- Email: [email protected]
Comparison of outcomes in ideal donor and extended criteria donor in deceased donor liver transplant: A prospective study
International Journal of Surgery 12 (2014) 774e777
Contents lists available at ScienceDirect
International Journal of Surgery journal homepage: www.journal-surgery.net
Original research
Comparison of outcomes in ideal donor and extended criteria donor in deceased donor liver transplant: A prospective study Dronacharya Routh*, Sanjay Sharma, C.S. Naidu, P.P. Rao, Anuj Kumar Sharma, Priya Ranjan Department of GI Surgery and Liver Transplantation, Army Hospital (Research and Referral), Delhi Cantt, New Delhi 110010, India
h i g h l i g h t s Extended criteria deceased donors are being increasingly used for liver transplant. There is an increased incidence of early graft dysfunction in this group. The use of marginal grafts did not increase the incidence of PNF. The overall survival has remained unchanged following use of marginal grafts.
a r t i c l e i n f o
a b s t r a c t
Article history: Received 10 March 2014 Received in revised form 5 June 2014 Accepted 11 June 2014 Available online 16 June 2014
Introduction: The number of patients who could benefit from liver transplantation markedly exceeds the number of available donors. This increasing gap has fuelled efforts to maximize existing donor pool and identify new avenues. Aims and objectives: To compare the outcome in deceased donor liver transplant (DDLT) based on extended donor selection criteria. Materials and methods: Donor and recipients' data were analyzed following DDLT from Mar 2007 to Feb 2013. Donors were grouped into either ideal donor (ID) or extended criteria donor (ECD) based on donor and graft related characteristics. Primary nonfunction (PNF) and patient survival were the primary endpoints while early graft dysfunction (EGD) and incidence of major postoperative complications were the secondary endpoints of the study. Results: We had a total of 6 mortalities (13%) at the end of 1 year. The Kaplan Meier survival analysis at 7 days, 3, 6 and 12 months were not statistically different (p > 0.05). PNF occurred in three (6.5%) patients and was not significantly different nor influenced by cumulative number of risk factors in the subgroup analysis (p < 0.3). However, the incidence of EGD was significantly influenced by the cumulative number of risk factors (p < 0.005). A total of 12 (26.1%) patients were graded with 3 or more complications according to the 'Clavien Dindo Grade' for major post operative complications, although it did not reach a statistical significance in the various subgroups. Univariate analysis of the donor risk factors showed that none of these factors were predictive for PNF and mortality in deceased donor liver transplant recipients. Conclusion: Although the incidence of early graft dysfunction is statistically more with increase in number of donor risk factors, the overall survival and outcome in extended criteria liver donors are similar to that of an ideal donor. With the supply demand gap widening, extended criteria for selection of deceased donors will definitely expand the donor pool without adversely affecting the outcome of liver transplantation. © 2014 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
Keywords: Extended criteria donor Marginal donor Liver transplantation
1. Introduction
* Corresponding author. E-mail address: [email protected] (D. Routh). http://dx.doi.org/10.1016/j.ijsu.2014.06.003 1743-9191/© 2014 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
Liver transplantation (LT) has been the only proven treatment for patients with end-stage liver disease or hepatocellular carcinoma in cirrhotic patients. With the widening indications, the demand for organs has been increasing steadily and exceeds the
D. Routh et al. / International Journal of Surgery 12 (2014) 774e777
number of available deceased donors. Ignorance among general population and scarcity of brain stem deaths has made living donor liver transplantation the more common mode of transplantation in India. However, unlike India and other Asian countries most transplant centres in the world still depend on the deceased donor pool as opposed to live donation. One of the main strategies to address this discrepancy is expansion of the Deceased Donor pool utilizing extended criteria donor (ECD) [1e3]. 2. Aims and objectives Till date we have one of the largest number of deceased donor liver transplantation (DDLT) in India. We wanted to compare the outcome in DDLT based on extended donor selection criteria. Primary non function (PNF) and patient survival were the primary endpoints while early graft dysfunction (EGD) and incidence of major postoperative complications were the secondary endpoints of the study.
775
immunosuppression consists of tacrolimus, MMF, and corticosteroids. The patients were weaned off corticosteroids within 3 months, except in cases of transplantation due to autoimmune hepatitis which were treated with corticosteroid continuously. 4. Statistical analysis Data are expressed as means ± standard deviation for continuous variables and as percentages for categorical variables wherever applicable. Other variables were expressed as medians. Data was compared with the 2-tailed chi-square test or Fisher's exact test for categorical variables and with the Student t test; analysis of variance and the median test were used for continuous variables. P values <0.05 were considered significant. Multivariate analysis of variables currently listed to define an ECD was used to assess the impact on recipient survival. Survival analysis was performed with the KaplaneMeier method; the log rank test was used to test for statistically significant observed differences. All statistical analysis was performed using Stata 9.0 (College Station, Texas, USA).
3. Materials and methods 5. Results We analyzed donors and recipients’ data following DDLT from Mar 2007 to Feb 2013 at our Transplant Centre. All donor and recipient data were stored in Access software, Windows Office 2007. All donors were grouped into either ideal donor (ID) or extended criteria donor (ECD) based on certain donor and graft related characteristics. An ECD was defined as follows: (1) age > 60 years; (2) macrovesicular steatosis >30%; (3) prolonged intensive care unit (ICU) stay (>4 days); (4) hemodynamic risk factors (any two of the following): prolonged hypotension (systolic blood pressure <60 mm Hg for more than 2 h), use of dopamine > 10 mcg/kg/ minute for more than 6 h to sustain blood pressure, and need for 2 inotropic drugs to sustain donor blood pressure for more than 6 h; (5) Deranged liver function test (any two of the following): Serum bilirubin > 2 mg/dl, AST > 170 IU/L, ALT > 140 IU/L; (6) Increased Total Leucocytes Count (TLC) > 12,000/cumm; (7) cold ischemic time > 12 h; and (8) hypernatremia (Na peak > 155 mEq/L) before aortic cross clamp. On presence of cumulative number of risk factors, these patients were further divided into 3 subgroups: the ID group receiving an ideal graft, the ECD1 group receiving a graft with 1 or 2 risk factors, and the ECD2 group receiving a graft with 3e4 risk factors. The donor management, retrieval, recipient evaluation, transplantation, and management were as per the protocol followed by our centre. 3.1. Exclusion criteria As per our institutional policy, we rejected grafts from patients with a history of malignancy, grossly fatty liver on inspection, cirrhotic liver, serum sodium >170 mEq/L, and those donors not showing decreasing trend with sodium-free fluid, TLC >15,000/ cumm, liver enzyme level >600 U/L, and serum bilirubin >4 mg%. 3.2. Assessment of outcomes Outcome parameters were assessed daily with serum peaks of ALT and AST, serum bilirubin, INR, hepatic encephalopathy, biliovascular complications, and patient survival at 1 week, 1, 3 and 6 months and at 1 year after transplantation. EGD was defined as presence of at least one of the following e serum bilirubin >10 mg/ dL on postoperative day 7, INR 1.6 on postoperative day 7, and ALT or AST > 2000 IU/mL within the first 7 days [4]. PNF was defined as non life-sustaining function of the liver requiring retransplantation or leading to death within 7 days after liver transplantation [5]. The
Between Mar 2007 and Feb 2013, of 122 brain deaths, 99 potential donors were counseled for organ donation by the counsellor, of which 49 consented for liver donation. Three cases were rejected during the organ procurement process, one due to cirrhosis on gross examination and the other two due to massive colonic and small bowel gangrene. 46 brain deaths underwent multiorgan retrieval. Of 46 grafts, 6 were subjected to intra operative biopsy on visual inspection of the liver and was found to have significant steatosis (>30%). There were 35 (76.1%) ECD grafts and 11 (23.9%) ID grafts. The ECD graft group was further subdivided into 2 subgroups: ECD1 with 23 (50%) patients and ECD2 with 12 (26.1%) patients. All the subgroups were well matched with respect to age, sex and indication of liver transplantation, Child Pugh Turcott Score (CTP), model for end-stage liver disease (MELD), warm ischemia time (WIT), blood loss and mean operative time (Table 1). There were 6 mortalities (13%) at the end of 1 year. The Kaplan Meier survival analysis in various subgroups at 7 days, 3, 6 and 12 months were not significantly different (p < 0.07) (Fig. 1). PNF occurred in 3 (6.5%) patients and was not significantly different nor influenced by cumulative number of risk factors on subgroup analysis (p < 0.3). The incidence of EGD was significantly influenced by the cumulative number of risk factors (p < 0.005) (Table 2). Although 12 (26.1%) patients were graded with 3 or more complications according to the ‘Clavien Dindo Grade’ for major postoperative complications, it did not reach a significant significance among the various subgroups. Univariate analysis of the donor risk factors showed that none of these factors were predictive for PNF and mortality in deceased donor liver transplant recipient (Table 3). 6. Discussion ECD grafts are being increasingly accepted due to the growing demand for deceased donor grafts. However, there is a lack of consensus on the definition of an ECD graft and the factors that should exclude a graft from use because of increased risk to the recipient. The use of ECD liver grafts has been debated for decades [6]. Several reports have failed to unify the criteria for ECD liver grafts that can be universally accepted [7]. The most important message from this body of literature is the acceptance of the increased risk of failure as determined by the use of ECD liver grafts. Although, on the positive side, their use will also expand the donor pool. Critical in this regard is the adoption of a policy of detailed
776
D. Routh et al. / International Journal of Surgery 12 (2014) 774e777
Table 1 Demographic and clinical data of the recipients in the subgroups. Characteristics
ID group (11)
Age (years) Sex Male Female CTP Score 9 >9 MELD Score 18 >18 Etiology HBV HCV Alcoholic Budd Chiari Cryptogenic Autoimmune Operative parameters WIT, (min) Operative time, (mins) Blood loss, (ml)
ECD1 group (23)
ECD2 group (12)
P Value
Number
Mean ± SD or %
Number
Mean ± SD or %
Number
Mean ± SD or %
11
39.3 ± 15.7
23
50.3 ± 19.1
12
40.3 ± 19.8
0.74
8 3 11 4 7 11 5 6
30.8% 15.0% 10.4 ± 1.3 23.5% 24.2% 18.5 ± 2.8 35.7% 18.8%
13 10 23 10 13 23 5 18
50.0% 50.0% 9.9 ± 1.6 58.8% 44.8% 18.7 ± 2.4 35.7% 56.3%
5 7 12 3 9 12 4 8
19.2% 35.0% 11.1 ± 1.9 17.7% 31.0% 18.7 ± 1.7 28.6% 24.9%
0.37
2 2 1 1 3 2
25.0% 22.2% 25.0% 25.0% 23.0% 25.0%
3 5 2 3 6 4
37.5% 55.6% 50.0% 75.0% 46.2% 50.0%
3 2 1 nil 4 2
37.5% 22.2% 25.0% 0% 30.8% 25.0%
0.17 0.08 0.08 0.06 0.47 0.08
11 11 11
35.9 ± 4.4 656.4 ± 78.1 447.3 ± 125.5
23 23 23
34.5 ± 5.1 663.5 ± 75.6 454.3 ± 94.4
12 12 12
34.8 ± 5.5 680.8 ± 67.9 450.8 ± 75.4
0.78 0.89 0.26
Fig. 1. Kaplan Meier estimate in between various subgroups.
informed consent that addresses both the risks generated by the use of that specific ECD graft and the risk generated by not using that graft for the specific clinical condition of the recipient. The decision to use a specific organ therefore depends on the centre's protocol, judgment of the transplant surgeon, and specific needs of the recipient. Numerous single-centre reports have identified
Table 2 Postoperative complications in the various subgroups. Variables
ID group, (%) ECD 1 group, ECD 2 group, P Value (%) (%)
PNF EGD Hepatic artery thrombosis Biliary complications Portal vein thrombosis Hepatic vein outflow tract obstruction Clavien Dindo Grade (III and above) Mortality
0 3 0 2 0 0
(0%) (25.0%) (0%) (28.6%) (0%) (0%)
1 2 1 2 0 0
(4.3%) (16.7%) (25.0%) (28.6%) (0%) (0%)
2 7 2 3 1 0
(16.7%) (58.3%) (75.0%) (42.8%) (100%) (0%)
0.30 0.005 0.11 0.42 0.50 e
2 (16.7%)
4 (33.3%)
6(50.0%)
0.11
0 (0%)
2 (33.3%)
4 (66.7%)
0.07
0.62
0.34
predictors of potentially poor graft function. Feng et al., [8] analyzed 20,000 transplants from the Scientific Registry of Transplant Recipients (SRTR) database and developed a DRI, which is calculated from seven donor and two transplant variables that were found to be independently associated with an increased risk of graft failure. These included donor >40 years, donor height, donation after cardiac death, split/partial grafts, cerebrovascular accident or other cause of death (except trauma, stroke, or anoxia), cold ischemia time, and organ sharing outside the local donor service area. Similarly, Rana et al., [9] identified 13 recipient factors, 4 donor factors, and 2 operative factors (warm and cold ischemia times) as significant predictors of recipient mortality 3 months after transplantation, using MELD era data and including retransplants. “Graft malfunction,” which is multifactorial in etiology, has varying degrees; the severest is the irreversible state of PNF, with less severe forms exhibiting reversible graft dysfunction termed as EGD. PNF is the most serious end result of initial poor allograft function and may occur in 1.4%e8.5% of cases after orthotopic liver transplantation and requires urgent retransplantation to avoid patient mortality [5,10e13]. The conditions of the donor, recipient, and surgery influence early function of the transplanted liver. This study focused on the identification of the effect of extended criteria donor on outcomes. Use of extended criteria donors, especially aged donors, has become more frequent recently. In Europe, donors over 60 years have increased from less than 5% in the early 1990s to
Table 3 Univariate analysis of donor and recipient factors causing PNF and mortality in recipients of ECD grafts. Criteria
Number of PNF (3) P Value Mortality (5) P Value donors (35)
Age >60 y Steatosis >30% ICU stay > 4 days Hemodynamic factors Deranged LFT TLC >12,000/cumm Sodium >155 meq/L CIT > 12 h
8 6 16 27 14 9 6 e
1 1 2 3 2 1 1 e
0.44 0.35 0.27 0.26 0.22 0.49 0.35 e
1 2 4 5 3 2 2 e
0.77 0.17 0.16 0.38 0.35 0.58 0.17 e
D. Routh et al. / International Journal of Surgery 12 (2014) 774e777
approximately 20% in the 2002 European Liver Transplantation Registry [14]. The drawback of this study is the small number of patients in the study groups. This small sample size is likely to result in a type 2 statistical error. On the basis of our data, the primary endpoints, PNF and patient survival were not significantly different, although there was a trend towards statistical significance. The small number of subjects is a major limitation in the present study. However, it is evident that EGD is influenced by cumulative risk factors in the ECD pool. The analysis of risk factors in the donors did not play a role in the adverse outcome of the transplant. Our experience suggests that a change in donor selection criteria, namely, a more aggressive acceptance of ECDs, did not negatively influence the overall outcome. It is critical to realize that there are no golden rules for identifying the best donor-recipient match, although there seems to be an overall benefit in accepting ECD liver grafts. Not accepting a donor liver from a marginal donor may result in the death of a patient requiring an urgent transplantation as another donor liver may not become available immediately. Marginal grafts should be transplanted in recipients with low risk, i.e. a low model for MELD score and fewer comorbidities. These grafts perform better in patients who can tolerate a bigger insult immediately following transplantation when compared with highrisk recipients. Patient and graft survival have been found to be significantly lower when marginal grafts were used in high-risk recipients [3,15,16]. 7. Conclusion With a small sample size it would be difficult to draw definite conclusion from the present study. However, the incidence of early graft dysfunction was significantly more with increase in number of donor risk factors in this study. The overall survival and outcome in extended criteria liver donors were similar to that of an ideal donor. So with the supply demand gap widening, extended criteria deceased donors if carefully selected would expand the donor pool without adversely affecting the outcome of liver transplantation. Ethical approval None. Conflicts of interest None.
777
Funding None. Author contribution Dronacharya Routh e study design and written the manuscript. Sanjay Sharma e Data collections. CS Naidu e Study design and data analysis. PP Rao e Data analysis. Anuj K Sharma e Data collection and analysis. Priya Ranjan e Data analysis and revision of draft. References [1] R.F. Saidi, Current status of liver transplantation, Arch. Iran. Med. 15 (2012) 772e776. [2] Saidi RF, Markmann JF, Jabbour N, et al. The faltering solid organ donor pool in the United States (2001e2010). World J. Surg.. 2012; 36:2909e2913. [3] R.W. Busuttil, K. Tanaka, The utility of marginal donors in liver transplantation, Liver Transpl. 9 (2003) 651e663. [4] K.M. Olthoff, L. Kulik, S. Benjamin, et al., Validation of a current definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors, Liver Transpl. 16 (2010) 943e949. [5] M. Deschenes, S.H. Belle, R.A. Krom, R.K. Zetterman, J.R. Lake, Early allograft dysfunction after liver transplantation: a definition and predictors of outcome. National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database, Transplantation 66 (1998) 302e310. [6] J.W. Alexander, W.K. Vaughn, The use of “marginal” donors for organ transplantation, Transplantation 51 (1991) 135e141. [7] J.F. Renz, C. Kin, M. Kinhabwala, D. Jan, R. Varadarajan, M. Goldstein, et al., Utilization of extended donor criteria liver allografts maximizes donor use and patient access to liver transplantation, Ann. Surg. 242 (2005) 556e565. [8] S. Feng, N.P. Goodrich, J.L. Bragg-Gresham, et al., Characteristics associated with liver graft failure: the concept of a donor risk index, Am. J. Transpl. 6 (2006) 783e790. [9] A. Rana, M.A. Hardy, K.J. Halazun, et al., Survival outcomes following liver transplantation (SOFT) score: a novel method to predict patient survival following liver transplantation, Am J Transpl. 8 (2008) 2537e2546. [10] E. Mor, G.B. Klintmalm, T.A. Gonwa, H. Solomon, M.J. Holman, J.F. Gibbs, The use of marginal donors for liver transplantation: a retrospective study of 365 liver donors, Transplantation 53 (1992) 383e386. [11] R.J. Ploeg, A.M. D’Alessandro, R.M. Hoffmann, D. Eckhoff, R. Isaacs, S.J. Knechtle, Impact of donor factors and preservation on function and survival after liver transplantation, Transpl. Proc. 25 (1993) 3031e3033. [12] R.J. Ploeg, A.M. d’Allessandro, S.J. Knechtle, et al., Risk factors for primary dysfunction after liver transplantation e a multivariate analysis, Transplantation 55 (1993) 807e813. [13] I.R. Marino, T.E. Starzl, L. Aldrighetti, et al., Risk factors and predictive indexes of early graft failure in liver transplantation, Ital. J. Gastroenterol. 28 (1996) 163e168. [14] Annual Report of the US Scientific Registry of Transplant Recipients and the Organ Procurement and Transplant Network: Transplant Data, 1989e2008. http://www.optn.org/data/annualReport.asp (accessed 10.06.10.). [15] M. Gastaca, A. Valdivieso, J. Pijoan, et al., Donors older than 70 yrs in liver transplantation, Transpl. Proc. 37 (2005) 3851e3854. [16] W.J. Wall, R. Mimeault, D.R. Grant, M. Bloch, The use of older donor livers for hepatic transplantation, Transplantation 49 (1990) 377e384.
Contents lists available at ScienceDirect
International Journal of Surgery journal homepage: www.journal-surgery.net
Original research
Comparison of outcomes in ideal donor and extended criteria donor in deceased donor liver transplant: A prospective study Dronacharya Routh*, Sanjay Sharma, C.S. Naidu, P.P. Rao, Anuj Kumar Sharma, Priya Ranjan Department of GI Surgery and Liver Transplantation, Army Hospital (Research and Referral), Delhi Cantt, New Delhi 110010, India
h i g h l i g h t s Extended criteria deceased donors are being increasingly used for liver transplant. There is an increased incidence of early graft dysfunction in this group. The use of marginal grafts did not increase the incidence of PNF. The overall survival has remained unchanged following use of marginal grafts.
a r t i c l e i n f o
a b s t r a c t
Article history: Received 10 March 2014 Received in revised form 5 June 2014 Accepted 11 June 2014 Available online 16 June 2014
Introduction: The number of patients who could benefit from liver transplantation markedly exceeds the number of available donors. This increasing gap has fuelled efforts to maximize existing donor pool and identify new avenues. Aims and objectives: To compare the outcome in deceased donor liver transplant (DDLT) based on extended donor selection criteria. Materials and methods: Donor and recipients' data were analyzed following DDLT from Mar 2007 to Feb 2013. Donors were grouped into either ideal donor (ID) or extended criteria donor (ECD) based on donor and graft related characteristics. Primary nonfunction (PNF) and patient survival were the primary endpoints while early graft dysfunction (EGD) and incidence of major postoperative complications were the secondary endpoints of the study. Results: We had a total of 6 mortalities (13%) at the end of 1 year. The Kaplan Meier survival analysis at 7 days, 3, 6 and 12 months were not statistically different (p > 0.05). PNF occurred in three (6.5%) patients and was not significantly different nor influenced by cumulative number of risk factors in the subgroup analysis (p < 0.3). However, the incidence of EGD was significantly influenced by the cumulative number of risk factors (p < 0.005). A total of 12 (26.1%) patients were graded with 3 or more complications according to the 'Clavien Dindo Grade' for major post operative complications, although it did not reach a statistical significance in the various subgroups. Univariate analysis of the donor risk factors showed that none of these factors were predictive for PNF and mortality in deceased donor liver transplant recipients. Conclusion: Although the incidence of early graft dysfunction is statistically more with increase in number of donor risk factors, the overall survival and outcome in extended criteria liver donors are similar to that of an ideal donor. With the supply demand gap widening, extended criteria for selection of deceased donors will definitely expand the donor pool without adversely affecting the outcome of liver transplantation. © 2014 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
Keywords: Extended criteria donor Marginal donor Liver transplantation
1. Introduction
* Corresponding author. E-mail address: [email protected] (D. Routh). http://dx.doi.org/10.1016/j.ijsu.2014.06.003 1743-9191/© 2014 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
Liver transplantation (LT) has been the only proven treatment for patients with end-stage liver disease or hepatocellular carcinoma in cirrhotic patients. With the widening indications, the demand for organs has been increasing steadily and exceeds the
D. Routh et al. / International Journal of Surgery 12 (2014) 774e777
number of available deceased donors. Ignorance among general population and scarcity of brain stem deaths has made living donor liver transplantation the more common mode of transplantation in India. However, unlike India and other Asian countries most transplant centres in the world still depend on the deceased donor pool as opposed to live donation. One of the main strategies to address this discrepancy is expansion of the Deceased Donor pool utilizing extended criteria donor (ECD) [1e3]. 2. Aims and objectives Till date we have one of the largest number of deceased donor liver transplantation (DDLT) in India. We wanted to compare the outcome in DDLT based on extended donor selection criteria. Primary non function (PNF) and patient survival were the primary endpoints while early graft dysfunction (EGD) and incidence of major postoperative complications were the secondary endpoints of the study.
775
immunosuppression consists of tacrolimus, MMF, and corticosteroids. The patients were weaned off corticosteroids within 3 months, except in cases of transplantation due to autoimmune hepatitis which were treated with corticosteroid continuously. 4. Statistical analysis Data are expressed as means ± standard deviation for continuous variables and as percentages for categorical variables wherever applicable. Other variables were expressed as medians. Data was compared with the 2-tailed chi-square test or Fisher's exact test for categorical variables and with the Student t test; analysis of variance and the median test were used for continuous variables. P values <0.05 were considered significant. Multivariate analysis of variables currently listed to define an ECD was used to assess the impact on recipient survival. Survival analysis was performed with the KaplaneMeier method; the log rank test was used to test for statistically significant observed differences. All statistical analysis was performed using Stata 9.0 (College Station, Texas, USA).
3. Materials and methods 5. Results We analyzed donors and recipients’ data following DDLT from Mar 2007 to Feb 2013 at our Transplant Centre. All donor and recipient data were stored in Access software, Windows Office 2007. All donors were grouped into either ideal donor (ID) or extended criteria donor (ECD) based on certain donor and graft related characteristics. An ECD was defined as follows: (1) age > 60 years; (2) macrovesicular steatosis >30%; (3) prolonged intensive care unit (ICU) stay (>4 days); (4) hemodynamic risk factors (any two of the following): prolonged hypotension (systolic blood pressure <60 mm Hg for more than 2 h), use of dopamine > 10 mcg/kg/ minute for more than 6 h to sustain blood pressure, and need for 2 inotropic drugs to sustain donor blood pressure for more than 6 h; (5) Deranged liver function test (any two of the following): Serum bilirubin > 2 mg/dl, AST > 170 IU/L, ALT > 140 IU/L; (6) Increased Total Leucocytes Count (TLC) > 12,000/cumm; (7) cold ischemic time > 12 h; and (8) hypernatremia (Na peak > 155 mEq/L) before aortic cross clamp. On presence of cumulative number of risk factors, these patients were further divided into 3 subgroups: the ID group receiving an ideal graft, the ECD1 group receiving a graft with 1 or 2 risk factors, and the ECD2 group receiving a graft with 3e4 risk factors. The donor management, retrieval, recipient evaluation, transplantation, and management were as per the protocol followed by our centre. 3.1. Exclusion criteria As per our institutional policy, we rejected grafts from patients with a history of malignancy, grossly fatty liver on inspection, cirrhotic liver, serum sodium >170 mEq/L, and those donors not showing decreasing trend with sodium-free fluid, TLC >15,000/ cumm, liver enzyme level >600 U/L, and serum bilirubin >4 mg%. 3.2. Assessment of outcomes Outcome parameters were assessed daily with serum peaks of ALT and AST, serum bilirubin, INR, hepatic encephalopathy, biliovascular complications, and patient survival at 1 week, 1, 3 and 6 months and at 1 year after transplantation. EGD was defined as presence of at least one of the following e serum bilirubin >10 mg/ dL on postoperative day 7, INR 1.6 on postoperative day 7, and ALT or AST > 2000 IU/mL within the first 7 days [4]. PNF was defined as non life-sustaining function of the liver requiring retransplantation or leading to death within 7 days after liver transplantation [5]. The
Between Mar 2007 and Feb 2013, of 122 brain deaths, 99 potential donors were counseled for organ donation by the counsellor, of which 49 consented for liver donation. Three cases were rejected during the organ procurement process, one due to cirrhosis on gross examination and the other two due to massive colonic and small bowel gangrene. 46 brain deaths underwent multiorgan retrieval. Of 46 grafts, 6 were subjected to intra operative biopsy on visual inspection of the liver and was found to have significant steatosis (>30%). There were 35 (76.1%) ECD grafts and 11 (23.9%) ID grafts. The ECD graft group was further subdivided into 2 subgroups: ECD1 with 23 (50%) patients and ECD2 with 12 (26.1%) patients. All the subgroups were well matched with respect to age, sex and indication of liver transplantation, Child Pugh Turcott Score (CTP), model for end-stage liver disease (MELD), warm ischemia time (WIT), blood loss and mean operative time (Table 1). There were 6 mortalities (13%) at the end of 1 year. The Kaplan Meier survival analysis in various subgroups at 7 days, 3, 6 and 12 months were not significantly different (p < 0.07) (Fig. 1). PNF occurred in 3 (6.5%) patients and was not significantly different nor influenced by cumulative number of risk factors on subgroup analysis (p < 0.3). The incidence of EGD was significantly influenced by the cumulative number of risk factors (p < 0.005) (Table 2). Although 12 (26.1%) patients were graded with 3 or more complications according to the ‘Clavien Dindo Grade’ for major postoperative complications, it did not reach a significant significance among the various subgroups. Univariate analysis of the donor risk factors showed that none of these factors were predictive for PNF and mortality in deceased donor liver transplant recipient (Table 3). 6. Discussion ECD grafts are being increasingly accepted due to the growing demand for deceased donor grafts. However, there is a lack of consensus on the definition of an ECD graft and the factors that should exclude a graft from use because of increased risk to the recipient. The use of ECD liver grafts has been debated for decades [6]. Several reports have failed to unify the criteria for ECD liver grafts that can be universally accepted [7]. The most important message from this body of literature is the acceptance of the increased risk of failure as determined by the use of ECD liver grafts. Although, on the positive side, their use will also expand the donor pool. Critical in this regard is the adoption of a policy of detailed
776
D. Routh et al. / International Journal of Surgery 12 (2014) 774e777
Table 1 Demographic and clinical data of the recipients in the subgroups. Characteristics
ID group (11)
Age (years) Sex Male Female CTP Score 9 >9 MELD Score 18 >18 Etiology HBV HCV Alcoholic Budd Chiari Cryptogenic Autoimmune Operative parameters WIT, (min) Operative time, (mins) Blood loss, (ml)
ECD1 group (23)
ECD2 group (12)
P Value
Number
Mean ± SD or %
Number
Mean ± SD or %
Number
Mean ± SD or %
11
39.3 ± 15.7
23
50.3 ± 19.1
12
40.3 ± 19.8
0.74
8 3 11 4 7 11 5 6
30.8% 15.0% 10.4 ± 1.3 23.5% 24.2% 18.5 ± 2.8 35.7% 18.8%
13 10 23 10 13 23 5 18
50.0% 50.0% 9.9 ± 1.6 58.8% 44.8% 18.7 ± 2.4 35.7% 56.3%
5 7 12 3 9 12 4 8
19.2% 35.0% 11.1 ± 1.9 17.7% 31.0% 18.7 ± 1.7 28.6% 24.9%
0.37
2 2 1 1 3 2
25.0% 22.2% 25.0% 25.0% 23.0% 25.0%
3 5 2 3 6 4
37.5% 55.6% 50.0% 75.0% 46.2% 50.0%
3 2 1 nil 4 2
37.5% 22.2% 25.0% 0% 30.8% 25.0%
0.17 0.08 0.08 0.06 0.47 0.08
11 11 11
35.9 ± 4.4 656.4 ± 78.1 447.3 ± 125.5
23 23 23
34.5 ± 5.1 663.5 ± 75.6 454.3 ± 94.4
12 12 12
34.8 ± 5.5 680.8 ± 67.9 450.8 ± 75.4
0.78 0.89 0.26
Fig. 1. Kaplan Meier estimate in between various subgroups.
informed consent that addresses both the risks generated by the use of that specific ECD graft and the risk generated by not using that graft for the specific clinical condition of the recipient. The decision to use a specific organ therefore depends on the centre's protocol, judgment of the transplant surgeon, and specific needs of the recipient. Numerous single-centre reports have identified
Table 2 Postoperative complications in the various subgroups. Variables
ID group, (%) ECD 1 group, ECD 2 group, P Value (%) (%)
PNF EGD Hepatic artery thrombosis Biliary complications Portal vein thrombosis Hepatic vein outflow tract obstruction Clavien Dindo Grade (III and above) Mortality
0 3 0 2 0 0
(0%) (25.0%) (0%) (28.6%) (0%) (0%)
1 2 1 2 0 0
(4.3%) (16.7%) (25.0%) (28.6%) (0%) (0%)
2 7 2 3 1 0
(16.7%) (58.3%) (75.0%) (42.8%) (100%) (0%)
0.30 0.005 0.11 0.42 0.50 e
2 (16.7%)
4 (33.3%)
6(50.0%)
0.11
0 (0%)
2 (33.3%)
4 (66.7%)
0.07
0.62
0.34
predictors of potentially poor graft function. Feng et al., [8] analyzed 20,000 transplants from the Scientific Registry of Transplant Recipients (SRTR) database and developed a DRI, which is calculated from seven donor and two transplant variables that were found to be independently associated with an increased risk of graft failure. These included donor >40 years, donor height, donation after cardiac death, split/partial grafts, cerebrovascular accident or other cause of death (except trauma, stroke, or anoxia), cold ischemia time, and organ sharing outside the local donor service area. Similarly, Rana et al., [9] identified 13 recipient factors, 4 donor factors, and 2 operative factors (warm and cold ischemia times) as significant predictors of recipient mortality 3 months after transplantation, using MELD era data and including retransplants. “Graft malfunction,” which is multifactorial in etiology, has varying degrees; the severest is the irreversible state of PNF, with less severe forms exhibiting reversible graft dysfunction termed as EGD. PNF is the most serious end result of initial poor allograft function and may occur in 1.4%e8.5% of cases after orthotopic liver transplantation and requires urgent retransplantation to avoid patient mortality [5,10e13]. The conditions of the donor, recipient, and surgery influence early function of the transplanted liver. This study focused on the identification of the effect of extended criteria donor on outcomes. Use of extended criteria donors, especially aged donors, has become more frequent recently. In Europe, donors over 60 years have increased from less than 5% in the early 1990s to
Table 3 Univariate analysis of donor and recipient factors causing PNF and mortality in recipients of ECD grafts. Criteria
Number of PNF (3) P Value Mortality (5) P Value donors (35)
Age >60 y Steatosis >30% ICU stay > 4 days Hemodynamic factors Deranged LFT TLC >12,000/cumm Sodium >155 meq/L CIT > 12 h
8 6 16 27 14 9 6 e
1 1 2 3 2 1 1 e
0.44 0.35 0.27 0.26 0.22 0.49 0.35 e
1 2 4 5 3 2 2 e
0.77 0.17 0.16 0.38 0.35 0.58 0.17 e
D. Routh et al. / International Journal of Surgery 12 (2014) 774e777
approximately 20% in the 2002 European Liver Transplantation Registry [14]. The drawback of this study is the small number of patients in the study groups. This small sample size is likely to result in a type 2 statistical error. On the basis of our data, the primary endpoints, PNF and patient survival were not significantly different, although there was a trend towards statistical significance. The small number of subjects is a major limitation in the present study. However, it is evident that EGD is influenced by cumulative risk factors in the ECD pool. The analysis of risk factors in the donors did not play a role in the adverse outcome of the transplant. Our experience suggests that a change in donor selection criteria, namely, a more aggressive acceptance of ECDs, did not negatively influence the overall outcome. It is critical to realize that there are no golden rules for identifying the best donor-recipient match, although there seems to be an overall benefit in accepting ECD liver grafts. Not accepting a donor liver from a marginal donor may result in the death of a patient requiring an urgent transplantation as another donor liver may not become available immediately. Marginal grafts should be transplanted in recipients with low risk, i.e. a low model for MELD score and fewer comorbidities. These grafts perform better in patients who can tolerate a bigger insult immediately following transplantation when compared with highrisk recipients. Patient and graft survival have been found to be significantly lower when marginal grafts were used in high-risk recipients [3,15,16]. 7. Conclusion With a small sample size it would be difficult to draw definite conclusion from the present study. However, the incidence of early graft dysfunction was significantly more with increase in number of donor risk factors in this study. The overall survival and outcome in extended criteria liver donors were similar to that of an ideal donor. So with the supply demand gap widening, extended criteria deceased donors if carefully selected would expand the donor pool without adversely affecting the outcome of liver transplantation. Ethical approval None. Conflicts of interest None.
777
Funding None. Author contribution Dronacharya Routh e study design and written the manuscript. Sanjay Sharma e Data collections. CS Naidu e Study design and data analysis. PP Rao e Data analysis. Anuj K Sharma e Data collection and analysis. Priya Ranjan e Data analysis and revision of draft. References [1] R.F. Saidi, Current status of liver transplantation, Arch. Iran. Med. 15 (2012) 772e776. [2] Saidi RF, Markmann JF, Jabbour N, et al. The faltering solid organ donor pool in the United States (2001e2010). World J. Surg.. 2012; 36:2909e2913. [3] R.W. Busuttil, K. Tanaka, The utility of marginal donors in liver transplantation, Liver Transpl. 9 (2003) 651e663. [4] K.M. Olthoff, L. Kulik, S. Benjamin, et al., Validation of a current definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors, Liver Transpl. 16 (2010) 943e949. [5] M. Deschenes, S.H. Belle, R.A. Krom, R.K. Zetterman, J.R. Lake, Early allograft dysfunction after liver transplantation: a definition and predictors of outcome. National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database, Transplantation 66 (1998) 302e310. [6] J.W. Alexander, W.K. Vaughn, The use of “marginal” donors for organ transplantation, Transplantation 51 (1991) 135e141. [7] J.F. Renz, C. Kin, M. Kinhabwala, D. Jan, R. Varadarajan, M. Goldstein, et al., Utilization of extended donor criteria liver allografts maximizes donor use and patient access to liver transplantation, Ann. Surg. 242 (2005) 556e565. [8] S. Feng, N.P. Goodrich, J.L. Bragg-Gresham, et al., Characteristics associated with liver graft failure: the concept of a donor risk index, Am. J. Transpl. 6 (2006) 783e790. [9] A. Rana, M.A. Hardy, K.J. Halazun, et al., Survival outcomes following liver transplantation (SOFT) score: a novel method to predict patient survival following liver transplantation, Am J Transpl. 8 (2008) 2537e2546. [10] E. Mor, G.B. Klintmalm, T.A. Gonwa, H. Solomon, M.J. Holman, J.F. Gibbs, The use of marginal donors for liver transplantation: a retrospective study of 365 liver donors, Transplantation 53 (1992) 383e386. [11] R.J. Ploeg, A.M. D’Alessandro, R.M. Hoffmann, D. Eckhoff, R. Isaacs, S.J. Knechtle, Impact of donor factors and preservation on function and survival after liver transplantation, Transpl. Proc. 25 (1993) 3031e3033. [12] R.J. Ploeg, A.M. d’Allessandro, S.J. Knechtle, et al., Risk factors for primary dysfunction after liver transplantation e a multivariate analysis, Transplantation 55 (1993) 807e813. [13] I.R. Marino, T.E. Starzl, L. Aldrighetti, et al., Risk factors and predictive indexes of early graft failure in liver transplantation, Ital. J. Gastroenterol. 28 (1996) 163e168. [14] Annual Report of the US Scientific Registry of Transplant Recipients and the Organ Procurement and Transplant Network: Transplant Data, 1989e2008. http://www.optn.org/data/annualReport.asp (accessed 10.06.10.). [15] M. Gastaca, A. Valdivieso, J. Pijoan, et al., Donors older than 70 yrs in liver transplantation, Transpl. Proc. 37 (2005) 3851e3854. [16] W.J. Wall, R. Mimeault, D.R. Grant, M. Bloch, The use of older donor livers for hepatic transplantation, Transplantation 49 (1990) 377e384.