Orthotopic liver transplantation is an established therapeutic option for patients with end-stage liver disease (ESLD).* The number of liver transplantations performed annually has been steadily rising, with over 3440 liver transplantations performed in the United States in 1993. Liver transplantation currently is being performed in adults for diverse causes of ESLD, including primary biliary cirrhosis, sclerosing cholangitis, cryptogenic cirrhosis, autoimmune hepatitis, viral hepatitis, alcoholic liver disease, hepatocellular carcinoma and other less-common causes (1).
Liver transplant surgery may be associated with substantial blood loss, resulting in hemodynamic instability, massive transfusion requirements, and significant fluid shifts. Patients are therefore at risk for substantial perioperative hemodynamic fluctuations, myocardial ischemia, arrhythmias, and congestive heart failure (2-5). Because of the extensive nature of the operation, patients being considered for liver transplantation undergo a comprehensive preoperative evaluation, including cardiovascular risk assessment and diagnostic testing. Although cardiac evaluation is recommended for many patients undergoing liver tranplant evaluation, the extent of coexistent cardiac pathology in patients with ESLD has not been well described. No comprehensive data exist to guide the preoperative cardiac assessment of patients under consideration for liver transplantation (6).
Assessment of left ventricular function is an integral component of the evaluation of a patient with known or suspected cardiac disease. Two-dimensional echocardiography is a readily available and highly versatile technique for evaluation of both global and regional left ventricular function. Although many patients with hepatic cirrhosis have a history of alcoholic abuse, the prevalence of overt alcohol-related left ventricular dysfunction among patients undergoing transplant evaluation has not been well established (7).
Dobutamine stress echocardiography is an accepted methodology for the detection of coronary artery disease (8-10). It has been shown to provide valuable prognostic information in patients with known or suspected coronary artery disease, for patients undergoing major vascular and noncardiac surgery (11-14), and more recently for patients undergoing kidney transplantation (15).
The purpose of this study was to evaluate the range of cardiovascular abnormalities in patients undergoing evaluation for orthotopic liver transplantation and to determine the prognostic implications of abnormal echocardiographic features, including ischemia during dobutamine stress echocardiography, in predicting perioperative cardiac events.
Study patients. The study group consisted of 190 patients with end-stage liver disease undergoing evaluation for orthotopic liver transplantation. All patients were referred for cardiac evaluation at the University of Michigan between July 1992 and June 1994. Outcome data were collected through November 1994. All patients were referred for cardiac evaluation if there was a history or clinical suspicion of cardiac-related disease, hypertension, diabetes mellitus, or age greater than 45 years. All patients with alcoholic liver disease who were considered suitable for transplantation underwent cardiac assessment. The etiologies of liver disease are presented in Table 1. All patients underwent two-dimensional echocardiography and 165 (87%) underwent dobutamine stress echocardiography. The decision to proceed with dobutamine stress echocardiography was based on age or clinical suspicion of ischemic heart disease. Patient demographics-including age, gender, and risk factors for coronary artery disease-appear in Table 2.
Two-dimensional echocardiography. All patients were studied with two-dimensional echocardiography. Standard left ventricular dimensions were measured in the parasternal long axis view according to the guidelines established by the American Society of Echocardiography (16). Left atrial enlargement was defined as a left atrial dimension >40 mm. Left ventricular hypertrophy was considered present if the septal or posterior wall thickness was >11 mm. Left ventricular enlargement was defined as a left ventricular internal diastolic dimension of >57 mm. Left ventricular systolic and diastolic volumes and ejection fraction were calculated from the apical four-chamber view using a modified Simpson's rule. Valvular regurgitation was quantified as mild, moderate, or severe using qualitative assessment of Doppler color flow imaging. Continuous wave Doppler of the tricuspid regurgitant jet was used to calculate right ventricular systolic pressure (17). The right atrial pressure was estimated to be 14 mmHg in all patients.
Right to left shunting attributed to pulmonary arteriovenous malformations was assessed using contrast two-dimensional echocardiography with intravenous injection of 10 ml of agitated isotonic saline at rest (n=125) and at peak dobutamine (n=99) (16-18). The number of cardiac cycles between injection and the appearance of contrast within the left atrium was recorded. Intrapulmonary shunts were identified by delayed (≥6 cardiac cycles) appearance of contrast within the left atrium. The degree of opacification of contrast within the left atrium was graded on a scale of 0 to 3 with 0 representing no shunting and 1, 2 and 3 representing mild (LA << RA), moderate (LA<RA) and severe (LA=RA) shunting, respectively.
Dobutamine stress echocardiography. Dobutamine stress echocardiography was performed according to a previously described protocol (10). Echocardiographic imaging was performed in the parasternal long and short axis and apical four- and two-chamber views at rest, at each stage of dobutamine infusion, and in recovery. Dobutamine was infused in 3 min stages at incremental doses of 10, 20, 30, and 40 μg/kg/min. Digital images were captured in a quad-screen format and interpreted off-line by experienced echocardiographers skilled in the analysis of stress echocardiograms. Regional wall motion was characterized as normal, hypokinetic, akinetic, or dyskinetic in each of 16 predefined segments. Ischemia was defined as a new or worsening wall motion abnormality during dobutamine infusion.
Cardiac catheterization. Cardiac catheterization with coronary angiography was performed in 18 (11%) patients, including 9 of 11 patients with an ischemic response on dobutamine echocardiography. An additional 9 patients, without inducible ischemia on dobutamine stress echocardiography, underwent coronary angiography because of a high clinical suspicion of coronary artery disease. Cineangiograms were analyzed by experienced angiographers at the time of the procedure. Significant coronary artery disease was defined as a stenosis of ≥50% maximal lumenal diameter in any major epicardial coronary artery.
Perioperative complications. Patients were followed prospectively for perioperative events from the time of initial cardiac consultation until the time of hospital discharge following liver transplantation. Clinical endpoints included cardiac death, myocardial infarction, clinical and/or chest radiographic appearance of pulmonary edema, and arrhythmia.
Statistical analysis. All results were expressed as mean ± one standard deviation unless otherwise specified. Comparisons between groups were made using chi-square tests for nominal variables. Unpaired t-tests were used for comparison of continuous variables. Comparisons within groups were performed using paired t tests. Tests were considered significant at a P value of less than 0.05.
Echocardiographic results. Results of two-dimensional echocardiography for standard chamber measurements-including left atrial size, ventricular end-diastolic and end-systolic dimensions, and volumes and ejection fraction-are presented in Table 3. There were no significant differences in left ventricular size or function between patients with alcoholic and nonalcoholic liver disease.
A summary of the abnormal echocardiographic features in all 190 patients undergoing transplant evaluation and in the 71 patients who subsequently underwent transplant are presented in Table 4. Fewer than 10% of patients had evidence of significant ventricular dysfunction or valvular disease on preoperative echocardiography.
Contrast echocardiography. Results of contrast echocardiography for detection of pulmonary arteriovenous malformations during baseline echocardiographic imaging and at peak dobutamine are displayed in Table 5. The presence of intrapulmonary shunting did not correlate with estimated right ventricular systolic pressure.
Dobutamine stress echocardiography. Dobutamine stress echocardiography was performed in 165 patients for preoperative assessment of ischemia. One hundred forty-eight patients (89%) had normal resting studies and no ischemia with dobutamine. Ischemia was induced with dobutamine stress in 11 patients (7%), 5 of whom had resting wall motion abnormalities. Six patients (4%) with resting wall motion abnormalities had no inducible ischemia.
Cardiac catheterization. Cardiac catheterization was performed in 9 of 11 patients with an ischemic response on dobutamine stress echocardiography and in 9 patients without ischemia. Of the 9 patients with inducible ischemia, only 3 patients had significant coronary artery disease on coronary angiography. All 3 patients were refused transplantation on the basis of significant ischemic disease. The regions of abnormal wall motion in the 6 patients without significant coronary artery disease were the inferior wall in 4 patients and apex in 2 patients. Of the 9 patients with no inducible ischemia who underwent catheterization for clinical suspicion of coronary artery disease, 8 had no significant coronary artery disease. One patient had significant three-vessel coronary artery disease. This patient subsequently underwent successful coronary artery bypass surgery.
Clinical outcome. Clinical outcomes for the 190 patients evaluated for transplantation between July 1992 and July 1994 are displayed in Table 6. Perioperative complications in the 71 patients who underwent transplantation included myocardial infarction (n=1), acute left ventricular dysfunction (n=4), arrhythmia (n=10), and pulmonary edema (n=39). There were no cardiac deaths or myocardial infarctions related to obstructive coronary artery disease.
Myocardial infarction occurred in one patient on the fourth postoperative day with a peak serum CPK of 185 mg/dl (normal 20 to 180) and 11% MB fraction (normal 0 to 6). The electrocardiogram showed evidence of acute anterior wall injury with new T wave inversions (Fig. 1). Two-dimensional echocardiography revealed an extensive anteroapical wall motion abnormality that was markedly out of proportion to the magnitude of the serum CPK. Cardiac catheterization revealed normal coronary arteries with no evidence of thrombus. There was near complete normalization of wall motion and electrocardiogram at 2 weeks.
Global left ventricular dysfunction developed acutely within the first postoperative week in 4 patients (ages, 37, 37, 67, and 54), all of whom had normal left ventricular function preoperatively. At the time of left ventricular decompensation, mean left ventricular ejection fraction was 20% (range, 10-29) in these patients. Left ventricular dysfunction persisted in 3 patients at 1 month postoperatively. Three patients had a history of alcoholic liver disease. All 4 patients required postoperative renal dialysis. Two patients had primary hepatic graft failure, necessitating retransplantation within 1 week of the initial transplantation.
Perioperative arrhythmias occurred in 10 (14%) patients. One patient had an asystolic cardiac arrest 4 weeks post-transplant following numerous surgical complications. There was no evidence of myocardial infarction, and two-dimensional echocardiography revealed normal left ventricular wall motion and ejection fraction. Eight patients had atrial arrythmias, consisting of supraventricular tachycardia (n=3) and atrial fibrillation (n=5). Nonsustained ventricular tachycardia occurred in one of the patients with postoperative dilated cardiomyopathy.
Chest radiographic appearance of pulmonary edema was present in 39 (56%) patients following transplantation. All 39 patients required postoperative diuretic therapy. The average volume of blood products transfused intraoperatively for all transplanted patients was 15.2 L/patient. The absolute volume of transfused did not correlate with development of postoperative pulmonary edema (P=NS).
Predictors of morbidity and mortality. No preoperative echocardiographic parameters, including ischemia with dobutamine stress, predicted the perioperative myocardial infarction in one patient or postoperative left ventricular dysfunction in four patients. Given the low incidence of ischemic cardiac events in this population, the predictive valve of dobutamine stress echocardiography in determining postoperative outcome could not be determined. However, there were no myocardial infarctions or deaths related to ischemic heart disease in the 145 patients with a negative dobutamine stress echocardiogram who did not undergo cardiac catheterization to exclude significant coronary artery disease.
Severe intrapulmonary shunting detected by contrast echocardiography using agitated saline predicted death prior liver transplantation. Four of 7 patients with severe (grade 3) shunting (Fig. 2) at rest or peak dobutamine died prior to transplantation (P=0.01). Three patients who died had documented hypoxemia with PaO2<75 mmHg prior to death. No data regarding hypoxemia was available on the fourth patient. One patient with severe shunting and hypoxemia underwent successful transplantation. His postoperative course was notable for intermittent mild arterial desaturation requiring supplemental oxygen.
Cardiomyopathy occurs in patients with alcohol abuse, the majority of whom do not have clinically evident hepatic cirrhosis (21-24). Urbano-Marquez et al., found that cardiomyopathy and skeletal myopathy occurred commonly among actively drinking persons with chronic alcoholism, and that alcohol produced toxicity in cardiac and skeletal muscle in a dose-dependent manner (24). In patients with documented cirrhosis evaluated in this study, there were no significant differences in left ventricular size and function, valvular regurgitation, pulmonary hypertension, or intrapulmonary shunting between the alcoholic and nonalcoholic groups. One possible important explanation for the low incidence of detected alcoholic cardiomyopathy in this population is that the majority of patients had been abstinent from alcohol for at least several months prior to transplantation. This is particularly true of transplant candidates undergoing outpatient assessment, who constituted a majority of patients evaluated in this study. It is feasible that the period of abstinence may allow for partial or total recovery of myocardial function (7). Although no overt cardiomyopathy was detected in the alcoholic group, subclinical cardiomyopathy could not be excluded on the basis of this study. Occult cardiomyopathy with depression of left ventricular function in response to volume and pressure overload has previously been demonstrated in a small (n=10) group of alcoholic patients with cirrhosis and normal resting function (25). The low systemic vascular resistance associated with end-stage liver disease may have masked subclinical left ventricular dysfunction in the population evaluated in this study.
Delayed intrapulmonary shunting consistent with pulmonary arteriovenous malformations was detected in 27% of patients in the resting state and in 41% of patients at peak dobutamine infusion. Previous reports evaluating smaller populations (n=40, n=53) of patients with end-stage liver disease have demonstrated a prevalance of intrapulmonary shunting in the resting state of 13.2% (18) and 47% (20), respectively. In this study, the majority of shunting was either trivial or mild in severity, both at rest and at peak dobutamine. Neither the presence nor the magnitude of intrapulmonary shunting correlated with pulmonary artery pressures. Severe (grade 3) intrapulmonary shunting, however, correlated significantly with early mortality. This result is in contrast to a previous report demonstrating improved mortality with more severe shunting (20). Three patients with severe intrapulmonary shunting who died prior to transplantation had concomitant hypoxemia, suggesting the diagnosis of the hepatopulmonary syndrome (26). This syndrome, consisting of the triad of liver disease, pulmonary vascular dilatations, and hypoxemia, carries a poor prognosis with a reported 3-year mortality of 40% (19, 27). Successful transplantation was performed in one patient in this series with probable hepatopulmonary syndrome. Transplantation in patients with the hepatopulmonary syndrome, however, remains of considerable controversy (21). The hypoxemia associated with the hepatopulmonary syndrome has been shown to resolve posttransplantation in isolated case reports (28-30). It has been suggested that worsening hypoxemia in the setting of the hepatopulmonary syndrome may eventually become an indication for transplantation (31).
Dobutamine stress echocardiography has been used to stratify patients into high- and low-risk subsets prior to major noncardiac surgery (11-14). In this study, because there were no myocardial infarctions or deaths related to obstructive coronary artery disease, the predictive value of dobutamine stress echocardiography in predicting perioperative cardiac events could not be determined. Ischemia during dobutamine stress occurred in only 7% of the study population, and of the 9 patients with ischemia who underwent coronary angiography, only 3 patients were found to have significant coronary artery disease. All three of these patients were refused transplantation. The six patients with false-positive results had regional wall motion abnormalities localized to the inferior and apical regions, areas known to have a high incidence of false-positive studies (32). The higher incidence of false-positive tests in this population may be related to extrinsic pressure on the inferior wall by the liver or tense ascites causing elevation of the diaphragm. These situations potentially may prevent full excursion of the inferior wall during peak stress. The reason for the single false-negative dobutamine stress echocardiogram is not entirely evident. It is possible that in the setting of low systemic vascular resistance and the hyperdynamic circulatory state characteristic of end-stage liver disease, the stress induced by dobutamine may not be sufficient to produce ischemic wall motion abnormalities in some patients.
Although the predictive value of dobutamine stress echocardiography in predicting postoperative events could not be determined due to the low incidence of perioperative cardiac events, there were no cardiac events related to obstructive coronary artery disease in the 145 patients who had a negative dobutamine stress echocardiogram and who did not undergo preoperative cardiac catheterization to specifically exclude coronary artery disease. Hence, dobutamine stress echocardiography appears to be a useful test in excluding patients with significant obstructive ischemic heart disease.
The mechanisms of the major perioperative events, including myocardial infarction and dilated cardiomyopathy, remain ill-defined. Possible explanations for the myocardial infarction, which was manifest as an extensive anteroapical wall motion abnormality with minimal elevation of serum CPK, include coronary vasospasm or thrombotic coronary occlusion with subsequent spontaneous lysis and resultant stunned myocardium. Similar occurrences of profound myocardial ischemia in the absence of significant obstructive coronary disease have been demonstrated following liver transplantation (33). A hypercoagulable state exists after liver transplantation and is thought to be responsible for hepatic artery thrombosis that may occur postoperatively (34). It has been suggested that this hypercoagulable state may also predispose patients to coronary thrombosis.
An echocardiographic pattern of global left ventricular dysfunction developed postoperatively in 4 patients, 3 of whom had a history of alcoholism. One potential mechanism for cardiomyopathy includes global multiorgan ischemia, suggested by the need for renal dialysis in all four patients. A second hypothesis is that occult cardiomyopathy, masked by a preoperative hemodynamic state characterized by high cardiac output and low systematic vascular resistance, may become clinically apparent postoperatively as cardiac output declines and peripheral resistance increases. In support of the hypothesis that occult left ventricular dysfunction may exist in alcoholic cirrhosis, Ahmed et al (24) have demonstrated decreases in left ventricular function in response to volume loading and increasing afterload in cirrhotics with normal baseline ejection fraction. The posttransplant setting, characterized by significant volume loading and increases in afterload, may mimic this experimental situation and result in over left ventricular dysfunction. On the basis of these experimental situations, it is not surprising that dobutamine stress echocardiography may not have detected subclinical nonischemic cardiomyopathy. Dobutamine increases myocardial oxygen consumption predominantly by augmentation of myocardial contractility and heart rate without significant increases in afterload. As a result, dobutamine infusion in patients with nonischemic cardiomyopathy results in an increase in left ventricular contractility, thereby potentially masking subclinical left ventricular dysfunction. It could be hypothesized that a more sensitive test for detection of occult cardiomyopathy may be one which primarily increases afterload.
The radiographic appearance of pulmonary edema, present in over 50% of patients, was most likely multifactorial in origin and related to significant transfusion requirements, increased capillary permeability, and prolonged intubation associated with orthotopic liver transplantation. Postoperative arrhythmias, predominantly atrial in origin, were most likely related to volume overload, anemia, fever, and postoperative stress.
The majority of patients with end-stage liver disease, including those with alcoholic cirrhosis, have structurally normal hearts on two-dimensional echocardiography. Major perioperative cardiac events, including myocardial infarction without evidence of obstructive coronary artery disease and acute left ventricular dysfunction, were not predicted by preoperative echocardiography, and in all likelihood, could not have been predicted by any of the current imaging modalities. In the future, pharmacologic stress testing with agents that primarily increase afterload may be more appropriate in this clinical setting.
Given the low incidence of coronary artery disease in this population, the predictive value of dobutamine stress echocardiography in predicting ischemic events could not be determined. Dobutamine stress echocardiography, however, correctly identified 3 patients found to have significant coronary artery disease, who were then excluded from transplantation. Furthermore, because there were no events related to obstructive cardiac disease in the patients with a negative dobutamine stress echocardiogram, this test may be useful in excluding patients with significant obstructive coronary artery disease.
Preoperative detection of severe (grade 3) intrapulmonary shunting by contrast echocardiography either at rest or peak dobutamine portended a poor prognosis. Future efforts in this patient population should include elucidation of the mechanisms responsible for coronary ischemia and cardiomyopathy in the postoperative setting, and methods for the preoperative detection of patients at risk for these complications.
Given the fact that the major perioperative cardiac events observed in this study, including myocardial infarction without obstructive coronary artery disease and global left ventricular dysfunction, could not have been predicted by current imaging modalities, the appropriate preoperative evaluation in this population of patients remains somewhat indeterminate. Despite this uncertainty, however, given the magnitude of cardiovascular stress imposed by liver transplantation, it is essential to evaluate for obstructive coronary artery disease and for left ventricular dysfunction, particularly in patients with alcoholic liver disease who have only recently become abstinent. Furthermore, given the poor prognosis of patients with severe intrapulmonary shunting and hypoxemia, it is necessary to identify these patients and expedite surgery in an effort to improve their prognosis. The preoperative evaluation of patients with end-stage liver disease is further confounded by the fact that symptoms are not a reliable indicator of cardiac illness and cannot be used to determine which patients should undergo noninvasive testing. The majority of patients with end-stage liver disease have reduced exercise tolerance and complain of dyspnea, largely related to abdominal ascites and deconditioning. Symptoms of dyspnea related to abdominal distension, left ventricular dysfunction, and intrapulmonary shunting are not easily distinguishable on the basis of the physical exam alone.
The algorithms presented in Figures 3 and 4 present general guidelines for preoperative risk stratification of adult patients undergoing orthotopic liver transplantation. For all patients, two-dimensional and contrast echocardiography are recommended to assess left ventricular function, estimate pulmonary artery pressure, and to exclude severe intrapulmonary shunting.
Currently, no data exist examining the postoperative outcome of patients with end-stage liver disease and preoperative left ventricular dysfunction. Clearly, patients with alcoholic liver disease who have not been abstinent for at least several months should undergo reassessment of left ventricular function following a 3-6-month period of abstinence. Patients with left ventricular dysfunction (LVEF<50%) of unclear etiology should be considered for cardiac catheterization to exclude underlying ischemic heart disease. Patients with any degree of left ventricular dysfunction may be at risk for pulmonary edema and prolonged intubation in the perioperative period, given the significant volume and transfusion requirements that often accompany surgery. No data currently exist defining a “cutoff” ejection fraction for declining operative intervention. Consideration for surgery in patients with left ventricular dysfunction must be made on an individual basis, given the potential risk for periooperative cardiac decompensation in patients with moderate to severe dysfunction. Patients with left ventricular dysfunction being considered for transplantation may benefit from medical treatment with angiotensin converting enzyme inhibitors, diuretics, and digoxin.
Patients with evidence of pulmonary hypertension by Doppler echocardiography using the right ventricular systolic pressure as a surrogate for pulmonary artery pressure should be referred for right heart catheterization in order to confirm elevated pressures. Management of patients with severe pulmonary hypertension remains controversial. Cases of both reversible and irreversible pulmonary hypertension following liver transplant surgery have been reported (36-40). Patients at increased risk for perioperative death or persistent postoperative pulmonary hypertension appear to include patients with very high preoperative pulmonary artery pressure (i.e., pulmonary systolic pressure > 80 mmHg (39-40), depressed right ventricular function (39-40), or concomitant coronary artery disease (35). Patients with mild or moderate pulmonary hypertension (pulmonary systolic pressure <60 mmHg) appear to do well following surgery (36-38).
In this study, severe intrapulmonary shunting secondary to intrapulmonary vascular dilatations, in association with hypoxemia, was found to be associated with increased mortality prior to liver transplantation. This syndrome, referred to as the “hepatopulmonary syndrome,” is only rarely associated with severe pulmonary hypertension, and has been shown in some instances to resolve with liver transplantation (28-30). Patients with severe intrapulmonary shunting by contrast echocardiography should undergo assessment of arterial blood gases to assess for hypoxemia. Patients documented to have severe hypoxemia (PaO2<70 mmHg) who respond to supplemental oxygen with an increase in oxygen saturation are likely to do well intraoperatively (27). Because of their increased preoperative mortality, therefore, patients with severe intrapulmonary shunting by contrast echocardiography and hypoxemia responsive to supplemental oxygen should be considered for more urgent transplantation.
For patients with known coronary artery disease, diabetes mellitus, or age ≥45 years, noninvasive stress testing with dobutamine stress echocardiography to exclude inducible ischemia is suggested. Patients with evidence of ischemic wall motion abnormalities should be referred for coronary angiography and consideration of percutaneous or surgical revascularization prior to transplantation. Patients without inducible ischemia can proceed to transplantation at low risk for ischemic cardiac complications.
Abbreviations: CABG, coronary artery bypass graft surgery; ESLD, end-stage liver disease; LA, left atrium; LV, left ventricle; LVEF, left ventricular ejection fraction; PAP, pulmonary artery pressure; PTCA, percutaneous transluminae coronary angioplasty; RA, right atrium; RV, right ventricle.
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