Liver grafts can be preserved overnight - aasld

0 downloads 0 Views 440KB Size Report
hours to avoid ischemic-type biliary complica- ... storage periods of up to 24 hours with good short- .... month (7.6% in group A and 12.2% in group B) was.
Liver Grafts Can B e Preserved Overnight Jean Vix, Philippe Compagnon,Jean-Paul Beller, Daniel Jaech, Philippe Wozf, and Karim Boudjema The introduction of University of Wisconsin solution has made liver transplantation a semi-elective procedure. However, many studies have suggested that cold storage must not exceed 12 hours to avoid ischemic-type biliary complications, to reduce the incidence of primary nonfunction and to improve graft and patient survival. The aim of this study was to compare the function of livers transplanted as soon as possible after the liver was harvested and those preserved overnight. Over a 42-month period, we studied 133 elective orthotopic liver transplantation procedures. When cold ischemia started after 6 PM, patients underwent transplantation the following morning (group A), whereas the remainder underwent transplantation immediately (group B). Cold ischemia lasted 13.7 hours and 9.5 hours in groups A and B, respectively (P < .001). The two groups were comparable in terms of initial and

late biochemical liver function, the rates of primary nonfunction (6.5% in group A, 6.8% in group B), acute rejection (45.6% in group A, 45.7% in group B), and vascular and infectious complications. No ischemic-typebiliary complicationswere observed. Graft and patient survival were similar in both groups (72.4% Y 75.4% and 72.9% v 75.8% in groups A and B, respectively). These results suggest that having taken a cut off at 6 PM to divide the groups into those that underwent transplantation consecutivelyand those deferredto the morning, the difference between the two groups in terms of storage is relatively modest. Elective liver transplantation can be performed after overnight graft storage without increasing short-term or long-term morbidity or mortality rates. Copyright o 1996 by the American Association for the Study of Liver Diseases

he introduction of University of Wisconsin (UW) solution has extended the maximum cold storage period for liver grafts making orthotopic liver transplantation (OLT) a semielective procedure. Kalayoglu et all and Todo et alz have reported cold storage periods of up to 24 hours with good shortterm clinical results. Since January 1990, we have performed OLT on the following day at 8 AM, when the graft IS clamped after 6 PM. Recently, Sanchez-Urdazpal et a13 and Sankary et a14 found a close link between the occurrence of ischemic-type biliary complications and extended preservation, and Adam et a15 suggested that prolongation of the cold ischemia time (CIT) was a risk factor for primary nonfunction (PNF) and graft failure at 1 month. Morbidity rates appeared to increase significantly when the cold storage period exceeded 12 or 13 hours in these three studies. In the light of these findings, we reviewed the results of our transplantation policy.

duodenopancreatrectomies, 1 cluster operation). The remaining 133 elective procedures form the basis of this analysis. Ninety-two procedures were performed after overnight storage of a graft harvested after 6 PM. Transplantation started at 8 AM. In the remaining 41 cases, the patlents underwent transplantation without delay, because the grafts were hatvested before 6 PM. The groups were compared for donor age, length of stay in the intensive care unit (ICU), and liver function6 (Table 1) Finally, the surgeon decided whether or not to use the graft on the basis of its gross aspect. Cirrhotic, tumorous, and steatotic livers (greater than 30% on frozen biopsy sections) were discarded.' Using the standard harvest technique,8 the donor liver was flushed in situ with UW solution at 4°C (3 L via the aorta, 2 L via the inferior mesenteric vein) and again after removal (700 mL of UW solution via the portal vein, 250 mL via the hepatic artery). The common bile duct and biliary tree were flushed with 5 0 mL of UW solution at 4°C using a nati-ow-gauge needle to flush out residual bile. The liver was then immersed in UW solution and stored in a sterile plastic bag at 4°C Prospective lymphocytotoxic cross-matching was not performed. The standard replacement

T

Patients and Methods From January 1990 to June 1993, we performed 197 OLTs. Emergency cases (23 for fulminant hepatitis, 19 for retransplantation) were excluded from the analysis. We also excluded procedures in which technical considerations might have complicated the interpretation of the results (18 reduced grafts, 3 combined

From the Centre de Chirurgie ViscPrale et de Tran~plantation, H6pitul Universitaire de Huutepierre, 67098 Strasbourg Cedex France. Address reprint requests to: Kurim Boudjetna, MD, Director, Liver Transplantation Program, Centre de Chirurgie ViscCrale et de Trunsplantation, HGpital Universitaire de Hautepiewe, 67098 Strasbourg Cedex France. Copyright 0 1996 by the American Ahsociation for the Study of Liver Diseases 1074-3022i96/0202-000783.O O i O

Liver Transplantationand S u r g q , Vol2, N o 2 (March), 1996:pp 105-110

105

106

Vix et al

Table 1. Donor Characteristics

Age (Yr) Male/female Length of ICU stay (h) Liver function AST (IU/L) ALT (IU/L) GammaGT (IU/L) PT (% of normal value) Bilirubin (pmol/L)

Group A

Group B

(N = 92)

(N = 41)

Table 2. Recipient Characteristics, and Transplantation Outcome Risk Factors

P

Group A

Group B

30.6 + 1.2 32.5 ? 1.96 ns 65/27 26/15 ns 41 2 5 45 5 6 ns

(N = 92)

(N = 41)

P

4 8 2 10 21-68 56/36

5 0 + 10 18-67 27/14

ns ns ns

89

3 0

39 1 1

ns ns ns

7 14 1 10

2 9 0 6

ns ns ns ns

0 0 3 4 17 35 22

0

ns ns ns ns ns ns ns

45.5 k 4.4 52.2 t 6.7 30.2 -c 3.9 35.3 t 7.5 19.6 t 2.0 18.8 + 2.6 65.2 ? 2.2 59.8 5 4.2 14.2 -c 1.3 22.6 2 4.7

Recipient Age (yr) * Range Male/female ABO match Identical Compatible Incompatible CMV Donor+ /recipientDonor+/recipient+ Donor age > 60 yr Recipient age > 60 yr HIA A B DR mismatch 0

ns ns ns ns ns

NOTE. Values are means ? SD. Abbreviations: ICU, intensive care unit; gammaGT, gamma glutamyl transpeptidase; PT, prothrombin time.

technique was used. Orthotopic implantation and veno-venous bypass were always used. While caval anastomosis was being performed, before revascularization, the liver was rinsed through the portal vein with 1 L of cold (4°C) 4% albumin solution. The biliary reconstruction method was either choledocho-choledochostomy (with or without a T-tube) or Roux-en-Y choledochojejunostomy. All patients received immunosuppression consisting of steroids (Prednisolone), azathioprine (2mg/kg), and cyclosporine (day I , 6 mg/kg; day 2, adjusted to achieve blood levels between 300 and 400 ng/mL; monoclonal radioimmunoassay). The two groups were compared for the followmg: (1) the operating time and total blood product administration, ( 2 ) asparrate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (tBil), and factor V (FV) levels 1 hour after reperfusion, then every day during the first week, (3) the monoethylglycinex)?idide (MEGX) test and cyclosporine blood levels on day 1 and day 2, (4) the incidence of PNF, defined as a combination of elevated liver enzyme activity ( > 2,000 IU/L), absence of bile production, coagulopathy and encephalopathy, (5) the frequency of vascular and biliary complications, ( 6 ) the incidence of bacterial, viral, or fungal infections requiring intravenous treatment, (7) the incidence of acute rejection episodes, defined as a combination of biochemical dysfunction and specific histological abnormalitie~.~ Acute rejection episodes were treated with bolus steroids (methylprednisolone 500 mg/d for 3 days). Monoclonal antilymphocyte antibodies (Om31 were used to treat steroid-resistant rejection episodes., (8) liver function tests I , 6, and 12 months after transplantation, and (9) graft and patient survival. Follow-up ranged from 1.5 to 5 years. Data were analysed using the x2 test and analysis ofvariance. Graft and patient survival were determined using Kaplan-Meier analyses and compared by means of the log-rank test. P values of less than .05 were considered significant.

0 2 5 11 11 9

*Mean ? SD. Abbreviations: ABO, blood group; CMV, anti-CMV immunoglobulin G.

Results As shown in Table 2, the recipients in the two groups were comparable at baseline. The indications for transplantation are shown in Table 3. The CIT was 13.7 -C 0.3 hours (range, 6.7 to 25 hours) in group A, and 9.5 -+ 0.5 hours (range 5-19.5) in group B (P < .0001). The operating time was 7.8 0.2 hours (range 4.5-14) in group A, and

I

I

Table 3. Indications for Transplantation Group A, Group 6, N=92

N=41

yo)

yo)

P

34 (83) 4 (1 0) 1 (2) 2 (5)

ns ns ns ns ns

68 (74) Cirrhosis 17 (19) Hepatocellular carcinoma Metastasis 3 (3) Cholangiocellular carcinoma 2 (2) 2 (2) Metabolic disease

0 (0)

107

Liver Grujt Overnight Storage

1000 -I

Hi

700 600

500

400 300 200 100

2o 0

D1

D2

D3

D4

D5

D6

D7

-

-

-

-

cantly higher in group A than in group B 1 hour after reperfusion (AST: 645 ? 55 IU/L versus 401 2 41 IU/L; P = ,006; ALT: 640 -+ 73 I U / L versus 388 t 47 IU/L, P = .03) but not after 24 hours. FV and tBil serum levels were similar in the two groups. Cyclosporine blood levels were 325 -+ 22 ng/mL and 52 ng/mL on day 1 in groups A and B, 387 respectively (P > .05). MEGXvalues on day 1 were 69 ? 38 ng/mL (A) and 56 2 30 ng/mL (B) (P > .05). Sixty-seven (72%) patients in group A and 29 (70%) patients in group B were extubated within 48 hours. Liver function during the first year was identical in the two groups, except for significantly higher ALT values 1 month postoperatively in group B (Table 4). The incidence of PNF (6.5% in group A and 9.5% in group 8 ) and retransplantation during the first month (7.6% in group A and 12.2% in group B) was not significantly different (Table 5). In group A, 7 (7.6%) patients died within 1 month after transplantation, of PNF (n = l ) , multiorgan failure (n = 4), sepsis (n = 11, or pancreatitis (n = 1). In group B, 3 (7.3%) patients died within 1 month, of PNF (n = 1) or multiorgan failure (n = 2). The incidence of vascular, biliary, and infectious complications is reported in Table 6. No ischemictype biliary complications were diagnosed, apart

*

1 HI

D1

D2

D3

D4

D5

D6

D7

Table 4. Liver Biochemistry at 1, 6, and 12 Months

50

O

i !

....... , D1

.

,

.

02

, D3

.

, D4

, D5

.

Group B (N = 41)

P

21.7 2 2.8 35 2 5.9 39.7 2 6.4

31.8 2 6.2 34.9 2 5.9 23.2 2 2.3

ns ns ns

AST (IU/L)

group A group B

.

Group A (N =92)

,

. D6

,

< D7

Postoperative days

Figure 1. Biochemical liver function during the first week after operation.

1* 6 12

ALT (IU/L) 1 6 12

45.5 rf- 7.6 87 2 26.1 0.047 ns 46.1 2 7.4 41.8 5 8.8 45.1 ? 10.7 23.5 2 2.7 ns

Bilirubin (Fmol/L)

7.7 2 0.4 hours (range, 4.5 to 12 hours) in group B (P = ns). There was no significant difference between the two groups as regards transfusion requirements: 16.8 ? 1.9 versus 13.9 ? 2.3 blood U; 24.1 2 2 versus 21.6 2.5 fresh frozen plasma U ; 5.6 ? I versus 4.8 1 platelet units, in groups A and B, respectively. No perioperative deaths occurred. Biochemical liver function during the first week is shown in Fig 1. Liver enzyme activities were signifi-

*

*

1 6 12 PT (%) 1 6 12

38 2 4.8 16.7 1.8 15.3 2 1.3

54.2 2 19.3 21.6 rf- 4.2 16.1 ? 1.6

ns ns ns

86.4 2 1.4 93.3 2 1.2 92.4 ? 1.3

87 2 2.3 94.6 2 1.9 90.2 2 4.5

ns ns ns

NOTE. Values are mean ? SD. Abbreviations: PT, prothrombin time *Months postsurgery.

108

Vix et a1

7

I

Table 5. Incidence of Primary Non function and Retransplantations

PNF n CIT (h) Retransplantations (< 1 month postoperation)

Group A (N = 92)

Group B (N = 41)

6 16 & 5.5

4 9 & 1.3

7

5

ns

P
12 hours),I2whereas the absence of intestinal blood derivation has been shown to favor microbial proliferation and endotoxin release affecting graft function.' One hour after reperfusion, AST and ALT levels, which reflect the volume of necrotic hepatocyte necrosis during cold storage and at the time of reperfusion,'+ were greater in group A because of the extended storage period. However, hepatocyte regeneration was not affected, because values were similar

3

2

Years

4

5

in groups A and B values after 24 hours and returned to normal within 6 days in both groups. We also analyzed changes in levels of factor V, which is exclusively synthesized by the liver and is representative of overall hepatic protein synthesis. Factor V blood levels are not influenced by blood product transfusion or vitamin K deficiency (frequent in chronically cholestatic patients). Values during the first week were similar in the two groups. Furthermore, groups A and B did not differ significantly in terms of the serum bilirubin concentration during the first week. An addition, the incidence of primary graft nonfunction was similar in the two groups. Careful flushing of the graft with UW solution via the aorta, portal vein, and biliary ducts immediately after removal may explain why we observed no biliary complications. The length of hospital stay and the incidence of bacterial and fungal infections were not affected by the longer cold storage period. However, CMV infections were significantly more frequent among the patients who underwent transplantation immediately after graft procurement, although donor CMV seropositivity rates and the CMV mismatch frequency between the donor and recipient were similar in the two groups. This difference could be caused by a lack of CMV-negative blood products on short notice. The incidence of acute rejection is greater when Eurocollins solution is used rather than UW solutionl5.lhand when preservation injury graft is present." This phenomenon could result in the expression of MHC class I1 antigens on the Kupffer cells at

110

V u et al

the time of ischemia-reper€~sion.’~ In our study, the incidence and severity of acute rejection were similar in the two groups, suggesting that MHC class I1 antigen expression by Kupffer cells and/or the recipient’s immune response were unaffected by the extended storage time. Graft and patient survival are the least specific but most important indexes of transplantation quality. Animal studies have clearly shown that survival decreases when the cold-storage time increases, yet we found no such effect in this clinical study. One explanation is that the relation between survival and cold storage time may be of the sigmoidal type, with a large plateau allowing the storage time to be increased safely. In conclusion, our results suggest that liver grafts harvested in the late afternoon, can be safely preserved overnight for transplantation during normal working hours. However, this policy can only be applied to elective indications and to liver grafts of good quality at the time of harvest.

References Kalayoglu M, Sollinger HW, Stratta RJ, D’Allessandro AR, Hoffman RM, Lirsh JD, et at. Extended preservation of the liver for clinical transplantation.Lancet 1988;1:617619. Todo S, Nery J, Yanaga K, Podesta L, Gordon RD, Starzl TE. Extended preservation of human liver grafts with UW solution. JAMA 1989;261:711-714. Sanchez-Urdazpal L, Gores GJ, Ward EM, Maus TP, Buckel EG, Steers JL, et al. Ischemic-type biliary complications after orthotopic liver transplantation. Hepatology 1992;16:49-53. Sankary HN, McChesney L, Hart M, Foster P, Williams J. Identification of donor and recipient risk factors associated with nonanastomotic biliary strictures in human hepatic allografts. Transplant Proc 1993;25: 1964-1967. Adam R, Bismuth H, Diamond D, Ducot B, Morino M. Effect of extended cold ischaemia with UW solution on graft function after liver transplantation.Lancet 1992;340: 1373-1376.

6. Ploeg RJ, D’Allessandro AM, Hoffmann RM, Eckoff D, lsaacs R. Impact of donor factors and preservation on function and survival after liver transplantation. Transplant Proc 1993;25:3031-3033. 7. D’Allessandro AM, Kalayoglu M, Sollinger HW, Hoffman RM, Reed A, Knechtle SJ, et al. The predictive value of donor liver biopsies for the development of primary nonfunction after orthotopic liver transplantation. Transplantation 1991;51:157-163. 8. Boudjema K, Ellero B, Odeh M, Wolf P, Jaeck D, Cinqualbre J. Technique des prelevements multiorganes. Editions techniques. Encycl Med Chir (ParisFrance). Techniques chirurgicales-Appareildigestif. 40O90,1993,14p. 9. Calmus Y, Bioulac-Sage P, Houssin D, Balabaud C. Le rejet en transplantation hepatique. Gastroenterol Clin Biol 1991;15:629-643. 10. Hayashi M, Tokunaga Y, Fujita T, Tanaka K, Yamaoka Y, Ozawa K. The effects of cold preservation on steatotic graft viability in rat liver transplantation. Transplantation 1993;56:282-287. 11. Ploeg RJ, D’Allessandro AM, Knechtle SJ, Stegall MD, Hoffman RM, Sollinger HW, et at. Risk factors for primary dysfunction after liver transplantation-A multivariate analysis. Transplantation 1993;55:807-813. 12. Belzer FO,D’Allessandro AM, Hoffmann RM, Knechtle SJ, Reed A, Kalayoglu M, et al. The use of UW solution in clinical transplantation. A 4 year experience. Ann Surg 1992;215:579-585. 13. Yokoyama I, Todo S, Miyata T, Selby R, Tzakis AG, Starzl TE. Endotoxemia and human liver transplantation. Transplant Proc 1989;21:3861-3862. 14. Howard TK, Klintmalm GBG, Cofer JB, Husberg BS, Goldstein RM, Gonwa TA. The influence of preservation injury on rejection in the hepatic transplant recipient. Transplantation 1990;49:103-107. 15. Cofer JB, Klintmalm GBG, Howard TK, Morris CV, Husberg BS, Goldstein RM, et al. A comparison of UW with eurocollins preservation solution in liver transplantation. Transplantation 1990;49:1088-1093. 16. Campbell DA Jr, Merion RM, Haem JM, Lucey MR, Henley KS, Turcotte G. Hepatic preservationwith university of Wisconsin solution is associated with reduced allograft rejection. Transplant Proc 1991;23:1547-1549. 17. Shackleton CR, Ettinger SL, McLoughlin M, Scudamore CH, Miller RR, Keown PA. Effect of recovery from ischemic injury on class I and class II MHC antigen expression. Transplantation 1990;49:641-643.