Introduction

Cardiac adverse events including death are one of the most feared complications of noncardiac surgery, for which several high-risk cardiac conditions have been defined and a number of risk scores have been developed.^[1],[2],[3] Model for end-stage liver disease (MELD) score was developed to predict clinical outcomes primarily in patients with liver disease,^[4],[5] but it has also been used in patients with multiorgan failure,^[6] heart failure,^[7] or left ventricular assist devices (LVADs).^[8],[9],[10] MELD-XI score is a derivative of MELD score, calculated by excluding international normalized ratio (INR) from the parameters for patients who use anticoagulants. MELD-XI score has also been shown to predict mortality in various cardiac conditions.^{[11],[12],[13],[14],[15],[16]} Herein, we aimed to study MELD-XI score to predict mortality among high-risk patients undergoing elective or urgent noncardiac surgery.

Materials and Methods

This study was approved by the Local Ethics Committee (Approval Date 25.04.2019, Approval No.: KA 19/156) and supported by the Local University Research Fund. The demographic, clinical, electrocardiographic, echocardiographic, and biochemical data of 84 patients who underwent elective or urgent noncardiac surgery under general anesthesia between January 1, 2013, and January 1, 2018, were retrospectively reviewed from written medical records and hospital data automation system.

The type of elective or urgent noncardiac surgery and risk status of the individual patients were recorded, and only high-risk noncardiac surgical candidates were enrolled.^[1] The elective noncardiac surgical operations included in the present the study were the ones that could not be delayed due to the severity of the underlying condition, where the risk of postponing surgery would outweigh surgical risk. The risk of noncardiac surgery was determined by the consulting cardiologist. The high-risk cardiac conditions included all vascular diseases undergoing surgery; severe aortic stenosis, as defined as a mean transaortic gradient ≥40 mmHg and/or a valve area <1.0 cm ² on transthoracic echocardiography; severe mitral stenosis, as defined as a mean transmitral gradient of ≥10 mmHg and/or a mitral valve area <1 cm ² on transthoracic echocardiography; severe pulmonary arterial hypertension defined as a mean pulmonary artery pressure of ≥70 mmHg on transthoracic echocardiography and/or a mean pulmonary artery pressure of ≥40 on a recent cardiac catheterization; multiple prosthetic heart valves; serious ventricular arrhythmias including ventricular tachycardia, ventricular flutter, or ventricular fibrillation, or frequent ventricular premature depolarizations with reduced left ventricular systolic function; atrial fibrillation or flutter with rapid ventricular rate response (>110/min at rest); recent or current acute coronary syndromes or myocardial infarction; severe decompensated or low-output heart failure; and uncontrollable angina pectoris despite maximal medical therapy or previous coronary intervention. None of the patients underwent surgical or percutaneous correction of high-risk cardiac conditions due to either urgency of noncardiac surgery or presence of multiple comorbidity risking procedural safety, such as hematological disorders (coagulopathies, bleeding diatheses, and anticoagulant use), acute renal failure, acute hepatic failure, contrast agent allergy, active infection, hypoxemia or decompensated heart failure, or overall poor patient status. All patients received appropriate therapy against individual high-risk cardiac conditions, including anti-ischemic therapy composed of oxygen, beta-blockers, nitrates, acetylsalicylic acid, and statins; appropriate antihypertensive therapy using intravenous or oral antihypertensives for uncontrolled or severe hypertension; heart rate control using digoxin, beta-blockers or non-dihydropyridine calcium channel blockers, and anticoagulation with low-molecular-weight heparin for atrial fibrillation or atrial flutter; prompt defibrillation or cardioversion plus amiodarone and electrolyte replacement for serious ventricular arrhythmias; loop diuretics, aldosterone antagonists, oxygen, nitrates, beta-blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for decompensated heart failure; and diuretics, beta-blockers, and/or calcium channel blockers for severe mitral stenosis.

Preoperative revised cardiac risk index (Lee score), which was developed for perioperative cardiac adverse events in 1999,^[3] was calculated for all patients using six risk factors including high-risk type of surgery (intraperitoneal, intrathoracic, or suprainguinal vascular), history of coronary artery disease (IHD), history of congestive heart failure, history of cerebrovascular disease, preoperative insulin treatment, and preoperative serum creatinine >2.0 mg/dL. MELD-XI score was calculated using the logarithmic conversions of serum creatinine and total serum bilirubin in the following manner: 5.11× ln (serum bilirubin in mg/dL) + 11.76 × ln (serum creatinine in mg/dL) +9.44. Serum creatinine and total bilirubin values below 1.0 mg/dL were rounded up to 1 mg/dL. Serum creatinine values of patients receiving hemodialysis were set to 4 mg/dL.

All in-hospital perioperative cardiac adverse events and deaths were recorded. Cardiac adverse events were defined as perioperative ischemia and/or infarction, pulmonary thromboembolism, ventricular tachycardia, fibrillation, asystole, high-grade atrioventricular block, supraventricular tachycardia with rapid ventricular response, and decompensated and/or low-output heart failure. Cardiac death was defined as that occurring due to the following: myocardial infarction and/or ischemia as evidenced by typical ischemic ECG changes and/or typical rise and fall of cardiac biomarkers of injury; serious ventricular tachyarrhythmias, serious bradyarrhythmias and asystole, supraventricular arrhythmias with rapid ventricular rate response, pericardial tamponade, acute aortic dissection, coronary dissection or embolism, and pulmonary thromboembolism. Information about postdischarge 1-year all-cause mortality was obtained from the records of the local births, deaths, and marriages registration office.

The exclusion criteria were as follows: undergoing cardiac or low-to-intermediate risk surgery; surgical or transcatheter correction of cardiac high-risk condition before noncardiac surgery, thus reducing perioperative risk; postdischarge deaths due to suicide, homicide, accidents, or intoxications; and unknown postdischarge survival status.

No patient consent was obtained from any patient due to the retrospective nature of the study.

Statistical analysis

The study data were analyzed using SPSS (Statistical Package for the Social Sciences) Windows 21.0 (IBM Inc, USA) software. The distribution of continuous variables was tested using the Kolmogorov–Smirnov test. The normally distributed continuous variables were expressed as mean ± standard deviation; the nonnormally distributed ones as median and interquartile range (IQR); and categorical variables as number and percentage. Normally distributed continuous variables were compared with the independent samples t-test; nonnormally distributed continuous variables with the Mann–Whitney-U-test; and the categorical variables with the Chi-square test.

The significant predictors of both in-hospital total and 1-year mortality were initially tested with a univariate analysis using all available demographic, clinical, biochemical, and echocardiographic variables. All univariate predictors of mortality with P < 0.25 were then used in a binary logistic regression model with backward LR method to determine the independent predictors of both mortality rates. Receiver operating characteristic (ROC) curve was drawn to determine a significant cutoff point of MELD-XI score for in-hospital cardiac and 1-year all-cause mortality. Log-rank test and Kaplan–Meier survival analysis were performed to assess the effect of MELD-XI score on 1-year all-cause survival. P < 0.05 was considered statistically significant for all tests.

Results

The overall characteristics of the study population are shown in [Table 1]. All patients underwent elective or urgent noncardiac surgery under general anesthesia, and the majority (71.4%) of patients underwent general surgery or orthopedic operations. A total of 60 (71.4%) operations were urgent; 24 (28.6%) operations were elective. The most common cardiac high-risk conditions were decompensated heart failure, atrial fibrillation/flutter with rapid ventricular response (each 21.8%), severe valvular stenosis (17.2%), and pulmonary hypertension (16.1%). Forty (47.6%) patients experienced perioperative adverse cardiac events [Table 2]. A total of 16 (19.0%) patients died during perioperative period and 24 (28.6%) patients died by 1 year after hospital discharge, so that a total of 40 (47.6%) patients died by 1 year. The documented cardiac adverse events and etiologies of in-hospital cardiac death are shown in [Table 2]. Those who died at hospital had a significantly higher serum creatinine level (P < 0.01), hemoglobin level (P < 0.05), and rate of angina pectoris (P < 0.05), but a lower rate of perioperative beta-blocker use (P < 0.05) compared to the survivors. Patients who died by the end of 1 year had a significantly lower hemoglobin level, a significantly higher serum AST level, and a significantly higher rate of pulmonary hypertension (P < 0.05 for all comparisons) than the survivors. Other clinical, demographic, and laboratory data were similar between the deceased and surviving patients [Table 3] and [Table 4].

The comparison of revised cardiac risk index (Lee) score between the deceased and survivor groups revealed that it was significantly higher in the patients with in-hospital mortality, but not in those that died by 1 year (3 [3] vs. 2 [1]; P < 0.05 and 2 [2] vs. 1.5 [1]; P = 0.141, respectively). MELD-XI score, on the other hand, was significantly higher in patients with both in-hospital and long-term mortality (12.23 [IQR: 6.53] vs. 9.66 [IQR: 3.81]; P = 0.001 and 10.80 [IQR: 6.31] vs. 9.70 [IQR: 3.70]; P = 0.037, respectively) [Table 3] and [Table 4], respectively]. In univariate analysis, in-hospital cardiac mortality was significantly correlated with MELD-XI score, revised cardiac risk index (Lee) score, cardiac adverse events, serum creatinine level, and serum hemoglobin count (P < 0.05 for all), while 1-year all-cause mortality was significantly correlated with MELD-XI score and hemoglobin count (P < 0.05 for both comparisons), but not to revised cardiac risk index (Lee) score. A multivariate analysis showed that MELD-XI score independently predicted in-hospital all-cause mortality (OR: 1.254 [95% confidence interval (CI): 1.028–1.530]; P < 0.05) and 1-year mortality (OR: 1.258 [95% CI: 1.057–1.498]; P < 0.01). In ROC analysis, a MELD-XI score of >10.70 significantly predicted in-hospital cardiac mortality with a sensitivity of 75.0% and a specificity of 63.2% (AUC: 0.760; 95% CI: 0.640–0.880; P = 0.01) [Figure 1]; a MELD-XI score of >9.87 was associated with 1-year all-cause mortality with a sensitivity of 80% and a specificity of 40.9% (AUC: 0.633; 95% CI: 0.513–0.753; P < 0.05) [Figure 2]. A survival analysis performed between the patients categorized into high (>9.87) and low (≤9.87) MELD-XI score groups showed that the patients with a high MELD-XI score (>9.87) had a significantly worse 1-year survival (log rank test; P < 0.05) [Figure 3].

Discussion

This study has some important findings. First, among patients with high-risk cardiac conditions who underwent elective or urgent noncardiac surgery, MELD-XI score was significantly higher in those with in-hospital cardiac and 1-year all-cause mortality compared to survivors. Second, MELD-XI score independently predicted in-hospital cardiac mortality and 1-year all-cause mortality. Collectively, these results suggest that MELD-XI score is a useful score for predicting prognosis after both elective and urgent noncardiac surgery among patients with high-risk cardiac conditions.

Cardiac risk is an important aspect of noncardiac surgery for both surgeons and patients.^[17],[18] On average, 7%–11% of all noncardiac surgical operations are complicated, and mortality rates range between 0.8% and 1.5%,^[17] with as much as 42% of all complications being of cardiac origin.^[18] Apart from emergent or cardiovascular procedures, several cardiac conditions increase the risk of a noncardiac procedure.^[1] However, not all high-risk patients die from or suffer adverse cardiovascular events, with other procedural, anesthetic, and patient-specific factors being operational in the perioperative period or in the long term. Although some high-risk cardiac conditions may be treated and cardiac risk may be reduced,^{[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34]} such procedures may not be performed due either to urgency of surgery or presence of multiple/severe comorbidities. Hence, other prognostic tools for advanced risk stratification of patients undergoing noncardiac surgery are needed.

MELD score was originally developed to predict clinical outcomes in liver disease.^[4] It was subsequently used in various cardiac conditions.^[7],[8],[9] The suggested mechanism by which MELD score predicts mortality in cardiac conditions is reduced forward cardiac output and end-organ perfusion (forward failure) as well as increased central venous pressure leading to hepatic and renal venous congestion (backward failure), which are reflected by increased serum creatinine, total bilirubin, and INR.^{[35],[36],[37]} MELD-XI score, a modification of the original MELD score excluding INR from the model, was developed to determine the prognosis of patients using anticoagulants. MELD-XI score has been successfully tested in various cardiac conditions ^{[11],[12],[13],[14],[15],[16]} and critically ill.^[38] Although MELD-XI score was tested in cardiac surgery and cardiac transplantation,^{[11],[12],[16],[39]} our study is the first to investigate it for advanced risk stratification of high-risk cardiac patients undergoing noncardiac surgery.

In the present study, MELD-XI score successfully independently predicted both in-hospital cardiac mortality and 1-year all-cause mortality. It was also highly correlated with revised cardiac risk index (Lee) score, which has been shown to accurately predict perioperative cardiac events.^[3] When hemodynamic burden of conditions requiring noncardiac surgery is added to high-risk cardiac conditions, overt or subclinical heart failure may develop, resulting in an elevated MELD-XI score. Hence, a higher MELD-XI score in high-risk surgical patients may indicate an even higher cardiac risk. Of note, our study found that MELD-XI score was not correlated with echocardiographic left ventricular ejection fraction (LVEF). However, heart failure may develop in patients with normal LVEF. In support of this view, MELD-XI score was positively correlated with the rates of heart failure (combination of diastolic and systolic failure). In addition, it was significantly and positively correlated with coronary artery disease, severe valvular lesions, and ST segment depression and significantly and negatively correlated with serum hemoglobin count, all of which may also be responsible for cardiovascular dysfunction.

Various studies have reported a range of MELD-XI scores for mortality prediction, and this variability may stem from different inclusion criteria and conditions. We found a MELD-XI cutoff point of 10.70 for in-hospital cardiac mortality, which is in agreement with an almost identical score reported by He et al.^[13] However, Wernly et al.^[10] and Critsinelis et al.^[11] reported much higher cutoff points (12 and 14, respectively) for in-hospital mortality among patients with critical illness and those undergoing LVAD implantation, respectively. Similarly, our MELD-XI cutoff point of 9.87 for long-term all-cause mortality is much lower than those reported by Yang et al.^[14] and Spieker et al.^[12] (17 and 16, respectively) after LVAD placement and percutaneous mitral valve repair, respectively. He et al.^[13] and Wernly et al.^[10] reported somewhat lower, albeit still higher, cutoff points (13 and 12, respectively) for prediction of long-term mortality after infective endocarditis and critical illness, respectively. According to our opinion, our MELD-XI cutoff points were lower than previously reported because our patients were at the highest risk of death caused by the risk of noncardiac surgery added to cardiac high-risk conditions, a higher median age (81 years) and a higher rate of heart failure (50%). Hence, lower MELD-XI scores may have predicted short-term and long-term mortality among our patients.

Limitations

This study had some limitations. First, it had a retrospective design. Second, the study population was relatively small because a sizeable portion of patients having high-risk cardiac conditions refuse to undergo noncardiac surgery due to heightened cardiac risk, or some surgeons refuse to operate such patients, particularly when there is no compelling indication for surgery. Furthermore, corrective or palliative cardiac procedures are performed prior to noncardiac surgery in some of patients with high-risk cardiac conditions. Third, we only took into consideration high-risk cardiac conditions; thus, it is unclear how noncardiac factors affected mortality rates. Fourth, although MELD-XI score gives an estimation of both renal and hepatic function, we also did not seek to answer whether MELD-XI score can predict all-cause in-hospital mortality. Fifth, since we only included in-hospital cardiac mortality, 1-year all-cause mortality rate did not include in-hospital noncardiac mortality. Therefore, 1-year all-cause mortality rate was in fact a combination of in-hospital cardiac and postdischarge all-cause mortality rates, which may have created heterogeneity.

Conclusion

MELD-XI score was predictive of in-hospital cardiac and 1-year all-cause mortality independently of high-risk cardiac factors among patients undergoing elective or urgent noncardiac surgery. Hence, MELD-XI score was able to further risk stratify noncardiac surgical candidates which are already at high cardiac risk. This score's role in perioperative risk estimation should be further evaluated by randomized controlled studies.

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Conflicts of interest
There are no conflicts of interest.