Pancreas Preservation With Viaspan, Celsior, and Custodiol Solutions: An Initial Experience M.C. Montiel-Casadoa,*, J.A. Pérez-Dagaa, J.A. Blanco-Elenaa, J.M. Aranda-Narváeza, B. Sánchez-Péreza, M. Cabello-Díazb, P. Ruiz-Estebanb, F.J. León-Díaza, C. Gutiérrez-de la Fuenteb, and J. Santoyo-Santoyoa a Department of Digestive Surgery and Transplantation, Hospital Regional Universitario Carlos Haya, Málaga, Spain; and bDepartment of Nephrology, Hospital Regional Universitario Carlos Haya, Málaga, Spain
ABSTRACT Background. There is still controversy about which preservation solution in pancreas transplantation could be the best. The aim of this study was to analyze our initial experience with Custodiol solution (CuS) compared with Viaspan solution (VS) and Celsior solution (CS) in pancreas transplantation. Methods. A retrospective study included 94 consecutive pancreatic transplants, from 2007 until 2015. We compared 3 groups, depending on preservation solution: Viaspan (n ¼ 41), Celsior (n ¼ 40), or Custodiol (n ¼ 13). The primary end point was patient and pancreas survival at 1 year after pancreas transplantation. Results. The recipient and donor characteristics were similar except in cold ischemia time; it was higher with Celsior. No differences were found in postoperative complications and pancreas graft function at 3 months, 6 months, and 1 year (glucose, HbA1c, C-peptide, creatinine). The pancreas and patient survival at 1 year was comparable (pancreas survival: VS, 80%; CS, 90%; CuS, 92%; log-rank, 0.875; and patient survival: VS, 92%; CS, 97%; CuS, 100%; log-rank, 0.9). Conclusions. In our institution, the Custodiol solution in pancreas transplantation presented similar outcomes in terms of postoperative complications, pancreas graft function, and 1-year survival.
T
HE WISCONSIN solution (WS) has been virtually the standard for abdominal organ preservation since 1987, when it was designed for pancreas graft preservation. Nonetheless, Custodiol solution (CuS), after being approved for renal graft preservation, rapidly replaced WS in many centers because of lower costs, reduced risk of reperfussion hyperkaliemia, and better cell perfusion due to lower viscosity [1]. The use of CuS in pancreatic transplantation has been recently considered. Most of the clinical studies aiming to compare pancreas transplantation preservation solutions report equivalent patient and graft survival for all the three solutions. Some studies suggest that in the case of prolonged cold ischemia, the usage of Custodiol could be detrimental. Recent studies find an ingreased risk of allograft pancreatitis and venous thrombosis for histidine-tryptofanketoglutarate (HTK)-preserved pancreatic grafts [2].
0041-1345/16 http://dx.doi.org/10.1016/j.transproceed.2016.07.042
3040
Current available evidence is still partial and insufficent, limited because of the small size of the series reported. This study analyzes the initial experience with Custodiol for the preservation of pancreatic allografts in our institution. METHODS We conducted an observational study based on a prospectively collected database comprising 94 consecutive pancreas transplants between January 2007 and October 2015. We compared 3 preservation solutions: Viaspan solution (VS), Celsior solution (CS) and CuS. The primary study end point was *Address correspondence to María Custodia Montiel-Casado, Hospital Regional Universitario Carlos Haya, Department of Digestive Surgery and Transplantation, Av. Carlos Haya s/n, CP 29010, Málaga, Spain. E-mail:
[email protected] ª 2016 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 48, 3040e3042 (2016)
PANCREAS PRESERVATION
3041
both patient and pancreatic graft survival at 3, 6, and 12 months. All grafts requiring <0.5 IU/kg of exogenous insulin for the maintenance of euglycemia and presenting a positive C-peptide (>.05) were considered as functional. Other secondary end points were related to postoperative complications. Serum creatinine, serum glucose, HbA1c, and C-peptide were monitored at 3, 6, and 12 months after transplant. Statistical analysis was performed with the use of SPSS 17.0. Variables are expressed as means and standard deviations or as median and interquartile ranges for those with an asymmetric distribution. The Fisher exact test was used for frequencies. Student or ANOVA tests were used for quantitative variables, and MannWhitney U or Kruskal-Wallis tests were used for variables with asymmetric distribution. Kaplan-Meier curves and Cox regression were used to analyze the influence of the preservative solution on long-term outcomes. The statistical significance threshold was set as P < .05 for every two-tailed hypothesis.
Amylase 1dy Pancreatitis Pancreatic fistula Intestinal fistula Thrombosis Digestive hemorrhage Intra-abdominal Hemorrhage Re-intervention Transplantectomy Acute rejection Humoral rejection Dindo-Clavien IIIb-IV
RESULTS Demographic Profile
Pancreas Graft Function
From January 2007 to October 2015, 94 consecutive pancreas transplantations were performed in our center. Forty-one were perfused with Viaspan solution (VS), 40 with CS, and 13 with CS. The three groups had similar characteristics regarding donor and recipient (Table 1). The cold ischemia time (CIT) was higher with CS (VS 643 vs CS 750 vs CuS 606; P ¼ .043). The simultaneous pancreaskidney transplant was performed in comparable rates in all groups. Re-transplantation was more frequent in the Celsior group, without significant difference (Table 2). Postoperative Complications
Serum amylase level at the first postoperative day was similar between groups. Pancreatitis was diagnosed more commonly with Celsior solution. There were no differences in postoperative events such as thrombosis, pancreatitis, pancreatic or intestinal fistula, need for re-operation or retransplantation, and acute cellular or humoral rejection. Intra-abdominal hemorrhage was identified more often in the CuS group. Finally, major complications (grade IIIb and IV with Dindo-Clavien score) also had similar distribution. Table 1. Donor, Recipient, and Graft Characteristics
Donor age Donor body mass index Male donor Trauma cause death CIT Recipient age Recipient weight Evolution diabetes Male recipient SPK Re-transplant
Viaspan n ¼ 41
Celsior n ¼ 40
Custodiol n ¼ 13
P
31 24 23 (56) 21 (51) 643 39 68 22 (78) 36 (88) 4 (10)
32 24 18 (45) 14 (35) 750 42 69 28 (63) 32 (80) 7 (18)
32 24 6 (46) 5 (39) 606 40 62 26 (46) 11 (85) 2 (15)
NS NS NS NS .043 NS NS NS NS NS NS
Continuous variables, mean; categorical variables, absolute value (%). CIT, cold ischemia time; SPK, simultaneous pancreas kidney transplantation.
Table 2. Postoperative Complications Viaspan
Celsior
Custodiol
P
185 3 (7) 0 0 7 (17) 5 (13) 1 (2) 7 (17) 5 (12) 1 (2) 1 (2) 8 (20)
188 9 (22) 1 (3) 2 (5) 6 (15) 7 (18) 3 (8) 8 (20) 4 (10) 4 (10) 1 (2) 8 (20)
253 1 (8) 1 (8) 0 1 (8) 2 (15) 4 (30) 3 (23) 1 (8) 0 0 3 (23)
NS NS NS NS NS NS 0.012 NS NS NS NS NS
Regarding hospital and intensive care stay, the three groups presented comparable results.
To assess pancreas graft function, fasting blood glucose, HbA1c, C-peptide, and creatinine levels were registered at 3 months, 6 months, and 1 year after transplant. No difference were idetified between the groups except in fasting blood glucose at 1 year [glucose at 3 months: VS 88 (9), CS 87 (18), CuS 88 (6); at 6 months: VS 90 (11), CS 91 (15), CuS 86 (11); at 1 year: VS 102 (38), CS 85 (12), CuS 92 (12); HbA1c at 3 months: VS 5.5 (0.2), CS 5,6 (0.6), CuS 5,8 (1); at 6 months: VS 5.5 (0.8), CS 5.5 (0.7), CuS 5.5 (0.4); at 1 year: VS 5.6 (0.6), CS 5.4 (0.6), CuS 5.4 (0.6); C-peptide at 3 months: VS 4.2 (2.1), CS 3.6 (2.2), CuS 3.5 (0.8), C-peptide at 6 months: VS 3.2, CS 3.1, Cus 2,4 ; C-peptide at 1 year: VS 3.1, CS 3.1 and Cus 2.8]. Patient and Pancreas Survival
The median follow-up was different among the three solutions (VS 65, CS 34, and CuS 13 months) because of the time when were administered. No difference was detected in pancreas and patient survival after 1 year of follow-up (1 year pancreas survival: VS 80%, CS 90%, and CuS 92%; log-rank, 0.875; and 1 year patient survival: VS 92%, CS 97%, and CuS 100%; log-rank, 0.9). In the case of Viaspan and Celsior with more follow-up, the 2-year pancreas survival was also comparable (VS 76% vs CS 78%). In the VS, four of the five deaths in the follow-up were with functioning pancreas graft. Ten pancreas grafts were lost; the main reasons were thrombosis and cronic rejection in the early and late postoperative periods, respectively. In the Celsior group, only one patient died with a functioning pancreas graft. Seven pancreas grafts were lost in a similar way to VS. No deaths were found with CuS, and only one pancreas graft was lost due to thrombosis in the early post-transplant period. DISCUSSION
Nowadays, VS is still considered the gold-standard preservation solution in pancreas transplantation. In the past
3042
decade, three randomize, controlled trials have been published to achieve better outcomes with others solutions such as Celsior or Custodiol in donation after brain deathe pancreas transplantation [1]. In 2004, Boggi [3] reported similar safety profiles within the range of cold ischemia time between CS and WS after pancreas transplantation at 1 year. In addition, Nicoluzzi compared 15 patients in each group, and no differences were found in edema, pancreatitis, or thrombosis rate at 6 months [4]. Schneeberger published the only randomized, controlled study comparing HTK (equivalent to Custodiol) and WS, but it had to be stopped by the steering committee. The numbers of patients in both arms were not equivalent, 27 versus 41, and the follow-up was only 6 months [5]. In a recent retrospective review from Indiana University Hospital, 258 pancreas transplants were preserved with HTK and 50 with University of Wisconsin. They concluded that in the context of lowto-moderate flush volume and short CIT (10 hours), no increased incidence of allograft pancreatitis or graft loss was observed [6]. Other retrospective studies have reported similar data, but the majority were small and with short follow-up (6 months or 1 year). In our center, the CuS was introduced by local transplant coordination in 2013. With caution at first, equivalent results were observed with this group compared with Viaspan and Celsior arms. With this study, we managed to confirm comparable results in terms of 1-year patient and pancreas graft survivals among the three arms. The graft function was also analysed by use of fasting blood glucose, HbA1c, C-peptide, and creatinine levels at 3 months, 6 months, and 1 year, as in the German study, with no clinical differences. On the other hand, others centers have published worse outcomes with HTK solution compared with VS. In this way, in 2008 Alonso et al [7] reviewed their experience with 16 HTK versus 81 University of Wisconsin solution. They found in pancreata flushed with HTK higher incidence of postoperative complications, including graft pancreatitis, use of octreotide, and a decreased rate of insulin independence at hospital discharge. A UNOS database analysis from 2004 to 2008 published that after adjusting for other recipient, donor, graft, and transplant center factors, HTK solution was independently associated with an increased risk of pancreas graft loss, especially in pancreas allografts with CIT 12 hours and a 1.54-fold-higher odds of early (<30 days) pancreas loss as compared with University of Wisconsin solution [2]. In contrast, our study with 13 cases in CuS had no increase of postoperative complications related to pancreas graft.
MONTIEL-CASADO, PÉREZ-DAGA, BLANCO-ELENA ET AL
The main limitation of our study was that it was a retrospective analysis in which the different solutions were administered in different periods (VS was used mostly from 2007 to 2009, CS from 2010 to 2012, and CuS from 2013 to 2015). Also, the Custodiol group comprised only 13 cases (versus 41 VS and 40 CS). The changes in the preservation solution were due to the local transplant logistics. However, the three arms had similar characteristics in terms of donor, recipient, and transplantation. The CIT was higher in CS (750 minutes), but all the groups were in accepted ranges of CIT. Two protocols of thromboembolic prophylaxis were used because of the rate of venous thrombosis during the first period. For this reason, intra-abdominal hemorraghe was more common in CuS. A decrease in pancreas graft thrombosis is being achieved with this strategy; however, more effort must be made to improve the hemorrhagic events. CONCLUSIONS
In the literature, pancreas transplantation outcomes with HTK preservation solution are still controversial. In our initial experience, no differences were observed in terms of postoperative complications, pancreas graft function, and pancreas and patient survival at 1-year follow-up. Randomized, controlled trials should be performed to clarify this issue. REFERENCES [1] Parsons RF, Guarrera JV. Preservations solutions for static cold storage of abdominal allografts: which is best? Curr Opin Organ Transplant 2014;19:100e17. [2] Stewart ZA, Cameron AM, Singer AL, et al. Histidinetryptofan-ketoglutarate (HTK) is associated with reduced graft survival in pancreas transplantation. Am J Transplant 2009;9:217e21. [3] Boggi U, Coletti L, Vistoli F, et al. Pancreas preservation with University of Wisconsin and Celsior Solutions. Transplant Proc 2004;36:563e5. [4] Nicoluzzi J, Macri M, Fukushima J, et al. Celsior versus Wisconsin solution in pancreas transplantation. Transplant Proc 2008;40:3305e7. [5] Schneeberger S, Biebl M, Steurer W, et al. A prospective randomized multicenter trial comparing histidine-tryptofaneketoglutarate versus University of Wisconsin perfusion solution in clinical pancreas transplantation. Transplant Int 2009;22:217e24. [6] Fridell JA, Mangus RS, Powelson JA. Histidine-tryptofaneketoglutarate for pancreas allograft preservation: The Indiana University Experience. Am J Transplant 2010;10:1284e9. [7] Alonso D, Dunn TB, Rigley T, et al. Increased pancreatitis in allografts flushed with histidine-tryptofane-ketoglutarate solution: A cautionaty tale. Am J Transplant 2008;8:1942e5.