Red Blood Cell Transfusion in Liver Transplantation: A Case-Control Study

Red Blood Cell Transfusion in Liver Transplantation: A Case-Control Study B. Nardo, R. Bertelli, R. Montalti, P. Beltempo, L. Puviani, V. Pacilè, and A. Cavallari ABSTRACT Introduction. We aimed to analyze the influence of intraoperative blood transfusion on postoperative complications and survival and to identify the preoperative variables associated with greater intraoperative bleeding. Materials and Methods. Thirty-one elective liver transplantations (OLT) without blood transfusion performed between 1986 and 2002 (group 1) were compared with 62 patients (group 2) who underwent elective OLT with intraoperative transfusion after matching for gender, disease severity, and chronology. Results. The hemoglobin and hematocrit values were significantly greater in group 1 compared to group 2. No significant differences were reported for the other parameters. In particular, the type of surgical technique had no influence on the blood requirement. As expected the nontransfused patients received less autologous packed red blood cells compared with the transfused patients. No differences were observed in either group for mean CIT, ICU and hospital stay, or acute rejection. A significant difference was observed in the number of postoperative infectious episodes, which was higher in group 2 (28 vs 5, P ⫽ .01). Graft and patient survivals at 3 months and 5 years did not differ significantly between groups. Conclusions. OLT without blood transfusion may be achieved in the presence of good recipient conditions. Lower preoperative hemoglobin and hematocrit values were associated with greater intraoperative transfusions.

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IVER TRANSPLANTATION (OLT) is often associated with considerable blood loss due to the technical difficulties of this procedure, which requires excessive intraoperative blood transfusions in some unpredictable circumstances.1 Factors leading to increased operative bleeding and transfusion requirements during OLT are coagulation disorders associated with the severity of end-stage liver disease. Improvements in surgical technique as well as enlarged operative experience of anesthesiologists and surgeons have contributed to a decreased need for blood transfusions over time in many transplant centers. Although lab tests are routinely used, transfusion reactions, alloimmunization, and the risk of transmission of various viral agents remain possible.2 The aim of the present study was to analyze the influence of intraoperative blood transfusion on postoperative complications and survival as well as to identify the preoperative variables associated with greater intraoperative bleeding. Thus, we compared a group of patients transplanted without the need for blood transfu-

sion with another group who received intraoperative blood transfusions during the same period. MATERIALS AND METHODS Thirty-one elective primary liver transplantations (OLT) without blood transfusions (Group 1 patients; n ⫽ 31) performed on adults between April 1986 and December 2002 were retrospectively compared with group 2 patients (n ⫽ 62) who underwent OLT with intraoperative blood transfusions. The patients in group 2 were matched for gender, CHILD score, and era of transplantation (⫾1 year). Moreover, there were no statistically significant differences between the two groups with regard to recipient age, OLT indication, as well as UNOS or MELD (UNOS modification) status. We From the Department of Surgery and Transplantation, University of Bologna, Bologna, Italy. Address reprint requests to Bruno Nardo, MD, University of Bologna, Department of Surgery and Transplantation, Massarenti, 9, Bologna 40138, Italy. E-mail: [email protected]. unibo.it

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0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.11.030

Transplantation Proceedings, 37, 4389 – 4392 (2005)

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NARDO, BERTELLI, MONTALTI ET AL Table 1. Donor Demographic, Clinical, and Preoperative Laboratory Characteristics Parameters

Age (yrs, range) Gender (Male/Female) Cause of death Cerebral hemorrhage Trauma Other ICU stay (days) Hemodynamic characteristics (steady/unsteady) Total bilirubin (mg/dL) ALT (U/L) AST (U/L) PT (%) ␥-GT (U/L) Kind of donor (marginal/ideal) Biopsies Mild steatosis Moderate steatosis

Group 1 (31 pts) No Transfusions

44 ⫾ 17.7 18/13 17 12 2 3.8 ⫾ 3.8 27/4 0.81 ⫾ 0.81 49 ⫾ 56 61.4 ⫾ 65.1 73.8 ⫾ 21.6 81.4 ⫾ 211.1 8/23 8/23 7 1

Group 2 (62 pts) Transfusions

P

47.3 ⫾ 17 35/27

NS NS

30 24 8 3.7 ⫾ 3.6 58/4 1.3 ⫾ 1.7 56.4 ⫾ 78.7 56.6 ⫾ 68.7 74.4 ⫾ 22.4 71.7 ⫾ 121.3 16/46 16/46 12 4

NS NS NS NS NS NS NS NS NS NS NS NS NS NS

ICU, intensive care unit; ALT, alanine aminotransferase; AST, aminoaspartase; ␥-GT, ␥-glutaryl transferase; PT, prothrombin time.

evaluated the following donor parameters: age, gender, length of ICU stay, hemodynamic characteristics prior to and during organ harvest as well as preharvest donor liver function tests. Liver biopsies were performed on the basis of the personal evaluation by the harvesting surgeon. The following recipient demographic data and preoperative laboratory parameters were collected: age, gender, LT indication, CHILD classification, UNOS status according to the United Network of Organ Sharing classification, MELD classification (UNOS modification), previous abdominal surgery, hemoglobin, hematocrit, PT, and platelet count. The intraoperative and postoperative parameters included surgical technique, cold ischemia time, operative time, transfusions of packed red blood cells (PRBCs) units (autologous and homologous), immunosuppression type, acute rejection rate, infection from CMV and other pathogen agents, length of ICU and hospital stay as well as 3-month, 1- and 5-year graft and patient survivals. The decision to administer blood transfusions during OLT was made by the intraoperative team of anesthesiologists and surgeons supported on the basis of active bleeding, clotting abnormalities or hemodynamic parameters. For the statistical analysis, categorical variables were analyzed using the chi-square test (Fisher exact test) with a level of significance set at 0.05. Continuous variables were analyzed using the parametric Students t test with a level of significance set at 0.05. Survival curves were computed using the Kaplan-Meier productlimit method and compared by a log-rank test.

RESULTS

Table 1 summarizes the main donor demographic, clinical, and preoperative laboratory characteristics as well as the type of donor (marginal vs ideal) and the results of liver biopsies, showing no significant differences. The demographic, clinical, and preoperative laboratory characteristics of the recipients are reported in Table 2. Both hemoglobin and hematocrit values were significantly greater in group 1 compared to group 2. No significant differences were reported for the other parameters, including previous abdominal surgical procedures. Table 3 shows the intraoperative

and postoperative recipient data. The incidence of HCV hepatitis recurrence within 6 months was 16.6% (2/12) in group 1 vs 30.5% (11/36) in group 2 (p ⫽ NS). The type of technique (Piggy-back vs standard) had no influence on blood requirement. The cold ischemia time was almost the same in both groups. Only a slightly longer mean duration of surgical procedure was observed in the transfused group compared with the nontransfused group. As expected, patients in group 1 received a smaller amount of autologous PRBCs compared with patients in group 2, albeit without significance. The patients in group 1 experienced a shorter ICU and hospital stay compared with group 2, but without statistical significance. The episodes of initial poor function and primary graft nonfunction did not differ significantly in both groups. No significant correlation was observed between either postoperative graft function or the kind of donor (ideal vs marginal) and the amount of transfusion. Table 4 reports the rate of acute rejection episodes and postoperative infections. The acute rejection rate was higher among group 2 than group 1 patients without achieving statistical significance. Regarding postoperative infection rates, group 2 patients displayed a significantly higher incidence of infective episodes compared with patients in group 1 (P ⫽ .01). A more detailed description is reported in Table 4. No significant differences were observed for graft and patient survival at 3 months, 1 and 5 years, respectively. DISCUSSION

Massive blood transfusion related to coagulation disorders occurring during the anhepatic and reperfusion phases remains a serious problem during liver transplantation. Increased blood loss is correlated with a lower survival rate.3 However, the number of units of blood products transfused during OLT operations has decreased over the

TRANSFUSION IN LIVER TRANSPLANT

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Table 2. Recipient Demographic, Clinical, and Preoperative Laboratory Characteristics Group 1 (31 pts) No Transfusions

Parameters

Age (yrs, range) Gender (Male/Female) Indication for LT Postnecrotic cirrhosis HCC on cirrhosis Cholestatic disease Alcoholic cirrhosis Other Child classification (A/B/Cⴱ) UNOS status (3/2B/2A/1) Anti-HCV positive Previous abdominal surgery Hemoglobin (g/dL) Hematocrit (%) PT (%) Platelet count (⫻103 mm3)

Group 2 (62 pts) Transfusions

47.7 ⫾ 10 23/8

50.7 ⫾ 9.5 46/16

14 8 2 2 5 9/18/4 14/15/2/0 12 (38.7%) 13 (41.9%) 13.7 ⫾ 1.6 41.2 ⫾ 4.5 60.1 ⫾ 20.7 94.3 ⫾ 68.2

33 16 4 4 5 18/36/8 33/25/4/0 36 (58%) 17 (27.4%) 11.8 ⫾ 1.9 33.9 ⫾ 5.3 53.5 ⫾ 20 72.7 ⫾ 49

P

NS NS NS NS NS NS NS NS NS NS NS ⬍.05 ⬍.05 NS NS

LT, liver transplantation; HCC, hepatocellular carcinoma; UNOS, United Network for Organ Sharing; PT, prothrombin time.

years in our own experience and that of other transplant teams.3–5 Blood loss and transfusion requirements depend primarily on the severity of liver disease, the quality of the donor liver, and the experience of the anesthesiology and surgical teams. These findings emphasized the need for appropriate intraoperative teamwork between anesthesiologists and surgeons during the transplant procedure and a critical reappraisal of current transfusion policy. In the present study, the two groups were matched for their severity of liver disease (CHILD status), which is known to be the most important risk factor for blood transfusion. The impact of preoperative coagulation status is controversial.3,4 Some investigators reported a correlation between blood loss during OLT and coagulation disorders. In our study the level of hemoglobin and hematocrit values were significantly greater in the nontransfused

as compared to the transfused group, but not PT%. From the technical point of view, it has been reported that the “piggy-back” technique with preservation of the inferior vena cava can be safely performed in selected patients with no additional requirement for blood transfusions compared with the standard procedure.6 In the present study the piggy-back procedure was the most frequent technique, leading to an almost equal distribution of the type of surgical procedure in both groups. The present data suggest that OLT may be safely performed using the piggy-back procedure without veno-venous bypass with no additional blood loss encountered when compared with the standard procedure. Only a slightly longer mean duration of the surgical procedure was observed in the transfused group as compared to the nontransfused group, likely due to the greater

Table 3. Intraoperative and Postoperative Recipients’ Data Parameters

Group 1 (31 pts) No Transfusions

Group 2 (62 pts) Transfusions

Surgical technique Piggy-back Conventional Cold ischemia time (min) Operative time (min) PRBCs (mL) autologous PRBCs (mL) homologous Immunosuppression basal drug Cyclosporine/Tacrolimus IPF PGNF HCV hepatitis recurrence Length of ICU stay (days) Length of hospital stay (days) 3-months survival (graft/patient) 1-year survival (graft/patient) 5-year survival (graft/patient)

25 (80%) 6 (19.4%) 467.5 ⫾ 116.9 428.6 ⫾ 77.5 266.9 ⫾ 478 0 27/4 2 2 2/12 3.6 ⫾ 1.5 17.3 ⫾ 10.7 90.3%/90.3% 80.6%/87.1% 70.2%/79.6%

45 (72.6%) 17 (27.4%) 517.4 ⫾ 124.7 459.9 ⫾ 97 453.9 ⫾ 1010.4 1520.2 ⫾ 1135.1 52/10 5 1 11/36 4.4 ⫾ 1.9 21.6 ⫾ 13.5 93.5%/93.5% 85.3%/88.6% 68.1%/73.1%

PRBC, packed red blood cells; ICU, intensive care unit; IPF, initial poor function; PGNF, primary graft nonfunction.

P

NS NS NS NS NS NA NS NS NS NS NS NS NS NS NS

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Table 4. Acute Rejection and Postoperative Infection Episodes Parameters

Acute Rejection No. patients No. episodes Timing 7–15 days 15–60 days ⬎60 days Grade Mild Moderate Severe Therapy Steroids OKT3 No. resolutions Postoperative Infections No. patients No. episodes Pathogens CMV Bacterial infections Fungal infections Viral infections

Group 1 (31 pts) No Transfusions

6 (19.3%) 7

Group 2 (62 pts) Transfusions

20 (32.2%) 27

P

NS NS

3 3 1 (5 months)

17 9 1 (2 years)

NS NS NS

1 6 0

6 15 6

NS NS NS

7 0 7/7

22 5 26/27

NS NS NS

5 (16.1%) 5 4 0 1 0

23 (37.1%) 28 13 5 4 6

.06 .01 NS NS NS NS

technical difficulty encountered during the surgical procedure. Unexpectedly, previous abdominal surgery did not influence the need for blood transfusions in our series, but the numbers are too small for any certain conclusion. Excessive operative blood transfusion has been correlated with an increased rate of infectious complications and lower survival rate after transplantation of the liver. Mor et al3 reported that septic episodes occurred more frequently among patients with an excessive operative blood loss. Those patients also tended to have a higher rate of severe CMV infections and a lower incidence of acute rejection episodes. In our series, the acute rejection rate was lower in the group of nontransfused compared with transfused patients (19.3% vs 32.2%) without achieving statistical significance. Moreover, the transfused patients in our series experienced a significantly higher incidence of infectious episodes compared with those not transfused. No statistical differences were seen in incidence of infective episodes caused by CMV or by other pathogenic agents, even if

CMV infections represented 80% of all infectious episodes in group 1 vs 46.4% in group 2. Concerning the HCV patients, although a higher incidence of recurrence was observed in group 2 compared with group 1 (30.5% vs 16.6%), it did not reach statistical significance. Patients who required more blood did not have a significantly prolonged stay in the ICU and postoperatively. In our series both early and long-term graft and patient survival rates were almost the same in both groups. Ramos et al7 recently reported the results of a prospective study on 122 liver transplantations. Forty-two of these patients (34%) did not require transfusion of packed red blood cells. The researchers found the transfusion of more than six units of PBRCs was associated with diminished survival. In conclusion, OLT without intraoperative transfusion of PRBCs depends on a less advanced liver disease and good pretransplant lab characteristics. In particular, lower hemoglobin and hematocrit preoperative values of the recipient were the only two parameters significantly related to intraoperative blood transfusions in our study. The postoperative course and survival rates were better if blood loss and transfusion requirements were avoided, but this series is too small to allow a conclusive statement. The extensive experience of the transplant team certainly remains an important key factor to achieve satisfactory results. REFERENCES 1. Butler P, Israel L, Nusbacher J, et al: Blood transfusion in liver transplantation. Transfusion 26:120, 1985 2. Rouch DA, Thistlethwaite JR, Lichtor L, et al: Effect of massive transfusion during liver transplantation on rejection and infection. Transplant Proc 20:1135, 1988 3. Mor E, Jennings L, Gonwa TA, et al: The impact of operative bleeding on outcome in transplantation of the liver. Surg Gynecol Obstet 176:219, 1993 4. Cacciarelli T, Keeffe E, Moore D, et al: Primary liver transplantation without transfusion of red blood cells. Surgery 120:698, 1996 5. Gordon PC, James MF, Spearman CW, et al: Decreasing blood product requirements after orthotopic liver transplantation. S Afr J Surg 40:468, 2002 6. Tzakis A, Todo S, Starzl TE: Orthotopic liver transplantation with preservation of the inferior vena cava. Ann Surg 210:649, 1989 7. Ramos E, Dalmau A, Sabate A, et al: Intraoperative red blood cell transfusion in liver transplantation: Influence on patient outcome, prediction of requirements, and measures to reduce them. Liver Transpl 9:1320, 2003