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Preoperative Dobutamine Stress Echocardiography, Intraoperative Events, and Intraoperative Myocardial Injury in Liver Transplantation
OTHER COMPLICATIONS
Preoperative Dobutamine Stress Echocardiography, Intraoperative Events, and Intraoperative Myocardial Injury in Liver Transplantation J.Y. Findlay, M.T. Keegan, P.P. Pellikka, C.B. Rosen, and D.J. Plevak ABSTRACT Introduction. The appropriate method of screening for coronary artery disease in patients who present for liver transplantation is currently uncertain. Methods. We assessed the utility of a screening protocol using dobutamine stress echocardiography (DSE) in 119 patients who underwent liver transplantation. Patients with cardiac risk factors had DSE performed, and those with positive results were referred for coronary angiography. Outcome was myocardial injury during liver transplantation determined by an elevation of cardiac troponin T measured after transplantation. Results. Seventy-three patients had DSE performed; eight were reported as positive for inducible ischemia. Seven of these patients underwent coronary angiography, and one had significant coronary artery disease. Postoperative troponin elevation occurred in 14 patients. There was no significant difference in the prevalence of troponin elevation in those patients with positive DSE versus those with negative DSE. No significant difference was identified in the prevalence of troponin elevation when comparing those patients with cardiac risk factors who underwent DSE with those patients with no risk factors and no DSE performed. DSE had a sensitivity of 0.2 and a specificity of 0.9 for myocardial injury. The prevalence of intraoperative hemodynamic instability was significantly higher in patients who had evidence of myocardial injury, but hemodynamic instability was no more common in patients who had a positive DSE. Conclusion. When used in accordance with our protocol a positive DSE does not reliably identify patients at high cardiac risk during liver transplantation, but a negative DSE is strongly predictive of no myocardial injury.
O
RTHOTOPIC LIVER TRANSPLANTATION (OLT) is a major surgical procedure resulting in significant physiological stress. The reported outcomes for patients with coronary artery disease (CAD) undergoing OLT are poor.1 It should, therefore, be advantageous to identify such patients during the pretransplant assessment. Currently dobutamine stress echocardiography (DSE) is the favored screening study,2 although there are conflicting reports of its utility.3–5 In addition, the actual prevalence of myocardial injury during OLT is unclear. Studies to date have reported the occurrence of adverse cardiac events identified
clinically; thus the interpretations of the utility of screening tests may be biased by the occurrence of undetected subclinical events. The ability to detect cardiac troponins
From the Department of Anesthesiology, the Division of Cardiovascular Diseases and the Division of Transplantation Surgery, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. Address reprint requests to Dr James Young Findlay; Mayo Clinic College of Medicine, Department of Anesthesiology, 200 Second Street SW, Rochester, MN 55905.
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.03.023
Transplantation Proceedings, 37, 2209 –2213 (2005)
2209
2210
has greatly increased the ability to detect tissue-specific myocardial damage.6 Since 1999 we have been following a cardiac screening algorithm similar to that described by Plevak et al.2 using DSE and have combined this with a routine post-OLT measurement of troponin. Herein we report our experience with this protocol in a cohort of patients who underwent OLT. Our aims were to document the rate of myocardial injury during OLT and identify the ability of DSE to predict myocardial injury during OLT. We hypothesized that DSE would be a good predictor of perioperative myocardial injury. METHODS Institutional Review Board approval was obtained prior to data collection and review. Since mid-1999 all patients being evaluated for OLT at Mayo Clinic, Rochester have undergone a cardiac evaluation involving the acquisition of a detailed history, physical examination and standard 12-lead electrocardiogram (ECG). All patients had a resting echocardiogram performed to assess left ventricular function, valvular function, and pulmonary artery pressures. Patients were referred for DSE if one or more of the following clinical predictors was identified: history consistent with CAD, symptoms concerning for CAD, diabetes mellitus, hypertension, arrhythmia or history of significant arrhythmia, family history of CAD, age ⬎ 50 years, obesity (body mass index ⬎ 30). All DSE examinations were carried out at the our institution using a standard protocol.7 Dobutamine was infused intravenously at increasing doses (5, 10, 20, 30, 40 g/kg/min) to a target heart rate, if this was not achieved atropine (up to 2 mg IV) was added. Images were interpreted by a cardiologist experienced in stress echocardiography in accordance with standard procedures. DSE examinations were read as positive for inducible ischemia if new regional wall motion abnormalities were seen with stress. Patients with DSE results read as positive for inducible ischemia were referred to cardiology for assessment and coronary angiography. Coronary angiograms were performed at our institution using standard techniques and interpreted by an experienced interventional cardiologist. OLT was carried out using a caval sparing technique. All patients received a similar anesthetic regimen and invasive hemodynamic monitoring including pulmonary artery catheterization. The occurrence of significant hemodynamic events during each case was noted from the anesthesia record. A significant hemodynamic event was defined as one of the following: significant hypotension (systolic blood pressure ⬍ 80 mm Hg for 10 or more sequential minutes), the requirement for a pressor infusion, significant new arrhythmia including cardiac arrest. All patients were transferred to the intensive care unit at the end of the procedure. Cardiac troponin T (cTnT) was measured on the first postoperative day. A standard 12-lead ECG was obtained on the same day and compared with one obtained in the immediate preoperative period. ECG readings were confirmed by a cardiologist. Statistical comparisons between rates were made using Fisher’s exact test.
RESULTS
Between January 2000 and December 2001, 119 patients who had been evaluated using the protocol described underwent OLT. Two patents were excluded from the analysis: one who underwent a combined heart and liver
FINDLAY, KEEGAN, PELLIKKA ET AL
transplant and another who underwent OLT within 1 week of a prior troponin elevation. The characteristics of the remainder are given in Table 1. Of the 117 patients analyzed 73 met criteria for DSE. The distribution of cardiovascular risk factors is given in Table 2. Target heart rate was not achieved in 14 of 73 DSE examinations (19%), attributed to beta-blockade in nine, termination of examination due to hypotension in three cases, and intolerable headache in two cases. Eight of the DSE examinations were reported as positive for inducible ischemia. Seven of these patients proceeded to coronary angiography; only one had significant coronary artery disease (occluded right main with good collateral flow, subsequently underwent uneventful OLT without cardiac intervention). Postoperative troponin elevation was observed in 14 patients (12%), occurring in 10/73 of patients with cardiovascular risk factors and 4/44 of those without (P ⫽ NS). On univariate analysis no individual risk factor was significantly associated with postoperative troponin elevation. In those patients who had undergone DSE troponin elevation occurred in 2/8 with a positive DSE versus 8/57 with a negative DSE (P ⫽ NS). DSE had a sensitivity of 0.2 and a specificity of 0.9 for myocardial injury; the positive predictive value was 0.25 (Tables 3 and 4). The rate of inadequate heart rate response was not significantly different in those patients exhibiting postoperative troponin elevation than in those who did not. Significant hemodynamic events were noted in 24 cases and occurred significantly more frequently in patients who exhibited an elevated postoperative troponin level (9/14) than in those who did not (15/103; P ⬍ .001; Table 4). For the patients who underwent DSE the prevalence of hemodynamic instability was not significantly different in those patients with a positive DSE (3/8) compared to those with a negative DSE (15/65). Perioperative events for the patients with elevated troponin levels are presented in Table 5. Postoperative ECG changes were identified in 26 patients (22%); 25 of these were nonspecific T-wave changes, one an axis change. Three changes occurred in patients with elevated troponin (3/14), 23 in the remainder (23/103, P ⫽ NS). Table 1. Characteristics of 117 Study Patients Gender Male Female Age (y) Diagnosis HCV Alcoholic cirrhosis HCV ⫹ alcohol PBC PSC Cryptogenic NASH Others
61 56 52 ⫾ 10 17 14 8 14 10 10 8 36
HCV, hepatitis C; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; NASH, nonalcoholic steatohepatitis.
PREOPERATIVE DOBUTAMINE STRESS ECHOCARDIOGRAPHY Table 2. Cardiovascular Risk Factors and Distribution of Risk Factors
2211 Table 4. Hemodynamically Significant Intraoperative Events* and Troponin
Prevalence
Risk factor History or symptoms suspicious for CAD Age ⬎ 50 y Hypertension Obesity Diabetes FH CAD Arrhythmia Number of risk factors 1 2 3 4
Troponin elevation No troponin elevation Total
24 25 23 23 20 10 8
No event
Total
9 15 24
5 88 93
14 103 117
Sensitivity of intraoperative event ⫽ 0.64; PPV ⫽ 0.6; Specificity of intraoperative event ⫽ 0.68; NPV ⫽ 0.95. *See text for definition.
17 39 16 1
Age ⬎ 50 years was the only risk factor in 12 cases. FH, family history; CAD, coronary artery disease.
DISCUSSION
Identifying CAD in liver transplant candidates is considered an important part of the screening procedure as the reported outcomes for patients with this condition are poor. Plotkin and coworkers reported a mortality of 50% and a morbidity of 81% in a series of such patients.1 DSE has been recommended as the test of choice for identifying CAD in the liver transplant population based on the characteristics of both the imaging modality and the stressor.2 However, the utility of DSE in this population is not settled. Plotkin and coworkers reported that inducible wall motion abnormalities correctly identified CAD in two patients of 40 with no false-negatives.3 Donovan and colleagues reported 11 positive DSE studies in 165 performed; CAD was confirmed on coronary angiography in only three of these 11.4 Williams and colleagues reported that DSE was a poor predictor of intraoperative cardiac events in 61 patients undergoing OLT.5 They also reported a very high rate (50%) of inadequate heart rate response during testing. We found that of eight positive DSE examinations CAD was confirmed in only one patient on subsequent coronary angiography; a second patient may have had CAD but was transplanted prior to angiography. Thus our study is at variance with the findings of Plotkin et al3 and more consistent with those of the other previously published studies.4,5 As the utility of a diagnostic test is influenced by the prevalence of the condition being sought in addition to the actual efficiency of the test, some of the discrepancy in results may be due to the different criteria used in the studies to select patients for DSE. In addition Table 3. DSE and Troponin
Troponin elevation No troponin elevation Total
Event
DSE positive
DSE negative
Total
2 6 8
8 57 65
10 63
Sensitivity of DSE ⫽ 0.2; PPV ⫽ 0.25; Specificity of DSE ⫽ 0.9; NPV ⫽ 0.88.
the reported endpoints differ in each study. Plotkin and colleagues3 report on 80 DSE examinations performed in patients selected from 220 OLT candidates on the basis of a history consistent with CAD, diabetes mellitus, age ⬎ 60 years or age ⬎ 50 years, with two or more risk factors. Efficacy of testing is calculated on 40 of these patients using the combined endpoints of result of coronary angiography or occurrence of a cardiac event during OLT. Donovan and colleagues4 report on DSE performed in 165 patients of 190 undergoing evaluation for OLT. DSE was performed based on age ⬎ 45 years or clinical suspicion of ischemic heart disease. Both the results of cardiac catheterizations and the occurrence of perioperative cardiac events in 71 of the patients who underwent OLT are reported. Williams and colleagues5 report a different approach: all patients with known CAD or symptoms consistent with myocardial ischemia went directly to cardiac catheterization. DSE is reported in 121 patients who had cardiac risk factors, atypical chest pain, or were aged ⬎ 60 years but did not meet criteria for angiography. Outcomes reported are perioperative cardiac events in 61 of the DSE patients who underwent OLT. Our selection criteria resulted in a greater proportion of our patients undergoing DSE than the criteria used by Plotkin; the proportion of our patients who underwent DSE was closer to that of Donovan, which may partially account for the difference in findings. In addition we report only on patients who underwent OLT. We acknowledge that this is a highly selected group, excluding those patients with liver failure never referred for transplant, those who are evaluated but not listed for transplant, and also those listed but who do not come to transplant. Our intention in reporting on this group of patients was to address the question of the predictive ability of DSE, used according to our assessment protocol, to identify perioperative cardiac morbidity. It was also for this reason that we chose cTnT as our outcome measure— by using this specific and sensitive marker we identified patients who sustained myocardial damage. This allows us to address the issue of whether a positive DSE with a normal coronary angiogram in OLT patients may still be meaningful, for example, in terms of indicating abnormal microvascular perfusion and an at-risk myocardium. Our results suggest that this is not the case. While the positive predictive value of DSE was not strong in our population, a negative DSE appears a strong predictor of OLT without
2212
FINDLAY, KEEGAN, PELLIKKA ET AL Table 5. Intraoperative Events and Outcomes of Patients With Troponin Elevation
Patient number
Intraoperative event
Outcome
1 2 3 4
Cardiac arrest Cardiac arrest Ventricular tachycardia Hypotension
5 6 7
Hypotension Hypotension Hypotension
8, 9 10–14
Hypotension No intraoperative event
Died POD 1 Uneventful recovery, negative coronary angiography Uneventful recovery Postoperative supraventricular tachycardia (known WPW), subsequently uneventful CHF POD 2, no evidence of CAD (global changes on echo) CHF POD 3, no evidence of CAD (global changes on echo) Known PPHTN—RHF POD 3, prolonged ICU course, died 1 month posttransplant Uneventful recovery Uneventful recovery
POD, post operative day; WPW, Wolff-Parkinson-White syndrome; CHF, congestive heart failure; CAD, coronary artery disease; PPHTN, portopulmonary hypertension; RHF, right heart failure; ICU, intensive care unit.
myocardial injury. This is in concurrence with the previously published series of OLT patients3–5 as well as with studies of DSE for risk stratification in vascular surgery.8 –11 The findings in our study also raise the question of the etiology of myocardial damage in OLT. We found a significantly higher rate of significant hemodynamic events in the patients who exhibited elevated cTnT compared to those who did not. We also found no association of intraoperative myocardial injury with any preoperative risk factor we examined, including positive or nondiagnostic DSE. We suggest therefore that myocardial injury occurring during OLT in the population as currently selected is a consequence of intraoperative stresses sufficient to result in a myocardial supply/demand discrepancy in the absence of significant cardiac vascular pathology. Thus the occurrence of myocardial injury during OLT should not be equated with the presence of underlying CAD. What are the implications of these findings for the use of DSE as a screening examination for CAD in liver transplant candidates? While DSE is a useful test in assessing patients for CAD, its utility depends upon the pretest probability of CAD in the population studied.12 The prevalence of CAD in the population presenting for OLT has been the subject of some debate: Carey and colleagues reported a prevalence of 27% in OLT candidates over the age of 50 years.13 The results obtained in our current study, and indeed in any study of patients who have undergone transplantation, should be treated with caution when extrapolating to a population being assessed for liver transplant candidacy for the reason of selection bias discussed earlier. Any recommendation for those patients should be based on studies in that group; however, the results presented here and those of previous studies imply that more stringent criteria to identify patients who should undergo DSE may improve the positive predictive value of such testing. The potential benefit of such an approach is the performance of fewer invasive coronary angiographic procedures for further investigation of positive results. Currently no validated guidelines specific to OLT assessment are available, but the recently published American College of Cardiology & American Heart Association (ACC/AHA) guideline for preoperative cardiovas-
cular evaluation for noncardiac surgery14 may be a useful starting place and provide a standardization that would be useful in interpreting future series. In addition to the evaluation of postoperative troponin data we also compared preoperative and postoperative ECG tracings and found that T-wave changes were common (21%) and not associated with myocardial injury. We suspect that these changes are due to electrolyte shifts in the perioperative period, but further investigation is required to confirm this and also to determine whether the changes resolve. In conclusion, we found that myocardial damage, as assessed by an elevation in cTnT, occurred in 12% of patients undergoing OLT. Used in accordance with our assessment protocol a positive DSE was a poor predictor of myocardial injury, but a negative DSE was strongly predictive of no myocardial injury. The role of DSE in the evaluation of patients prior to OLT requires further assessment. Future investigators should consider the adoption of the AHA/ACC guidelines to standardize the criteria for the performance of DSE in OLT candidates. REFERENCES 1. Plotkin JS, Scott VL, Pinna A, et al: Morbidity and mortality in patients with coronary artery disease undergoing orthotopic liver transplantation. Liver Transpl Surg 2:426, 1996 2. Plevak DJ: Stress echocardiography identifies coronary artery disease in liver transplant candidates. Liver Transplant Surg 4:337, 1998 3. Plotkin JS, Benitez RM, Kuo PC, et al: Dobutamine stress echocardiography for preoperative cardiac risk stratification in patients undergoing orthotopic liver transplantation. Liver Transpl Surg 4:253, 1998 4. Donovan CL, Marcovitz PA, Punch JD, et al: Two-dimensional and dobutamine stress echocardiography in the preoperative assessment of patients with end-stage liver disease prior to orthotopic liver transplantation. Transplantation 61:1180, 1996 5. Williams K, Lewis JF, Davis G, et al: Dobutamine stress echocardiography in patients undergoing liver transplantation evaluation. Transplantation 69:2354, 2000 6. Jaffe A, Ravkilde J, Roberts R, et al: It’s time to change to a troponin standard. Circulation 102:1216, 2000 7. Pellikka P, Roger V, Oh J, et al: Stress echocardiography. Part II. Dobutamine stress echocardiography: techniques, imple-
PREOPERATIVE DOBUTAMINE STRESS ECHOCARDIOGRAPHY mentation, clinical applications and correlations. Mayo Clin Proc 70:16, 1995 8. Ballal R, Kapadia S, Secknus M, et al: Prognosis of patients with vascular disease after clinical evaluation and dobutamine stress echocardiography. Am Heart Jo 137:469, 1999 9. Pellika P, Roger V, Oh J, et al: Safety of performing dobutamine stress echocardiography in patients with abdominal aortic aneurysm ⬎4cm in diameter. Am J Cardiol 77:413, 1996 10. Poldermans D, Fioretti P, Forster T, et al: Dobutamine stress echocardiography for assessment of perioerative and late cardiac risk in patients undergoing major vascular surgery. European Journal of Vascular Surgery 8:286, 1994 11. Davila-Roman V, Waggoner A, Sicard G, et al: Dobutamine stress echocardiography predicts surgical outcome in patients with
2213 an aortic aneurysm and peripheral vascular disease. J Am Coll Cardiol 21:957, 1993 12. Cheitlin M, Alpert J, Armstrong W, et al: ACC/AHA guidelines for the clinical application of echocardiography. A report of the American College of Cardiology/American Heart Association task force on practice guidelines (committee on clinical application of echocardiography). Developed in collaboration with the American Society of Echocardiography. Circulation 95:1686, 1997 13. Carey W, Dumot J, Pimentel R, et al: The prevalence of coronary artery disease in liver transplant candidates over age 50. Transplantation 59:859, 1995 14. Eagle P, Calkins H, Chaitman B, et al: ACC/AHA guideline update for perioperative evaluation for non-cardiac surgery— executive summary. J Am Coll Cardiol 39:542, 2002
Preoperative Dobutamine Stress Echocardiography, Intraoperative Events, and Intraoperative Myocardial Injury in Liver Transplantation J.Y. Findlay, M.T. Keegan, P.P. Pellikka, C.B. Rosen, and D.J. Plevak ABSTRACT Introduction. The appropriate method of screening for coronary artery disease in patients who present for liver transplantation is currently uncertain. Methods. We assessed the utility of a screening protocol using dobutamine stress echocardiography (DSE) in 119 patients who underwent liver transplantation. Patients with cardiac risk factors had DSE performed, and those with positive results were referred for coronary angiography. Outcome was myocardial injury during liver transplantation determined by an elevation of cardiac troponin T measured after transplantation. Results. Seventy-three patients had DSE performed; eight were reported as positive for inducible ischemia. Seven of these patients underwent coronary angiography, and one had significant coronary artery disease. Postoperative troponin elevation occurred in 14 patients. There was no significant difference in the prevalence of troponin elevation in those patients with positive DSE versus those with negative DSE. No significant difference was identified in the prevalence of troponin elevation when comparing those patients with cardiac risk factors who underwent DSE with those patients with no risk factors and no DSE performed. DSE had a sensitivity of 0.2 and a specificity of 0.9 for myocardial injury. The prevalence of intraoperative hemodynamic instability was significantly higher in patients who had evidence of myocardial injury, but hemodynamic instability was no more common in patients who had a positive DSE. Conclusion. When used in accordance with our protocol a positive DSE does not reliably identify patients at high cardiac risk during liver transplantation, but a negative DSE is strongly predictive of no myocardial injury.
O
RTHOTOPIC LIVER TRANSPLANTATION (OLT) is a major surgical procedure resulting in significant physiological stress. The reported outcomes for patients with coronary artery disease (CAD) undergoing OLT are poor.1 It should, therefore, be advantageous to identify such patients during the pretransplant assessment. Currently dobutamine stress echocardiography (DSE) is the favored screening study,2 although there are conflicting reports of its utility.3–5 In addition, the actual prevalence of myocardial injury during OLT is unclear. Studies to date have reported the occurrence of adverse cardiac events identified
clinically; thus the interpretations of the utility of screening tests may be biased by the occurrence of undetected subclinical events. The ability to detect cardiac troponins
From the Department of Anesthesiology, the Division of Cardiovascular Diseases and the Division of Transplantation Surgery, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. Address reprint requests to Dr James Young Findlay; Mayo Clinic College of Medicine, Department of Anesthesiology, 200 Second Street SW, Rochester, MN 55905.
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.03.023
Transplantation Proceedings, 37, 2209 –2213 (2005)
2209
2210
has greatly increased the ability to detect tissue-specific myocardial damage.6 Since 1999 we have been following a cardiac screening algorithm similar to that described by Plevak et al.2 using DSE and have combined this with a routine post-OLT measurement of troponin. Herein we report our experience with this protocol in a cohort of patients who underwent OLT. Our aims were to document the rate of myocardial injury during OLT and identify the ability of DSE to predict myocardial injury during OLT. We hypothesized that DSE would be a good predictor of perioperative myocardial injury. METHODS Institutional Review Board approval was obtained prior to data collection and review. Since mid-1999 all patients being evaluated for OLT at Mayo Clinic, Rochester have undergone a cardiac evaluation involving the acquisition of a detailed history, physical examination and standard 12-lead electrocardiogram (ECG). All patients had a resting echocardiogram performed to assess left ventricular function, valvular function, and pulmonary artery pressures. Patients were referred for DSE if one or more of the following clinical predictors was identified: history consistent with CAD, symptoms concerning for CAD, diabetes mellitus, hypertension, arrhythmia or history of significant arrhythmia, family history of CAD, age ⬎ 50 years, obesity (body mass index ⬎ 30). All DSE examinations were carried out at the our institution using a standard protocol.7 Dobutamine was infused intravenously at increasing doses (5, 10, 20, 30, 40 g/kg/min) to a target heart rate, if this was not achieved atropine (up to 2 mg IV) was added. Images were interpreted by a cardiologist experienced in stress echocardiography in accordance with standard procedures. DSE examinations were read as positive for inducible ischemia if new regional wall motion abnormalities were seen with stress. Patients with DSE results read as positive for inducible ischemia were referred to cardiology for assessment and coronary angiography. Coronary angiograms were performed at our institution using standard techniques and interpreted by an experienced interventional cardiologist. OLT was carried out using a caval sparing technique. All patients received a similar anesthetic regimen and invasive hemodynamic monitoring including pulmonary artery catheterization. The occurrence of significant hemodynamic events during each case was noted from the anesthesia record. A significant hemodynamic event was defined as one of the following: significant hypotension (systolic blood pressure ⬍ 80 mm Hg for 10 or more sequential minutes), the requirement for a pressor infusion, significant new arrhythmia including cardiac arrest. All patients were transferred to the intensive care unit at the end of the procedure. Cardiac troponin T (cTnT) was measured on the first postoperative day. A standard 12-lead ECG was obtained on the same day and compared with one obtained in the immediate preoperative period. ECG readings were confirmed by a cardiologist. Statistical comparisons between rates were made using Fisher’s exact test.
RESULTS
Between January 2000 and December 2001, 119 patients who had been evaluated using the protocol described underwent OLT. Two patents were excluded from the analysis: one who underwent a combined heart and liver
FINDLAY, KEEGAN, PELLIKKA ET AL
transplant and another who underwent OLT within 1 week of a prior troponin elevation. The characteristics of the remainder are given in Table 1. Of the 117 patients analyzed 73 met criteria for DSE. The distribution of cardiovascular risk factors is given in Table 2. Target heart rate was not achieved in 14 of 73 DSE examinations (19%), attributed to beta-blockade in nine, termination of examination due to hypotension in three cases, and intolerable headache in two cases. Eight of the DSE examinations were reported as positive for inducible ischemia. Seven of these patients proceeded to coronary angiography; only one had significant coronary artery disease (occluded right main with good collateral flow, subsequently underwent uneventful OLT without cardiac intervention). Postoperative troponin elevation was observed in 14 patients (12%), occurring in 10/73 of patients with cardiovascular risk factors and 4/44 of those without (P ⫽ NS). On univariate analysis no individual risk factor was significantly associated with postoperative troponin elevation. In those patients who had undergone DSE troponin elevation occurred in 2/8 with a positive DSE versus 8/57 with a negative DSE (P ⫽ NS). DSE had a sensitivity of 0.2 and a specificity of 0.9 for myocardial injury; the positive predictive value was 0.25 (Tables 3 and 4). The rate of inadequate heart rate response was not significantly different in those patients exhibiting postoperative troponin elevation than in those who did not. Significant hemodynamic events were noted in 24 cases and occurred significantly more frequently in patients who exhibited an elevated postoperative troponin level (9/14) than in those who did not (15/103; P ⬍ .001; Table 4). For the patients who underwent DSE the prevalence of hemodynamic instability was not significantly different in those patients with a positive DSE (3/8) compared to those with a negative DSE (15/65). Perioperative events for the patients with elevated troponin levels are presented in Table 5. Postoperative ECG changes were identified in 26 patients (22%); 25 of these were nonspecific T-wave changes, one an axis change. Three changes occurred in patients with elevated troponin (3/14), 23 in the remainder (23/103, P ⫽ NS). Table 1. Characteristics of 117 Study Patients Gender Male Female Age (y) Diagnosis HCV Alcoholic cirrhosis HCV ⫹ alcohol PBC PSC Cryptogenic NASH Others
61 56 52 ⫾ 10 17 14 8 14 10 10 8 36
HCV, hepatitis C; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; NASH, nonalcoholic steatohepatitis.
PREOPERATIVE DOBUTAMINE STRESS ECHOCARDIOGRAPHY Table 2. Cardiovascular Risk Factors and Distribution of Risk Factors
2211 Table 4. Hemodynamically Significant Intraoperative Events* and Troponin
Prevalence
Risk factor History or symptoms suspicious for CAD Age ⬎ 50 y Hypertension Obesity Diabetes FH CAD Arrhythmia Number of risk factors 1 2 3 4
Troponin elevation No troponin elevation Total
24 25 23 23 20 10 8
No event
Total
9 15 24
5 88 93
14 103 117
Sensitivity of intraoperative event ⫽ 0.64; PPV ⫽ 0.6; Specificity of intraoperative event ⫽ 0.68; NPV ⫽ 0.95. *See text for definition.
17 39 16 1
Age ⬎ 50 years was the only risk factor in 12 cases. FH, family history; CAD, coronary artery disease.
DISCUSSION
Identifying CAD in liver transplant candidates is considered an important part of the screening procedure as the reported outcomes for patients with this condition are poor. Plotkin and coworkers reported a mortality of 50% and a morbidity of 81% in a series of such patients.1 DSE has been recommended as the test of choice for identifying CAD in the liver transplant population based on the characteristics of both the imaging modality and the stressor.2 However, the utility of DSE in this population is not settled. Plotkin and coworkers reported that inducible wall motion abnormalities correctly identified CAD in two patients of 40 with no false-negatives.3 Donovan and colleagues reported 11 positive DSE studies in 165 performed; CAD was confirmed on coronary angiography in only three of these 11.4 Williams and colleagues reported that DSE was a poor predictor of intraoperative cardiac events in 61 patients undergoing OLT.5 They also reported a very high rate (50%) of inadequate heart rate response during testing. We found that of eight positive DSE examinations CAD was confirmed in only one patient on subsequent coronary angiography; a second patient may have had CAD but was transplanted prior to angiography. Thus our study is at variance with the findings of Plotkin et al3 and more consistent with those of the other previously published studies.4,5 As the utility of a diagnostic test is influenced by the prevalence of the condition being sought in addition to the actual efficiency of the test, some of the discrepancy in results may be due to the different criteria used in the studies to select patients for DSE. In addition Table 3. DSE and Troponin
Troponin elevation No troponin elevation Total
Event
DSE positive
DSE negative
Total
2 6 8
8 57 65
10 63
Sensitivity of DSE ⫽ 0.2; PPV ⫽ 0.25; Specificity of DSE ⫽ 0.9; NPV ⫽ 0.88.
the reported endpoints differ in each study. Plotkin and colleagues3 report on 80 DSE examinations performed in patients selected from 220 OLT candidates on the basis of a history consistent with CAD, diabetes mellitus, age ⬎ 60 years or age ⬎ 50 years, with two or more risk factors. Efficacy of testing is calculated on 40 of these patients using the combined endpoints of result of coronary angiography or occurrence of a cardiac event during OLT. Donovan and colleagues4 report on DSE performed in 165 patients of 190 undergoing evaluation for OLT. DSE was performed based on age ⬎ 45 years or clinical suspicion of ischemic heart disease. Both the results of cardiac catheterizations and the occurrence of perioperative cardiac events in 71 of the patients who underwent OLT are reported. Williams and colleagues5 report a different approach: all patients with known CAD or symptoms consistent with myocardial ischemia went directly to cardiac catheterization. DSE is reported in 121 patients who had cardiac risk factors, atypical chest pain, or were aged ⬎ 60 years but did not meet criteria for angiography. Outcomes reported are perioperative cardiac events in 61 of the DSE patients who underwent OLT. Our selection criteria resulted in a greater proportion of our patients undergoing DSE than the criteria used by Plotkin; the proportion of our patients who underwent DSE was closer to that of Donovan, which may partially account for the difference in findings. In addition we report only on patients who underwent OLT. We acknowledge that this is a highly selected group, excluding those patients with liver failure never referred for transplant, those who are evaluated but not listed for transplant, and also those listed but who do not come to transplant. Our intention in reporting on this group of patients was to address the question of the predictive ability of DSE, used according to our assessment protocol, to identify perioperative cardiac morbidity. It was also for this reason that we chose cTnT as our outcome measure— by using this specific and sensitive marker we identified patients who sustained myocardial damage. This allows us to address the issue of whether a positive DSE with a normal coronary angiogram in OLT patients may still be meaningful, for example, in terms of indicating abnormal microvascular perfusion and an at-risk myocardium. Our results suggest that this is not the case. While the positive predictive value of DSE was not strong in our population, a negative DSE appears a strong predictor of OLT without
2212
FINDLAY, KEEGAN, PELLIKKA ET AL Table 5. Intraoperative Events and Outcomes of Patients With Troponin Elevation
Patient number
Intraoperative event
Outcome
1 2 3 4
Cardiac arrest Cardiac arrest Ventricular tachycardia Hypotension
5 6 7
Hypotension Hypotension Hypotension
8, 9 10–14
Hypotension No intraoperative event
Died POD 1 Uneventful recovery, negative coronary angiography Uneventful recovery Postoperative supraventricular tachycardia (known WPW), subsequently uneventful CHF POD 2, no evidence of CAD (global changes on echo) CHF POD 3, no evidence of CAD (global changes on echo) Known PPHTN—RHF POD 3, prolonged ICU course, died 1 month posttransplant Uneventful recovery Uneventful recovery
POD, post operative day; WPW, Wolff-Parkinson-White syndrome; CHF, congestive heart failure; CAD, coronary artery disease; PPHTN, portopulmonary hypertension; RHF, right heart failure; ICU, intensive care unit.
myocardial injury. This is in concurrence with the previously published series of OLT patients3–5 as well as with studies of DSE for risk stratification in vascular surgery.8 –11 The findings in our study also raise the question of the etiology of myocardial damage in OLT. We found a significantly higher rate of significant hemodynamic events in the patients who exhibited elevated cTnT compared to those who did not. We also found no association of intraoperative myocardial injury with any preoperative risk factor we examined, including positive or nondiagnostic DSE. We suggest therefore that myocardial injury occurring during OLT in the population as currently selected is a consequence of intraoperative stresses sufficient to result in a myocardial supply/demand discrepancy in the absence of significant cardiac vascular pathology. Thus the occurrence of myocardial injury during OLT should not be equated with the presence of underlying CAD. What are the implications of these findings for the use of DSE as a screening examination for CAD in liver transplant candidates? While DSE is a useful test in assessing patients for CAD, its utility depends upon the pretest probability of CAD in the population studied.12 The prevalence of CAD in the population presenting for OLT has been the subject of some debate: Carey and colleagues reported a prevalence of 27% in OLT candidates over the age of 50 years.13 The results obtained in our current study, and indeed in any study of patients who have undergone transplantation, should be treated with caution when extrapolating to a population being assessed for liver transplant candidacy for the reason of selection bias discussed earlier. Any recommendation for those patients should be based on studies in that group; however, the results presented here and those of previous studies imply that more stringent criteria to identify patients who should undergo DSE may improve the positive predictive value of such testing. The potential benefit of such an approach is the performance of fewer invasive coronary angiographic procedures for further investigation of positive results. Currently no validated guidelines specific to OLT assessment are available, but the recently published American College of Cardiology & American Heart Association (ACC/AHA) guideline for preoperative cardiovas-
cular evaluation for noncardiac surgery14 may be a useful starting place and provide a standardization that would be useful in interpreting future series. In addition to the evaluation of postoperative troponin data we also compared preoperative and postoperative ECG tracings and found that T-wave changes were common (21%) and not associated with myocardial injury. We suspect that these changes are due to electrolyte shifts in the perioperative period, but further investigation is required to confirm this and also to determine whether the changes resolve. In conclusion, we found that myocardial damage, as assessed by an elevation in cTnT, occurred in 12% of patients undergoing OLT. Used in accordance with our assessment protocol a positive DSE was a poor predictor of myocardial injury, but a negative DSE was strongly predictive of no myocardial injury. The role of DSE in the evaluation of patients prior to OLT requires further assessment. Future investigators should consider the adoption of the AHA/ACC guidelines to standardize the criteria for the performance of DSE in OLT candidates. REFERENCES 1. Plotkin JS, Scott VL, Pinna A, et al: Morbidity and mortality in patients with coronary artery disease undergoing orthotopic liver transplantation. Liver Transpl Surg 2:426, 1996 2. Plevak DJ: Stress echocardiography identifies coronary artery disease in liver transplant candidates. Liver Transplant Surg 4:337, 1998 3. Plotkin JS, Benitez RM, Kuo PC, et al: Dobutamine stress echocardiography for preoperative cardiac risk stratification in patients undergoing orthotopic liver transplantation. Liver Transpl Surg 4:253, 1998 4. Donovan CL, Marcovitz PA, Punch JD, et al: Two-dimensional and dobutamine stress echocardiography in the preoperative assessment of patients with end-stage liver disease prior to orthotopic liver transplantation. Transplantation 61:1180, 1996 5. Williams K, Lewis JF, Davis G, et al: Dobutamine stress echocardiography in patients undergoing liver transplantation evaluation. Transplantation 69:2354, 2000 6. Jaffe A, Ravkilde J, Roberts R, et al: It’s time to change to a troponin standard. Circulation 102:1216, 2000 7. Pellikka P, Roger V, Oh J, et al: Stress echocardiography. Part II. Dobutamine stress echocardiography: techniques, imple-
PREOPERATIVE DOBUTAMINE STRESS ECHOCARDIOGRAPHY mentation, clinical applications and correlations. Mayo Clin Proc 70:16, 1995 8. Ballal R, Kapadia S, Secknus M, et al: Prognosis of patients with vascular disease after clinical evaluation and dobutamine stress echocardiography. Am Heart Jo 137:469, 1999 9. Pellika P, Roger V, Oh J, et al: Safety of performing dobutamine stress echocardiography in patients with abdominal aortic aneurysm ⬎4cm in diameter. Am J Cardiol 77:413, 1996 10. Poldermans D, Fioretti P, Forster T, et al: Dobutamine stress echocardiography for assessment of perioerative and late cardiac risk in patients undergoing major vascular surgery. European Journal of Vascular Surgery 8:286, 1994 11. Davila-Roman V, Waggoner A, Sicard G, et al: Dobutamine stress echocardiography predicts surgical outcome in patients with
2213 an aortic aneurysm and peripheral vascular disease. J Am Coll Cardiol 21:957, 1993 12. Cheitlin M, Alpert J, Armstrong W, et al: ACC/AHA guidelines for the clinical application of echocardiography. A report of the American College of Cardiology/American Heart Association task force on practice guidelines (committee on clinical application of echocardiography). Developed in collaboration with the American Society of Echocardiography. Circulation 95:1686, 1997 13. Carey W, Dumot J, Pimentel R, et al: The prevalence of coronary artery disease in liver transplant candidates over age 50. Transplantation 59:859, 1995 14. Eagle P, Calkins H, Chaitman B, et al: ACC/AHA guideline update for perioperative evaluation for non-cardiac surgery— executive summary. J Am Coll Cardiol 39:542, 2002