EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Survival in liver transplant after end-stage liver disease is associated with major cardiac functions. In a significant number of patients with end-stage liver disease, cardiac dysfunctions may be observed, which can include high-output heart failure, cardiac valve disease, and pulmonary venous and arterial hypertension. All of these affect perioperative survival.

The aim of our study was to determine whether preoperative and postoperative echocardiographic parameters, specifically right heart-related tricuspid regurgitation, estimated systolic pulmonary arterial pressure, and tricuspid annular plane systolic excursion, are associated with rejection and mortality in liver transplant patients.

Materials and Methods: Adult patients (> 18 years old) who underwent liver transplant at our center between January 2011 and March 2017 were included in the study, with 64 patients retrospectively screened. The echocardiographic images that were taken immediately before and immediately after liver transplant were evaluated. The patients were divided into 2 groups according to rejection data and mortality. All parameters were analyzed for both variables.

Results: For the 24 patients with liver rejection and 40 patients without liver rejection, there were no statistically significant differences in terms of demographic data, echocardiographic parameters, and laboratory data. However, when patients were evaluated according to survival, there was a statistically significant difference between these 2 groups concerning the echocardiography parameters of systolic pulmonary arterial pressure (P = .005), tricuspid annular plane systolic excursion (P = .001), and postoperative right ventricular width (P = .01).

Conclusions: Echocardiography, being a simple and easily accessible technique that is reliable in excluding pulmonary hypertension diagnosis, can be used as a guide in the evaluation of right ventricular function and tricuspid regurgitation, particularly in patients who are not hemodynamically stable before and after liver transplant.

Key words : Echocardiography, Pulmonary arterial pressure, Rejection, Tricuspid annular plane systolic excursion

Survival in patients with liver transplant following end-stage liver disease is associated with major cardiac functions. In a significant number of patients with end-stage liver disease, cardiac dysfunctions may be observed. These can include high-output heart failure, cardiac valve disease, and pulmonary venous and arterial hypertension, which all affect perioperative survival.^1,2 Mean pulmonary artery pressure (PAP), measured by right heart catheterization and pulmonary vascular resistance, has been previously associated with survival after liver transplant.³ Increased PAP was found to have cardiac causes, including right-sided heart failure and ventricular arrhythmia.³ However, although right heart catheterization provides useful information about hemodynamic parameters, it has certain limitations. These include its invasive nature and the fact that it only gives information about the current hemodynamic state, with no data provided regarding the structure and function of the myocardium.

Two-dimensional/Doppler echocardiography is a widely used technique for predicting cardiac hemodynamics.⁴ Currently, the American Association for the Study of Liver Diseases recommends routine echocardiography for all liver recipient candidates for the assessment of cavity in diameters, hypertrophy, systolic and diastolic functions, and valve functions.⁵

In the literature, there are few studies examining the effects of echocardiographic parameters on mortality in liver transplant patients. However, to the best of our knowledge, none of these studies has investigated the relationship between these parameters and rejection. Therefore, this study aimed to determine whether preoperative and postoperative echocardiographic parameters, specifically right heart-related tricuspid regurgitation, estimated systolic PAP (sPAP), and tricuspid annular plane systolic excursion (TAPSE), are associated with rejection and mortality in liver transplant patients.

Materials and Methods

Adult patients (> 18 years old) who underwent liver transplant at our center between January 2011 and March 2017 were included in the study. During this period, liver transplant was performed on a total of 174 patients, of whom 103 were pediatric and 9 others excluded from the study due to data loss for various reasons. As a result, 64 patients were retrospectively screened. The results of postoperative biopsy were evaluated in terms of the presence and grade of acute cellular rejection after transplant. Patient survival rate was calculated in months. Creatinine levels, hemoglobin levels, leukocyte counts, and platelet counts were recorded from preoperative laboratory parameters of all patients. To investigate the effects of these parameters on mortality, the data from patients who survived and those who died were compared.

Echocardiography
Pretransplant and posttransplant echocardiography studies were performed on all patients by a cardiologist who had a certification of competence. All cardiac measurements were conducted in accordance with the recommendations of the European Association of Cardiovascular Imaging.^6,7 The echocardiographic images that were taken immediately before and immediately after liver transplant were evaluated. From these images, the left ventricular end-diastolic volume, presence of diastolic dysfunction, ejection fraction, presence of left ventricular hypertrophy, mitral regurgitation grade, tricuspid regurgitation grade, estimated sPAP, right ventricular cavity dimension, and TAPSE showing the right ventricular function were recorded. The estimated sPAPs of patients were calculated using the modified Bernoulli equation (4V2 + estimated right atrium pressure, where V is velocity of tricuspid regurgitant jet) based on the tricuspid regurgitant jet.

Statistical analyses
Patients were divided according to the presence of graft rejection and survival. All parameters were analyzed for both variables. Logistic regression analyses were performed to determine the factors that affected mortality in liver transplant patients. Data are expressed as mean and standard deviation unless otherwise stated. Categorical data were analyzed using Fisher exact test and the chi-square test. P < .05 was considered to be statistically significant. All analyses were undertaken using the SPSS statistical program (version 17; SPPS, Chicago, IL, USA).

Our study included 64 patients. Table 1 presents the demographic characteristics and the clinical and laboratory data of the study patients. Of the 64 patients, 45 were on tacrolimus treatment, 7 were on cyclosporine, 4 were on everolimus, and the remaining patients were on combination therapy. Regarding donation type, 44 patients had living donor transplant and 20 had deceased donor transplant. Table 2 shows the comparisons of patients based on the presence of rejection. Between the 24 patients who had liver rejection and 40 patients who did not have liver rejection, there were no statistically significant differences in terms of demographic data, echocardiographic parameters, and laboratory data. However, when patients were analyzed according to survival, there was a statistically significant difference between these 2 groups concerning the echocardiography parameters of sPAP (P = .005), TAPSE (P = .001), and postoperative right ventricular width (P = .01). Similarly, the need for postoperative renal replacement treatment (RRT) was found to be associated with mortality (P = .001). The comparative data are presented in Table 3.

Our multivariate regression analysis showed a statistically significant relationship between mortality and sPAP and TAPSE values (Table 4). Because sPAP of patients was calculated based on the tricuspid regurgitant output, this value could not be recorded in patients who did not present with tricuspid regurgitation. The postoperative TAPSE value was found to predict mortality (95% confidence interval) with 71% sensitivity and 78% specificity.

Echocardiography is a widely used method to evaluate left ventricular dysfunction and pulmonary hypertension in liver transplant patients.^8,9 Pulmonary vascular diseases including portopulmonary hypertension are important complications that may develop after liver transplant, and they are also of value in prognosis.¹⁰ Liver transplant can be safely performed on patients with mild portopulmonary hypertension. However, vasodilator treatment should be initiated in patients with moderate to high portopulmonary hypertension (mean PAP of 35-45 mm Hg in right heart catheterization) and continued in the postoperative period.¹⁰ If the sPAP measured by echocardiography is ≥ 30 mm Hg, the positive predictive value for the diagnosis of portopulmonary hypertension is 59% and the negative predictive value is 100%.¹¹ Previous studies have explored mortality predictors after liver transplant; however, this is the first study that investigated whether echocardiographic parameters are associated with rejection. Our study showed that none of the echocardiographic parameters were associated with rejection. This may be because rejection was detected at the pathologic level before reaching a level of systemic effect.

Regarding echocardiographic parameters and survival, we observed statistically significant differences between mortality and postoperative TAPSE, sPAP, and right ventricular width values. In a study of 216 patients, Kia and associates12 investigated the association between preoperative echocardiographic data and mortality. According to the results of their univariate analysis, the presence of mild and greater tricuspid regurgitation, posttransplant RRT, and history of spontaneous bacterial peritonitis were accompanied by adverse events, whereas their multivariate analysis showed that only mild and greater tricuspid regurgitation levels were factors in mortality (P = .002, hazard ratio = 3.91, 95% confidence interval, 1.62-9.44) and organ failure (P = .001, hazard ratio = 3.70, 95% confidence interval, 1.70-8.06).

In the same study, posttransplant echocardiography was also analyzed and the pretransplant and posttransplant data were compared in 31 patients. However, a statistical analysis was not performed due to the low number of patients. Regarding posttransplant echocardiography images, the severity of tricuspid regurgitation was observed to be similar in 69.6% of patients, increased in 21.7% of patients, and decreased in 8.7% of patients. In our present study, sPAP, TAPSE, and right ventricular width were found to be significant in the univariate analysis of postoperative echocardiography; however, none of the echocardiographic parameters were found to be significant in predicting rejection. Furthermore, when we compared groups in terms of survival rate, we found that, in patients who survived versus those who did not posttransplant, sPAP was significantly lower [30.6 mm Hg (range 20-50 mm Hg) vs 37.8 mm Hg (range, 25-55 mm Hg); P = .001], TAPSE was significantly higher [24.6 mm (range, 15-30 mm) vs 22.1 mm (range, 19-27 mm); P = .001], and postoperative right ventricular diameter was significantly smaller [32.4 mm (range, 26-41) vs 34.7 mm (range, 30-40 mm); P = .01]. This indicates that echocardiography performed after transplant is at least as valuable as preoperative echocardiography and offers useful information about survival.

In particular, TAPSE under 23.5 mm predicted survival with a sensitivity of 71% and a specificity of 78%. This demonstrates the negative effects of hemodynamically significant right-side volume loading and consequently right ventricular dysfunction. In the postoperative period, fluid balance was maintained by invasive monitoring; periodic echocardiography follow-up can be used as a guide at this stage. In a study conducted by Le Pavec and associates¹³ in 97 patients with tricuspid regurgitation jet, the cut off limit for 1-year survival was reported to be 3.0 m/s with a relative risk of 3.98 times mortality in those with higher values. In the present study, preoperative sPAP was 32.3 mm Hg (range, 20-60 mm Hg) in patients who survived and 31.1 mm Hg (range, 20-45 mm Hg) in patients who did not survive (P = .664). This shows that PAP increased significantly in cases resulting in death. This suggests that sPAP calculated based on the tricuspid regurgitant jet in cases of posttransplant adverse events can be used for prognosis. It is not clear how the development of portopulmonary hypertension increases the risk after liver transplant in patients with cirrhosis. However, pleural effusion, right ventricular failure, perioperative and postoperative fluid shift, hypoxia, and surgical trauma are considered to be possible mechanisms.

Although echocardiography is a reliable and easily accessible method, it has certain limitations. In particular, in patients with ascites, there may be difficulties in measuring basal parameters due to low image quality. Furthermore, because sPAP is estimated using tricuspid output by adding the estimated right atrium pressure, it is not a criterion standard diagnostic method. Thus, in cases where sPAP is measured to be high, right ventricular catheterization is recommended to confirm results.

In our study, postoperative RRT was required significantly less in surviving patients than in those who did not survive (P = .001). It is known that perioperative dialysis is used in 5% to 35% of patients who have undergone liver transplant.¹⁴ Isolated liver transplant recipients who remain on RRT during the posttransplant period have lower survival rates than those who undergo subsequent kidney transplant.^15,16 Likewise, a Canadian registry study found significantly decreased survival in patients after liver transplant who underwent RRT than in matched chronic dialysis patients, with 5-year patient survival rates of 17% versus 43% for patients with liver transplant versus chronic

dialysis control patients (P = .01).17 In a retrospective study, Sirivatanauksorn showed that prolonged intraoperative hypotension and postoperative hypotension were independent risk factors for acute kidney injury after liver transplant.¹⁸ In a study that evaluated risk factors in patients requiring RRT within 90 days of liver transplant, Andreoli and associates¹⁹ reported that fulminant hepatic failure, the absence of preoperative transplant hypertension, lower intraoperative fresh-frozen plasma transfusion volume, and not undergoing preoperative intermittent hemodialysis were associated with the need for RRT within the postoperative period of 90 days. In this study, we did not investigate the causes of posttransplant RRT; however, the effects of RRT on mortality were compatible with results reported in the literature. However, the relationship between rejection and RRT was not demonstrated.

Our study was retrospective, and the time for echocardiography was variable and ranged widely after transplant, which would affect sPAP and right ventricular characteristics. Changes in PAP can occur in the long term after transplant. Therefore, the effects of time of echocardiography require further prospective investigations to evaluate how time could change PAP and TAPSE results.

Postoperative sPAP, TAPSE, and right ventricular width are important parameters for posttransplant mortality. However, none of these parameters was associated with rejection. Because echocardiography is a simple and easily accessible technique that is reliable in excluding portopulmonary hypertension diagnosis, it can be used as a guide in the evaluation of right ventricular function and tricuspid regurgitation, particularly in patients who are not hemodynamically stable before and after liver transplant.

Volume: 18 Issue: 2 April 2020

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