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Liver Transplantation in Recipients With High Model for End-stage Liver Disease Score
Liver Transplantation in Recipients With High Model for End-stage Liver Disease Score S. González Martínez*, A. Molina Raya, A. Becerra Massare, K. Muffak Granero, T. Villegas Herrera, J.M. Villar del Moral, and Y. Fundora Suárez General, Digestive Surgery, and Liver Transplantation Department, Virgen de las Nieves University Hospital, Granada, Spain
ABSTRACT Objectives. The score in the Model of End-stage Liver Disease, or MELD, is a good indicator of the survival in patients on the liver transplant waiting list. In this study, an analysis is performed on the benefits of liver transplant on those patients with a very high MELD score and who thus start from a very severe baseline state that could affect the surgical outcome. Materials and methods. A prospective study was conducted on a cohort of 331 patients that received a liver transplant between 2002 and 2014. The patients were divided into 2 groups according to the MELD score (<28 vs 28), and differences in age, postoperative complications, stay in the intensive care unit (ICU), hospital stay, and survival were compared. Results. Of the total of 331 patients, 21 (6.3%) had a MELD score 28. The mean age of the group with MELD score 28 was lower than the age in the group with MEDL score < 28 (42.5 vs 53.7 years; P < .0001). No significant increase was observed in postoperative complications. Although there were also no differences in survival, the group with MELD score 28 did have a longer stay in ICU and a longer hospital stay (with a mean of 6.7 days in ICU and 41.5 days admission vs 4.1 and 26.9, respectively). Conclusions. A very high MELD score is associated with a longer stay in ICU and more days of hospital admission, although no differences were observed in postoperative complications or survival. Therefore, there does not seem to be any contraindication in transplantation in this group of patients.
T
HE MODEL for End-stage Liver Disease (MELD) score has been shown to be good indicator of mortality in patients with chronic liver disease of any origin, regardless of the development of complications such as ascites, spontaneous bacterial peritonitis, encephalopathy, or gastrointestinal bleeding. There are situations in which the MELD does not reflect the prognosis, mainly those in which the prognosis does not depend on the degree of hepatic dysfunction, such as the metabolic diseases, hepatopulmonary syndrome, and especially hepatocarcinoma [1,2]. This model began to be used in the United States in 2002 and has been incorporated into the majority of liver transplant programs all over the world, with Andalusia being a pioneer in Spain. Various studies have demonstrated that MELD estimates the survival at 3 months better than other prognostic indices, mainly because it incorporates renal
ª 2017 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 50, 595e597 (2018)
function in its calculation, and the renal dysfunction that frequently appears in advanced chronic liver disease is closely associated with mortality in these patients [1,3]. Thus, the MELD gives us information on the baseline situation of the patient that is going to be subjected to a surgical intervention of great importance, like a liver transplant. In this context, a very high MELD score is going to assume a poor functional reserve of the patient, and it is worthwhile analyzing if the transplant in these cases is beneficial as far as mortality and the complications that may occur in the surgery, as well as in the postoperative period [4].
*Address correspondence to Selene González Martínez, University of Granada, Avda Andalucía 3 P4 7 C, 18015 Granada, Spain. Tel: 626459499. E-mail: [email protected] 0041-1345/18 https://doi.org/10.1016/j.transproceed.2017.12.032
595
596
MARTÍNEZ, RAYA, MASSARE ET AL Table 2. Actuarial Survival (P [ .294)
Table 1. Demographical and Clinical Features MELD 28
n (%) 310 (93.6%) 21 (6.3%) Age 53 8.516 42 11.830 Male sex 247 (79.7%) 16 (76.2%) Etiology of cirrhosis Alcohol 114 (36.8%) 6 (28.6%) Hepatitis B virus 10 (3.2%) 0 (0%) Hepatitis C virus 105 (33.9%) 1 (4.8%) Liver carcinoma 69 (22.3%) 0 (0%) Other 74 (23.8%) 14 (66.6%) ICU stay 4.1 (4.0) 6.7 (3.9%) Hospital stay 26.9 (20.8) 41.5 (23.8) Donor type Brain death 297 (95.8%) 21 (100%) Cardiac death 13 (4.2%) 0 (0%) Biliary complications 63 (21%) 8 (38.1%) Vascular complications 49 (16.2%) 4 (19%) Ischemic 19 (6.3%) 1 (4.8%) cholangiopathy Acute rejection 77 (25.4%) 6 (28.6%) Chronic rejection 8 (2.6%) 1 (4.8%) Post reperfusion 49 (16.2%) 6 (28.6%) syndrome Re-transplantation 16 (5.2%) 3 (14.3%) Survival 90.797 (3.979) 96.872 (12.191)
P Value
<.001 .78 >.99 >.99 .012 .01 >.99 <.001 .002 >.99 >.99 .098 .76 >.99 .95 .457 .126 .11 .294
Abbreviations: ICU, intensive care unit; MELD, Model for End-stage Liver Disease.
In this study, we analyze the differences in survival, morbidity, and mortality in patients with a very high MELD score that received a liver transplant. MATERIALS AND METHODS This is a prospective cohort study of patients that received a liver transplant in the Virgen de las Nieves University Hospital, Granada, Spain, between January 2002 and December 2014. Patients in whom the estimation of MELD was not significant owing to changes in international normalized ratio due to taking oral anticoagulants, and those who did not complete a minimum follow-up of 6 months were excluded. The patients were divided into 2 groups. The first group included those who at the time of inclusion on the waiting list had a MELD score < 28, with those with a MELD 28 in the second group. The differences in age, gender, appearance of complications (reperfusion syndrome, deep venous thrombosis or pulmonary thromboembolism, biliary or vascular complications, need for reintervention, acute or chronic rejection, need of retransplant), overall mortality rate, cause of mortality, stay in intensive care unit (ICU), hospital stay, and survival were compared (Table 1). The data were processed using the SPSS 19.0 software package (Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp). The quantitative variables were expressed as mean and median and were analyzed using nonparametric tests (Kruskal-Wallis and Mann-Whitney U). The qualitative variables were studied using the Fisher and c2 tests. We performed a multivariate analysis using Cox regression model. The survival was measured using Kaplan Meier curve. P < .05 was considered significant.
6 mo 12 mo 3y 5y
MELD < 28 (%)
MELD 2 (5)8
85 78.9 69.2 63
88.9 88.9 83.3 69.2
Abbreviation: MELD, Model for End-stage Liver Disease.
Of the 331 patients, 310 (93.6%) had a MELD score < 28, and 21 (6.3%) a MELD score 28. The mean age of the first group was 53.7 years, and that of the second group was 42.5 years, with the differences being statistically significant (P < .0001). Older people had higher risk of death (P ¼ .027). No significant difference was observed in surgical or postsurgical complications or in rejection (acute or chronic). The mortality rate was also similar in both groups, both overall as well as separating by causes (intraoperative complications, medical causes, graft dysfunction of biliary or vascular origin, or relapse). The overall retransplant rate was 5.7%: 5.2% in the group with a MELD score less than 28, and 14.3% in the group with a MELD score 28. These differences were not significantly different, either (P ¼ .110). Differences were found in the ICU stay and overall hospital stay, with a mean of 6.7 (3.9) days in ICU and 41.5 (23.8) days admission in the patient group with a MELD score 28, and 4.1 (4.0) days in ICU and 26.9 (20.8) in the group with a MELD score < 28. People who stayed more days in ICU had also higher risk of death (P ¼ .004). The actuarial survival of both groups is shown in Table 2. The mean survival time was 90.79 (3.97) months in patients with MELD < 28 and 96.87 (12.19) months in patients with MELD 28. The Kaplan-Meier curve (Fig 1)
Survival
MELD < 28
RESULTS
Out of a total of 340 patients, 9 were excluded, leaving a total of 331 patients participating (263 male and 68 female patients).
Follow-up (months) Fig 1. Kaplan Meier curve.
RECIPIENTS WITH HIGH MELD SCORE
shows the survival in the 2 groups. The differences are not statistically significant (P ¼ .294). DISCUSSION
The MELD score is an objective method for estimating survival at 3 months in patients on a liver transplant waiting list [1,3]. Higher MELD scores thus imply more severe liver disease, which makes the perioperative management of these patients more complex, and although it may be the sole therapeutic option, it is worthwhile analyzing to see if the transplant will be of benefit to patients with a very high MELD or whether it will cause greater morbidity and mortality. There are predictive models of survival after liver transplant that take into account the MELD score, as well as other factors, although none of them clearly establishes a MELD score above which a transplant has no benefits [5,6]. There are also studies that demonstrate that a high MELD score is associated with greater morbidity and mortality, but none show significant differences in the outcomes of patients after transplant. Our results are in agreement with these studies [2,7,8]. On comparing the 2 patient groups, those with a MELD score 28 had a longer stay in ICU after transplant and a longer hospital stay. But no differences were found in complications or survival compared with those patients with a MELD score < 28. Thus, we cannot contraindicate a liver transplant in patients with a very high MELD score.
597
REFERENCES [1] Roth JA, Chrobak C, Schädelin S, Hug BL. MELD score as a predictor of mortality, length of hospital stay, and disease burden. A single-center retrospective study in 39,323 inpatients. Medicine 2017;96(24):e7155. [2] Machicao VI. Model for End-Stage Liver DiseaseeSodium Score. The evolution in the prioritization of liver transplantation. Clin Liver Dis 2017;21:275e87. [3] Martın-Llah M, Guevara M, Torre A, Fagundes C, Restuccia T, Gilabert R, et al. Prognostic importance of the cause of renal failure in patients with cirrhosis. Gastroenterology 2011;140:488e96. [4] Teh SH, Nagorney DM, Stevens SR, Offord KP, Therneau TM, Plevak DJ, et al. Risk factors for mortality after surgery in patients with cirrhosis. Gastroenterology 2007;132: 1261e9. [5] Rana A, Jie T, Porubsky M, Habib S, Rilo H, Kaplan B, et al. The survival outcomes following liver transplantation (SOFT) score: validation with contemporaneous data and stratification of high-risk cohorts. Clin Transplant 2013;27: 627e32. [6] Dutkowski P, Oberkofler CE, Slankamenac K, Puhan MA, Schadde E, MVullhaupt B, et al. Are there better guidelines for allocation in liver transplantation? A novel score targeting justice and utility in the Model for End- Stage Liver Disease era. Ann Surg 2011;254:745e53. [7] Yadav SK, Saraf N, Saigal S, Choudhary NS, Goja S, Rastogi A, et al. High MELD score does not adversely affect outcome of living donor liver transplantation: experience in 1000 recipients. Clin Transplant 2017;31:e13006. [8] O’Leary JG, Orloff SL, Levitsky J, Martin P, Foley DP. Keeping high Model for End-Stage Liver Disease Score liver transplantation candidates alive. Liver Transpl 2015;21:1428e37.
ABSTRACT Objectives. The score in the Model of End-stage Liver Disease, or MELD, is a good indicator of the survival in patients on the liver transplant waiting list. In this study, an analysis is performed on the benefits of liver transplant on those patients with a very high MELD score and who thus start from a very severe baseline state that could affect the surgical outcome. Materials and methods. A prospective study was conducted on a cohort of 331 patients that received a liver transplant between 2002 and 2014. The patients were divided into 2 groups according to the MELD score (<28 vs 28), and differences in age, postoperative complications, stay in the intensive care unit (ICU), hospital stay, and survival were compared. Results. Of the total of 331 patients, 21 (6.3%) had a MELD score 28. The mean age of the group with MELD score 28 was lower than the age in the group with MEDL score < 28 (42.5 vs 53.7 years; P < .0001). No significant increase was observed in postoperative complications. Although there were also no differences in survival, the group with MELD score 28 did have a longer stay in ICU and a longer hospital stay (with a mean of 6.7 days in ICU and 41.5 days admission vs 4.1 and 26.9, respectively). Conclusions. A very high MELD score is associated with a longer stay in ICU and more days of hospital admission, although no differences were observed in postoperative complications or survival. Therefore, there does not seem to be any contraindication in transplantation in this group of patients.
T
HE MODEL for End-stage Liver Disease (MELD) score has been shown to be good indicator of mortality in patients with chronic liver disease of any origin, regardless of the development of complications such as ascites, spontaneous bacterial peritonitis, encephalopathy, or gastrointestinal bleeding. There are situations in which the MELD does not reflect the prognosis, mainly those in which the prognosis does not depend on the degree of hepatic dysfunction, such as the metabolic diseases, hepatopulmonary syndrome, and especially hepatocarcinoma [1,2]. This model began to be used in the United States in 2002 and has been incorporated into the majority of liver transplant programs all over the world, with Andalusia being a pioneer in Spain. Various studies have demonstrated that MELD estimates the survival at 3 months better than other prognostic indices, mainly because it incorporates renal
ª 2017 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 50, 595e597 (2018)
function in its calculation, and the renal dysfunction that frequently appears in advanced chronic liver disease is closely associated with mortality in these patients [1,3]. Thus, the MELD gives us information on the baseline situation of the patient that is going to be subjected to a surgical intervention of great importance, like a liver transplant. In this context, a very high MELD score is going to assume a poor functional reserve of the patient, and it is worthwhile analyzing if the transplant in these cases is beneficial as far as mortality and the complications that may occur in the surgery, as well as in the postoperative period [4].
*Address correspondence to Selene González Martínez, University of Granada, Avda Andalucía 3 P4 7 C, 18015 Granada, Spain. Tel: 626459499. E-mail: [email protected] 0041-1345/18 https://doi.org/10.1016/j.transproceed.2017.12.032
595
596
MARTÍNEZ, RAYA, MASSARE ET AL Table 2. Actuarial Survival (P [ .294)
Table 1. Demographical and Clinical Features MELD 28
n (%) 310 (93.6%) 21 (6.3%) Age 53 8.516 42 11.830 Male sex 247 (79.7%) 16 (76.2%) Etiology of cirrhosis Alcohol 114 (36.8%) 6 (28.6%) Hepatitis B virus 10 (3.2%) 0 (0%) Hepatitis C virus 105 (33.9%) 1 (4.8%) Liver carcinoma 69 (22.3%) 0 (0%) Other 74 (23.8%) 14 (66.6%) ICU stay 4.1 (4.0) 6.7 (3.9%) Hospital stay 26.9 (20.8) 41.5 (23.8) Donor type Brain death 297 (95.8%) 21 (100%) Cardiac death 13 (4.2%) 0 (0%) Biliary complications 63 (21%) 8 (38.1%) Vascular complications 49 (16.2%) 4 (19%) Ischemic 19 (6.3%) 1 (4.8%) cholangiopathy Acute rejection 77 (25.4%) 6 (28.6%) Chronic rejection 8 (2.6%) 1 (4.8%) Post reperfusion 49 (16.2%) 6 (28.6%) syndrome Re-transplantation 16 (5.2%) 3 (14.3%) Survival 90.797 (3.979) 96.872 (12.191)
P Value
<.001 .78 >.99 >.99 .012 .01 >.99 <.001 .002 >.99 >.99 .098 .76 >.99 .95 .457 .126 .11 .294
Abbreviations: ICU, intensive care unit; MELD, Model for End-stage Liver Disease.
In this study, we analyze the differences in survival, morbidity, and mortality in patients with a very high MELD score that received a liver transplant. MATERIALS AND METHODS This is a prospective cohort study of patients that received a liver transplant in the Virgen de las Nieves University Hospital, Granada, Spain, between January 2002 and December 2014. Patients in whom the estimation of MELD was not significant owing to changes in international normalized ratio due to taking oral anticoagulants, and those who did not complete a minimum follow-up of 6 months were excluded. The patients were divided into 2 groups. The first group included those who at the time of inclusion on the waiting list had a MELD score < 28, with those with a MELD 28 in the second group. The differences in age, gender, appearance of complications (reperfusion syndrome, deep venous thrombosis or pulmonary thromboembolism, biliary or vascular complications, need for reintervention, acute or chronic rejection, need of retransplant), overall mortality rate, cause of mortality, stay in intensive care unit (ICU), hospital stay, and survival were compared (Table 1). The data were processed using the SPSS 19.0 software package (Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp). The quantitative variables were expressed as mean and median and were analyzed using nonparametric tests (Kruskal-Wallis and Mann-Whitney U). The qualitative variables were studied using the Fisher and c2 tests. We performed a multivariate analysis using Cox regression model. The survival was measured using Kaplan Meier curve. P < .05 was considered significant.
6 mo 12 mo 3y 5y
MELD < 28 (%)
MELD 2 (5)8
85 78.9 69.2 63
88.9 88.9 83.3 69.2
Abbreviation: MELD, Model for End-stage Liver Disease.
Of the 331 patients, 310 (93.6%) had a MELD score < 28, and 21 (6.3%) a MELD score 28. The mean age of the first group was 53.7 years, and that of the second group was 42.5 years, with the differences being statistically significant (P < .0001). Older people had higher risk of death (P ¼ .027). No significant difference was observed in surgical or postsurgical complications or in rejection (acute or chronic). The mortality rate was also similar in both groups, both overall as well as separating by causes (intraoperative complications, medical causes, graft dysfunction of biliary or vascular origin, or relapse). The overall retransplant rate was 5.7%: 5.2% in the group with a MELD score less than 28, and 14.3% in the group with a MELD score 28. These differences were not significantly different, either (P ¼ .110). Differences were found in the ICU stay and overall hospital stay, with a mean of 6.7 (3.9) days in ICU and 41.5 (23.8) days admission in the patient group with a MELD score 28, and 4.1 (4.0) days in ICU and 26.9 (20.8) in the group with a MELD score < 28. People who stayed more days in ICU had also higher risk of death (P ¼ .004). The actuarial survival of both groups is shown in Table 2. The mean survival time was 90.79 (3.97) months in patients with MELD < 28 and 96.87 (12.19) months in patients with MELD 28. The Kaplan-Meier curve (Fig 1)
Survival
MELD < 28
RESULTS
Out of a total of 340 patients, 9 were excluded, leaving a total of 331 patients participating (263 male and 68 female patients).
Follow-up (months) Fig 1. Kaplan Meier curve.
RECIPIENTS WITH HIGH MELD SCORE
shows the survival in the 2 groups. The differences are not statistically significant (P ¼ .294). DISCUSSION
The MELD score is an objective method for estimating survival at 3 months in patients on a liver transplant waiting list [1,3]. Higher MELD scores thus imply more severe liver disease, which makes the perioperative management of these patients more complex, and although it may be the sole therapeutic option, it is worthwhile analyzing to see if the transplant will be of benefit to patients with a very high MELD or whether it will cause greater morbidity and mortality. There are predictive models of survival after liver transplant that take into account the MELD score, as well as other factors, although none of them clearly establishes a MELD score above which a transplant has no benefits [5,6]. There are also studies that demonstrate that a high MELD score is associated with greater morbidity and mortality, but none show significant differences in the outcomes of patients after transplant. Our results are in agreement with these studies [2,7,8]. On comparing the 2 patient groups, those with a MELD score 28 had a longer stay in ICU after transplant and a longer hospital stay. But no differences were found in complications or survival compared with those patients with a MELD score < 28. Thus, we cannot contraindicate a liver transplant in patients with a very high MELD score.
597
REFERENCES [1] Roth JA, Chrobak C, Schädelin S, Hug BL. MELD score as a predictor of mortality, length of hospital stay, and disease burden. A single-center retrospective study in 39,323 inpatients. Medicine 2017;96(24):e7155. [2] Machicao VI. Model for End-Stage Liver DiseaseeSodium Score. The evolution in the prioritization of liver transplantation. Clin Liver Dis 2017;21:275e87. [3] Martın-Llah M, Guevara M, Torre A, Fagundes C, Restuccia T, Gilabert R, et al. Prognostic importance of the cause of renal failure in patients with cirrhosis. Gastroenterology 2011;140:488e96. [4] Teh SH, Nagorney DM, Stevens SR, Offord KP, Therneau TM, Plevak DJ, et al. Risk factors for mortality after surgery in patients with cirrhosis. Gastroenterology 2007;132: 1261e9. [5] Rana A, Jie T, Porubsky M, Habib S, Rilo H, Kaplan B, et al. The survival outcomes following liver transplantation (SOFT) score: validation with contemporaneous data and stratification of high-risk cohorts. Clin Transplant 2013;27: 627e32. [6] Dutkowski P, Oberkofler CE, Slankamenac K, Puhan MA, Schadde E, MVullhaupt B, et al. Are there better guidelines for allocation in liver transplantation? A novel score targeting justice and utility in the Model for End- Stage Liver Disease era. Ann Surg 2011;254:745e53. [7] Yadav SK, Saraf N, Saigal S, Choudhary NS, Goja S, Rastogi A, et al. High MELD score does not adversely affect outcome of living donor liver transplantation: experience in 1000 recipients. Clin Transplant 2017;31:e13006. [8] O’Leary JG, Orloff SL, Levitsky J, Martin P, Foley DP. Keeping high Model for End-Stage Liver Disease Score liver transplantation candidates alive. Liver Transpl 2015;21:1428e37.