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Evaluation of cardiac risk prior to noncardiac surgery
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Evaluation of cardiac risk prior to noncardiac surgery
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2016. | This topic last updated: Jun 28, 2016.

INTRODUCTION — Many patients undergoing major noncardiac surgery are at risk for a cardiovascular event. The risk is related to patient- and surgery-specific characteristics. Identification of increased risk provides the patient (and surgeon) with information that helps them better understand the benefit-to-risk ratio of a procedure and may lead to interventions that decrease risk.

This topic will review the initial preoperative cardiac evaluation, which includes an attempt to quantify risk. The management of cardiac risk (in an attempt to reduce morbidity and mortality) and issues related to the perioperative evaluation and management of heart failure or myocardial infarction are discussed separately. (See "Management of cardiac risk for noncardiac surgery" and "Perioperative myocardial infarction after noncardiac surgery" and "Management of perioperative heart failure in patients undergoing noncardiac surgery".)

INCIDENCE AND MECHANISM — The incidence of an adverse cardiovascular outcome is related to the baseline risk.

A 1995 review of major published series found that the pooled average rates of selective outcome of myocardial infarction (MI) and cardiac death varied with the population studied [1]:

Among unselected patients over age 40 – Perioperative MI in 1.4 percent and cardiac death in 1.0 percent

Among consecutive surgical patients with some selection criteria – Perioperative MI in 3.2 percent and cardiac death in 1.7 percent.

In a retrospective study of 663,635 adults not taking beta blockers who underwent major noncardiac surgery in 2000 and 2001, in-hospital mortality increased progressively from 1.4 to 7.4 percent according to a preoperative assessment of risk using the revised cardiac risk index described below [2] (table 1). (See 'Revised cardiac risk index' below.)

Patients with underlying cardiovascular disease, including peripheral artery disease or stroke, have an increased risk of perioperative cardiac complications compared to patients without extant atherosclerosis for two reasons:

They constitute a selected population with a high incidence of significant coronary artery disease [3,4]. In addition, left ventricular systolic dysfunction (left ventricular ejection fraction ≤40 percent) is five times more common in patients with cerebrovascular disease or peripheral artery disease compared with matched controls [5].

Physiologic factors associated with surgery predisposed to myocardial ischemia, which is more pronounced in patients with underlying coronary disease. These include volume shifts and blood loss, enhanced myocardial oxygen demand from elevations in heart rate and blood pressure secondary to stress from surgery, and an increase in postoperative platelet reactivity [6].

Despite the increased risk in the population with vascular disease, the rates of MI and death have been falling significantly. For example, perioperative mortality after carotid endarterectomy is approximately 1 percent and for abdominal aortic aneurysm repair is <3 percent [7].

OUR APPROACH — All patients scheduled to undergo noncardiac surgery should have an assessment of the risk of a cardiovascular perioperative cardiac event (algorithm 1) [8,9]. The purpose of this assessment is to help the patient and healthcare providers weigh the benefits and risks of the surgery and optimize the timing of the surgery. On occasion, risk assessment will uncover undiagnosed problems or suboptimally treated prior conditions that need attention. The clinician uses information obtained from the history, physical examination, and type of surgery in order to develop an initial estimate of perioperative cardiac risk. (See 'Initial preoperative evaluation' below.)

Risk models estimate the risk based on information obtained from the history, physical examination, electrocardiogram, and type of surgery. When assessing preoperative cardiac risk, we use either the revised cardiac risk index (RCRI), also referred to as the Lee index (table 1) [10], or the American College of Surgeons’ National Surgical Quality Improvement Program risk (ACS-NSQIP) model calculator [11]. The RCRI is simpler and has been widely used and validated over the past 15 years. The ACS-NSQIP calculator is more complex and has yet to be validated in other populations. A simpler tool also derived from the NSQIP database is the Gupta MI or cardiac arrest (MICA) calculator. Practitioners should become familiar with one model and use it regularly. (See 'Estimating perioperative risk' below.)

These models provide the user with the risk of a cardiac complication in percent. For patients at low risk (<1 percent), no further testing is indicated. For patients at higher risk, caregivers need to ask the question whether further cardiovascular testing will change management and hopefully improve the outcome. In most cases, the reason to perform additional testing will be based not on desire to lower risk at the time of surgery, but rather lowering long-term risk. That is, the patient should have additional testing done irrespective of the need for surgery. There are few circumstances in which testing should be performed solely because the patient has upcoming surgery.

Very high-risk patients — Patients with recent myocardial infarction (MI) or unstable angina, decompensated heart failure (HF), high-grade arrhythmias, or hemodynamically important valvular heart disease (aortic stenosis in particular) are at very high risk for perioperative MI, HF, ventricular fibrillation or primary cardiac arrest, complete heart block, and cardiac death. All such patients should be optimally treated, with possible referral to a cardiologist for further evaluation and management [12]. (See "Noncardiac surgery in patients with aortic stenosis" and "Management of perioperative heart failure in patients undergoing noncardiac surgery", section on 'Risk classification by heart failure syndrome'.)

Emergent or urgent surgery — Patients who require emergent or urgent surgery are at increased risk of a perioperative cardiovascular event at any level of baseline risk. In these cases, risk indices derived from elective surgery cohorts are not accurate, although they may provide an estimate of the minimal risk.

In many cases, there is not sufficient time for an extensive evaluation of the severity of a patient’s cardiovascular problem and in most cases the benefit of proceeding with surgery outweighs the risk of waiting to perform additional testing. In the absence of pre-operative assessment because of the minimal time available before surgery, clinicians must be available postoperatively to help manage the possible cardiovascular complications in at-risk patients.

INITIAL PREOPERATIVE EVALUATION — Once a determination is made that noncardiac surgery will be considered, the patient should be evaluated for the risk of a cardiovascular complication. This evaluation is generally performed by a primary care physician. The information obtained is used to assess risk. In patients assessed to be at elevated (intermediate or high) cardiovascular risk, a referral to a cardiologist for further evaluation may be indicated.

At the time of the initial preoperative evaluation, the physician should inquire about symptoms such as angina, dyspnea, syncope, and palpitations as well as a history of heart disease including ischemic, valvular, or myopathic disease, and a history of hypertension, diabetes, chronic kidney disease, and cerebrovascular or peripheral artery disease.

In addition, cardiac functional status should be determined. Functional status can be expressed in metabolic equivalents (1 MET is defined as 3.5 mL O2 uptake/kg per min, which is the resting oxygen uptake in a sitting position). Various activity scales provide the clinician with a set of questions to determine a patient's functional capacity [13]. Indicators of functional status include the following:

Can take care of self, such as eat, dress, or use the toilet (1 MET)

Can walk up a flight of steps or a hill or walk on level ground at 3 to 4 mph (4 METs)

Can do heavy work around the house such as scrubbing floors or lifting or moving heavy furniture or climb two flights of stairs (between 4 and 10 METs).

Can participate in strenuous sports such as swimming, singles tennis, football, basketball, and skiing (>10 METs)

One important indicator of poor functional status and an increased risk of postoperative cardiopulmonary complications after major noncardiac surgery is the inability to climb two flights of stairs or walk four blocks [14,15]. However, in patients with limitations to walking such as orthopedic problems, it may be hard to assess cardiac functional status. One may use bicycle or arm ergometry stress testing to evaluate a patient’s functional capacity when the inability to walk limits testing.

The physical examination should focus on the cardiovascular system, and include blood pressure measurements, auscultation of the heart and lungs, abdominal palpation, and examination of the extremities for edema and vascular integrity. Important findings include evidence of heart failure or a murmur suspicious for hemodynamically significant valvular heart disease. (See 'Risk factors used in risk prediction models' below.)

Similar to recommendations made in the 2014 American College of Cardiology/American Heart Association and European Society of Cardiology/European Society of Anesthesiology guidelines on noncardiac surgery, we obtain an electrocardiogram (ECG) in many patients with known cardiovascular disease, significant arrhythmia, or significant structural heart disease unless the patient is undergoing low-risk surgery [8,9,16]. A preoperative ECG can be obtained in asymptomatic patients without known cardiovascular disease, but it is rarely helpful. Some ECG abnormalities seem to be associated with a worse prognosis in observational studies, but the association is inconsistent across studies. ECG abnormalities are not part of either the Revised Cardiac Risk Index or the National Surgical Quality Improvement Plan because of the lack of prognostic specificity associated with these findings. (See 'Estimating perioperative risk' below.)

The rationale for obtaining a preoperative ECG comes from the utility of having a baseline ECG should a postoperative ECG be abnormal.

For those patients who receive a preoperative ECG, it should be evaluated for the presence of Q waves or significant ST-segment elevation or depression, which raises the possibility of myocardial ischemia or infarction, left ventricular hypertrophy, QTc prolongation, bundle-branch block, or arrhythmia [17].

RISK FACTORS USED IN RISK PREDICTION MODELS — The following clinical and surgery-specific factors are associated with an increase in perioperative risk of a cardiovascular event and are used in one or both of the models discussed below (Revised Cardiac Risk Index [RCRI] or MICA calculator derived from the National Surgical Quality Improvement Plan [NSQIP]). The newer ACS-NSQIP calculator includes 20 patient risk factors in addition to the surgical procedure. (see 'Estimating perioperative risk' below):

Surgery specific risk (RCRI and NSQIP). The reported rate of cardiac death or nonfatal myocardial infarction is more than 5 percent in high-risk procedures, between 1 and 5 percent in intermediate-risk procedures, and less than 1 percent in low-risk procedures. Institutional and/or individual surgeon experience with the procedure may increase or lower the risk. Emergency surgery is associated with particularly high risk, as cardiac complications are two to five times more likely than with elective procedures (table 2).

History of ischemic heart disease (RCRI)

History of heart failure (RCRI)

History of cerebrovascular disease (RCRI)

Insulin dependent diabetes mellitus (RCRI)

Preoperative serum creatinine ≥2.0 mg/dL (RCRI) or >1.5 mg/dL (NSQIP)

Increasing age (NQSIP)

American Society of Anesthesiologist class (NSQIP)

Preoperative functional status (NSQIP)

The value of these risk indicators may be diminishing over time as the cardiovascular risk of surgery is declining. For example, in a large study of noncardiac surgery, neither the presence of history of coronary artery disease, transient ischemic attack history, nor diabetes predicted three-day mortality [18]. This may result from the changing nature of postoperative myocardial infarction, from a type 1, plaque rupture, myocardial infarction (MI) to a type 2, hemodynamic MI. In the PeriOperative ISchemic Evaluation trial of 8351 patients at high risk for or with atherosclerosis undergoing noncardiac surgery, only 35 (0.4 percent) required coronary revascularization postoperatively [19]. Thus, the value of risk prediction models may be waning as the end point of interest decreases.

Other clinical predictors — While not included in the risk factors above, the following patient characteristics have been associated with increased risk:

Atrial fibrillation – A retrospective, administrative database study demonstrated an association between a history of prior admission for atrial fibrillation (AF) and postoperative complications [20]. The risk associated with AF was higher than that associated with a diagnosis of coronary artery disease.

Obesity – Obese patients are at increased risk for adverse cardiovascular events at the time of noncardiac surgery. However, obesity has not been shown to be an independent predictor. (See "Obesity, weight reduction, and cardiovascular disease", section on 'Coronary disease'.)

The issue of whether the preoperative approach to obese patients should differ from that in the general population is uncertain. A 2009 scientific advisory on cardiovascular evaluation and management of severely obese patients undergoing surgery from the American Heart Association states that specific tests should be performed only if the results will change management [21].

ESTIMATING PERIOPERATIVE RISK — The history, physical examination, and 12-lead electrocardiogram identify patient-specific risk factors. This information, combined with the risk associated with the surgery, is used to estimate perioperative risk of adverse cardiac events (table 3).

The risk will determine whether surgery should proceed without further cardiovascular testing, be postponed pending further testing such as stress testing, echocardiography, or 24-hour ambulatory monitoring, changing the planned surgery to a lesser risk procedure (if possible) or a non-surgical alternative (eg, palliative care), or cancelled so that a procedure such as coronary revascularization or heart valve replacement can take place. Multivariable analyses have identified combinations of factors that can be used to estimate perioperative risk [3]. Perioperative risk is expressed as the likelihood (in percent) that a patient will suffer a cardiac complication at the time of noncardiac surgery.

Models such as the Revised (Lee) cardiac risk index (RCRI) and the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) risk prediction calculators (Gupta myocardial infarction/cardiac arrest [MICA] or Bilimoria ACS surgical risk calculator) have included patients with high-risk characteristics and who have been managed with more current standards of care. For these reasons, we suggest using one of these models. The MICA calculator outperformed the RCRI in some circumstances, and the newer ACS-NSQIP surgical risk calculator is more comprehensive and procedure specific. However, as mentioned previously, neither of these have yet to be validated externally. Furthermore, direct comparison of the various tools is difficult due to their different definitions of risk factors, complications, and outcomes [22]. We do not recommend using older models such as the original Goldman cardiac risk index [23], the Detsky modified risk index, or the Eagle criteria [24-29]. Risk assessment should include information from the chosen scoring system with the inherent risk of the surgery.

Gupta MICA NSQIP database risk model — The NSQIP database was used to determine risk factors associated with intraoperative/postoperative myocardial infarction or cardiac arrest (MICA) [30]. Among over 200,000 patients who underwent surgery in 2007, 0.65 percent developed perioperative MICA. On multivariate logistic regression analysis, five factors were identified as predictors of MICA:

Type of surgery;

Dependent functional status;

Abnormal creatinine;

American Society of Anesthesiologists’ class (table 4);

Increased age.

A risk model was developed using these five factors and subsequently validated on a 2008 data set (n = 257,385). The risk model had a relatively high predictive accuracy (C statistic of 0.874) and outperformed the RCRI (C statistic of 0.747). An easy-to-use calculator was developed from this model.

Revised cardiac risk index — The RCRI, sometimes referred to as the Lee index, was published in 1999 and has been used worldwide since then [10]. In the derivation of the index, 2893 patients (mean age 66) undergoing elective major noncardiac procedures were monitored for major cardiac complications (cardiac death, acute MI, pulmonary edema, ventricular fibrillation/cardiac arrest, and complete heart block) (table 1). The index was validated in a cohort of 1422 similar individuals. The predictive value was significant in all types of elective major noncardiac surgery except for abdominal aortic aneurysm surgery (figure 1).

A 2009 systematic review evaluated the ability of the RCRI to predict cardiac complications and mortality after major noncardiac surgery in various populations and settings [31]. The RCRI performed moderately well in distinguishing patients at low compared to high risk for all types of noncardiac surgery, but was somewhat less accurate in patients undergoing only vascular noncardiac surgery. In addition, RCRI did not predict all-cause mortality well. However, this is expected, as it does not capture risk factors for noncardiac causes of perioperative mortality and only one-third of perioperative deaths are due to cardiac causes.

The risk of major cardiac complications (cardiac death, nonfatal MI, nonfatal cardiac arrest, postoperative cardiogenic pulmonary edema, complete heart block) varied according to the number of risk factors. The following rates of adverse outcomes were seen in various studies [32]:

No risk factors – 0.4 percent

One risk factor – 1 percent

Two risk factors – 2.4 percent

Three or more risk factors – 5.4 percent

In a large retrospective analysis on mortality, the perioperative risk was evaluated in 663,665 adults with no contraindications to beta blockers who underwent major noncardiac surgery in 2000 and 2001 at 329 hospitals in the United States [2]. In-hospital mortality in patients not treated with beta blockers increased progressively from 1.4 percent at a score of 0, to 7.4 percent at a score ≥4. The rate of mortality in this study was higher at the same RCRI than the combined end point of cardiac death, nonfatal MI, and nonfatal cardiac arrest in the earlier RCRI (Goldman) population [32].

In the POISE randomized trial of over 8000 patients undergoing noncardiac surgery between 2002 and 2007, the combined rate of cardiovascular death, nonfatal MI, and nonfatal cardiac arrest was 6.9 percent in the placebo group [33]. The majority of these individuals were RCRI 1 or 2. (See "Management of cardiac risk for noncardiac surgery", section on 'Beta blockers'.)

There are several factors that probably contribute to the higher event rate in these two later studies:

The original RCRI risk prediction model did not take all-cause mortality into account [10]

RCRI only included in-patient complications, not 30-day event rates.

In earlier studies, creatine kinase MB fraction was used to diagnose MI, rather than troponins, which are more sensitive.

The type of myocardial infarction after surgery is changing. The incidence of a type 1, plaque rupture, MI is decreasing while type 2, hemodynamic MI, is increasing.

One study re-examined the original six risk factors to confirm their validity in a large modern prospective database, including 9519 patients aged ≥50 undergoing elective non-cardiac surgery with an expected length of stay ≥2 days at two major tertiary-care teaching hospitals [34]. Compared with the RCRI, a simplified five-factor model ("reconstructed RCRI") using high-risk type of surgery, history of ischemic heart disease, congestive heart failure, cerebrovascular disease, and preoperative GFR <30 mL/min (but not including diabetes or insulin treatment) resulted in superior prediction of major cardiac complications following elective noncardiac surgery.

VSGNE risk index — As the RCRI, discussed directly above, did not perform well in patients undergoing vascular surgery, the Vascular Study Group of New England (VSGNE) developed a risk index specifically for those patients [35]. In multivariate analysis of the VSGNE cohort, independent predictors of adverse cardiac events (MI, arrhythmia, heart failure, but not mortality) were (odds ratio [OR]) increasing age (1.7 to 2.8), smoking (1.3), insulin-dependent diabetes (1.4), coronary artery disease (1.4), CHF (1.9), abnormal cardiac stress test (1.2), long-term beta-blocker therapy (1.4), chronic obstructive pulmonary disease (1.6), and creatinine ≥1.8 mg/dL (1.7). Prior cardiac revascularization was protective (OR, 0.8). The calculators for the various procedures are available online. The RCRI substantially underestimated in-hospital cardiac event in patients undergoing elective or urgent vascular surgery, especially after lower extremity bypass, endovascular abdominal aortic aneurysm repair, and open infrarenal abdominal aortic aneurysm. This risk index also has not been externally validated and did not include mortality as an end point.

ACS-NSQIP universal surgical risk calculator — A universal surgical risk calculator model [11] has been developed using a web-based tool consisting of 20 patient factors plus the surgical procedure. This model had excellent performance for mortality (c-statistic = 0.944; Brier score = 0.011 [where scores approaching 0 are better]), morbidity (c-statistic = 0.816, Brier score = 0.069), and six additional complications (c-statistics > 0.8). While more comprehensive than the other risk calculators, it is more cumbersome, which may limit its use. In addition, this calculator has not yet been externally validated.

MANAGEMENT BASED ON RISK — We use estimated risk (see 'Estimating perioperative risk' above) to categorize patients into low- or higher-risk groups.

Low-risk patients — Patients whose estimated risk of death is less than 1 percent are labeled as being low risk and require no additional cardiovascular testing.

Higher-risk patients — Patients whose risk of death is 1 percent or higher may require additional cardiovascular evaluation. Often, these are patients with known or suspected coronary artery or valvular heart disease. Further evaluation may include stress testing, echocardiography, 24-hour ambulatory monitoring, or cardiologist consultation. We generally perform these tests if they are indicated for the patient even if they were not having surgery. Many studies of patients not at low risk have shown that performing some form of stress testing can further stratify the risk of an adverse perioperative event [21,27,28,36-45]. However, no study has shown that interventions performed consequent to the results of the test improves outcomes.  

When we consider further cardiovascular evaluation for higher-risk patients, we use the approach suggested in the 2014 American College of Cardiology/American Heart Association guideline of perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery [8,9]. In this approach, the patient’s functional capacity plays an important role (algorithm 1). In patients who can perform ≥4 METs of activity, we do not order additional tests. For those whose functional capacity is lower or unknown, additional testing may be indicated if it will influence perioperative care.  

FURTHER CARDIAC TESTING — In patients with known or suspected heart disease (ie, cardiovascular disease, significant valvular heart disease, symptomatic arrhythmias), we perform further cardiac evaluation (echocardiography, stress testing, or 24-hour ambulatory monitoring) only if it is indicated in the absence of proposed surgery. There is no evidence that further diagnostic or prognostic evaluation improves surgical outcomes, although some of our experts routinely obtain preoperative stress imaging in patients who are scheduled for major vascular surgery. Preoperative cardiac evaluation and testing may differ for patients being evaluated for liver or kidney transplant. (See "Liver transplantation in adults: Patient selection and pretransplantation evaluation", section on 'Cardiac stress testing'.)

For patients in whom a decision has been made to perform additional cardiovascular testing, its timing should be determined by the urgency of the clinical situation.

Stress testing — Stress testing is not indicated in the perioperative patient solely because of the surgery if there is no other indication. (See "Stress testing for the diagnosis of obstructive coronary heart disease" and "Stress testing in patients with left bundle branch block or a paced ventricular rhythm" and "Noninvasive testing and imaging for diagnosis in patients at low to intermediate risk for acute coronary syndrome" and "Screening for coronary heart disease in patients with diabetes mellitus" and "Stress testing to determine prognosis of coronary heart disease".).

Stress testing with exercise (with or without imaging) and pharmacologic stress testing with imaging have been well studied in patients scheduled to undergo noncardiac surgery. Although there is a clear relationship between the degree of myocardial ischemia found and prognosis, there is no evidence that prophylactic revascularization only to prevent ischemia at the time of surgery improves outcomes [36,45-53].

Resting echocardiography — Resting echocardiography is not indicated in the perioperative patient unless there is another indication, such as to evaluate valve function in patients with a murmur or left ventricular systolic function in patients with HF or dyspnea of unknown cause. (See "Transesophageal echocardiography: Indications, complications, and normal views" and "Echocardiographic evaluation of prosthetic heart valves" and "Role of echocardiography in atrial fibrillation" and "Echocardiographic evaluation of the aortic valve" and "Echocardiographic evaluation of the mitral valve".)

The presence of significant left ventricular systolic dysfunction or severe valvular heart disease is associated with a worse outcome, particularly postoperative heart failure, at the time of noncardiac surgery [37,54-58].

24-hour ambulatory monitoring — As with echocardiography and stress testing, we do not recommend 24-hour ambulatory monitoring for perioperative diagnostic or prognostic purposes if it is not otherwise indicated. Its use has not been shown to improve outcomes in this setting [1,59,60]. The indications for 24-hour ambulatory monitoring are discussed elsewhere and are primarily for patients with syncope or significant bradycardia or tachycardia if not previously evaluated. (See "Ambulatory ECG monitoring" and "Overview of palpitations in adults" and "Evaluation of syncope in adults" and "Ventricular premature beats" and "Supraventricular premature beats" and "Evaluation of the survivor of sudden cardiac arrest" and "Sustained monomorphic ventricular tachycardia: Diagnosis and evaluation".)

Troponin and BNP — The potential role of troponin and brain natriuretic peptide testing in perioperative risk stratification is discussed elsewhere. (See "Perioperative myocardial infarction after noncardiac surgery", section on 'Troponin' and "Natriuretic peptide measurement in non-heart failure settings", section on 'Postoperative complications'.)

RECOMMENDATIONS OF OTHERS — Our approach to the evaluation of patients scheduled to undergo noncardiac surgery is generally similar to that presented in the 2014 American College of Cardiology/American Heart Association(ACC/AHA) and European Society of Cardiology/European Society of Anesthesiology (ESC/ESA) guidelines on noncardiac surgery [8,9,16]. Despite collaborative efforts of the two societies to minimize discrepancies between their guidelines, there are differences in recommendations. We prefer the algorithm and recommendations in the ACC/AHA guideline (algorithm 1).


All patients scheduled to undergo noncardiac surgery should have an assessment of the risk of a cardiovascular perioperative cardiac event (algorithm 1). (See 'Our approach' above.)

Identification of risk factors is derived from the history, physical examination, and type of proposed surgery. (See 'Initial preoperative evaluation' above.)

We use either the Revised (Lee) Cardiac Risk Index or the ACS-National Surgical Quality Improvement Program risk prediction rule to establish the patient’s risk. (See 'Estimating perioperative risk' above.)

We obtain an electrocardiogram in patients with cardiac disease (except in those undergoing low-risk surgery) in large part to have a baseline available should a postoperative test be abnormal. (See 'Initial preoperative evaluation' above.)

For patients with known or suspected heart disease (ie, cardiovascular disease, significant valvular heart disease, symptomatic arrhythmias), we only perform further cardiac evaluation (echocardiography, stress testing, or 24-hour ambulatory monitoring) if it is indicated in the absence of proposed surgery. (See 'Further cardiac testing' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff would like to thank Drs. James P. Morgan and Jonathan B. Shammash for their contributions as authors to previous versions of this topic review.

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