- Email: [email protected]
Does Procurement Technique Affect Posttransplant Graft Function in Deceased Donor Liver Transplantation?
Does Procurement Technique Affect Posttransplant Graft Function in Deceased Donor Liver Transplantation? S.W. Jung, D.-S. Kim, Y.D. Yu, W.B. Ji, P.J. Park, S.B. Choi, J.W. Park, S.Y. Yoon, H.J. Han, T.J. Song, S.Y. Choi, and S.O. Suh ABSTRACT Introduction. Various techniques have been described deceased donor liver transplantation (DDLT) procurement. One is a technique whereby almost total dissection is done in the porta hepatis and perihepatic detachment is carried out before cross-clamping the donor aorta. In another approach, after the donor aorta is cross-clamped, rapid and minimal en bloc dissection is performed with minimal manipulation. We evaluated early posttransplant graft function among liver procurement techniques. Method. Between January 2008 and August 2012, we performed 45 consecutive adult DDLTs. One patient was excluded from this analysis due to early death from sepsis after transplantation. The 44 included patients were divided into two cohorts according to the procurement technique: A warm dissection (n ¼ 23; 52%) and a cold dissection group (n ¼ 21; 48%). We compared early posttransplant graft function using the aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (T-bil), and prothrombin time (PT) values of the two groups from the first to seventh postoperative day. Result. The AST values in the warm group were significantly greater than those in the cold group on postoperative days 3 and 5. In addition, the ALT values in the warm group were greater than those in the cold group on postoperative days 4, 5, and 6. Moreover, the T-bil values in the warm group were greater than those in the cold group on postoperative days 2, 3, 4, 5, 6, and 7. However, there were no differences in PT values. Conclusion. During liver procurement for DDLT, rapid en bloc procurement with minimal manipulation after clamping the donor aorta achieved better early graft function posttransplantation.
S
EVERAL RETROSPECTIVE analyses of donor and recipient variables have sought to identify risk factors predictive of both patient and graft outcomes after deceased donor liver transplantation (DDLT). Donor- and recipient-associated risk factors shown to adversely affect posttransplant liver graft function include donor age, gender, liver function test results, cytotoxic cross-match, length of intensive care unit stay, vasopressor use, preservation time, recipient Model for End-stage Liver Disease (MELD) score, renal insufficiency, and prolonged prothrombin time (PT).1e3 Unfortunately, these studies have not identified procurement techniquerelated factors that possibly contribute to early graft function after DDLT, as we attempted to evaluate in this study.
PATIENTS AND METHODS Between January 2008 and August 2012, we performed 45 consecutive adult DDLTs. One patient was excluded from this analysis due to early death from sepsis after transplantation. The remaining 44 patients were entered into this study.
From the Department of Surgery, Korea University College of Medicine, Seoul, Korea. Supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2011-0014581). Address reprint requests to Dong-Sik Kim, MD, PhD, Division of HBP Surgery and Liver Transplantation, Department of Surgery, Korea University College of Medicine, Inchon-ro 73, Seongbuk-gu, Seoul, Korea. E-mail: [email protected]
0041-1345/13/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.08.084
ª 2013 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2880
Transplantation Proceedings, 45, 2880e2885 (2013)
EFFECT OF DONOR PROCUREMENT TECHNIQUE
2881 Table 3. Evaluation of Operative Procedure
Table 1. Donor Characteristics
Donor age (y) Mean 50 <50 Donor Gender Male Female Donor liver fatty change Macro Micro Donor BMI Use of inotropics Used Not used Donorerecipient gender match Match Mismatch Graft GWBW (%)
Warm Group
Warm Group (n ¼ 23)
Cold Group (n ¼ 21)
P
48 11.5 7 (30.4%) 15 (69.6%)
46 14.25 8 (38.1%) 13 (61.9%)
.151 .138 .087
18 (78.3%) 5 (21.7%)
16 (76.2%) 5 (23.8%)
.273 .373
28% 32% 22.5 4.7
25% 41% 23.03 3.51
.479 .25 .921
20 (87%) 3 (13%)
21 (100%) 0 (0%)
.89 .91
11 (48%) 12 (52%) 2.27 1.6
10 (48%) 11 (52%) 2.34 1.8
.7 .67 .9
Abbreviations: BMI, body mass index; GWBW, graft weight per recipient’s body weight.
Graft total ischemic time (min) Operating time (min) Intraoperative blood transfusion (U) Red blood cells Fresh-frozen plasma Platelet concentrate Cryoprecipitate
406.8 188.08 589.05 121.13
37.36 38.23 19.14 0.55
20.94 25.89 11.89 1.63
Cold Group
P
441.86 129.22
.152
700 74.38
24 25 11 2
17.24 15.13 11.33 3.02
.784
.451 .185 .233 .423
A virus infection (n ¼ 8; 18.18%), metabolic liver cirrhosis (n ¼ 1; 2.27%), alcoholic liver cirrhosis (n ¼ 10; 22.73%), biliary cirrhosis (n ¼ 1; 2.27%), primary sclerosing cholangitis (n ¼ 1; 2.27%), or toxic hepatitis (n ¼ 3; 6.82%). We reviewed retrospectively age, gender, fatty liver change, body mass index (BMI), inotropic use, donorerecipient gender match, and graft weight per recipient body weight (GWBW). Preoperative recipient variables included age, gender, MELD score, primary diagnosis for liver transplantation, and human leukocyte antigen (HLA) cross-match. HLA typing and lymphocytotoxic crossmatching were performed retrospectively; they played no role in
DDLT was performed in recipients with the warm (n ¼ 23; 52%) or cold dissection technique (n ¼ 21; 48%). Indications for DDLT were hepatitis B virus-associated liver cirrhosis (n ¼ 17; 38.64%), hepatitis C virus-associated liver cirrhosis (n ¼ 3; 6.82%), hepatitis
Table 2. Perioperative Recipient Variables Warm Group (n ¼ 23)
Recipient age (y) Mean 50.96 10.29 65 1 (4.3%) <65 22 (95.7%) Recipient Gender Male 15 (65.2%) Female 8 (34.8%) Recipient MELD score Mean 27.43 7.12 20 5 (21.74%) <20 18 (78.26%) Recipient original disease Hepatitis B virus associated 9 (39%) liver cirrhosis Hepatitis C virus associated 3 (13%) liver cirrhosis Hepatitis A virus infection 2 (9%) Metabolic liver cirrhosis 0 (0%) Alcoholic liver cirrhosis 6 (26%) Biliary cirrhosis 0 (0%) PSC 0 (0%) Toxic hepatitis 3 (0%) HLA cross-match Positive 5 (21%) Negative 18 (79%)
Cold Group (n ¼ 21)
P
50 9.3 1 (4.8%) 20 (95.2%)
.342 .45 .895
10 (47.6%) 11 (52.4%)
.27 .13
23 9.9 .418 11 (52.38%) .032* 10 (47.62%) .013* 8 (38%)
.572
0 (0%)
.61
6 1 4 1 1 0
.725 .231 .428 .517 .854 .248
(29%) (5%) (19%) (5%) (5%) (0%)
4 (19%) 17 (81%)
.48 .51
Abbreviations: MELD, Model for End-stage Liver Disease; PSC, primary sclerosing cholangitis; HLA, human leukocyte antigen. *P < .05.
Fig 1. Postoperative changes in recipient serum aspartate aminotransferase (AST) levels. *P < .05.
2882
JUNG, KIM, YU ET AL
Fig 2. Postoperative changes in recipient serum alanine aminotransferase (ALT) levels. *P < .05.
Fig 3. Postoperative changes in recipient serum total bilirubin (T-bil) levels. *P < .05
recipient selection. The DDLT procedure was evaluated by graft ischemic time, operative time and intraoperative blood transfusions, with red blood cells, fresh-frozen plasma, platelet concentrate, or cryoprecipitate. Patient death or retransplantation within 90 days of transplantation was considered to be early postoperative graft loss; early postoperative graft function was determined by values of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (T-bil), and prothrombin time (PT). Results are expressed as mean value standard deviations. Frequencies of qualitative data and the presence of early graft loss in each group were determined using Pearson’s chi-square test. Comparison of the significance among the three groups was performed according to analysis of variance for donor and recipient quantitative data. Results were considered significant for P < .05. Multivariate analysis was performed using logistical regression technique.
searching for an aberrant right hepatic artery originating from the SMA. A Carrel patch of the aorta was excised, with care not to injure the origins of the renal arteries. Warm Dissection Technique (n ¼ 23). This approach differed from the cold dissection technique in that the right and left side mobilization and dissection of the liver hilum occurred before aortic cross-clamping and cannulation of the distal portal vein with a larger caliber catheter for quick portal perfusion. This preliminary dissection allowed more selective, rapid cooling of the liver compared with the cold dissection technique. These additional preparatory steps required 30 to 45 minutes. All hepatic allografts were perfused and preserved in histidinee tryptophaneketoglutarate solution, using the previously described technique. All patients received similar perioperative intensive care and immunosuppressant therapy, consisting of oral tacrolimus (Prograf, Astellas USA, Inc, Deerfield, IL), with daily adjustments according to drug blood levels of oral mycophenolate mofetil (Cellcept; Roche Pharmaceuticals, Nutley, NJ), and corticosteroids.
Donor Organ Procurement and Perioperative Management Cold Dissection Technique (n ¼ 21). This technique has been described in detail elsewhere.4,5 Briefly, both the terminal aorta and the inferior mesenteric vein were dissected to insert aortic and portal perfusion cannulae. The supraceliac abdominal aorta was encircled and cross-clamped. After cardiectomy, dissection of the liver hilum was performed in a bloodless field. Following identification in the retropancreatic portion, the right side of the superior mesenteric artery (SMA) was dissected toward the aorta,
RESULT Characteristics of Liver Donors and Recipients
The characteristics of liver donors are listed in Table 1. Mean donor age was 48 11.5 years in the warm versus 46 14.25 years in the cold group. The numbers of the donors
P
EFFECT OF DONOR PROCUREMENT TECHNIQUE
Cold Group
.843 .489 .002*
Fig 4. Postoperative changes in recipient prothrombin time (PT) levels. *P < .05.
Warm Group
100% 0% 9.52%
Table 4. Results After 90 Days Follow-up
91.30% 8.70% 47.83%
aged older than 50 years were 7 (30.4%) in the warm and 8 (38.1%) in the cold group. Use of inotropics were 20 (87%) in the warm and 21 (100%) in the cold group. Donore recipient gender mismatch was 12 (52%) in the warm and 11 (52%) in the cold group GWBW was 2.27 1.6% in the warm and 2.34 1.8% in the cold group. There were no differences in donor age, number of inotropics used, donorerecipient gender mismatch, or GWBW between the two groups. In addition, there were no significant differences in donor characteristics of gender, liver fatty change, or BMI. The perioperative recipient variables and evaluation of the DDLT procedure are listed in Table 2 and Table 3. There were no differences in peroperative parameters including recipient age, gender, mean MELD score, primary
*P < .05.
Graft survival Mortality Morbidity
Table 5. Multivariate Analysis for AST, ALT, T-bil, and Morbidity Rate AST (Postoperative Day 3) AST (Postoperative Day 5) ALT (Postoperative Day 5) T-bil (Postoperative Day 2) T-bil (Postoperative Day 3)
Donor age (50 vs <50 y) Donor sex (male vs female) Donor inotropics (used vs not used) Donorerecipient gender match (match vs mismatch) Recipient age (65 vs <65 y) Recipient sex (male vs female) Recipient MELD score (20 vs <20) HLA cross-match (positive vs negative) Dissection method (warm vs cold)
P
OR
95% CI
P
OR
95% CI
OR
95% CI
OR
95% CI
P
1.08 1.21 1.18 1.33
0.78e1.38 0.81e1.57 0.89e1.54 0.74e1.74
.69 .2 .25 .1
1.3 1.21 1.18 1.19
0.74e1.79 0.83e1.8 0.6e1.3 0.8e1.7
.6 .48 .561 .1
1.18 0.6e1.3 .561 1.19 0.8e1.7 .1 1.08 0.78e1.38 .69 1.21 0.81e1.57 .2
1.25 0.81e1.41 .19 1.19 0.83e2.13 .1 1.24 0.7e1.42 .07 1.25 0.81e1.41 .19
1.3 0.74e1.79 .65 1.21 0.83e1.8 .48 1.18 0.6e1.3 .561 1.22 0.88e1.54 .2
1.27 0.87e1.85 .32 1.25 0.91e1.77 .2 1.20 0.7e1.53 .67 1.17 0.89e1.51 .21
1.21 1.25 1.17 1.22 2.13
0.84e1.63 0.69e1.35 0.91e1.37 0.88e1.54 1.16e3.91
.15 .2 .52 .2 .018*
1.15 1.21 1.3 1.21 1.78
0.6e1.87 0.84e1.75 0.77e1.84 0.82e1.48 1.13e2.80
.41 .87 .39 .6 .042
1.19 0.8e1.7 .1 1.22 0.9e1.65 .78 1.25 0.78e1.67 .2 1.19 0.68e1.35 .87 2.13 1.14e3.25 .048*
1.19 1.08 1.21 1.18 2.21
1.25 1.08 1.21 1.08 1.92
1.24 1.19 1.25 1.15 3.8
0.83e2.13 0.78e1.38 0.81e1.57 0.89e1.54 1.01e3.51
P
.1 .69 .2 .25 .037*
OR
95% CI
0.69e1.35 0.78e1.38 0.81e1.57 0.78e1.38 1.1e3.21
P
Morbidity Rate
.2 .69 .2 .69 .021*
OR
95% CI
0.7e1.42 0.74e1.57 0.91e1.77 0.94e1.41 1.98e5.21
P
.07 .7 .29 .6 .001*
Abbreviations: MELD, Model for End-stage Liver Disease; HLA, human leukocyte antigen; OR, odds ratio; CI, confidence interval. * P < .05.
2883
2884
diagnosis for liver transplantation, and number of positive HLA mismatching. Among operative parameters, the mean amount of intraoperative transfusion of red blood cells, fresh-frozen plasma, or platelet concentrates were higher in the warm group albeit without a significant difference. Posttransplant Early Graft Function and Survival
The AST values in the warm group were significantly higher than those in the cold group on postoperative days 3 and 5 (Fig 1), but without significant differences at 1, 2, 4, 6, and 7 days. There appeared to be a for AST values in the warm group to be higher than those in the cold group on these days. In addition, the ALT values were higher in the warm than the cold group on postoperative days 4, 5, and 6 (Fig 2). Moreover, T-bil values in the warm group were higher than those in the cold group on postoperative days 2, 3, 4, 5, 6, and 7 (Fig 3). There were no differences in PT values (Fig 4). The mean of peak AST, ALT, and T-bil values in the warm group (1731.3 130.4 U/L, 689.5 35.7 U/L, and 8.59 mg/dL, respectively) were significantly higher than those in the cold group (1287.1 98.3 U/L, 530.2 27.1 U/L, and 5.72 mg/dL, respectively; P < .05). Morbidity was significantly higher among the warm group (postoperative bleeding (n ¼ 10) or bile leak (n ¼ 1)) than the cold group (cytomegalovirus infection [n ¼ 2]), whereas there were no differences in recipient mortality and graft survivals between the two groups (Table 4). To find significant factors affecting posttransplant early graft function and morbidity rate, we performed univariate and multivariate analyses. Univariate analysis showed dissection method (warm versus cold dissection) and MELD score higher than 20 were significant factors affecting posttransplant early graft function and morbidity. Dissection method was a significant factor affecting AST values on postoperative day 3 (P ¼ .04), day 5 (P ¼ .042), ALT value on postoperative day 4 (P ¼ .038), day 5 (P ¼ .001), and day 6 (P ¼ .04). T-bil value on postoperative days 2 to 7 and morbidity rates were also significantly (P < .05) influenced by the dissection method. MELD score higher than 20 was a significant factor for only AST values on postoperative days 3 and 4. Multivariate analysis revealed that only dissection method was a significant factor affecting posttransplant early graft function, such as AST on postoperative day 3 (P ¼ .018) and day 5 (P ¼ .042), ALT on postoperative day 5 (P ¼ .048), T-bil on postoperative days 2 (P ¼ .037) and day 3 (P ¼ .021), as well as morbidity rate (P ¼ .001; Table 5). DISCUSSION
The organ transplantation procedure can be subdivided into three phases: Procurement, cold storage, and implantation. Previous studies on the mechanism of graft injury leading to primary nonfunction or initial poor graft function have
JUNG, KIM, YU ET AL
focused mainly on the cold strorage5e8 and reperfusion phases.8e10 In this report, we examined procurement technique-related factors that possibly contribute to early graft function after DDLT. In experimental rat transplantation, Schemmer et al11 suggested that injury results from gentle manipulation of the liver during procurement. Manipulation dramatically, decreased survival with increased serum AST and liver necrosis postoperatively. Furthermore, proteolytic activity in the graft rinse solution was elevated after procurement and the microcirculation was disturbed by manipulation. These observations are important because manipulation of the liver during procurement cannot be completely prevented in clinical transplantation.10,11 Imagawa et al12,13 showed that warm dissection of the porta hepatis as well as extensive organ mobilization during combined pancreaseliver procurements may cause posttransplant liver dysfunction. Utilizing a rapid en bloc procurement technique with minimal warm dissection and division of the liver and pancreas ex vivo, they concluded that this technique decreased operative time and minimized procurement-related liver graft injury without compromising pancreas graft function. This study had limitations of its retrospective nature, however, it did reveal that rapid procurement with minimal manipulation and dissection of graft should be emphasized in the era of current expansion of marginal graft use. In conclusion, our present retrospective study, showed that a cold dissection technique for liver procurement with minimal manipulation of the organ by avoiding its mobilization achieved remarkably better early graft function and decreased morbidity compared with a warm dissection technique.
REFERENCES 1. Pruim J, van Woerden WF, Knol E, et al. Donor data in liver grafts with primary nonfunctiondA preliminary analysis by European liver registry. Transplant Proc. 1989;21:2383e2384. 2. Ploeg RJ, D’Alessandro AM, Knechtle SJ, et al. Risk factors for primary dysfunction after liver transplantationda multivariate analysis. Transplantation. 1993;55:807e813. 3. Marino IR, Doyle HR, Aldrighetti L, et al. Effect of donor age and sex on the outcome of liver transplantation. Hepatology. 1995;22:1754e1762. 4. Starzl TE, Miller C, Broznick B, et al. An improved technique for multiple organ harvesting. Surg Gynecol Obstet. 1987;165: 343e348. 5. Ploeg RJ, D’Alessandro AM, Knechtle SJ, et al. Risk factors for primary dysfunction after liver transplantation. Transplantation. 1993;55:807. 6. In S, Harvey PRC, Makowka L, et al. Markers of allograft viability in the rat. Transplantation. 1987;44:562. 7. Strasberg SM, Howard TK, Molmenti EP, et al. Selecting the donor liver: risk factors for poor function after orthotopic liver transplantation. Hepatology. 1994;20:829. 8. Caldwell-Kenkel JC, Currin RT, Tanaka Y, et al. Reperfusion injury to endothelial cells following cold ischemic storage of rat liver. Hepatology. 1987;10:292. 9. Marzi I, Zhong Z, Zimmermann FA, et al. Xanthine and hypoxanthine accumulation during storage may contribute to
EFFECT OF DONOR PROCUREMENT TECHNIQUE reperfusion injury following liver transplantation in the rat. Transplantation. 1989;21:1319. 10. Gao W, Currin RT, Lemasters JJ, et al. Reperfusion rather than storage injury predominates following long-term (48hrs) cold storage of graft in UW solution: studies with Carolina Rinse in transplanted rat liver. Transpl Int. 1992;5:S329. 11. Schemmer P, Schoonhoven R, Swenberg JA. Gentle in situ liver manipulation during organ harvest decreases
2885 survival after rat liver transplantation. Transplantation. 1998;65: 1015e1020. 12. Imagawa DK, Olthoff KM, Yersiz H, et al. Rapid en bloc technique for pancreas-liver procurement. Transplantation. 1996;61: 1605e1609. 13. Yanaga K, Tzakis AG, Starzl TE, et al. Personal experience with the procurement of 132 liver allografts. Transpl Int. 1989;2: 137e142.
S
EVERAL RETROSPECTIVE analyses of donor and recipient variables have sought to identify risk factors predictive of both patient and graft outcomes after deceased donor liver transplantation (DDLT). Donor- and recipient-associated risk factors shown to adversely affect posttransplant liver graft function include donor age, gender, liver function test results, cytotoxic cross-match, length of intensive care unit stay, vasopressor use, preservation time, recipient Model for End-stage Liver Disease (MELD) score, renal insufficiency, and prolonged prothrombin time (PT).1e3 Unfortunately, these studies have not identified procurement techniquerelated factors that possibly contribute to early graft function after DDLT, as we attempted to evaluate in this study.
PATIENTS AND METHODS Between January 2008 and August 2012, we performed 45 consecutive adult DDLTs. One patient was excluded from this analysis due to early death from sepsis after transplantation. The remaining 44 patients were entered into this study.
From the Department of Surgery, Korea University College of Medicine, Seoul, Korea. Supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2011-0014581). Address reprint requests to Dong-Sik Kim, MD, PhD, Division of HBP Surgery and Liver Transplantation, Department of Surgery, Korea University College of Medicine, Inchon-ro 73, Seongbuk-gu, Seoul, Korea. E-mail: [email protected]
0041-1345/13/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.08.084
ª 2013 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2880
Transplantation Proceedings, 45, 2880e2885 (2013)
EFFECT OF DONOR PROCUREMENT TECHNIQUE
2881 Table 3. Evaluation of Operative Procedure
Table 1. Donor Characteristics
Donor age (y) Mean 50 <50 Donor Gender Male Female Donor liver fatty change Macro Micro Donor BMI Use of inotropics Used Not used Donorerecipient gender match Match Mismatch Graft GWBW (%)
Warm Group
Warm Group (n ¼ 23)
Cold Group (n ¼ 21)
P
48 11.5 7 (30.4%) 15 (69.6%)
46 14.25 8 (38.1%) 13 (61.9%)
.151 .138 .087
18 (78.3%) 5 (21.7%)
16 (76.2%) 5 (23.8%)
.273 .373
28% 32% 22.5 4.7
25% 41% 23.03 3.51
.479 .25 .921
20 (87%) 3 (13%)
21 (100%) 0 (0%)
.89 .91
11 (48%) 12 (52%) 2.27 1.6
10 (48%) 11 (52%) 2.34 1.8
.7 .67 .9
Abbreviations: BMI, body mass index; GWBW, graft weight per recipient’s body weight.
Graft total ischemic time (min) Operating time (min) Intraoperative blood transfusion (U) Red blood cells Fresh-frozen plasma Platelet concentrate Cryoprecipitate
406.8 188.08 589.05 121.13
37.36 38.23 19.14 0.55
20.94 25.89 11.89 1.63
Cold Group
P
441.86 129.22
.152
700 74.38
24 25 11 2
17.24 15.13 11.33 3.02
.784
.451 .185 .233 .423
A virus infection (n ¼ 8; 18.18%), metabolic liver cirrhosis (n ¼ 1; 2.27%), alcoholic liver cirrhosis (n ¼ 10; 22.73%), biliary cirrhosis (n ¼ 1; 2.27%), primary sclerosing cholangitis (n ¼ 1; 2.27%), or toxic hepatitis (n ¼ 3; 6.82%). We reviewed retrospectively age, gender, fatty liver change, body mass index (BMI), inotropic use, donorerecipient gender match, and graft weight per recipient body weight (GWBW). Preoperative recipient variables included age, gender, MELD score, primary diagnosis for liver transplantation, and human leukocyte antigen (HLA) cross-match. HLA typing and lymphocytotoxic crossmatching were performed retrospectively; they played no role in
DDLT was performed in recipients with the warm (n ¼ 23; 52%) or cold dissection technique (n ¼ 21; 48%). Indications for DDLT were hepatitis B virus-associated liver cirrhosis (n ¼ 17; 38.64%), hepatitis C virus-associated liver cirrhosis (n ¼ 3; 6.82%), hepatitis
Table 2. Perioperative Recipient Variables Warm Group (n ¼ 23)
Recipient age (y) Mean 50.96 10.29 65 1 (4.3%) <65 22 (95.7%) Recipient Gender Male 15 (65.2%) Female 8 (34.8%) Recipient MELD score Mean 27.43 7.12 20 5 (21.74%) <20 18 (78.26%) Recipient original disease Hepatitis B virus associated 9 (39%) liver cirrhosis Hepatitis C virus associated 3 (13%) liver cirrhosis Hepatitis A virus infection 2 (9%) Metabolic liver cirrhosis 0 (0%) Alcoholic liver cirrhosis 6 (26%) Biliary cirrhosis 0 (0%) PSC 0 (0%) Toxic hepatitis 3 (0%) HLA cross-match Positive 5 (21%) Negative 18 (79%)
Cold Group (n ¼ 21)
P
50 9.3 1 (4.8%) 20 (95.2%)
.342 .45 .895
10 (47.6%) 11 (52.4%)
.27 .13
23 9.9 .418 11 (52.38%) .032* 10 (47.62%) .013* 8 (38%)
.572
0 (0%)
.61
6 1 4 1 1 0
.725 .231 .428 .517 .854 .248
(29%) (5%) (19%) (5%) (5%) (0%)
4 (19%) 17 (81%)
.48 .51
Abbreviations: MELD, Model for End-stage Liver Disease; PSC, primary sclerosing cholangitis; HLA, human leukocyte antigen. *P < .05.
Fig 1. Postoperative changes in recipient serum aspartate aminotransferase (AST) levels. *P < .05.
2882
JUNG, KIM, YU ET AL
Fig 2. Postoperative changes in recipient serum alanine aminotransferase (ALT) levels. *P < .05.
Fig 3. Postoperative changes in recipient serum total bilirubin (T-bil) levels. *P < .05
recipient selection. The DDLT procedure was evaluated by graft ischemic time, operative time and intraoperative blood transfusions, with red blood cells, fresh-frozen plasma, platelet concentrate, or cryoprecipitate. Patient death or retransplantation within 90 days of transplantation was considered to be early postoperative graft loss; early postoperative graft function was determined by values of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (T-bil), and prothrombin time (PT). Results are expressed as mean value standard deviations. Frequencies of qualitative data and the presence of early graft loss in each group were determined using Pearson’s chi-square test. Comparison of the significance among the three groups was performed according to analysis of variance for donor and recipient quantitative data. Results were considered significant for P < .05. Multivariate analysis was performed using logistical regression technique.
searching for an aberrant right hepatic artery originating from the SMA. A Carrel patch of the aorta was excised, with care not to injure the origins of the renal arteries. Warm Dissection Technique (n ¼ 23). This approach differed from the cold dissection technique in that the right and left side mobilization and dissection of the liver hilum occurred before aortic cross-clamping and cannulation of the distal portal vein with a larger caliber catheter for quick portal perfusion. This preliminary dissection allowed more selective, rapid cooling of the liver compared with the cold dissection technique. These additional preparatory steps required 30 to 45 minutes. All hepatic allografts were perfused and preserved in histidinee tryptophaneketoglutarate solution, using the previously described technique. All patients received similar perioperative intensive care and immunosuppressant therapy, consisting of oral tacrolimus (Prograf, Astellas USA, Inc, Deerfield, IL), with daily adjustments according to drug blood levels of oral mycophenolate mofetil (Cellcept; Roche Pharmaceuticals, Nutley, NJ), and corticosteroids.
Donor Organ Procurement and Perioperative Management Cold Dissection Technique (n ¼ 21). This technique has been described in detail elsewhere.4,5 Briefly, both the terminal aorta and the inferior mesenteric vein were dissected to insert aortic and portal perfusion cannulae. The supraceliac abdominal aorta was encircled and cross-clamped. After cardiectomy, dissection of the liver hilum was performed in a bloodless field. Following identification in the retropancreatic portion, the right side of the superior mesenteric artery (SMA) was dissected toward the aorta,
RESULT Characteristics of Liver Donors and Recipients
The characteristics of liver donors are listed in Table 1. Mean donor age was 48 11.5 years in the warm versus 46 14.25 years in the cold group. The numbers of the donors
P
EFFECT OF DONOR PROCUREMENT TECHNIQUE
Cold Group
.843 .489 .002*
Fig 4. Postoperative changes in recipient prothrombin time (PT) levels. *P < .05.
Warm Group
100% 0% 9.52%
Table 4. Results After 90 Days Follow-up
91.30% 8.70% 47.83%
aged older than 50 years were 7 (30.4%) in the warm and 8 (38.1%) in the cold group. Use of inotropics were 20 (87%) in the warm and 21 (100%) in the cold group. Donore recipient gender mismatch was 12 (52%) in the warm and 11 (52%) in the cold group GWBW was 2.27 1.6% in the warm and 2.34 1.8% in the cold group. There were no differences in donor age, number of inotropics used, donorerecipient gender mismatch, or GWBW between the two groups. In addition, there were no significant differences in donor characteristics of gender, liver fatty change, or BMI. The perioperative recipient variables and evaluation of the DDLT procedure are listed in Table 2 and Table 3. There were no differences in peroperative parameters including recipient age, gender, mean MELD score, primary
*P < .05.
Graft survival Mortality Morbidity
Table 5. Multivariate Analysis for AST, ALT, T-bil, and Morbidity Rate AST (Postoperative Day 3) AST (Postoperative Day 5) ALT (Postoperative Day 5) T-bil (Postoperative Day 2) T-bil (Postoperative Day 3)
Donor age (50 vs <50 y) Donor sex (male vs female) Donor inotropics (used vs not used) Donorerecipient gender match (match vs mismatch) Recipient age (65 vs <65 y) Recipient sex (male vs female) Recipient MELD score (20 vs <20) HLA cross-match (positive vs negative) Dissection method (warm vs cold)
P
OR
95% CI
P
OR
95% CI
OR
95% CI
OR
95% CI
P
1.08 1.21 1.18 1.33
0.78e1.38 0.81e1.57 0.89e1.54 0.74e1.74
.69 .2 .25 .1
1.3 1.21 1.18 1.19
0.74e1.79 0.83e1.8 0.6e1.3 0.8e1.7
.6 .48 .561 .1
1.18 0.6e1.3 .561 1.19 0.8e1.7 .1 1.08 0.78e1.38 .69 1.21 0.81e1.57 .2
1.25 0.81e1.41 .19 1.19 0.83e2.13 .1 1.24 0.7e1.42 .07 1.25 0.81e1.41 .19
1.3 0.74e1.79 .65 1.21 0.83e1.8 .48 1.18 0.6e1.3 .561 1.22 0.88e1.54 .2
1.27 0.87e1.85 .32 1.25 0.91e1.77 .2 1.20 0.7e1.53 .67 1.17 0.89e1.51 .21
1.21 1.25 1.17 1.22 2.13
0.84e1.63 0.69e1.35 0.91e1.37 0.88e1.54 1.16e3.91
.15 .2 .52 .2 .018*
1.15 1.21 1.3 1.21 1.78
0.6e1.87 0.84e1.75 0.77e1.84 0.82e1.48 1.13e2.80
.41 .87 .39 .6 .042
1.19 0.8e1.7 .1 1.22 0.9e1.65 .78 1.25 0.78e1.67 .2 1.19 0.68e1.35 .87 2.13 1.14e3.25 .048*
1.19 1.08 1.21 1.18 2.21
1.25 1.08 1.21 1.08 1.92
1.24 1.19 1.25 1.15 3.8
0.83e2.13 0.78e1.38 0.81e1.57 0.89e1.54 1.01e3.51
P
.1 .69 .2 .25 .037*
OR
95% CI
0.69e1.35 0.78e1.38 0.81e1.57 0.78e1.38 1.1e3.21
P
Morbidity Rate
.2 .69 .2 .69 .021*
OR
95% CI
0.7e1.42 0.74e1.57 0.91e1.77 0.94e1.41 1.98e5.21
P
.07 .7 .29 .6 .001*
Abbreviations: MELD, Model for End-stage Liver Disease; HLA, human leukocyte antigen; OR, odds ratio; CI, confidence interval. * P < .05.
2883
2884
diagnosis for liver transplantation, and number of positive HLA mismatching. Among operative parameters, the mean amount of intraoperative transfusion of red blood cells, fresh-frozen plasma, or platelet concentrates were higher in the warm group albeit without a significant difference. Posttransplant Early Graft Function and Survival
The AST values in the warm group were significantly higher than those in the cold group on postoperative days 3 and 5 (Fig 1), but without significant differences at 1, 2, 4, 6, and 7 days. There appeared to be a for AST values in the warm group to be higher than those in the cold group on these days. In addition, the ALT values were higher in the warm than the cold group on postoperative days 4, 5, and 6 (Fig 2). Moreover, T-bil values in the warm group were higher than those in the cold group on postoperative days 2, 3, 4, 5, 6, and 7 (Fig 3). There were no differences in PT values (Fig 4). The mean of peak AST, ALT, and T-bil values in the warm group (1731.3 130.4 U/L, 689.5 35.7 U/L, and 8.59 mg/dL, respectively) were significantly higher than those in the cold group (1287.1 98.3 U/L, 530.2 27.1 U/L, and 5.72 mg/dL, respectively; P < .05). Morbidity was significantly higher among the warm group (postoperative bleeding (n ¼ 10) or bile leak (n ¼ 1)) than the cold group (cytomegalovirus infection [n ¼ 2]), whereas there were no differences in recipient mortality and graft survivals between the two groups (Table 4). To find significant factors affecting posttransplant early graft function and morbidity rate, we performed univariate and multivariate analyses. Univariate analysis showed dissection method (warm versus cold dissection) and MELD score higher than 20 were significant factors affecting posttransplant early graft function and morbidity. Dissection method was a significant factor affecting AST values on postoperative day 3 (P ¼ .04), day 5 (P ¼ .042), ALT value on postoperative day 4 (P ¼ .038), day 5 (P ¼ .001), and day 6 (P ¼ .04). T-bil value on postoperative days 2 to 7 and morbidity rates were also significantly (P < .05) influenced by the dissection method. MELD score higher than 20 was a significant factor for only AST values on postoperative days 3 and 4. Multivariate analysis revealed that only dissection method was a significant factor affecting posttransplant early graft function, such as AST on postoperative day 3 (P ¼ .018) and day 5 (P ¼ .042), ALT on postoperative day 5 (P ¼ .048), T-bil on postoperative days 2 (P ¼ .037) and day 3 (P ¼ .021), as well as morbidity rate (P ¼ .001; Table 5). DISCUSSION
The organ transplantation procedure can be subdivided into three phases: Procurement, cold storage, and implantation. Previous studies on the mechanism of graft injury leading to primary nonfunction or initial poor graft function have
JUNG, KIM, YU ET AL
focused mainly on the cold strorage5e8 and reperfusion phases.8e10 In this report, we examined procurement technique-related factors that possibly contribute to early graft function after DDLT. In experimental rat transplantation, Schemmer et al11 suggested that injury results from gentle manipulation of the liver during procurement. Manipulation dramatically, decreased survival with increased serum AST and liver necrosis postoperatively. Furthermore, proteolytic activity in the graft rinse solution was elevated after procurement and the microcirculation was disturbed by manipulation. These observations are important because manipulation of the liver during procurement cannot be completely prevented in clinical transplantation.10,11 Imagawa et al12,13 showed that warm dissection of the porta hepatis as well as extensive organ mobilization during combined pancreaseliver procurements may cause posttransplant liver dysfunction. Utilizing a rapid en bloc procurement technique with minimal warm dissection and division of the liver and pancreas ex vivo, they concluded that this technique decreased operative time and minimized procurement-related liver graft injury without compromising pancreas graft function. This study had limitations of its retrospective nature, however, it did reveal that rapid procurement with minimal manipulation and dissection of graft should be emphasized in the era of current expansion of marginal graft use. In conclusion, our present retrospective study, showed that a cold dissection technique for liver procurement with minimal manipulation of the organ by avoiding its mobilization achieved remarkably better early graft function and decreased morbidity compared with a warm dissection technique.
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EFFECT OF DONOR PROCUREMENT TECHNIQUE reperfusion injury following liver transplantation in the rat. Transplantation. 1989;21:1319. 10. Gao W, Currin RT, Lemasters JJ, et al. Reperfusion rather than storage injury predominates following long-term (48hrs) cold storage of graft in UW solution: studies with Carolina Rinse in transplanted rat liver. Transpl Int. 1992;5:S329. 11. Schemmer P, Schoonhoven R, Swenberg JA. Gentle in situ liver manipulation during organ harvest decreases
2885 survival after rat liver transplantation. Transplantation. 1998;65: 1015e1020. 12. Imagawa DK, Olthoff KM, Yersiz H, et al. Rapid en bloc technique for pancreas-liver procurement. Transplantation. 1996;61: 1605e1609. 13. Yanaga K, Tzakis AG, Starzl TE, et al. Personal experience with the procurement of 132 liver allografts. Transpl Int. 1989;2: 137e142.