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Primary dysfunction after liver transplantation: donor or recipient fault?
Primary Dysfunction After Liver Transplantation: Donor or Recipient Fault? A.W. Avolio, S. Agnes, A.S.A. Chirico, and M. Castagneto
O
UTCOME of liver transplantation has been correlated with several factors.1– 8 These can be classified into two well-defined categories: donor factors and recipient factors. The large number of components involved explains the difficulty in predicting outcome in terms of primary dysfunction and patient survival. Primary dysfunction (PD) after liver transplantation has an incidence ranging from 5% to 35%, as defined by restrictive or extensive criteria.5–11 The aims of this study are the identification of risk factors associated with primary dysfunction, the quantification of the relative role of each one, and the analysis of results. MATERIALS AND METHODS Donor Population One-hundred ten consecutive multiorgan donors were analysed. Donor age range was from 7 to 64 years. The most common causes of death were head trauma and cerebral vascular accident. Perfusion was carried out by University of Wisconsin (UW) solution. Marginal donors and overweight donors were not included in this analysis.
Recipient Population One-hundred ten consecutive orthotopic first-liver transplants were included in the study. Indications for transplantation were-post– hepatitis B cirrhosis, 20% (22 patients); post– hepatitis C cirrhosis, 32.7% (36 patients); post– hepatitis B/C cirrhosis, 6.4% (7 patients), alcoholic cirrhosis, 11.8% (13 patients); cryptogenetic cirrhosis, 5.5% (6 patients); acute liver failure 5.5% (6 patients); primary biliary cirrhosis, 2.7% (3 patients); congenital hepatobiliary disease, 10.9% (12 patients); and miscellaneous, 4.5% (5 patients). Primary dysfunction was defined as a peak transaminase level (ALT and/or AST) .3500 IU/L in the first 5 days after liver transplantation.
Statistics All data were collected from donor and recipient charts and a 130 variable database was filled. Data were evaluated by the BioMedical data package using life-table analysis, univariate methods, and Cox regression analysis. To avoid any additional effect of late events on patient survival, a 6-month endpoint was chosen.
RESULTS
Kaplan–Meier life-table analysis showed that patients with PD (N 5 19) displayed 1-, 2-, 3-, 4-, 5-, and 6-month graft 0041-1345/99/$–see front matter PII S0041-1345(98)01694-7
Fig 1. Actuarial 1- to 6-month graft survival of patients with and without primary dysfunction (PD). The rates at 6 months were 47% and 85%, respectively (P , .01, Wilcoxon test).
survival rates (74%, 58%, 47%, 47%, 47%, and 47%) that were significantly lower (Wilcoxon, P , .01) than in patients without PD (N 5 91) (98%, 93%, 90%, 90%, 89%, and 85%) (Fig 1). Univariate analysis showed that none of the donor data (age, gender, cause of death, hematochemical and hemodynamic parameters) was significantly correlated with PD; however, high preoperative recipient bilirubin level (P , .05), high intraoperative blood product infusion (P , .05), and long bypass time (P , .05) were associated with PD (Fig 2). Logistic regression analysis showed that, among donor parameters, age (P , .01, R2 5 .24) and systolic blood pressure (P , .01, R2 5 .12) were significantly correlated with PD. However, the R2 values were low. Among intraoperative recipient parameters, blood product infusion (P , .001, R2 5 .28) and length of bypass time (P , .001, R2 5 .32) showed a good level of correlation with PD. Stepwise logistic multiple-regression analysis identified that preoperative recipient bilirubin 1 intraoperative blood
From the Division of Organ Transplantation, Department of Surgery, Catholic University of Rome, Rome, Italy. Address reprint requests to Dr Alfonso W. Avolio, Division of Organ Transplantation, Department of Surgery, Catholic University of Rome, Largo F-Vito 1, 00168 Rome, Italy. © 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
434
Transplantation Proceedings, 31, 434–436 (1999)
POST-LTX PRIMARY DYSFUNCTION
435
Fig 2. Mean values and standard deviations in preoperative bilirubin level, intraoperative transfusion of packed red blood cell units (PRBC), and length of bypass time in patients with and without primary dysfunction (P , .05, Mann–Whitney U test).
product infusion showed the best correlation with PD (P , .001, F 5 166, R2 5 .81). DISCUSSION
In early clinical experience, after liver transplantation, patients with a poorly functioning liver were condemned to death.12 This observation induced Starzl to introduce the retransplant procedure.13 Recently, improvements in knowledge of liver physiopathology and the adoption of new methodology in intensive care management (glucose and branched-chain amino-acid infusion, fresh frozen plasma support, prostaglandin administration, prevention of renal failure by diuretic stimulation and control of fluid overload), have led to progressive improvements in the treatment of patients with liver failure.9, 14 –17 Today, these factors and the properties of the new perfusion-preservation solution (ie, UW), have allowed the reduction of liver damage related to the harvest/storage procedure.18 Consequently, the role of liver retransplantation in cases complicated by severe primary dysfunction is an object of debate, particularly in Italy where the donor pool is limited and donor quality is less than optimal.19 Thirty-five years after the first clinical liver transplantation, primary dysfunction still remains a strong predictor of outcome. Recovery after liver transplantation indeed presents a variety of patterns of evolution ranging from early and complete function of the graft to complete absence of liver function, which can lead to patient death when liver retransplantation is not performed. Many different definitions of primary dysfunction have been proposed.5–11 In the postoperative period of liver transplantation, liver dysfunction is manifested by hepatic cytolysis, hepatic jaundice, hepatic encephalopathy, liverrelated coagulation deficit, and hepatic hemodynamic insta-
bility. Most investigators define primary nonfunction as the condition after liver transplantation that requires retransplantation using clinical criteria. According to a more recent approach to the problem, we suggest use of the term “primary dysfunction” for all cases of impaired liver function. Indeed, primary dysfunction presents different degrees of severity, ranging from initial poor function (benign condition responding to support therapy) to primary nonfunction (the most serious condition leading to fatal outcome if prompt retransplantation is not performed). Of the different indicators of primary dysfunction, trend of liver cytolysis enzymes in the first postoperative week is the method most widely used. Nevertheless, the cutoff level in relation to the prognosis is not definitively known. In our experience, patients with transaminase peak levels .3500 IU/L present the poorest prognosis, as determined by the Kaplan–Meier method (Wilcoxon, P , .05). In this study, regarding the donor data, donor age and systolic blood pressure are correlated with primary dysfunction although with low R2 values. Gender, cause of death, length of donor stay in ICU, donor weight, transaminase level, prothrombin time, donor Na, bilirubin level, arterial partial pressure of oxygen, systolic blood pressure, central venous pressure, and dopamine infusion rate did not correlate with PD. Successful liver transplantation with liver procurement from elderly donors (.70 years) has recently been reported,20 nevertheless, larger cumulative experiences, such as that of the European Liver Transplant Registry and that of the United Network for Organ Sharing, show inferior graft survival figures for patients transplanted with organs from donors .50 years (approximately 5% difference at 1 year and 10% difference at 5 years).21 In the present study, the oldest donor was a 64-year-old female patient whose graft was transplanted into a child C patient
436
who presented primary dysfunction with a successful outcome. Statistical analysis of our data shows that the weight of donor parameters was small and not assessable by univariate methods but detectable only by the logistic regression method, which, all cases, gave low levels of R2 (age, systolic blood pressure). High donor weight has been correlated with PD and with poor outcome because of liver steatosis.11 In our series, overweight donors and donors with long ICU stays (.2 weeks) were not considered suitable for liver harvesting. The prognostic value of donor serum sodium level on transplant outcome has been reported since 1991 by our group.1 Three years later, other investigators with a larger database agreed on this matter.6 More recently, a multicentre study confirmed that in an evaluation of more than 600 cases.23 In the present series, we failed to find correlation between donor sodium and graft survival using the Cox regression method. We explain this finding as being due to the present policy of not accepting donors with high sodium levels. In this study, recipient factors seem more important in predicting PD after liver transplantation. We did not observe any correlation between etiology of liver disease and PD. The role of the preoperative recipient status, as represented by the UNOS class or CHILD class, has been reported in several previous series.5– 8 In our experience, the preoperative bilirubin level correlates with PD. Probably, in the patient with chronic end-stage liver disease, the high preoperative bilirubin level is representative of the overall poor general condition, which, in the postoperative period, leads to a slow recovery from liver harvesting trauma. We postulate that patients transplanted in poor condition present respiratory, renal, metabolic, and hemodynamic alterations that often induce additional damage to the graft. This fact is probably more deleterious in cases of nonoptimal grafts. Intraoperative blood infusion data and bypass time, which are probably related to the preoperative conditions of the recipient, play a similar role and may induce a negative catalytic effect on postoperative recovery. In conclusion, primary dysfunction after liver transplantation, today remains an important determinant of patient survival even with recent improvements in postoperative support therapy. PD is a multifactorial event and donor factors probably play a minor role in determining PD; recipient factors, particularly preoperative bilirubin level, intraoperative blood infusion, and bypass time are the strongest predictors of PD. Finally, the combination of
AVOLIO, AGNES, CHIRICO ET AL
donor and recipient factors, their multiplicity, and the low grade of correlation between each factor and PD explain the difficulty in the reduction of primary dysfunction after liver transplantation. REFERENCES 1. Avolio AW, Agnes S, Magalini SC, et al: Transplant Proc 23:2451, 1991 2. Avolio AW, Agnes S, Magalini S, et al: Transplant Proc 24:2707, 1992 3. Avolio AW, Agnes S, Magalini SC, et al: Transplant Proc 25:1868, 1993 4. Avolio AW, Agnes S, Pelosi G, et al: Transplant Proc 23:2263, 1991 5. Baliga P, Merion RM, Turcott JG, et al: Surgery 112:704, 1992 6. Gonzales FX, Rimola A, Grande L, et al: Hepatology 20:565, 1994 7. Ploeg RJ, D’Alessandro AM, Knechtle SJ, et al: Transplantation 55:807, 1993 8. Clavienn PA, Harvey PRC, Strasberg SM: Transplantation 53:957, 1992 9. Greig PD, Woolf GM, Sinclaire SB, et al: Transplantation 48:447, 1989 10. Mimeault R, Grant D, Ghent C, et al: Transplant Proc 21:2355, 1989 11. Mor E, Klintmalm GB, Gonwa TA, et al: Transplantation 53:383, 1992 12. Starzl TE, Cormann J, Groth CG, et al: Transplant Proc 4:759, 1972 13. Shaw BW, Gordon RD, Iwatsuki S, et al: Transplant Proc 21:264, 1985 14. Reilly J, Mehta R, Teperman L, et al: JPEN 14:386, 1990 15. Chen SC, Cunneen SA, Colquhoun SD, et al: Am Surg 64:926, 1998 16. Giovannini I, Boldrini G, Chiarla C, et al: World J Surg 202:11, 1987 17. Chiarla C, Giovannini I, Siegel JH, et al: Crit Care Med 18:32, 1990 18. Todo S, Nevy J, Yanaga K, et al: JAMA 261:711, 1989 19. Agnes S, Avolio AW, Magalini SC, et al: Transplant Int 5(suppl):S170, 1992 20. Emre S, Schwartz ME, Altaca G, et al: Transplantation 62:62, 1996 21. 1997 Annual Report of the European Liver Transplant Registry, Paris, 1998 22. 1997 Annual Report of the United Network for Organ Sharing, 1998 23. Figureas J, Busquets J, Grande L, et al: Transplantation 61:410, 1996
O
UTCOME of liver transplantation has been correlated with several factors.1– 8 These can be classified into two well-defined categories: donor factors and recipient factors. The large number of components involved explains the difficulty in predicting outcome in terms of primary dysfunction and patient survival. Primary dysfunction (PD) after liver transplantation has an incidence ranging from 5% to 35%, as defined by restrictive or extensive criteria.5–11 The aims of this study are the identification of risk factors associated with primary dysfunction, the quantification of the relative role of each one, and the analysis of results. MATERIALS AND METHODS Donor Population One-hundred ten consecutive multiorgan donors were analysed. Donor age range was from 7 to 64 years. The most common causes of death were head trauma and cerebral vascular accident. Perfusion was carried out by University of Wisconsin (UW) solution. Marginal donors and overweight donors were not included in this analysis.
Recipient Population One-hundred ten consecutive orthotopic first-liver transplants were included in the study. Indications for transplantation were-post– hepatitis B cirrhosis, 20% (22 patients); post– hepatitis C cirrhosis, 32.7% (36 patients); post– hepatitis B/C cirrhosis, 6.4% (7 patients), alcoholic cirrhosis, 11.8% (13 patients); cryptogenetic cirrhosis, 5.5% (6 patients); acute liver failure 5.5% (6 patients); primary biliary cirrhosis, 2.7% (3 patients); congenital hepatobiliary disease, 10.9% (12 patients); and miscellaneous, 4.5% (5 patients). Primary dysfunction was defined as a peak transaminase level (ALT and/or AST) .3500 IU/L in the first 5 days after liver transplantation.
Statistics All data were collected from donor and recipient charts and a 130 variable database was filled. Data were evaluated by the BioMedical data package using life-table analysis, univariate methods, and Cox regression analysis. To avoid any additional effect of late events on patient survival, a 6-month endpoint was chosen.
RESULTS
Kaplan–Meier life-table analysis showed that patients with PD (N 5 19) displayed 1-, 2-, 3-, 4-, 5-, and 6-month graft 0041-1345/99/$–see front matter PII S0041-1345(98)01694-7
Fig 1. Actuarial 1- to 6-month graft survival of patients with and without primary dysfunction (PD). The rates at 6 months were 47% and 85%, respectively (P , .01, Wilcoxon test).
survival rates (74%, 58%, 47%, 47%, 47%, and 47%) that were significantly lower (Wilcoxon, P , .01) than in patients without PD (N 5 91) (98%, 93%, 90%, 90%, 89%, and 85%) (Fig 1). Univariate analysis showed that none of the donor data (age, gender, cause of death, hematochemical and hemodynamic parameters) was significantly correlated with PD; however, high preoperative recipient bilirubin level (P , .05), high intraoperative blood product infusion (P , .05), and long bypass time (P , .05) were associated with PD (Fig 2). Logistic regression analysis showed that, among donor parameters, age (P , .01, R2 5 .24) and systolic blood pressure (P , .01, R2 5 .12) were significantly correlated with PD. However, the R2 values were low. Among intraoperative recipient parameters, blood product infusion (P , .001, R2 5 .28) and length of bypass time (P , .001, R2 5 .32) showed a good level of correlation with PD. Stepwise logistic multiple-regression analysis identified that preoperative recipient bilirubin 1 intraoperative blood
From the Division of Organ Transplantation, Department of Surgery, Catholic University of Rome, Rome, Italy. Address reprint requests to Dr Alfonso W. Avolio, Division of Organ Transplantation, Department of Surgery, Catholic University of Rome, Largo F-Vito 1, 00168 Rome, Italy. © 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
434
Transplantation Proceedings, 31, 434–436 (1999)
POST-LTX PRIMARY DYSFUNCTION
435
Fig 2. Mean values and standard deviations in preoperative bilirubin level, intraoperative transfusion of packed red blood cell units (PRBC), and length of bypass time in patients with and without primary dysfunction (P , .05, Mann–Whitney U test).
product infusion showed the best correlation with PD (P , .001, F 5 166, R2 5 .81). DISCUSSION
In early clinical experience, after liver transplantation, patients with a poorly functioning liver were condemned to death.12 This observation induced Starzl to introduce the retransplant procedure.13 Recently, improvements in knowledge of liver physiopathology and the adoption of new methodology in intensive care management (glucose and branched-chain amino-acid infusion, fresh frozen plasma support, prostaglandin administration, prevention of renal failure by diuretic stimulation and control of fluid overload), have led to progressive improvements in the treatment of patients with liver failure.9, 14 –17 Today, these factors and the properties of the new perfusion-preservation solution (ie, UW), have allowed the reduction of liver damage related to the harvest/storage procedure.18 Consequently, the role of liver retransplantation in cases complicated by severe primary dysfunction is an object of debate, particularly in Italy where the donor pool is limited and donor quality is less than optimal.19 Thirty-five years after the first clinical liver transplantation, primary dysfunction still remains a strong predictor of outcome. Recovery after liver transplantation indeed presents a variety of patterns of evolution ranging from early and complete function of the graft to complete absence of liver function, which can lead to patient death when liver retransplantation is not performed. Many different definitions of primary dysfunction have been proposed.5–11 In the postoperative period of liver transplantation, liver dysfunction is manifested by hepatic cytolysis, hepatic jaundice, hepatic encephalopathy, liverrelated coagulation deficit, and hepatic hemodynamic insta-
bility. Most investigators define primary nonfunction as the condition after liver transplantation that requires retransplantation using clinical criteria. According to a more recent approach to the problem, we suggest use of the term “primary dysfunction” for all cases of impaired liver function. Indeed, primary dysfunction presents different degrees of severity, ranging from initial poor function (benign condition responding to support therapy) to primary nonfunction (the most serious condition leading to fatal outcome if prompt retransplantation is not performed). Of the different indicators of primary dysfunction, trend of liver cytolysis enzymes in the first postoperative week is the method most widely used. Nevertheless, the cutoff level in relation to the prognosis is not definitively known. In our experience, patients with transaminase peak levels .3500 IU/L present the poorest prognosis, as determined by the Kaplan–Meier method (Wilcoxon, P , .05). In this study, regarding the donor data, donor age and systolic blood pressure are correlated with primary dysfunction although with low R2 values. Gender, cause of death, length of donor stay in ICU, donor weight, transaminase level, prothrombin time, donor Na, bilirubin level, arterial partial pressure of oxygen, systolic blood pressure, central venous pressure, and dopamine infusion rate did not correlate with PD. Successful liver transplantation with liver procurement from elderly donors (.70 years) has recently been reported,20 nevertheless, larger cumulative experiences, such as that of the European Liver Transplant Registry and that of the United Network for Organ Sharing, show inferior graft survival figures for patients transplanted with organs from donors .50 years (approximately 5% difference at 1 year and 10% difference at 5 years).21 In the present study, the oldest donor was a 64-year-old female patient whose graft was transplanted into a child C patient
436
who presented primary dysfunction with a successful outcome. Statistical analysis of our data shows that the weight of donor parameters was small and not assessable by univariate methods but detectable only by the logistic regression method, which, all cases, gave low levels of R2 (age, systolic blood pressure). High donor weight has been correlated with PD and with poor outcome because of liver steatosis.11 In our series, overweight donors and donors with long ICU stays (.2 weeks) were not considered suitable for liver harvesting. The prognostic value of donor serum sodium level on transplant outcome has been reported since 1991 by our group.1 Three years later, other investigators with a larger database agreed on this matter.6 More recently, a multicentre study confirmed that in an evaluation of more than 600 cases.23 In the present series, we failed to find correlation between donor sodium and graft survival using the Cox regression method. We explain this finding as being due to the present policy of not accepting donors with high sodium levels. In this study, recipient factors seem more important in predicting PD after liver transplantation. We did not observe any correlation between etiology of liver disease and PD. The role of the preoperative recipient status, as represented by the UNOS class or CHILD class, has been reported in several previous series.5– 8 In our experience, the preoperative bilirubin level correlates with PD. Probably, in the patient with chronic end-stage liver disease, the high preoperative bilirubin level is representative of the overall poor general condition, which, in the postoperative period, leads to a slow recovery from liver harvesting trauma. We postulate that patients transplanted in poor condition present respiratory, renal, metabolic, and hemodynamic alterations that often induce additional damage to the graft. This fact is probably more deleterious in cases of nonoptimal grafts. Intraoperative blood infusion data and bypass time, which are probably related to the preoperative conditions of the recipient, play a similar role and may induce a negative catalytic effect on postoperative recovery. In conclusion, primary dysfunction after liver transplantation, today remains an important determinant of patient survival even with recent improvements in postoperative support therapy. PD is a multifactorial event and donor factors probably play a minor role in determining PD; recipient factors, particularly preoperative bilirubin level, intraoperative blood infusion, and bypass time are the strongest predictors of PD. Finally, the combination of
AVOLIO, AGNES, CHIRICO ET AL
donor and recipient factors, their multiplicity, and the low grade of correlation between each factor and PD explain the difficulty in the reduction of primary dysfunction after liver transplantation. REFERENCES 1. Avolio AW, Agnes S, Magalini SC, et al: Transplant Proc 23:2451, 1991 2. Avolio AW, Agnes S, Magalini S, et al: Transplant Proc 24:2707, 1992 3. Avolio AW, Agnes S, Magalini SC, et al: Transplant Proc 25:1868, 1993 4. Avolio AW, Agnes S, Pelosi G, et al: Transplant Proc 23:2263, 1991 5. Baliga P, Merion RM, Turcott JG, et al: Surgery 112:704, 1992 6. Gonzales FX, Rimola A, Grande L, et al: Hepatology 20:565, 1994 7. Ploeg RJ, D’Alessandro AM, Knechtle SJ, et al: Transplantation 55:807, 1993 8. Clavienn PA, Harvey PRC, Strasberg SM: Transplantation 53:957, 1992 9. Greig PD, Woolf GM, Sinclaire SB, et al: Transplantation 48:447, 1989 10. Mimeault R, Grant D, Ghent C, et al: Transplant Proc 21:2355, 1989 11. Mor E, Klintmalm GB, Gonwa TA, et al: Transplantation 53:383, 1992 12. Starzl TE, Cormann J, Groth CG, et al: Transplant Proc 4:759, 1972 13. Shaw BW, Gordon RD, Iwatsuki S, et al: Transplant Proc 21:264, 1985 14. Reilly J, Mehta R, Teperman L, et al: JPEN 14:386, 1990 15. Chen SC, Cunneen SA, Colquhoun SD, et al: Am Surg 64:926, 1998 16. Giovannini I, Boldrini G, Chiarla C, et al: World J Surg 202:11, 1987 17. Chiarla C, Giovannini I, Siegel JH, et al: Crit Care Med 18:32, 1990 18. Todo S, Nevy J, Yanaga K, et al: JAMA 261:711, 1989 19. Agnes S, Avolio AW, Magalini SC, et al: Transplant Int 5(suppl):S170, 1992 20. Emre S, Schwartz ME, Altaca G, et al: Transplantation 62:62, 1996 21. 1997 Annual Report of the European Liver Transplant Registry, Paris, 1998 22. 1997 Annual Report of the United Network for Organ Sharing, 1998 23. Figureas J, Busquets J, Grande L, et al: Transplantation 61:410, 1996