Pulmonary hypertension is not uncommonly encountered

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1 Accuracy of Doppler Echocardiography in the Assessment of Pulmonary Hypertension in Liver Transplant Candidates W. Ray Kim, * Michael J. Krowka, * David J. Plevak, Jaeho Lee, Steven R. Rettke, Robert P. Frantz, and Russell H. Wiesner * Pulmonary hypertension has been associated with poor outcome after liver transplantation. We assessed the diagnostic accuracy of Doppler echocardiography in detecting significant pulmonary hypertension. Seventyfour potential liver transplant candidates underwent Doppler echocardiography in which the systolic right ventricular pressure (RVsys) was used to estimate the systolic pulmonary artery pressure (PAsys). Group 1 included 39 consecutive patients with RVsys H50 mm Hg who underwent elective right heart catheterization. Group 2 consisted of 35 patients with RVsys F50 mm Hg in whom pulmonary artery pressures were measured at the beginning of the transplantation procedure. The accuracy of the estimates by Doppler echocardiography was assessed against measurements made by direct catheterization. Patients in groups 1 and 2 were comparable in their demographic and liver disease characteristics. There was a strong correlation between RVsys by Doppler echocardiography and PAsys by right heart catheterization (r.78, P F.01). Of the 39 patients in group 1, 29 (72%) had at least moderate pulmonary hypertension (mean pulmonary artery pressure [MPAP] H35 mm Hg), including 12 (30%) with severe pulmonary hypertension (MPAP H50 mm Hg). Only 1 of the group 2 patients had MPAP H35 mm Hg. Thus, in the diagnosis of moderate to severe pulmonary hypertension, the sensitivity of echocardiography was 97% and specificity was 77%. Doppler echocardiography is an accurate screening test to detect moderate to severe pulmonary hypertension. We advise that liver transplant candidates with RVsys H50 mm Hg undergo right heart catheterization to fully characterize pulmonary hemodynamics. (Liver Transpl 2000;6: ) Pulmonary hypertension is not uncommonly encountered in patients with advanced liver disease. Portopulmonary hypertension (PPH) is the most significant type of pulmonary hypertension, and it may be seen in up to 9% of patients with advanced liver disease. 1,2 PPH is defined hemodynamically by increased mean pulmonary artery pressure (MPAP 25 mm Hg) and normal volume status or pulmonary capillary wedge pressure (PCWP 15 mm Hg) in patients with chronic liver disease and portal hypertension. 3 An additional criterion of increased pulmonary vascular resistance (PVR 120 dyne s cm 5 ) is favored by some investigators. 4 This latter condition further emphasizes the pulmonary arterial pressureflow relationship. The exact pathophysiologic mechanism causing pulmonary arterial hypertension in these patients remains to be elucidated. 5 It is believed that pulmonary vasoconstriction and the high flow state associated with hepatic dysfunction plays an important part early in the pathogenesis. 1 Autopsy studies have shown vascular medial hypertrophy, intimal fibrosis, and plexogenic arteriopathy with or without thrombotic change in varying degrees. 6 The hemodynamic correlates and reversibility of these lesions are poorly understood. In the context of orthotopic liver transplantation (OLT), PPH has been associated with poor outcome. In particular, increased mortality and morbidity have been reported in patients with moderate (MPAP 35 mm Hg) or severe (MPAP 50 mm Hg) pulmonary hypertension Given the potentially devastating impact of undiagnosed PPH in liver transplant recipients, Doppler echocardiography has been used as a screening test for pulmonary hypertension. However, the accuracy and utility of Doppler echocardiography in estimating the pressure of the pulmonary circulation in patients with PPH are not well established. Thus, the aim of this study was to assess the diagnostic accuracy of Doppler echocardiography in detecting pulmonary hypertension in liver transplant candidates, by (1) examining the correlation between the systolic right ventricular pressure (RVsys) measured by Doppler echocardiography and the systolic pulmonary artery pressure (PAsys) measured by cardiac catheterization, and (2) evaluating the sensitivity and specificity of Doppler echocardiography in the diagnosis of clinically significant pulmonary hypertension (MPAP 35 mm Hg). From the *Division of Gastroenterology and Hepatology, Division of Pulmonary and Critical Care Medicine and Internal Medicine, Department of Anesthesiology, and Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic and Foundation, Rochester, MN. Address reprint requests to W. Ray Kim, MD, Division of Gastroenterology and Hepatology (W19), Mayo Clinic and Foundation, 200 First St, SW, Rochester, MN Telephone: ; FAX: ; kim.woong@mayo.edu Copyright 2000 by the American Association for the Study of Liver Diseases /00/ $3.00/0 doi: /jlts Liver Transplantation, Vol 6, No 4 ( July), 2000: pp

2 454 Kim et al Methods Patients This study was based on 2 groups of patients (n 74) who were referred for liver transplantation at the Mayo Clinic from 1996 to 1999 (Table 1). Doppler echocardiography was performed routinely as a pretransplant screening test in all liver transplant candidates. Group 1 (n 39) consisted of consecutive potential liver transplant candidates who had an RVsys 50 mm Hg by Doppler echocardiography. All of these patients underwent elective right-heart catheterization with measurement of pulmonary artery pressures and cardiac output. Group 2 (n 35) included a random sample of liver transplant recipients who underwent transplant evaluation during the same period as group 1. All had RVsys 50 mm Hg by Doppler echocardiography. Pulmonary artery pressures were measured under anesthesia at the beginning of the transplantation procedure, in all patients who underwent OLT, including 6 patients in group 1. This study was approved by the Institutional Review Board of the Mayo Foundation. Hemodynamic Measurement Clinically stable patients in group 1 underwent outpatient right-heart catheterization. Using a balloonfloatation catheter, main pulmonary artery systolic and diastolic measurements were obtained. MPAP and PCWP were measured. In all patients who underwent liver transplantation, pulmonary artery catheters were routinely placed before the procedure and hemodynamic measurements were obtained after the induction of anesthesia with the patients intubated and breathing 40% inspired oxygen. Doppler Echocardiography Complete 2-dimensional and Doppler transthoracic echocardiography were recorded using various models of commercially available echocardiographic equipment. Continuous-wave Doppler recording of the tricuspid regurgitant signal was obtained from the parasternal, apical, and subcostal views. Dopplerderived RVsys was then calculated from the peak tricuspid regurgitant velocity (TR) using the modified Bernouilli equation and an estimate of the right atrial pressure (RA): RVsys 4x(TR) 2 RA. RA pressure Table 1. Patient Characteristics of the Two Groups Group 1 Pumonary Hypertension N 39 Group 2 Control N 35 Age 53 (21-65) 55 (26-71).14 Gender (% female) Diagnosis (%).32 Viral 8 (21) 6 (17) Alcohol 8 (21) 4 (11) Autoimmune* 12 (30) 18 (51) Other 11 (28) 7 (2) Bilirubin (mg/dl) 2.6 ( ) 2.5 ( ).88 Albumin (g/dl) 2.9 ( ) 3.1 ( ).32 Prothrombin time (sec) 13.0 ( ) 12.5 ( ).20 Creatinine (mg/dl) 1.0 ( ) 1.0 ( ).86 Ascites (% present) 27 (69) 22 (63).56 Encephalopathy (% present) 11 (28) 13 (37).41 RVsys by Doppler echo (mm Hg) 69 (50-112) 32 (21-44).01 PAsys by cardiac catheterization (mm Hg) 66 (28-135) 26 (14-55).01 Time interval between echo and catheterization 18 (0-91) 105 (0-399).01 NOTE. Median (range) values are shown unless noted otherwise. Group 1 includes patients with RVsys 50 mm Hg and group 2 those with RVsys 50 mm Hg by Doppler echocardiography. *Autoimmune etiologies included chronic autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune cholangitis, and sarcoidosis. P

3 Pulmonary Hypertension 455 was estimated to be either 5, 10, or 14 mm Hg depending on the degree of vascular filling of the inferior vena cava. Because no patients in either group had right ventricular outflow obstruction, PAsys was considered equivalent to RVsys. Data Analysis Baseline patient characteristics in groups 1 and 2 included age, gender, liver disease diagnosis, presence/ absence of ascites and encephalopathy, and laboratory data (total bilirubin, albumin, prothrombin time, and creatinine). The 2 groups were compared using the Wilcoxon s rank sum test for continuous variables and the chi-square test for categorical variables. The correlation between the RVsys measured by Doppler echocardiography and PAsys by cardiac catheterization was examined using the Pearson correlation and linear regression analyses. A Bland-Altman plot was generated to further examine the relationship between the 2 methods of hemodynamic measurements. 12 The sensitivity and specificity of the RVsys measured by Doppler echocardiography in detecting clinically significant pulmonary hypertension were calculated. This included a moderate degree of pulmonary hypertension defined as MPAP 35 mm Hg and severe pulmonary hypertension with MPAP 50 mm Hg. Results Figure 1. Correlation between RVsys by echocardiography and PAsys by right-heart catheterization. Group 1 (RVsys H50 mm Hg) and group 2 (RVsys F50 mm Hg) are shown. The correlation between RVsys and PAsys was strong (r.78) and significant (P F.01). The only patient who had PAsys G50 in group 2 had volume overload. Table 1 summarizes characteristics of patients of the 2 groups. Except for the hemodynamic data, the 2 groups were comparable. With regard to the etiology of liver disease, the frequency of diseases of presumed autoimmune cause was not higher in group 1, which may suggest that pulmonary hypertension observed in patients with cirrhosis may be pathogenetically distinct from primary pulmonary hypertension, which is frequently associated with autoimmune disorders. Figure 1 shows the correlation between the RVsys measured by Doppler echocardiography and PAsys measured by right-heart catheterization. A robust correlation was found between systolic pulmonary artery pressures measured by the 2 methods (r.78, P.01). Figure 2 represents a Bland-Altman plot showing the differences between the 2 measurement methods using the pulmonary artery pressure by cardiac catheterization as the gold standard. The mean difference between the 2 methods was 2.8 mm Hg (SD, 16.1), a small discrepancy considering the magnitude of pulmonary artery pressures encountered in this population. Among patients in group 1, the MPAP measured by cardiac catheterization was 45 mm Hg (SD, 14). Of group 1 patients, 17 (42%) had moderate pulmonary hypertension (35 mm Hg MPAP 50 mm Hg), whereas 12 (30%) had severe pulmonary hypertension (MPAP 50 mm Hg). Table 2 summarizes the sensitivity and specificity of Doppler echocardiography in the detection of clinically significant pulmonary hypertension as defined by MPAP 35 mm Hg. The sensitivity for the Doppler echocardiography to detect moderate to severe pulmonary hypertension was 97% and specificity was 77%. Table 3 compares hemodynamic measurements taken (1) at the time elective catheterization during pretransplant evaluation, and (2) at the beginning of the transplantation procedure in 6 patients in group 1 who underwent liver transplantation. The 2 measurements in each category were closely correlated, indicating reproducibility of hemodynamic measurements by cardiac catheterization and lack of significant variabil-

4 456 Kim et al Figure 2. A Bland-Altman plot showing that there is little systematic difference between the measurements made by echocardiography and right-heart catheterization. Except for the 2 patients with extremely high PAsys in whom the echocardiography underestimated the pulmonary artery pressure, the bias had a strong central tendency. ity introduced by general anesthesia at the time of transplantation. Discussion Hemodynamic definition of portopulmonary hypertension includes (1) elevated mean pulmonary artery pressure (MPAP 25 mm Hg), (2) increased pulmonary vascular resistance (PVR 120dyne s cm 5 ), and (3) normal pulmonary capillary wedge pressure (PCWP 15 mm Hg). 3,4 Thus, not all patients with elevated pulmonary artery pressure have portopulmonary hypertension. It is not uncommon for cirrhotic patients to have hyperdynamic circulation or fluid overload, which may elevate the pulmonary artery Table 2. Diagnostic Accuracy of Doppler Echocardiography in the Detection of Moderate to Severe Pulmonary Hypertension Echocardiography MPAP 35 mm Hg Cardiac Catheterization MPAP 35 mm Hg Group I (RVsys 50 mm Hg) Group II (RVsys 50 mm Hg) 34 1 NOTE. Sensitivity of Doppler echocardiography in the diagnosis of clinically significant pulmonary hypertension (MPAP 35 mm Hg) 97%. Specificity of Doppler echocardiography in the diagnosis of clinically significant pulmonary hypertension (MPAP 35 mm Hg) 77%. pressure without the defining changes in the pulmonary vascular bed. 4 Nonetheless, elevated pulmonary artery pressure is the cardinal feature of this syndrome, which can be measured by noninvasive diagnostic modalities, as shown in this study. The rationale for screening for pulmonary hypertension in liver transplant candidates is that the outcome of OLT in patients with significant PPH may be substantially compromised. Firstly, PPH has been associated with increased risk of intra- and posttransplant mortality Clinically significant PPH that constitutes a high-risk mortality may be characterized by (1) MPAP 35 mm Hg, (2) PVR 250 dyne s cm 5, or (3) cardiac output 8 L/min. In our recent literature review of 43 liver transplant recipients in 19 reports, MPAP 35 mm Hg was Table 3. Hemodynamic Data in Six Patients With Pulmonary Hypertension Who Underwent Two Pulmonary Hemodynamic Evaluations (one preoperatively [Pre] and again at the beginning of the transplantation procedure [Intra]) Case PAsys* (mm Hg) MPAP* (mm Hg) No. Pre Intra Pre Intra *Difference not significant.

5 Pulmonary Hypertension 457 associated with 48% perioperative mortality, PVR 250 dyne s cm 5 with 55%, and cardiac output 8 L/min with 35%. 13 Secondly, to avoid further morbidity, liver transplant recipients with significant PPH require close hemodynamic monitoring and careful perioperative cardiopulmonary support. 14,15 Thirdly, in patients who survive the transplant procedure, pulmonary hypertension may or may not improve subsequently This study showed that Doppler echocardiography is a useful screening tool to detect of clinically significant pulmonary hypertension. Doppler echocardiography was able to estimate the PAsys by measuring the RVsys. Moreover, the RVsys by Doppler echocardiography was sensitive and specific in detecting clinically significant pulmonary hypertension as defined above. Overall, Doppler echocardiography appears to be a valuable initial step in assessing pulmonary hemodynamics in liver transplant candidates. There is virtually no documentation in the literature evaluating the diagnostic accuracy of Doppler echocardiography in the assessment of pulmonary hypertension in patients with suspected PPH. Studies undertaken in patients with other types of pulmonary hypertension appear to support the validity of our study. 19,20 In one such study in patients with primary pulmonary hypertension and systemic sclerosis, nearly identical results were reported with a sensitivity of 90% and specificity of 75% and a correlation coefficient of The diagnostic accuracy of echocardiography may be lower in other types of pulmonary hypertension such as pulmonary embolism or cor pulmonale, because of other complicating factors specific to these entities. 21,22 One caveat of this study is that the direct measurement of right-heart pressures was undertaken in dissimilar settings, i.e., by elective catheterization in group 1 and under anesthesia at the time of the transplantation procedure in group 2. This is also reflected in the time interval between echocardiography and catheterization (Table 1). While longer time intervals in group 2 may have introduced more variability in the 2 measurements, there was no correlation between the time interval and the degree of discrepancy between the 2 measurements. In addition, the influence of anesthetic agents on the pulmonary vascular bed may potentially alter pulmonary artery pressures. We had only 6 patients in which to examine this possibility (Table 3). Despite the small number, no systematic or significant differences were found between pulmonary artery pressures measured in the 2 settings in the same individuals. In summary, we showed a strong correlation between Doppler echocardiographic assessment and direct hemodynamic measurement of pulmonary artery pressures in patients with end-stage liver disease. Doppler echocardiography is highly sensitive and specific in detecting clinically significant pulmonary hypertension. We conclude that liver transplant candidates with systolic right ventricular pressure 50 mm Hg by Doppler echocardiography should undergo right-heart catheterization preoperatively to assess perioperative risk and establish baselines for potential treatment. References 1. Herve P, Lebrec D, Brenot F, Simonneau G, Humbert M, Sitbon O, Duroux P. Pulmonary vascular disorders in portal hypertension. Eur Respir J 1998;11: Castro M, Krowka MJ, Schroeder DR, Beck KC, Plevak DJ, Rettke SR, et al. Frequency and clinical implication of increased pulmonary artery pressures in liver transplant patients. Mayo Clin Proc 1996;71: Krowka M. Hepatopulmonary syndrome versus portopulmonary hypertension: Distinctions and dilemmas. Hepatology 1997;25: Kuo PC, Plotkin JS, Gaine S, Schroeder RA, Rustgi VK, Rubin LJ, Johnson LB. Portopulmonary hypertension and the liver transplant candidate. Transplantation 1999;67: Mandell MS, Groves BM. Pulmonary hypertension in chronic liver disease. Clin Chest Med 1996;17: Edwards BS, Weir EK, Edwards WD, Ludwig J, Dykoski RK, Edwards JE. Coexistent pulmonary and portal hypertension: Morphologic and clinical features. J Am Coll Cardiol 1987;10: De Wolf AM, Scott VL, Gasior T, Kang Y. Pulmonary hypertension and liver transplantation. Anesthesiology 1993;78: Ramsey MAE, Simpson BR, Nguyen AT, Ramsay KJ, East C, Klintmalm GB. Severe pulmonary hypertension in liver transplant candidates. Liver Transpl Surg 1997;3: De Wolf AM, Gasior T, Kang Y. Pulmonary hypertension in a patient undergoing liver transplantation. Trans Proc 1991;23: Cheng EY, Woehlck HJ. Pulmonary artery hypertension complicating anesthesia for liver transplantation. Anesthesiology 1992; 77: Gillies BS, Perkins JD, Cheney FW. Abdominal aortic compression to treat circulatory collapse caused by severe pulmonary hypertension during liver transplantation. Anesthesiology 1996; 85: Bland JM, Altman DG. Statistical methods for assessing agreement between two measures of clinical measurement. Lancet 1986;8476: Krowka MJ, Plevak DJ, Findlay JY, Rosen CB, Wiesner RH, Krom RAF. Pulmonary hemodynamics and perioperative cardiopulmonary-related mortality in patients with portopulmonary hypertension undergoing liver transplantation. Liver Transpl 2000;6; Krowka M, Frantz RP, McGoon MD, Severson C, Plevak DJ,

6 458 Kim et al Wiesner RH. Improvement in pulmonary hemodynamics during intravenous epoprostenol (prostacyclin): A study of 15 patients with moderate to severe portopulmonary hypertension. Hepatology 1999;30: Madell SM, Duke J. Nitric oxide reduces pulmonary hypertension during hepatic transplantation. Anesthesiology 1994;81: Prager MC, Cauldwell CA, Ascher NL, Roberts JP, Wolfe CL. Pulmonary hypertension associated with liver disease is not reversible after liver transplantation. Anesthesiology 1992;77: Liu G, Knudsen KE, Secher NH. Orthotopic liver transplantation in a patient with primary pulmonary hypertension. Anesth Intes Care 1996;2: Scott V, DeWolf A, Kang Y, Martin M, Selby R, Fung J, et al. Reversibility of pulmonary hypertension after liver transplantation: A case report. Trans Proc 1993;25: Currie PJ, Seward JB, Chan KL, Fyfe DA, Hagler DJ, Mair DD, et al. Continuous wave Doppler determination of right ventricular pressure: A simultaneous Doppler-catheterization study in 127 patients. J Am Coll Cardiol 1985;6: Denton CP, Cailes JB, Phillips GD, Wells AU, Black CM, Bois RM. Comparison of Doppler echocardiography and right heart catheterization to assess pulmonary hypertension in systemic sclerosis. Br J Rheumatol 1997;36: Nakayama Y, Sugimachi M, Nakanishi N, Takaki H, Okano Y, Satah T, et al. Noninvasive differential diagnosis between chronic pulmonary thromboembolism and primary pulmonary hypertension by means of Doppler ultrasound measurement. J Am Coll Cardiol 1998;31: Zompatori M, Battaglia M, Rimondi MR, Battista G, Stambazzi C. Hemodynamic estimation of chronic cor pulmonale by Doppler echocardiography. Clinical value and comparison with other noninvasive imaging techniques. Rays 1997;22:73-93.