivity troponin T measurement that was greater than or equal to the peak postoperative troponin
value. In this cohort with high-sensitivity troponin T measurements, 3904 patients (17.9 percent)
were adjudicated as having suffered MINS, and among these patients, 21.7 percent fulfilled the
universal definition of MI.

● A 2017 prospective, diagnostic study of 2018 patients (2546 surgeries) at increased cardiovascular risk
and undergoing noncardiac surgery routinely measured hs-cTnT before and after surgery [13].
Perioperative myocardial injury was defined as an absolute increase in hs-CTnT of ≥14 ng/L above
preoperative values. Perioperative myocardial injury occurred in 16 percent of surgeries. Of these, 6
percent had typical chest pain, 18 percent had any ischemic symptom, and 29 percent had one or more
of the following: an ischemic symptom, a diagnostic change on an ECG, or evidence of loss of
myocardial viability on imaging.

Additional information regarding incidence of perioperative MI in the troponin era comes from over 8000
patients in the randomized POISE trial of perioperative beta blocker therapy in patients at increased
cardiovascular risk undergoing noncardiac surgery [14]. In POISE, perioperative MI was defined as an
elevated cardiac biomarker or enzyme level (with separate definitions for troponin or creatine kinase MB
fraction), and one or more of the following: ischemic symptoms, ECG changes in two contiguous leads (ie,
development of pathologic Q waves, ST-segment elevation, ST-segment depression, or T-wave inversion),
coronary artery intervention, or evidence of MI on cardiac imaging or autopsy [14]. The incidence of MI in
POISE was 5 percent at 30 days (4.2 and 5.7 in the beta blocker and placebo groups, respectively), and the
majority of these MIs (74 percent) occurred within 48 hours of surgery [12]. It is not clear that guideline-
recommended cut-off values were used in POISE, which relied on local values. Thus, from the biochemical
perspective, these data probably underestimate the true frequency of elevated cTn measurements and thus
perhaps the true frequency of MI as well. In POISE, 65 percent of the patients who had a perioperative MI did
not experience ischemic symptoms. Perioperative, asymptomatic MIs were associated with a similar
increased risk of 30-day mortality (adjusted odds ratio 4; 95% CI 2.65-6.06) as with symptomatic MIs
(adjusted odds ratio, 4.76; 95% CI 2.68-8.43). (See "Management of cardiac risk for noncardiac surgery",
section on 'Patients without indications for long-term therapy'.)

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PREDICTORS — Risk factors for cardiovascular events (including myocardial infarction [MI]) after noncardiac
surgery have been identified and incorporated into validated risk models. The revised Goldman cardiac risk
index is the best validated risk index and appears to have greater predictive value than other risk indices
(table 1). Risk factors include high-risk surgery, history of ischemic heart disease, heart failure,
cerebrovascular disease, diabetes mellitus requiring treatment with insulin, and preoperative serum creatinine
>2.0 mg/dL. (See "Evaluation of cardiac risk prior to noncardiac surgery", section on 'Estimating perioperative
risk'.)

The CARP trial specifically evaluated predictors of MI in patients with coronary artery disease undergoing
elective vascular surgery [15]. In this very-high-risk group, age greater than 70 years, abdominal aortic
surgery, diabetes mellitus, angina, and baseline ST-T abnormalities were significantly associated with the
development of MI.

While high-risk surgery such as abdominal aortic surgery is associated with the development of perioperative
MI, other surgeries such as total hip and knee replacement also place patients at risk. (See "Evaluation of
cardiac risk prior to noncardiac surgery", section on 'Risk factors used in risk prediction models'.)

In the POISE trial, in addition to the Goldman risk predictors, serious bleeding (disabling or requiring ≥2 units
of blood) and an increase in every 10 beats in baseline heart rate were significant independent predictors of
perioperative MI (adjusted odds ratio 3.62, 95% CI 2.07-6.36; and 1.29, 95% CI 1.13-1.50, respectively) [12].

Perioperative hemorrhage as a predictor of MI (or stroke) was also evaluated in a study of 651,775 patients
who underwent surgery between 2005 and 2009 at centers participating in the United States National
Surgical Quality Improvement Program [16]. Major hemorrhage, defined as bleeding necessitating transfusion
of more than four units of packed red blood cells or whole blood, occurred in 0.80 percent of patients. Q-wave
MI occurred in 0.24 percent, and stroke in 0.20 percent. Hemorrhage was independently associated with MI
(hazard ratio [HR] 2.7, 95% CI 2.1-3.4) and stroke (HR 2.3, 95% CI 1.9-3.3), and the risk was related to the
severity of bleeding. The risk of MI may be an underestimate due to the use of Q-wave MI as the definition of
MI, rather than the use of biomarkers and clinical findings.

In the POISE-2 trial comparing low-dose aspirin with placebo and low-dose clonidine with placebo in 10,010
adults undergoing noncardiac surgery, the following preoperative independent predictors of perioperative MI
were found: history of coronary artery disease, peripheral arterial disease, congestive heart failure, estimated
glomerular filtration rate <60 mL/minute/1.73m2, and age ≥75 years. Intraoperative and postoperative
predictors included clinically important hypotension and all major bleeds that occurred before MI [17]. (See
"Management of cardiac risk for noncardiac surgery", section on 'Antiplatelet therapy'.)

PREVENTION — All patients undergoing noncardiac surgery, and in particular those at increased risk of a
perioperative myocardial infarction, should have their risk of a cardiovascular event assessed and managed
prior to surgery. (See "Evaluation of cardiac risk prior to noncardiac surgery", section on 'Our approach' and
"Management of cardiac risk for noncardiac surgery".)

CLINICAL PRESENTATION — Patients with perioperative myocardial infarction (MI) may have symptoms
and (rarely) signs similar to the broad group of patients with an acute coronary syndrome. (See "Initial
evaluation and management of suspected acute coronary syndrome (myocardial infarction, unstable angina)
in the emergency department", section on 'Clinical presentation'.)

However, due to the influence of anesthetic/analgesic/amnestic agents, symptoms are often muted, atypical,
or absent. In the POISE trial, approximately 65 percent of the patients with MI did not experience ischemic
symptoms [14]. We recommend that all patients with symptoms or signs suggestive of myocardial ischemia or

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those suspected for other reasons, such as hemodynamic instability or respiratory distress, receive a 12-lead
electrocardiogram and serial (two or three) troponin measurements.

DIAGNOSIS — In the setting of noncardiac surgery, the diagnosis of perioperative myocardial infarction (MI)
is confirmed with a highly sensitive troponin with at least one of the following present: symptoms of ischemia,
new or presumed new significant ST-segment/T wave changes or new left bundle branch block, development
of pathological Q waves on the electrocardiogram (ECG), new or presumed new imaging evidence of loss of
viable myocardium or regional wall motion abnormality, or identification of an intracoronary thrombus by
angiography or autopsy [2]. (See "Electrocardiogram in the diagnosis of myocardial ischemia and infarction".)

Since the key to the diagnosis of MI is the presence of a rising and/or falling pattern of values of cardiac
troponin (see 'Definitions of myocardial infarction and myocardial injury' above), an attempt should be made to
compare the postoperative value with a preoperative one.

In patients in whom troponin was not measured or was measured at a time that could have missed the clinical
event, we believe that new pathologic Q waves on the ECG can define acute MI. For patients in whom the
diagnosis remains uncertain after considering symptoms, ECG changes, and the results of biomarker testing,
information from additional noninvasive studies (such as a new wall-motion abnormality or fixed defect on
echocardiography, or radionuclide myocardial perfusion imaging) may be needed. (See "Noninvasive testing
and imaging for diagnosis in patients at low to intermediate risk for acute coronary syndrome".)

For those patients who have an elevated troponin, the ECG shows a new ischemic abnormality in a minority.
In the first VISION study, which used non-high sensitivity troponin (see 'Definitions of myocardial infarction
and myocardial injury' above), about 35 percent of patients had an ischemic ECG finding. T wave inversion
and ST depression were the most common findings (23 and 16 percent, respectively). It is likely that a higher
proportion of patients who suffer myocardial injury after noncardiac surgery (MINS) experienced ischemic
ECG changes at some point in their postoperative course, but these changes are likely frequently missed for
the following reasons: Most patients do not experience ischemic symptoms to trigger obtaining an ECG during
the period of ischemia; most ECGs are obtained after detection of an elevated troponin, which is usually
obtained at 24-hour intervals after surgery; and a troponin elevation only occurs hours after the initiation of an
ischemic event. If clinicians are suspicious, additional studies are warranted.

Some may find it appropriate to only use the diagnosis of MINS (see 'Definitions of myocardial infarction and
myocardial injury' above) when a diagnosis of acute MI is not fulfilled. In this case, MINS would be deemed
present when there is an elevated troponin but no symptoms or ECG or noninvasive testing abnormalities. In
addition, these patients should have had a nonischemic cause of an elevated troponin excluded. (See
'Definitions of myocardial infarction and myocardial injury' above and 'Differential diagnosis' below.)

DIFFERENTIAL DIAGNOSIS — Potential causes of an elevated troponin in the absence of criteria for MI or
MINS include pulmonary embolus, sepsis, rapid atrial fibrillation, or chronic kidney disease. This issue is
discussed in detail elsewhere. (See "Elevated cardiac troponin concentration in the absence of an acute
coronary syndrome".)

SCREENING — Screening for myocardial injury after noncardiac surgery (MINS) refers to the perioperative
measurement of troponin and procurement of an electrocardiogram (ECG) in the perioperative period in
patients who have no symptoms (or signs) of myocardial ischemia but who are at relatively high risk (table 1).
(See "Troponin testing: Clinical use", section on 'Noncardiac surgery'.)

Troponin — We suggest screening for perioperative MINS in patients at high risk for a perioperative
myocardial infarction (MI). High risk is defined as in-hospital surgery with one or more additional risk factors

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from the revised cardiac risk score (table 1). A highly sensitive troponin should be obtained at 6 to 12 hours
and on days one, two, and three after surgery (see 'Predictors' above). In addition, we obtain a baseline
preoperative cardiac troponin (cTn) in these patients since an isolated elevated postoperative cTn may
represent a chronic process rather than an acute event.

The risk of MI is elevated, and the likelihood of missing the diagnosis based on symptoms or ECG changes is
significant, as was shown in the POISE trial discussed above [18] (see 'Incidence' above). The principal
argument against obtaining a baseline troponin is that patients in whom an elevation is identified (such as
those with chronic elevations) may have their surgery unnecessarily postponed.

Some experts have suggested that somewhat lower-risk patients, such as those with risk factors for
cardiovascular disease (eg, smoking, hypertension, or dyslipidemia), undergo screening given the worse
short- and long-term outcomes associated with perioperative MI [12]. As the use of screening has not been
well studied in these patients, we do not routinely screen them. (See 'Prognosis' below.)

Screening with troponin may identify individuals with MINS; that is, they did not have symptoms of myocardial
ischemia and the ECG was normal, unchanged, or nondiagnostic. The rationale for this screening
recommendation is that a positive troponin will lead to recommendations for preventative therapies such as
aspirin and statin use and will prompt evaluation by additional ECGs or imaging studies that might not
otherwise be done, which could reveal an MI. (See 'Myocardial injury patients' below.)

For patients found to have an elevated screening perioperative troponin, two issues should be kept in mind
before a diagnosis of MINS is made (see 'Definitions of myocardial infarction and myocardial injury' above):

● The diagnosis should not be based only on a postoperative elevation in troponin, as this may represent a
chronic elevation. This possibility is why a baseline troponin value is so important. The baseline
(preoperative) value may be available either because it had been performed as a routine test, as
discussed below, or because a preoperative residual sample can be tested. The diagnosis requires either
a normal baseline value or a typical rise and fall of the biomarker. A challenge to clinicians is that many
patients may not have a preoperative baseline troponin value to compare. In such instances, a prior
sample may be available and used to test for cTn.

In the VISION high-sensitivity cohort study (see 'Incidence' above), among the patients who had an
elevated perioperative troponin measurement, 13.8 percent had a preoperative high-sensitivity troponin T
measurement that was greater than or equal to the peak postoperative troponin value. This study
highlights the importance of a baseline value to differentiate if an elevated troponin represents a new
event that occurred during or after surgery started.

● Elevated troponin measurements after surgery can occur due to nonischemic etiologies and should
prompt an evaluation of the patient to ensure a nonischemic etiology has not been missed. (See
'Mechanism' above and 'Differential diagnosis' above.)

Role of BNP — Although pre- and postoperative elevations in plasma B-type natriuretic peptide (BNP) are
associated with an increased risk of adverse cardiovascular events (including MI) at 30 days, its role in the
care of patients undergoing noncardiac surgery has not been established (see 'Prognosis' below). Until this
issue is studied further, some of our contributors routinely order BNP before noncardiac surgery for prognostic
purposes. The use of BNP in other settings is discussed separately. (See "Natriuretic peptide measurement in
heart failure" and "Natriuretic peptide measurement in non-heart failure settings".)

A 2009 meta-analysis, which included seven studies of 2841 patients, found a statistically significant

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association between a preoperative elevation in BNP and the cardiovascular outcomes of death, cardiac
death, and nonfatal MI at 30 days (adjusted odds ratio 19.3) [19]. A 2011 meta-analysis that evaluated
mortality at six months or later came to a similar conclusion [20].

Electrocardiogram — We suggest at least one 12-lead ECG in all patients with symptoms of myocardial
ischemia. However, similar to troponin measurement, the issue of when to obtain a screening ECG(s) in
asymptomatic patients is not well studied. Although the evidence to support the routine performance of a
postoperative ECG(s) in high-risk patients is weak compared with that for the use of troponin, some of our
experts believe such practice is reasonable. High risk is defined as in-hospital surgery with one or more
additional risk factors of the revised cardiac risk score or any patients with complications of a possible
cardiovascular etiology (table 1). Some of our experts routinely perform a postoperative ECG in lower-risk
patients, such as those with risk factors for coronary heart disease [9]. (See "Electrocardiogram in the
diagnosis of myocardial ischemia and infarction", section on 'Unexpected absence of diagnostic findings'.)

Similar to our rationale to obtain a preoperative troponin in high-risk patients, we obtain a baseline ECG in
these patients. (See 'Troponin' above.)

Recommendations of others — The 2014 American College of Cardiology/American Heart Association

guideline on the perioperative cardiovascular evaluation and management of patients undergoing noncardiac
surgery states that the usefulness of postoperative screening of high-risk patients using troponin and ECG is
uncertain [21,22].

The 2014 European Society of Cardiology perioperative guidelines state that assessment of cardiac troponins
in high-risk patients, both before and 48 to 72 hours after major surgery, may be considered [23].

The third Universal Definition of MI international expert consensus document recommends measuring
troponin before and up to 48 to 72 hours after noncardiac surgery in high-risk patients [2].

The 2017 Canadian Cardiovascular Society Guidelines for patients undergoing noncardiac surgery
recommend obtaining daily cTn measurements for 48 to 72 hours after noncardiac surgery in patients with a
baseline risk >5 percent for cardiovascular death or nonfatal MI at 30 days after surgery (ie, patients with an
elevated NT-proBNP/BNP measurement before surgery or, if there is no NT-proBNP/BNP measurement
before surgery, in those who have a Revised Cardiac Risk Index [RCRI] score ≥1, age 45 to 64 years with
significant cardiovascular disease, or age ≥65 years) [24].

PROGNOSIS — Short- and long-term mortality are significantly increased in patients with a perioperative
increase in cardiac troponin (cTn) irrespective of whether they are labelled as having myocardial infarction
(MI) or myocardial injury after noncardiac surgery (MINS) [3,12,25-29]. In addition, nonfatal perioperative MI is
an important independent risk factor for recurrent nonfatal acute coronary syndrome, nonfatal cardiac arrest,
heart failure, or progressive angina requiring revascularization later after surgery [5,9,12,15,30].

Multiple studies have found an increase in short-term (in-hospital and 30-day) mortality, with in-hospital
mortality ranging between 5 and 25 percent [3,12,25-28]. The following are representative examples:

● In the 2017 report from the VISION study (see 'Incidence' above), death within 30 days occurred in 1.2
percent [8]. An absolute change of 5 ng/L across any two perioperative measurements of high sensitivity
cTn (hs-cTn) was independently associated with an increase in 30-day mortality (adjusted hazard ratio
4.69; 95% CI 3.52-6.25). In addition, the peak value had prognostic significance. Compared with a
reference group (peak hs-TnT <5 ng/L), patients with peak postoperative hs-TnT levels of 20 to less than
65 ng/L, 65 to less than 1000 ng/L, and 1000 ng/L or higher had 30-day mortality rates of 3.0, 9.1, and

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29.6 percent (adjusted hazard ratios 23.63, 70.34, and 227.01, respectively, and all statistically
significant).

● In the 2017 prospective, diagnostic study of 2018 patients discussed above (see 'Incidence' above),
crude 30-day mortality was 8.9 percent in patients with myocardial injury compared with 1.5 percent in
patients without (adjusted hazard ratio 2.7, 95% CI 1.5-4.8) [13]. Importantly, the study also found no
difference in 30-day mortality between those with myocardial injury not fulfilling any other criteria for
acute MI and those with at least one addition criterion (10.4 versus 8.7 percent; P = 0.684). Both the
absolute hs-TnT value and the increase from the baseline value (the "delta") were associated with
increasing mortality rates.

Long-term mortality is increased in patients with MINS. In the 2017 study mentioned above, mortality at one
year was significantly higher in patients with MINS (22.5 versus 9.3 percent, respectively). Similarly, in a 2011
meta-analysis of 15 studies (over 4000 patients) of various types of noncardiac surgery with follow-up ranging
between 3 and 48 months, an elevation of either troponin or creatine kinase MB fraction was associated with
a significantly increased risk of all-cause mortality (adjusted odds ratio 3.4, 95% CI 2.2-5.2; and 2.5, 95% CI
1.5-4.0, respectively) [29]. Despite the clear relationship between perioperative MI or MINS and prognosis,
the benefit from screening all patients for perioperative MI has not been established. Our recommendations
for screening are presented above. (See 'Screening' above.)

Outcomes in the subset of perioperative MI patients who are referred for coronary angiography within seven
days of noncardiac surgery were evaluated in a 2016 report from the Cleveland Clinic [28]. In this study, 1093
such individuals were referred for angiography for marked elevations of cTn (>fivefold). It is unclear if a rising
and/or falling pattern of values was observed. Overall mortality at 30 days and one year was 5.2 and 15
percent, respectively. Of these 1093 patients, 281 (40 ST-elevation MI and 241 non-ST elevation MI)
underwent percutaneous coronary intervention. Mortality at 30 days was 11.3 percent; the 30-day death rates
in the ST-elevation and non-ST elevation MI cohorts were 31.2 and 8.5 percent, respectively. Risk factors for
30-day mortality after PCI were a bleeding event after PCI (odds ratio [OR] 4.33), peak troponin T level (OR
1.2), and underlying peripheral artery disease (OR 4.86). Important risk predictors for long-term mortality were
bleeding after PCI, renal insufficiency, and vascular surgery.

The relationship between postoperative B-type natriuretic peptides (BNP) and cardiovascular outcomes was
evaluated in a 2013 meta-analysis of 18 studies (n = 2051) in which BNP was sampled less than seven days
after surgery [31]. The primary outcome of death or nonfatal MI at 30 days occurred more often in patients
with a BNP ≥245 pg/mL or an N-terminal proBNP ≥718 pg/mL (adjusted odds ratios 4.5, 95% CI 2.74-7.4). A
subsequent analysis of these 18 studies found that the addition of a postoperative BNP enhanced risk
stratification for the composite outcomes of death or nonfatal MI at 30 days and >180 days compared with a
preoperative BNP [32].

MANAGEMENT — The optimal management strategy for those patients who sustain a myocardial infarction
(MI) in the perioperative period is unknown given the paucity of data upon which recommendations can be
made. We believe that the care of such patients needs to be individualized and based on characteristics such
as likely mechanism of MI (see 'Mechanism' above), risks of therapy, information derived from subsequent
risk stratification, and comorbidities.

At a minimum, all such individuals should receive aspirin and a statin. (See "Overview of the acute
management of non-ST elevation acute coronary syndromes" and "Overview of the non-acute management
of unstable angina and non-ST elevation myocardial infarction".)

Evidence to support the use of aspirin and statin in patients with perioperative MI comes from the broad

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population of patients with MI who benefit from these drugs, as well as from the POISE trial [12]. In an
observational sub-study of POISE, aspirin and statin use were each associated with a reduction in the risk for
30-day mortality among patients who had suffered a perioperative MI (adjusted odds ratios 0.54, 95% CI
0.29-0.99; and 0.26, 95% CI 0.13-0.54, respectively). (See "Management of cardiac risk for noncardiac
surgery", section on 'Patients taking beta blockers'.)

We typically start atorvastatin 80 mg (40 mg in patients who cannot receive 80 mg daily) and aspirin 81 to 325
mg (when the risk of bleeding after surgery is acceptable); patients are discharged on the same daily dose of
atorvastatin and aspirin 75 to 100 mg daily. (See "Low density lipoprotein-cholesterol (LDL-C) lowering after
an acute coronary syndrome", section on 'Summary and recommendations' and "Antiplatelet agents in acute
non-ST elevation acute coronary syndromes", section on 'Aspirin for all patients'.).

In addition to aspirin and statin, continuous electrocardiographic monitoring (potentially in a monitored setting)
for at least 24 hours is advised, particularly if the diagnosis is made within the first 24 hours of surgery.

The following discussion presents our recommendations based on the type of perioperative event: ST-
elevation MI (STEMI), non-ST elevation MI (NSTEMI), and troponin elevation without other criteria for MI
(MINS).

ST-elevation MI — Patients with perioperative STEMI are at high risk for death without usual STEMI care,
including reperfusion therapy, and are at high risk for a bleeding complication with it. In most patients,
fibrinolytic therapy is not an option given the recent surgical procedure. We usually proceed with urgent
primary percutaneous coronary intervention after careful discussion of the benefits and risks with all
managing healthcare providers. The patient and family are involved in this process.

We recommend aspirin and statin for these STEMI patients. A P2Y12 receptor blocker is added as soon as a
decision is made to implant an intracoronary stent. For patients who receive no reperfusion therapy, we also
recommend one year of aspirin plus a P2Y12 receptor blocker (dual antiplatelet therapy). (See "Antiplatelet
agents in acute ST elevation myocardial infarction", section on 'No reperfusion therapy'.)

We also recommend starting a beta blocker in these patients. However, the potential for hypotension should
be considered in the choice of timing and dose.

The general approach to MI patients is discussed elsewhere. (See 'Management' above and "Overview of the
acute management of ST-elevation myocardial infarction" and "Overview of the non-acute management of ST
elevation myocardial infarction".)

Non-ST elevation MI — Our approach to the management of patients with perioperative NSTEMI is as
follows:

● We start aspirin (when the bleeding risk is acceptable) and statin in all such patients, as the benefit-to-
risk ratio is likely to be in favor of their use. (See 'Management' above.)

● Our experts have differing approaches to the use of beta blockers, with some recommending their use in
all patients and some recommending use only in those with moderate or large MI, untreated
hypertension, or those who need rate control in atrial fibrillation. If possible, we wait until day two or three
postoperatively prior to initiating a beta blocker (in patients not already on beta blockers) in an attempt to
avoid hypotension during this period.

● For hemodynamically unstable patients or those with recurrent ischemia, we recommend early coronary
angiography. The decision to revascularize and use aggressive antithrombotic therapy (including dual

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antiplatelet therapy) will need to take into consideration the benefits and risks of such an approach in the
patient with recent surgery.

● For hemodynamically stable patients without evidence of recurrent ischemia, we perform risk stratification
when feasible after surgery. Risk stratification can be with noninvasive testing, coronary angiography, or
both. We recommend coronary angiography when it is felt that the knowledge of the coronary anatomy
will influence decisions regarding revascularization or changes in medical therapy. (See "Coronary
angiography and revascularization for unstable angina or non-ST elevation acute myocardial infarction",
section on 'Conservative approach'.)

Myocardial injury patients — For patients who are troponin positive but do not meet the criteria for MI (see
'Definitions of myocardial infarction and myocardial injury' above), we start aspirin and a statin, as they are
likely to have coronary artery disease with fixed obstruction. Since the troponin rise may have been due to
supply-demand mismatch, rather than plaque rupture or fissure, we are not prepared to recommend adding a
second antiplatelet agent. This recommendation for aspirin and statin in this population is based on
extrapolation of evidence of benefit in the broad population of patients with coronary artery disease. (See
"Prevention of cardiovascular disease events in those with established disease or at high risk", section on
'Summary and recommendations'.)

Our experts have differing approaches to the use of beta blockers in this population with some starting them
and others not.

Evidence to support the initiation of secondary preventive measures after MINS comes from a propensity-
matched study of 66 MINS patients and 132 matched non-MINS patients who underwent major vascular
surgery [33]. Among MINS patients, 43 received therapeutic intensification of ≥1 of 4 cardiac medications
(aspirin, statin, beta-blocker, or angiotensin converting enzyme inhibitor) and 23 patients did not receive
therapeutic intensification after MINS. The primary end point was 12-month survival without a major cardiac
event (ie, death, MI, coronary revascularization, or pulmonary edema requiring hospitalization). MINS patients
not receiving therapeutic intensification had a hazard ration (HR) for the primary outcome of 1.77; 95% CI
1.13-2.42, whereas MINS patients receiving therapeutic intensification had HR 0.63; 95% CI, 0.10-1.19.

For these patients who become symptomatic or in whom there is a concern about a high risk of arrhythmia,
we suggest continuous electrocardiographic monitoring for 24 to 48 hours. (See "Overview of primary
prevention of coronary heart disease and stroke" and "Prevention of cardiovascular disease events in those
with established disease or at high risk", section on 'Summary and recommendations'.)

When the patient has recovered from surgery, risk stratification with stress testing is reasonable unless
another clear explanation for an elevated troponin is present.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected
countries and regions around the world are provided separately. (See "Society guideline links: Perioperative
cardiovascular evaluation and management".)

SUMMARY AND RECOMMENDATIONS

● Myocardial infarction (MI) in patients undergoing noncardiac surgery is defined as a rise in troponin in
association with suggestive symptoms or electrocardiographic changes. Myocardial injury after
noncardiac surgery (MINS) requires only an elevated troponin postoperatively when there is no evidence
of a non-ischemic cause. (See 'Diagnosis' above.)

● With regard to measurement of troponin (see 'Troponin' above):

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• We recommend troponin measurement in all perioperative patients with symptoms or

electrocardiographic changes suggestive of ischemia or MI (two or three serial troponin values).

• For all asymptomatic patients at high cardiac risk, we recommend screening with high sensitivity
troponin (Grade 1B). High risk is defined as in-hospital surgery with one or more additional risk
factors of the revised cardiac risk score (table 1). We suggest obtaining troponin before surgery and
at 6 to 12 hours, and days one, two, and three after surgery. Some of our experts routinely perform
screening of lower-risk patients.

● With regard to obtaining a 12-lead electrocardiogram (see 'Management' above):

• We recommend performing 12-lead electrocardiography for all patients with symptoms of myocardial
ischemia.

• For all asymptomatic patients at high cardiac risk for perioperative MI (table 1), we suggest obtaining
a 12-lead electrocardiogram (Grade 2C). We obtain one at baseline and daily for two and possibly
three days.

● For all patients with perioperative MI or MINS, we recommend treatment with statin and aspirin therapy
(Grade 1B). On day one of therapy, we typically give atorvastatin 80 mg and aspirin 81 to 325 mg; we
continue with the same dose of atorvastatin and aspirin 75 to 100 mg daily.

● For patients with ST-elevation MI, we recommend treatment with a beta blocker (Grade 1B).

In addition, we usually proceed with urgent primary percutaneous coronary intervention after careful
discussion of the benefits and risks with all managing healthcare providers. (See 'ST-elevation MI'
above.)

● For patients with non-ST elevation MI, our experts have differing approaches to the use of beta blockers,
with some recommending their use in all patients and some recommending their use only in those with
moderate or large MI, untreated hypertension, or those who need rate control in atrial fibrillation. (See
'Non-ST elevation MI' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff would like to thank Drs. Jonathan B. Shammash and
Stephen E. Kimmel, and Dr. Scott Solomon, for their contributions as authors and section editor, respectively,
to previous versions of this topic review.

We are saddened by the death of Emile R Mohler, III, MD, who passed away in October 2017. UpToDate
wishes to acknowledge Dr. Mohler’s work as our Section Editor for Vascular Medicine.

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

1. Thygesen K, Alpert JS, White HD, et al. Universal definition of myocardial infarction. Circulation 2007;
116:2634.
2. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Circulation
2012; 126:2020.
3. Botto F, Alonso-Coello P, Chan MT, et al. Myocardial injury after noncardiac surgery: a large,

11 de 16 15/06/2018 10:28 p. m.
Perioperative myocardial infarction or injury after noncardiac surgery - ... https://www.uptodate.com/contents/perioperative-myocardial-infarction-o...

international, prospective cohort study establishing diagnostic criteria, characteristics, predictors, and
30-day outcomes. Anesthesiology 2014; 120:564.
4. 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.
5. Landesberg G, Shatz V, Akopnik I, et al. Association of cardiac troponin, CK-MB, and postoperative
myocardial ischemia with long-term survival after major vascular surgery. J Am Coll Cardiol 2003;
42:1547.
6. Landesberg G, Mosseri M, Shatz V, et al. Cardiac troponin after major vascular surgery: the role of
perioperative ischemia, preoperative thallium scanning, and coronary revascularization. J Am Coll
Cardiol 2004; 44:569.
7. Landesberg G, Beattie WS, Mosseri M, et al. Perioperative myocardial infarction. Circulation 2009;
119:2936.
8. Writing Committee for the VISION Study Investigators, Devereaux PJ, Biccard BM, et al. Association of
Postoperative High-Sensitivity Troponin Levels With Myocardial Injury and 30-Day Mortality Among
Patients Undergoing Noncardiac Surgery. JAMA 2017; 317:1642.
9. Devereaux PJ, Goldman L, Yusuf S, et al. Surveillance and prevention of major perioperative ischemic
cardiac events in patients undergoing noncardiac surgery: a review. CMAJ 2005; 173:779.
10. van Waes JA, Nathoe HM, de Graaff JC, et al. Myocardial injury after noncardiac surgery and its
association with short-term mortality. Circulation 2013; 127:2264.
11. Beattie WS, Karkouti K, Tait G, et al. Use of clinically based troponin underestimates the cardiac injury in
non-cardiac surgery: a single-centre cohort study in 51,701 consecutive patients. Can J Anaesth 2012;
59:1013.
12. Devereaux PJ, Xavier D, Pogue J, et al. Characteristics and short-term prognosis of perioperative
myocardial infarction in patients undergoing noncardiac surgery: a cohort study. Ann Intern Med 2011;
154:523.
13. Puelacher C, Lurati Buse G, Seeberger D, et al. Perioperative Myocardial Injury After Noncardiac
Surgery: Incidence, Mortality, and Characterization. Circulation 2018; 137:1221.
14. POISE Study Group, Devereaux PJ, Yang H, et al. Effects of extended-release metoprolol succinate in
patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet 2008;
371:1839.
15. McFalls EO, Ward HB, Moritz TE, et al. Predictors and outcomes of a perioperative myocardial infarction
following elective vascular surgery in patients with documented coronary artery disease: results of the
CARP trial. Eur Heart J 2008; 29:394.
16. Kamel H, Johnston SC, Kirkham JC, et al. Association between major perioperative hemorrhage and
stroke or Q-wave myocardial infarction. Circulation 2012; 126:207.
17. Devereaux PJ, Mrkobrada M, Sessler DI, et al. Aspirin in patients undergoing noncardiac surgery. N
Engl J Med 2014; 370:1494.
18. Mohler ER 3rd, Mantha S, Miller AB, et al. Should troponin and creatinine kinase be routinely measured
after vascular surgery? Vasc Med 2007; 12:175.
19. 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

12 de 16 15/06/2018 10:28 p. m.
Perioperative myocardial infarction or injury after noncardiac surgery - ... https://www.uptodate.com/contents/perioperative-myocardial-infarction-o...

Am Coll Cardiol 2009; 54:1599.

20. Lurati Buse GA, Koller MT, Burkhart C, et al. The predictive value of preoperative natriuretic peptide
concentrations in adults undergoing surgery: a systematic review and meta-analysis. Anesth Analg
2011; 112:1019.
21. Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA guideline on perioperative
cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the
American College of Cardiology/American Heart Association Task Force on practice guidelines. J Am
Coll Cardiol 2014; 64:e77.
22. Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA guideline on perioperative
cardiovascular evaluation and management of patients undergoing noncardiac surgery: executive
summary: a report of the American College of Cardiology/American Heart Association Task Force on
Practice Guidelines. Circulation 2014; 130:2215.
23. Kristensen SD, Knuuti J, Saraste A, et al. 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.
24. 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.
25. Badner NH, Knill RL, Brown JE, et al. Myocardial infarction after noncardiac surgery. Anesthesiology
1998; 88:572.
26. Shah KB, Kleinman BS, Sami H, et al. Reevaluation of perioperative myocardial infarction in patients
with prior myocardial infarction undergoing noncardiac operations. Anesth Analg 1990; 71:231.
27. Devereaux PJ, Goldman L, Cook DJ, et al. Perioperative cardiac events in patients undergoing
noncardiac surgery: a review of the magnitude of the problem, the pathophysiology of the events and
methods to estimate and communicate risk. CMAJ 2005; 173:627.
28. Parashar A, Agarwal S, Krishnaswamy A, et al. Percutaneous Intervention for Myocardial Infarction After
Noncardiac Surgery: Patient Characteristics and Outcomes. J Am Coll Cardiol 2016; 68:329.
29. Levy M, Heels-Ansdell D, Hiralal R, et al. Prognostic value of troponin and creatine kinase muscle and
brain isoenzyme measurement after noncardiac surgery: a systematic review and meta-analysis.
Anesthesiology 2011; 114:796.
30. Kim LJ, Martinez EA, Faraday N, et al. Cardiac troponin I predicts short-term mortality in vascular
surgery patients. Circulation 2002; 106:2366.
31. Rodseth RN, Biccard BM, Chu R, et al. Postoperative B-type natriuretic peptide for prediction of major
cardiac events in patients undergoing noncardiac surgery: systematic review and individual patient
meta-analysis. Anesthesiology 2013; 119:270.
32. 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.
33. Foucrier A, Rodseth R, Aissaoui M, et al. The long-term impact of early cardiovascular therapy
intensification for postoperative troponin elevation after major vascular surgery. Anesth Analg 2014;
119:1053.

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Topic 69 Version 38.0

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GRAPHICS

Revised cardiac risk index (RCRI)

Six independent predictors of major cardiac complications [1]

High-risk type of surgery (examples include vascular surgery and any open intraperitoneal or intrathoracic
procedures)

History of ischemic heart disease (history of myocardial infarction or a positive exercise test, current complaint of
chest pain considered to be secondary to myocardial ischemia, use of nitrate therapy, or ECG with pathological Q
waves; do not count prior coronary revascularization procedure unless one of the other criteria for ischemic heart
disease is present)

History of heart failure

History of cerebrovascular disease

Diabetes mellitus requiring treatment with insulin

Preoperative serum creatinine >2.0 mg/dL (177 micromol/L)

Rate of cardiac death, nonfatal myocardial infarction, and nonfatal cardiac arrest
according to the number of predictors [2]
No risk factors – 0.4% (95% CI: 0.1-0.8)
One risk factor – 1.0% (95% CI: 0.5-1.4)
Two risk factors – 2.4% (95% CI: 1.3-3.5)
Three or more risk factors – 5.4% (95% CI: 2.8-7.9)
Rate of myocardial infarction, pulmonary edema, ventricular fibrillation, primary
cardiac arrest, and complete heart block [1]
No risk factors – 0.5% (95% CI: 0.2-1.1)
One risk factor – 1.3% (95% CI: 0.7-2.1)
Two risk factors – 3.6% (95% CI: 2.1-5.6)
Three or more risk factors – 9.1% (95% CI: 5.5-13.8)
ECG: electrocardiogram.

References:
1. 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.
2. Devereaux PJ, Goldman L, Cook DJ, et al. Perioperative cardiac events in patients undergoing noncardiac
surgery: A review of the magnitude of the problem, the pathophysiology of the events, and methods to estimate
and communicate risk. CMAJ 2005; 173:627.

Graphic 57075 Version 13.0

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Contributor Disclosures
PJ Devereaux, MD, PhD Grant/Research/Clinical Trial Support: Abbott [Cardiac biomarker (hsTnl assays)];
Boehringer Ingelheim [Perioperative ischemia (Clonidine) and Myocardial injury (Dabigatran and
Omeprazole)]; Roche [Predictive biomarker (NT-proBNP assays)]. Jeroen J Bax, MD, PhD Grant/Research
/Clinical Trial Support: The Department of Cardiology of the Leiden University Medical Center, The
Netherlands, has received unrestricted research grants from Boston Scientific, Medtronic, Biotronik, and
Edwards LifeScience. Allan S Jaffe, MD Consultant/Advisory Boards: Beckman; Alere; Abbott; ET
Healthcare; Siemens; Outpost Medical; Sphingotec; Novartis [Biomarkers (Diagnostic tests)]; Becton
Dickinson [Point of Care/Laboratory Applications]; Quindel [hs--cTnI assay]. Gordon M Saperia, MD,
FACC Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform
to UpToDate standards of evidence.

Conflict of interest policy

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