The increase in the number of liver transplant candidates

Transcription

1 Evaluation of Potential Liver Donors: Limits Imposed by Donor Variables in Liver Transplantation Ramón Rull, Oscar Vidal, Dulce Momblan, Francisco Xavier González, Miguel Angel López-Boado, Jose Fuster, Luis Grande, Miguel Bruguera, Katiana Cabrer, Juan Carlos García-Valdecasas The aim of this study was to evaluate the predictive value of different donor and recipient parameters that have been recognised previously as proven and to suggest prognostic factors for immediate liver function and final outcome after liver transplantation. We evaluated a total of 228 liver grafts transplanted in the last 3 years in our institution. Parameters were recorded for the donor (age, polytransfusion, atherosclerosis, presence of infection, episodes of hypoxia or hypotension, use of vasoactive drugs, intensive care unit stay, steatosis, and ischemia time) and recipient (red blood cell requirements, immediate liver function [score], incidence of hepatic artery thrombosis, survival, and cause of death or retransplantation). Liver biopsy after reperfusion of the donor liver was performed before closure of the abdomen. Donor age over 65 years and presence of steatosis were associated significantly with initial poor function. The mortality rate at 6 months was related to donor age over 65 years. When donor age over 65 years was combined with transfusion requirement of > 10 U of red blood cells (RBC), the incidence of graft loss increased to 53%. The probability of graft survival at two years decreased when donor age was over 65 years. Moreover, when donor age over 65 years was combined with requirement of >10units RBC the probability of 2-year survival was significantly reduced. This study shows, for the first time, that the use of donor livers from older donors in liver transplant procedures, requiring more than 10 U of RBC, results in a significantly worse prognosis in terms of immediate liver function and long-term survival. (Liver Transpl 2003;9: ) The increase in the number of liver transplant candidates has led to a dramatic rise in waiting list mortality. The increased demand for donor organs has resulted in changes in donor characteristics because of the expanded donor selection criteria; this increase was confirmed by a recent report by the Spanish National Organization for Transplantation (ONT). 1 Although in 1992 the mean age for an organ donor was years, in 2000 mean age increased to years. Moreover, the cause of brain death changed from 43% trauma in 1992 to 55% cerebral hemorrhage. 1 This critical shortage of organ donors is the reason that many transplant centers are accepting lifesaving organs from so-called marginal or suboptimal donors, who would not have been considered suitable for transplantation previously. 2,3 Abnormal liver function tests, long stay in the intensive care unit (ICU), hemodynamic instability (prolonged hypoxia or hypotension), old donor age (over 65), and steatosis are no longer absolute contraindications for organ retrieval. 2,3 Although the outcome of liver transplantation does not seem to have been affected by the use of these donor organs, and real effect remains still to be determined. The current study analyzes several donor and recipient variables associated with liver transplantation, with particular emphasis on immediate graft function and graft survival. Patients and Methods From January, 1997 to December, 1999, 228 consecutive orthotopic liver transplantations (OLTs) were performed in 215 adult patients. Using previously described techniques for multiorgan procurement, 4,5 all donor livers were preserved with University of Wisconsin (UW) solution. In the recipient, liver transplantation was performed using the vena cava sparing technique (piggyback technique). 6-8 All recipients received similar perioperative intensive care management. Postoperative immunosuppression regimen consisted of intravenous cyclosporine A, with daily adjustments according to the serum (trough) levels and intravenous methylprednisolone, which was tapered from 200 to 20 mg/d during the first postoperative days. Biopsy-proven rejection episodes were treated by 500 mg of methylprednisolone (bolus) per day during 3 days. 9 One hundred eighty-six patients had nonbiliary cirrhosis, 15 cholestatic disease, 14 acute liver failure, and 13 patients were retransplanted for chronic rejection or recurrence of the disease. A total of 228 liver grafts were evaluated. Donor Variables The following donor parameters were evaluated: age, obesity (body mass index [BMI] [weight in kg/(height in m) 2 ] 35), From the Liver Transplantation Unit, Hospital Clinic i Provincial de Barcelona, Barcelona, Spain. Address reprint requests to Juan Carlos García-Valdecasas, MD, Liver Transplant Unit, Hospital Clinic i Provincial de Barcelona, Villarroel 170, Barcelona 08036, Spain. Telepone: ; FAX: ; jcvalde@medicina.ub.es Copyright 2003 by the American Association for the Study of Liver Diseases /03/ $30.00/0 doi: /jlts Liver Transplantation, Vol 9, No 4 (April), 2003: pp

2 390 Rull et al alcoholism (defined as 80 g/d by family history), uncontrolled arterial hypertension, polytransfusion ( 4 U red blood cells [RBC]), atherosclerosis (significant calcifications in the aorta), presence of infection (abnormal chest radiograph, fever, or both), prolonged hypoxia or hypotension ( 15 minutes), the use of vasoactive drugs, ICU stay, and total ischemia time. Ninety grafts were further evaluated by liver biopsy, taken after reperfusion of the donor liver. In addition, the following histologic parameters were studied: fatty infiltration (macro- and micro-), mild cholestasis, hepatocyte necrosis, hydropic degeneration, and centrilobular necrosis. 10 Recipient Variables Recipient variables included age, sex, diagnosis, perioperative RBC requirements, immediate liver function (score), 9 the incidence of hepatic artery thrombosis, graft survival, and cause of death or retransplantation. Initial poor function (IPF) was defined as alanine aminotransferase (ALT) 2,500 UI, prothrombin activity 60%, and bile output 40 ml/d on the third postoperative day. 9 Statistical analysis was evaluated using the analysis of variance (factorial) and the contingency table (chi-square), with significance being considered as P.05. The results were expressed in mean values with standard error, or median value and range. The graft survival rates were calculated using the Kaplan-Meier method and compared by the log-rank and Breslow tests. Results Donor characteristics are shown in Table 1. It is important to note than 25% (58 of 228) of the donors were over 65 years of age, with 38 being over 70 years (65%) and 6 donors over 80 years. Usually, vasoactive drugs were used to maintain hemodynamic stability of the potential donor. Whereas almost all donors received dopamine, more than half of the donors (121 of 228) received two vasoactive drugs (dopamine and dobutamine), and in 26% (31 of 121) three drugs were used. Twenty-five percent of the donors (57 of 228) stayed in the ICU longer than 5 days. Postreperfusion biopsy showed macrovesicular steatosis in 34% (31 of 90), with severity varying from 33% fat in 76% of the grafts (24 of 31), between 33% and 66% in 6, to over 66% in 1 case. The mean total ischemia time was of 321 minutes (median, 290 minutes; range, 130 to 990 minutes). Only 32 (14%) grafts had an ischemia time over 8 hours, but 9 of these 32 grafts were procured from donors older than 65 years. Perioperative RBC requirements were 6 5 U, (median, 5 U; range, 0 to 30 U). Furthermore, 10% (23 of 228) of our patients required more than 10 RBC U. Table 1. Donor Characteristics Yes No 2 Vasoactive drugs (n 223) Hypoxia/anoxia episodes (n 228) Presence of infection (n 225) Macrovesicular steatosis (n 90) Alcohol (n 227) HTA (n 227) Atherosclerosis (n 225) Obesity (n 225) Polytransfusion (n 225) Abnormal chest x-ray (n 207) ICU stay (n 228) 5 d 57 5 d 171 Immediate Liver Function Grafts were divided into two different groups according to the liver function score 9 : good liver function 3-5 and initial poor liver function 6-9 (Table 2). IPF was present in 67 cases (29%). Donor age over 65 years was significantly associated with IPF (P.04). However, no significant difference was found with respect to ICU stay, the need for vasoactive drugs, the presence of infection, and the presence of episodes of hypoxia or hypotension. Importantly, the presence of steatosis in the graft was significantly associated with IPF. Finally, the presence of more than three different risk factors showed a trend towards IPF (P.06). The association of any of the donor risk factors with transfusion requirement of 10 RBC U did not increase the incidence of IPF. Survival at 6 Months Of the 228 patients, 35 patients died, 8 underwent retransplantation, and 43 patients were lost during the follow-up. Graft survival was significantly related to donor age over 65 years (P.01). None of the other risk factors were associated with increased graft loss. (Table 3). In 205 patients with at least one risk factor, graft loss was found to be 16% (30 of 187). However, when this was combined with the perioperative requirement of 10 U of RBC, the incidence of graft loss increased to 39% (7 of 18) (P.02). Furthermore, if donor age of 65 years was combined with the requirement of 10 U RBC, the incidence of graft loss increased to 53%. Because the donor liver experienced a prolonged total ischemia time (over 8 hours) in only 32 patients, the combination of any donor risk factor with prolonged

3 Evaluation of Potential Liver Donors 391 total ischemia time did not influence 6-month graft survival. Probability of Survival The overall probability of 2-year graft survival was 85%. However, in patients who received a graft from a donor who was older than 65 years, the probability of survival decreased to 70% (P.01). All other donor risk factors, by themselves, were not related to diminished 2-year graft survival (Fig. 1). However, when donor age over 65 years was combined with a transfusion requirement of 10 U RBC, the probability of 2-year graft survival was found to be reduced to 48% (P.04; Fig. 2). Table 2. Immediate Liver Function No. of Patients Good Liver Function Poor Liver Function Age (yr) ICU stay (d) NS NS Infection* 225 No NS Yes NS Hypoxia/anoxia episodes 228 No NS Yes Vasoactive drugs 223 No NS Yes NS Macrovesicular steatosis 90 No Yes Risk factors NOTE. Immediate function score is based on peak alanine aminotransferase (units per liter) levels, prothrombin activity, (percent), and bile output (milliliters per day) evaluated during the first 3 days as good liver function (score, 3 to 5) or poor liver function (score, 6 to 9) in Gonzalez et al. 9 Abbreviation: NS, not significant. *Infection in donor confirmed by microbiology laboratory. During ICU stay. P Discussion Table 3. Graft Survival at 6 Months No. of Patients Alive Lost P Age (yr) ICU stay (d) NS Infection* 225 No Yes NS Hypoxia/anoxic episodes 228 No Yes NS 2 Vasoactive drugs 223 No Yes NS Macrovesicular steatosis 90 No Yes NS Risk factors 228 0/ NS *Infection in the donor confirmed by microbiology laboratory. During the ICU stay. Despite the apparently worsening quality of donor livers, the results of liver transplantation, according to recent literature, 11 have remained unchanged or are even getting better. During recent years, a significant improvement in outcome has been seen because of better surgical management and better immunosuppression regimens. In our institution, the overall graft survival rate after liver transplantation is 85% at 1 year and 72 % at 5 years, which is similar to that of the European Liver Transplant Registry (ELTR), which is 79% at 1 year and 69% at 5 years. Therefore, it appears that expansion of donor criteria, triggered by organ shortage, has not affected the final outcome of this procedure. 11 Nevertheless, it can be expected that the use of these so-called marginal grafts may have an effect on patient survival rate. Many investigators have identified factors that may affect immediate outcome, such as steatosis, hypernatremia, long cold ischemia time, donor age, abnormal liver function tests, and so on. 2,9,13-15 However, whereas some have shown that these factors have

4 392 Rull et al Figure 1. Probability of graft survival. Probability of survival at 2 years shows that patients transplanted with a graft over 65 years of age have a significantly worse survival when compared to the other two groups. specific predictive value, others have shown different results. For example, in our experience, old age of the donor does not affect immediate or long-term survival rate. 15,16 Conversely, the results of the ELTR clearly show that donor age over 65 years affects 1- and 5-year graft survival rate (73% and 55%, respectively). According to the last report of the ELTR, the incidence of primary nonfunction or severe graft dysfunction has remained the same during recent years. 12 In summary, although some medical aspects in the donor may affect immediate and long-term survival rate, the use of such grafts does not seem to have influenced the overall results. The ideal donor can be described as 50 years old or younger; without hepatobiliary disease; with hemodynamic and respiratory stability (systolic blood pressure 100 mm Hg and central venous pressure 5cm H 2 O); with acceptable PaO 2 and hemoglobin level; without severe abdominal trauma, systemic infection, or cancer; with diuresis 50 ml/hr and normal creatinine; and, lastly, with dopamine requirement 10 g/kg/min. 2 However, this ideal donor is far from the norm, and most often the potential donor is older than 50 years (51.7%), is hemodynamically unstable (54.3%), and has been treated in the ICU for of least 5 days (21%). Also, features of the donor liver itself may be predictive for poor immediate function. The presence of steatosis always has been shown to affect immediate liver function and graft survival. 10,18 Although not all donors were evaluated for hepatic steatosis, it was found to be relatively infrequent and usually of low to moderate degree. Despite this fact, the presence of steatosis was significantly associated with a worse outcome. 14 Our study confirms previously published results showing that age and liver steatosis significantly affect immediate liver function as well as graft survival at 6 months and probability of survival. Inotropic support and prolonged hypotension appeared not to have a significant effect on early graft function. 19 Furthermore, prolonged hypotension and the use of high doses of dopamine did not increase graft loss at 3 months, 20 which is similar to what we found in this study. Prolonged ICU stay does not appear to correlate with graft loss; however, intensive hemodynamic and nutritional management may improve the quality of the donor liver. In our study, the length of ICU stay was not found to influence early liver function and graft sur- Figure 2. Probability of graft survival (donor age and RBC requirements) w: > 10 U RBC, w/t: < 10 U RBC. Graft survival is significantly affected, if donor age over 65 years is associated to the need of a significant amount of blood transfusion (> 10 U RBC).

5 Evaluation of Potential Liver Donors 393 vival. Finally, until recently, the presence of infection was considered to be an exclusion factor for donor acceptance. 21 However, we did not find any relation between graft loss and the presence of infection in the donor. Nonetheless, do other factors, apart from those involving the donor, affect patient survival? We believe so, because we showed, for the first time, that the use of marginal quality grafts for surgically challenging recipients results in a significantly worse prognosis in terms of immediate liver function and long-term graft survival. This is shown by the fact that the use of liver grafts from donors older than 65 years in recipients requiring more than 10 U RBC resulted in a significantly worse outcome than similar grafts in recipients that needed fewer blood transfusions during the transplant procedure. It is even more interesting to note that, as long as the recipient did not have a significant blood product requirement, graft survival was the same, regardless of whether the liver originated from donors younger or older than 65 years. This fact is very important because it is our policy that, when a donor liver becomes available, it should be given to the first recipient on the waiting list. However, surgically challenging recipients (those undergoing retransplantation, those with severe portal hypertension, and so on) should not receive a marginal quality liver because the probability of survival will be significantly lower. References 1. Strasberg S, Howard T, Molmenti E, Hertlz M. Selecting the donor liver: Risk factors for poor function after liver orthotopic liver transplantation. Hepatology 1994;20: Loinaz C, Gonzalez EM. Marginal donors in liver transplantation. Hepatogastroenterology 2000;47: De Carlis L, Colella G, Sansalone CV, Aseni P, Rondinara GF, Slim AO, et al. Marginal donors in liver transplantation: The role of donor age. Transplant Proc 1999;31: Starzl T, Hakala T, Shaw B. A flexible procedure for multiple cadaveric organ procurement. Sur Gybecol Obstet 1984;158: Garcia-Valdecasas JC, Gonzalez F, Grande L, Rimola A, Fuster J, Lacy AM, et al. Study of liver preservation: The use of University of Wisconsin or Euro-collins solutions alone or in a combined method. Transplant Proc 1991;23: Gonzalez FX, Garcia-Valdecasas JC, Grande L, Pacheco JL, Cugat E, Fuster J, et al. Vena cava vascular reconstruction during orthotopic liver transplantation: a comparative study. Liver Transpl Surg 1998;4: Muralidhar V, Jayalaxmi TS. Anaesthesia for liver transplantation: perioperative problems and management. Trop Gastroenterol 1995;15: Stieber AC. One surgeon s experience with the piggyback versus the standard technique in orthotopic liver transplantation: Is one better than the other? Hepatogastroenterology 1995;42: Gonzalez F, Rimola A, Grande L, Antolin M, García-Valdecasas JC, Fuster J, et al. Predictive factors of early postoperative graft function in human liver transplantation. Hepatology 1994;20: D Alessandro A, Kalayoglu M, Sollinger H, Hoffman R, Reed A, Knechtle S, et al. The predective value of donor liver biopsies for the development of primary nonfunction after orthotopic liver transplantation. Transplantation 1990;51: European Liver Transplant Registry. Annual Report. Data Analysis. Booklet 05/ / Adam R, Bismuth H, Diamond T, Ducot B, Morino M, Astarcioglu I, et al. Effect of extended cold ischaemia with UW solution on graft function after liver transplantation. Lancet 1992;340: Busquests J, Figueras J, Torras J, Fabregat J, Rafecas A, Ramos E, et al. Liver donors: Is age a risk factor? Transplant Proc 1999;31: Karatzas T, Olson L, Ciancio G, Burke GW III, Spires G, Cravero L, et al. Expanded liver donor age over 60 years for hepatic transplantation. Transplant Proc 1997;29: Marsman W, Wiesner R. Use of fatty donor liver is associated with diminished early patient and graft survival. Transplant Proc 1996;62: Grande L, Rull R, Rimola A, Garcia-Valdecasas JC, Manyalic M, Cabrer C, et al. Outcome of patients undergoing orthotopic liver transplantation with elderly donors (over 60 years). Transplant Proc 1997;29: Grande L, Matus D, Rimola A, Manyalic M, Cabrer C, Garcia- Valdecasas JC, et al. Expanded liver donor age over 60 years for hepatic transplantation. Clin Transpl 1998; Adam R, Reynes M, Johann M. The outcome of steatosic grafts in liver transplantation. Transplant Proc 1991;23: Mimeault R, Grant D, Ghent C, Duff J, Wall W. Analysis of donor and prediction of outcome in clinical liver trasplantation. Transplant Proc 1998;21: Mor E, Klintmalm G, Gonwa T, Solomon H, Holman M, Gibbs J. The use of marginal donors for liver transplantation. Transplantation 1992;53: Nery J, Weppler D, Ketchum P. Donor infection and prymari nonfunction in liver transplantation. Transplant Proc 1997; 29: