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Real World Utility of Dobutamine Stress Echocardiography in Predicting Perioperative Cardiovascular Morbidity and Mortality after Orthotopic Liver Transplantation

Background and Objectives Stress echocardiography is the current standard for cardiac risk stratification of patients undergoing orthotopic liver transplantation (OLT). We aim to evaluate the role of dobutamine stress echocardiography (DSE) in predicting perioperative major adverse cardiac event (MACE) in patients undergoing OLT. Methods This was a single-center retrospective study including 144 OLT patients. Of 144 patients, 118 had DSE. MACE included myocardial infarction (MI), heart failure (HF), cardiovascular and all-cause death 1 year after OLT. Results Our study cohort included 118 patients. The mean age was 57.3±8.2 years (range, 25–72 years). There were 85 men and 33 women, male to female ratio being 2.6:1. Of 118, 15 (13%) had positive DSE and 103 (87%) had negative DSE. Perioperative MACE incidence was 5.9% (95% confidence interval [CI], 2.6–12.3%). In predicting MACE, DSE had sensitivity of 5.6% (95% CI, 0.2–29.4%), specificity 86% (95% CI, 77.3–91.9%), positive predictive value 6.7% (95% CI, 0.3–33.4%), and negative predictive value (NPV) 83.5% (95% CI, 74.6–89.8%). Eighteen patients had MACE in first year post OLT (15%, 95% CI, 9.5–23.3%). Adverse events included cardiogenic shock (2/18), systolic HF (2/18), non-ST-elevated MI (7/18), cardiac mortality (3/18), and all-cause mortality (7/18). The overall complication rate of DSE was 17% (20/118). Conclusions In our cohort, DSE had a low sensitivity but high NPV in predicting perioperative MACE post OLT. A similar trend was noted for DSE in predicting 1-year MACE post OLT. We reiterate the need of a better screening and risk stratification tool for OLT.


INTRODUCTION
Liver transplantation has revolutionized the management of end-stage liver disease (ESLD), and is an established therapeutic option for diverse causes of ESLD. 1) Because of the extensive risk of hemodynamic instability with liver transplant surgery, 2) patients considered for orthotopic liver transplantation (OLT) undergo comprehensive preoperative evaluation including cardiac risk stratification.
Dobutamine stress echocardiography (DSE) is a commonly used modality for cardiac evaluation prior to OLT. According to the 2013 Practice Guidelines by the American Association for the Study of Liver Disease and the American Society of Transplantation, stress echocardiography receives class 1-B evidence as an initial screening test, with subsequent cardiac catheterization as clinically indicated. 3) American College of Cardiology (ACC) and American Heart Association recommend considering noninvasive stress testing for patients undergoing liver transplant with no active cardiac conditions on the basis of multiple coronary artery disease (CAD) risk factors. The specific number of risk factors that should be used to prompt testing remains to be determined, but the committee considered 3 or more to be reasonable (class IIb: level of evidence C). 4) There is limited data for DSE as a screening modality for significant CAD and major adverse cardiac event (MACE) in ESLD population undergoing OLT evaluation. We hypothesize that DSE is not a sensitive screening test for perioperative MACE amongst patients undergoing OLT. Our study aimed at calculating sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV) of DSE in predicting perioperative MACE for patients undergoing OLT. We also report 1-year MACE rate for these patients.

METHODS
A retrospective chart review of 144 patients who underwent OLT at Albert Einstein Medical Center between 2011 and 2015 was performed. Pre-and post-transplant (1-year follow-up) clinical, laboratory and imaging data including transthoracic echocardiogram, DSE and left heart catheterization (LHC) were reviewed. A written permission was granted by the Ethics committee of the Institutional Research Board to access the patient's data (approval number: 4843). The reviewers were licensed internal medicine residents practicing in the same hospital. The population was divided as shown in Figure 1 based on whether the DSE was performed or not. Twenty-six patients did not undergo DSE due to either low cardiac risk (22/26) or high risk (4/26), who were deemed appropriate for LHC as the initial step.
Before transplantation, most patients (n=118) underwent DSE as per the following protocol. A 12-lead electrocardiogram (ECG), baseline blood pressure and pulse oximetry was obtained at rest. Dobutamine was initiated at 10 mcg/kg/min and infused for approximately 3 minutes. It was titrated at 10 mcg increments to a maximum dose of 40 mcg/kg/min. Atropine in divided doses of 0.25 and 0.5 mg to a total of 2.0 mg was given as an adjunct to the dobutamine to achieve target heart rate. Target heart rate was defined as 85% of the age predicted maximum heart rate. Continuous ECG monitoring was done, blood pressure monitored during each stage and patients' symptoms were recorded. Echocardiography exam was used to obtain baseline images, low-dose images and peak-dose images and regional and global left ventricular function at rest and stress was assessed. The procedure was terminated if patient developed moderate to severe dyspnea, angina, unresponsiveness, dysrhythmia, ST changes, abnormal blood pressure response or technical problems. The study was interpreted by certified cardiologists and was referred to as positive and negative on the basis of electrocardiographic and echocardiographic criteria. DSE was considered positive if myocardial ischemia was identified as new wall motion abnormalities or worsening wall motion abnormalities in at least 2 segments, greater than 2 mV down sloping ST-segment depression measured 80 ms after J point as compared with baseline or both. Complications of the study included arrhythmia like new onset atrial fibrillation and non-sustained ventricular tachycardia which required termination of the study. Premature atrial contraction (PAC) and premature ventricular contractions (PVC) were noted, but not included as a complication of the study. Persistent hypotension with systolic blood pressure <90 mmHg or diastolic blood pressure <60 mmHg was another complication of the procedure which required early termination of the procedure. The clinical decision whether to undergo cardiac catheterization after a positive DSE was made by the consulting cardiologist. The charts of patients with positive DSE who underwent LHC (10/118) were reviewed. Significant CAD was defined as 50% or greater occlusion in the left main vessel or 70% or greater in other major coronary vessels.
Medical record of all patients was reviewed for MACE including myocardial infarction (MI), heart failure (HF), cardiogenic shock, cardiovascular death, and all-cause death within a year of transplant. MACE was further categorized into 3 groups: 1) group 1, perioperative (including intraoperative and 7 days' post OLT); 2) group 2, MACE >7 days, ≤30 days' post OLT; and 3) group 3, MACE >30 days up to 1-year post OLT. HF was defined as a new onset of systolic dysfunction with ejection fraction <50% and clinical signs of HF. MI was defined by the presence of chest pain or angina equivalents with rise in troponin with or without significant ST segment elevation in the ECG.

DISCUSSION
DSE is commonly used for cardiac risk stratification among patients undergoing OLT. The purpose of cardiac evaluation before liver transplant is to assess perioperative risk and to exclude concomitant cardiac disorders that would preclude a good long-term outcome. 5) Advanced liver disease typically results in hemodynamic states that are characterized by systemic hypotension due to peripheral vasodilatation. Nevertheless, CAD is at least as  1 Data are shown as mean±standard deviation or number (%). BMI = body mass index; CAD = coronary artery disease; CKD = chronic kidney disease; DSE = dobutamine stress echocardiography; MACE = major adverse cardiac event. *The CAD risk factors included are diabetes mellitus, prior cardiovascular disease, left ventricular hypertrophy, age >60 years, smoking, hypertension, dyslipidemia. 4) frequent in OLT candidates as in the general population. 6) Therefore, noninvasive testing with echocardiography is indicated for all adult OLT candidates. 7) A crucial component of risk stratification is prediction of MACEs after surgery. The systematic review by Nguyen et al. 8) had a total incidence rate of 11% for perioperative cardiac events after OLT, with sensitivity of DSE in predicting 'hard cardiac event' including MI, cardiac death, and cardiac arrest to be 20%.
The composite incidence of MACE in our population was 15% over 1-year period post OLT. The MACE rate for group 1 was 5.9%, higher than group 2 (5%) and 3 (4.2%). This suggests a decreasing risk of MACE over time post transplant. All the MACE events in group 1 patients had negative DSE during the pre OLT work up. Thus, the calculated sensitivity of DSE for perioperative MACE was 0% (0/7). There might be perioperative events like excessive blood loss, fluid overload or procedural complications which predispose a patient with negative DSE to develop MACE in post OLT. A negative DSE was successful in predicting non-occurrence of MACE in 86% of our study cohort. At the same time, none of the patients with positive DSE (15/118) had perioperative MACE suggestive of poor PPV (0%). Of these 15 patients with positive DSE, 6 had LHC (non-significant CAD) and the rest 9 were deemed appropriate for OLT without the need for further cardiac work up by the consulting cardiologist. We thereby, reiterate the need of a better screening and risk stratification tool in liver transplant patients.
In general population, overall sensitivity of DSE in predicting future cardiac events is shown to be around 85%. 9) Nicolau-Raducu et al. 10) observed the sensitivity of DSE in predicting long-term MACE (median follow-up time of 3.4 years) for patients with OLT to be 9%. In our study, 11 out of 118 patients (9.3%, 95% CI, 4.9-16.4%) had MACE 1-year after OLT (excluding the first 7 days postoperative). All except one had negative DSE in pre OLT work up. In our cohort, in predicting long-term MACE, DSE had sensitivity of 9% (95% CI, 0.4-4.2%) and specificity of 86.9% (95% CI, 78.6-92.4%). Multiple factors contribute to higher cardiovascular complications after OLT. These include pre-existing metabolic factors and immunosuppressive therapy due to their metabolic effects. 11) Knowing this, we currently lack a surveillance protocol for cardiovascular disease post OLT. Among patients with OLT, cardiovascular disease continues to be the second most important cause for morbidity and mortality after malignancy. 11) Efforts to improve cardiovascular outcomes among OLT patients is an ongoing challenge and more research is needed to guide physicians achieve this goal.
Complications, such as arrhythmias and hypotension, are known to occur after administration of dobutamine. There have been reports in smaller populations showing 10% to 14% occurrence of hypotension during DSE. [12][13][14] This might be related to dynamic left ventricular obstruction 12) to cardiovascular reflexes secondary to beta-1 stimulating effect of dobutamine, 14) or caused by vasovagal reflex. However, the complications of DSE in advanced liver disease have not been well reported. In our study population, hypotension during procedure was observed in 12 (10%) patients, PVC in 18 (15%) and PAC in 9 (8%). This might be biased as these patients usually have systemic vasodilation. Ventricular fibrillation, observed in a previous study 15) was not observed in any our patients, but 9 patients (7%) developed arrhythmia, including atrial fibrillation and non-sustained ventricular tachycardia during the procedure. All complications improved with medical management, none leading to mortality. Around 6,000 liver transplants are performed annually in United States. Our study being small in size may not be reflective of general population. The limitations of our study include its small sample size and single-center retrospective experience. Additionally, we excluded 4 patients who underwent LHC directly without undergoing DSE. Though this is a small number, it could have biased our results. Larger prospective studies with longer post OLT follow-up are needed to answer few raised questions of our study like post OLT cardiovascular risk surveillance. Newer imaging modalities like myocardial perfusion imaging (MPI) with real-time myocardial contrast echocardiography (RTMCE) may be studied in more depth to find its role in preoperative risk stratification. Tsutsui et al. 16) appreciated it as a useful tool in predicting mortality in patients with advanced liver disease. Head to head comparison trials between alternative screening modalities for predicting MACE among OLT candidates are needed to ascertain the true sensitivity of individual tests and guide our future approach to these patients with standardized protocols.