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Transfusion Rate for 500 Consecutive Liver Transplantations

Experience of One Liver Transplantation Center

Massicotte, Luc1,6; Denault, André Y.1; Beaulieu, Danielle1; Thibeault, Lynda2; Hevesi, Zoltan3; Nozza, Anna4; Lapointe, Réal5; Roy, André5

doi: 10.1097/TP.0b013e318250fc25
Clinical and Translational Research
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Background Orthotopic liver transplantation (OLT) has been associated with major blood loss and the need for blood product transfusions. During the last decade, improved surgical and anesthetic management has reduced intraoperative blood loss and blood product transfusions. A first report from our group published in 2005 described a mean intraoperative transfusion rate of 0.3 red blood cell (RBC) unit per patient for 61 consecutive OLTs. Of these patients, 80.3% did not receive any blood product. The interventions leading to those results were a combination of fluid restriction, phlebotomy, liberal use of vasopressor medications, and avoidance of preemptive transfusions of fresh frozen plasma. This is a follow-up observational study, covering 500 consecutive OLTs.

Methods Five hundred consecutive OLTs were studied. The transfusion rate of the first 61 OLTs was compared with the last 439 OLTs. Furthermore, multivariate logistic regression was used to determine the main predictors of intraoperative blood transfusion.

Results A mean (SD) of 0.5 (1.3) RBC unit was transfused per patient for the 500 OLTs, and 79.6% of them did not receive any blood product. There was no intergroup difference except for the final hemoglobin (Hb) value, which was higher for the last 439 OLTs compared with the previously reported smaller study (94 [20] vs. 87 [20] g/L). Two variables, starting Hb value and phlebotomy, correlated with OLT without transfusion.

Conclusions In our center, a low intraoperative transfusion rate could be maintained throughout 500 consecutive OLTs. Bleeding did not correlate with the severity of recipient’s disease. The starting Hb value showed the strongest correlation with OLT without RBC transfusion.

1 Department of Anesthesiology, Centre Hôspitalier de l’Université de Montréal – Hôpital Saint-Luc, Montreal, Canada.

2 Epidemiology Department, Centre Hôspitalier de l’Université de Montréal, Montreal, Quebec, Canada.

3 Department of Anesthesiology, University of Wisconsin, Madison, WI.

4 Biostastician, Institut de Cardiologie de Montréal, Montreal, Quebec, Canada.

5 Hepatopancreatobilliary Surgery, Centre Hôspitalier de l’Université de Montréal, Montreal, Quebec, Canada.

The authors declare no funding or conflicts of interest.

6 Address correspondence to: Luc Massicotte, M.D., Department of Anesthesiology, Centre Hôspitalier de l’Université de Montréal – Hôpital Saint-Luc, 1058, St-Denis, Montreal, Quebec, Canada H2X 3J4.

E-mail: luc.massicotte@umontreal.ca

L.M., R.L., and A.R. participated in making the research design, writing the article, and performing the research. A.Y.D. and L.T. participated in making the research design, writing the article, and analyzing the data. D.B. and Z.H. participated in making the research design and writing the article. A.N. participated in analyzing the data.

Received 30 November 2011. Revision requested 22 December 2011.

Accepted 13 February 2012.

Historically, orthotopic liver transplantation (OLT) has been associated with major blood loss and the need for massive blood product transfusions (1). A significant decrease in blood loss and blood product requirement has been observed during OLT over the past 10 years (2). This decrease can be explained by increasing experience, improvements in surgical and anesthetic techniques, and a better understanding of the various hemostatic abnormalities encountered during OLT. However, a wide range of blood product transfusion rates still exist between organ transplantation centers, even in patients who do not have significant coagulation defects. Transfusion rates vary between a median of 2 and 13 red blood cell (RBC) units per patient (3–5). Occasionally, the transfusion rate can be much worse; there are reports of transfusion in excess of 100 RBC units and as much as 117 units of fresh frozen plasma (FFP) used for a single OLT (6). A substantial body of evidence suggests that the use of blood products during an OLT is associated with morbidity and mortality (2, 7–14).

The cause of bleeding during OLT is multifactorial (15). The extensive surgical trauma plays a major role in the origin of bleeding. This bleeding can be accelerated by defects of the hemostatic system. Hemostatic defects can be divided into those present before the operation and those originating during the surgery. The latter can be classified according to the three main systems of hemostasis: coagulation, platelet function, and fibrinolysis.

Hyperfibrinolysis is an important cause of nonsurgical bleeding during OLT. The plasma concentration of tissue-type plasminogen activators increases during the anhepatic stage and after graft reperfusion because of insufficient hepatic clearance (15–18). Consequently, a main contributing factor in the recent improvement during OLT is the common evidence-based use of antifibrinolytic drugs such as aprotinin, [Latin Small Letter Open E]-aminocaproic acid, and tranexamic acid (19–27).

Another contributing factor in decreasing blood loss is the adoption of a “volume-restrictive substitution therapy” during the dissection phase, a maintenance of decreased venous pressure in the surgical field, and a lower intravascular volume in portal collaterals as compared with the traditional generous fluid loading to maintain arterial blood pressure and renal perfusion (2, 28–30).

In 2000, we noticed that our transfusion rate seemed lower than the published rate of other liver transplantation centers. Therefore, we decided to undertake a retrospective study of our clinical practices to verify our results and look at the predicting factors of outcome (5, 11). The findings were interesting: despite the fact that the patients’ severity of disease and threshold for RBC transfusions were exactly the same for all anesthesiologists, there was a great disparity in blood product transfusions by the various clinicians in our center. Some would transfuse as much as three times more blood products than others (4.7 vs. 1.6 RBC units per patient and 6.2 vs. 2.0 units of FFP).

Furthermore, the study showed that the transfusion of plasma for the purpose of correcting coagulation defects was not associated with a reduction in RBC transfusion. In fact, the opposite occurred. Transfusion of plasma was the variable with the strongest link to RBC transfusion (2) and to a decreased 1-year survival rate (11). Moreover, some anesthesiologists used to transfuse FFP (10–15 mL/kg) at the beginning of the surgery by means of a large-bore central venous catheter in a short period. As a result, the central venous pressure (CVP)—monitored from the side port of the pulmonary artery catheter—increased precipitously, and the abnormally high intravascular volume resulted in portal venous congestion and accelerated bleeding. By contrast, patients who showed lower CVP bled less. Thus, we realized that—much like in hepatic resection surgery—decreased intravenous fluid administration and low CVP were crucial factors in preventing surgical bleeding. In essence, our data confirmed two previous reports that advocated volume-restrictive substitution therapy during the dissection phase and emphasized that it was not necessary to correct coagulation defects before the anhepatic phase (31, 32).

At the conclusion of that retrospective review, we decided to change our practice for OLT. We implemented a uniform protocol that focused on maintaining a low CVP through the practice of minimized intravenous fluid administration before the anhepatic phase, intraoperative phlebotomy as appropriate, and avoiding all FFP transfusion. The results for the first 61 OLTs were published in 2005. The patients received a mean of 0.3 RBC units per patient without FFP, and 80.3% of the patients of this series did not receive any blood products (33).

The aim of this present study was to verify the preliminary results on a larger scale: Could we apply these new principles to 500 consecutive liver transplantations? Were anesthesiologists and surgeons able to undertake OLTs safely without correcting coagulation defects preoperatively or intraoperatively? We also sought to identify some independent variables leading to diminished bleeding and reduced transfusion rate during a liver transplantation.

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RESULTS

In 461 patients, 503 OLTs were performed. There were three intraoperative deaths. One patient died shortly after the induction, probably from massive infarct. Two other patients died shortly after unclamping the vena cava, from malignant arrhythmia (ventricular fibrillation) and pulmonary embolism. When these patients died, they had not received any blood product. The results for these three patients have been retrieved. All the livers came from brain-dead donors; they were 48.3-year-olds, and 54% were men.

The first 300 OLTs were performed using aprotinin; and the last 200 OLTs, using tranexamic acid as antifibrinolytic. Five patients already underwent an OLT before the study began. Thirty-eight patients underwent two OLTS, and two patients underwent three OLTs. Figure 1 shows the number of patients by the number of RBC units transfused. Three hundred ninety-eight patients (79.6% of the OLTs) did not receive any blood product; 7.6% received 1 RBC unit, and 8.2% received 2 RBC units. Only six patients received more than 5 RBC units.

FIGURE 1

FIGURE 1

Table 1 compares the demographic and health characteristics for the whole group of 500 patients, the first 61 patients, and the last 439 patients; they were essentially the same. Table 2 depicts the surgical characteristics; there was no difference between groups, except for the final hemoglobin (Hb) value and the percentage of use of cell salvage and phlebotomy, which were higher for the last 439 OLTs.

TABLE 1

TABLE 1

TABLE 2

TABLE 2

For the whole group of 500 patients and the last 439 patients, the mean intraoperative transfusion rates per OLT was 0.5 (1.3) RBC units, 0.2 (1.2) FFP units, and 0.2 (1.2) platelet units. This was not different from the first 61 OLTs. Neither albumin nor cryoprecipitate was used. The final Hb value for the whole group was 94.1 (24.3) g/L and was the same for the last 439 OLTs.

Phlebotomy was possible in 60.3% of the time, with a mean of 559 (217) mL of blood retrieved. It was possible to retransfuse from the cell saver (CS) in 64.0% of the cases, with a mean of 338 (295) mL. Phlebotomy was performed more frequently after the first 61 OLTs. The mean decrease in Hb for the whole group was 15 g/L. The patients who did not receive any blood product showed a decrease of their Hb value of 18 g/L (115 [41] to 97 [25] g/L, P<0.0001), and the patients who received transfusion showed a decrease of 8 g/L (88 [16] to 80 [11] g/L, P<0.0001). The mean baseline CVP decreased significantly from 14 (6) to 7 (4) mm Hg (P<0.0001) just before clamping the vena cava.

Table 3 shows blood loss according to the median of variables; disease severity at baseline did not correlate with intraoperative bleeding. There was no difference between men and women in transfusion rate and bleeding. Patients who underwent retransplantation received more RBC transfusions than patients with their first OLT (1.2 [1.9] vs. 0.4 [1.2] RBC units per patient, P<0.0001). Bleeding was the same for these two groups (116 [1008] vs. 1038 [928] mL per patient), but the starting Hb value was lower with patients who underwent retransplantation (91.1 [17.7] vs. 111.5 [40.2] g/L, P=0.001).

TABLE 3

TABLE 3

Table 4 summarizes the logistic regression analysis and odds ratio for no RBC transfusion. Univariate and multivariate analyses demonstrated correlation between no RBC transfusion and the two variables: starting Hb value and phlebotomy. For each increase of 1 g/L of starting Hb concentration, the risk of transfusing RBC was decreased by 1.1%. Similarly, the risk of transfusing RBC was decreased by a factor of 4 when phlebotomy was performed.

TABLE 4

TABLE 4

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DISCUSSION

Numerous reports established a link between transfusion of blood products and mortality or morbidity during OLT (7–9, 11–13, 34, 35). Consequently, it is in the patients’ best interest to minimize bleeding and the need for blood transfusion. Three variables must be kept in mind to achieve this goal: patient-related factors, surgeon, and anesthetic strategy. Patient’s characteristics include demographics, diagnosis, laboratory test results (starting Hb, international normalized ratio [INR], platelet count, fibrinogen concentration, creatinine, bilirubin, aspartate aminotransferase, and alanine aminotransferase), Model for End-Stage Liver Disease (MELD) score, and Child-Turcotte-Pugh (CTP) score. The second variable is the surgeon and his skill. It can be safely presumed without any scientific study that the surgeon is probably the most important variable in the equation of bloodless OLT. As far as anesthetic strategy is concerned, keeping the CVP low by restrictive intravenous fluid use and phlebotomy when tolerated is desirable to minimize portal congestion–related bleeding. In addition, the use of antifibrinolytics and CS should be considered as appropriate (36, 37).

The conventional approach to maintain arterial blood pressure and renal perfusion during OLT involved generous fluid administration, but this approach became controversial about a decade ago (28). Nowadays, there is an increased awareness that distribution of blood volume is altered in patients with cirrhosis (28). We learned over time that rapid expansion of blood volume results in a blunted cardiac output increase and splanchnic pooling when portal hypertension is present (28, 38). Knowing this, we decided to change our practice for OLT. We implemented a clinical protocol that focused on maintaining a low CVP through the practice of intraoperative phlebotomy and minimal volume replacement before the anhepatic phase. In addition, we avoided FFP transfusion altogether. Our first report was published in 2005, which covers 61 consecutive OLTs. It demonstrated an intraoperative transfusion rate of 0.3 RBC units per patient and no FFP use. In fact, 80.3% of the patients of this series did not receive any blood products (33). The observational study was continued for 500 consecutive OLTs, and demographic and health characteristics were exactly the same for the whole group as for the 61 first OLTs. The low transfusion rate was maintained throughout 500 OLTs, despite the addition of three new surgeons and numerous anesthesiologists. The only difference that we noted in our transfusion practice was the use of phlebotomy and CS. Phlebotomy was performed more frequently after the first 61 OLTs, and CS was used for every case after the first 75 OLTs. These changes did not translate in a decrease of transfusion rate or an increase in cases without transfusion (Table 2). However, we observed an increase of the final Hb value (84.6 [18.5] and 94.1 [24.3] g/L, P=0.001). All these results were possible by keeping a low CVP. Nonetheless, caution is advised when maintaining a low CVP because low CVP does not always accurately reflect intravascular volume and cardiac output when phlebotomy and vasopressor infusion are used. In fact, portal venous pressure may decrease with phlebotomy without any change in CVP (29).

In our setting, bleeding was not related to the severity of recipients’ disease as indicated by the starting Hb value, INR, platelet count, CTP score, MELD score, or any of these components (Table 3). These results are consistent with previous reports (14, 39). Table 4 summarizes the logistic regression model for no RBC transfusion. The only two variables that were linked were starting Hb and the use of phlebotomy. Again, these results are still consistent with our previous reports (2, 14, 37, 39). The mean intraoperative bleeding was still the same—approximately 1000 mL—throughout this large series, independently of severity of the patients’ disease. The mean decrease in Hb value was 15 g/L. If the threshold to transfuse RBC was set at 60 g/L, every patient with a starting Hb value lower than 75 g/L is needed to have transfusion. This shows the strength of the correlation between the starting Hb concentration and the incidence of RBC transfusion. Regarding phlebotomy, it may be somewhat of a confounding factor because it was used only when the starting Hb value was higher than 85 g/L. Contrary to traditional thinking, coagulation defects were not related to bleeding or transfusion of blood products. This is consistent with a previous report (14) and a new way of thinking of coagulopathy in chronic liver disease (14, 40). Classical testing of hemostasis (INR and platelet count) is not adequate to dictate transfusion practice during OLT because they do not predict bleeding accurately. This is why some experts advocate the use of thromboelastography to guide transfusion practice (41). In summary, the only laboratory test that predicted transfusion of RBCs was the starting Hb level.

Specialists of liver transplantation often argued about cohort effect (patients who are “less sick,” lower MELD score, and less patients with renal dysfunction). For MELD score, our patients were as sick as other series (10, 12, 41–43). Liver transplantation centers in the United States use the MELD score to prioritize their recipients for OLT, and many have difficulty obtaining comparable results as ours (44). We recognize that the MELD score creates a selection bias, selecting patients with the highest serum creatinine level, which limits the use of phlebotomy or a low CVP strategy. However, our data showed no correlation between creatinine concentration and blood loss; the starting Hb level was the only laboratory test that predicted the need for RBC transfusion. To optimize resource utilization and outcome, we suggest it be included in a new system to prioritize patients for OLTs (39).

Intraoperative blood product transfusion is linked to postoperative morbidity (7–14, 34, 35), so it is important to limit the use of transfusions. As demonstrated by our previous reports, our strategy was not deleterious to the postoperative creatinine value or the 1-year survival rate (2, 14, 37). Survival was not an outcome for this work, but the survival rate at 1 month was 94.1%, and at 1 year, the survival rate for the first 400 patients was 85.7%. In Massicotte et al. (2), we can find a comparison for postoperative creatinine value between patients who underwent phlebotomy and patients who did not. The patients who underwent phlebotomy showed a lower creatinine value in the postoperative period. Furthermore, the median of all blood products for the postoperative period (3 days) was 0. The next step for us is to validate that the model predicts survival based on the amount of the blood product transfused during an OLT. We know it is difficult to establish a link between two rare events: transfusion and mortality (37), especially when the number of cases is small (500).

The goal of our work was not to prescribe the optimal anesthetic strategy for liver transplantation or to define the exact threshold for blood product transfusions and the best final Hb level after OLT. We just want to share our experience and our results to the scientific community to minimize the use of blood products during a liver transplantation as supported by published evidence to increase patient safety and reduce transfusion-related morbidity. We sincerely believe that most OLTs could be performed without transfusion of blood products. Our work should serve as the starting point for a reflection on the prevalent transfusion practices and the reevaluation of old notions about coagulation and transfusion.

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CONCLUSIONS

Despite the fact that there was no control group, we think that a low CVP strategy and avoidance of preemptive FFP transfusion helped to keep a low transfusion rate for 500 consecutive OLTs safely. Baseline Hb value was the only laboratory test linked with the frequency of intraoperative RBC transfusion, and there was no link between the severity of the recipients’ disease or the preexisting coagulation defects and bleeding.

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MATERIALS AND METHODS

After approval by the Ethics Committee of the Centre Hôspitalier de l’Université de Montréal – Hôpital Saint-Luc, a nonexperimental comparative study (45) was undertaken. Between October 2002 and June 2011, 503 consecutive OLTs performed on adults were investigated.

All the OLTs were performed by 7 hepatobiliary surgeons, and 21 anesthesiologists were involved throughout the study period. Monitoring was standardized in all patients, as was the anesthesia technique (pulmonary artery catheter, arterial catheter, sufentanil, propofol, and rocuronium) (2, 14, 29). In the absence of uncontrollable bleeding, coagulation disorders were not corrected before or at the time of transplantation. No FFP, platelets, or cryoprecipitate were given; a “wait-and-see” approach of rescue therapy was used instead of prophylactic or preventive interventions. The triggering Hb level for RBC transfusion was set at 60 g/L. An effort was made to start RBC transfusion after the blood losses were controlled. Aprotinin was administered in every case for the first 300 OLTs according to the Hammersmith protocol: 2 million units as a bolus at the incision and 0.5 million units per hr until portal vein anastomosis was completed (46). The last 200 OLTs received tranexamic acid according to the BART (Blood Conservation using Antifibrinolytics in a Randomized Trial) protocol: 30 mg/kg as a bolus and 16 mg/kg per hr as an infusion (47).

Each anesthesiologist tried to lower the CVP before the anhepatic phase by approximately 33% by restrictive volume infusion, phlebotomy without volume replacement, or a combination of both techniques. CVP was monitored from the proximal port of the pulmonary artery catheter. Phlebotomy consisted of withdrawing blood (from the introducer of the pulmonary artery catheter), at the beginning of the case without any crystalloid or colloid volume replacement. Criteria for phlebotomy were an Hb value higher than 85 g/L and a normal renal function. The quantity of blood withdrawn varied according to the patient’s mass (7–10 mL/kg). The phlebotomy was interrupted if the arterial blood pressure dropped by more then 20% of the baseline value despite vasopressor (phenylephrine) administration. Vasopressin was added as needed during the anhepatic phase. The CVP was slowly corrected after unclamping the inferior vena cava to avoid hepatic congestion. The previously harvested whole blood was returned to the patient at the end of surgery (unless indicated earlier by an Hb value lower than our predefined transfusion trigger). A CS device was used for every case after the initial 75 cases.

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Statistical Analyses

Data are expressed as mean (SD), otherwise as percentage. Statistical analysis was performed by using the Student t test or Welch t test as appropriate. The chi-square was used to compare percentages. The independent variables of gender, age, weight, height, starting Hb, starting INR, starting platelet count, CTP score, MELD score, starting creatinine, serum bilirubin, phlebotomy, use of CS, CVP before clamping, FFP transfusion, platelet transfusion, duration of surgery, duration of cold ischemia, and clamping time were analyzed by univariate and multivariate methods to find linkage with the absence of RBC transfusion. The dependent variable “RBC transfusion” was considered as dichotomic. Gender, phlebotomy, and CS were coded in binary fashion (yes or no); the other variables were analyzed as continuous values. Moreover, Hb, INR, platelet count, creatinine, bilirubin, CTP score, and MELD score were also analyzed as dichotomic variables using the median to split the variables. Three separate regression models were performed. The models were constructed with the use of backward stepwise variable selection, and a probability value of 0.05 was used as the criterion for variable selection. The C index and the Hosmer-Lemeshow goodness-of-fit test are also reported for the appropriateness of the mode. Statistical analyses were performed using SAS version 8.02 (SAS Institute Inc., Cary, NC).

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ACKNOWLEDGMENTS

The authors thank Ms. Denise Bois for her secretarial work, Mr. Gunther Herbet for the data processing, and Ms. Louise Réhel and Ms. Brigitte Junius from Québec Transplant.

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Keywords:

Liver transplantation; Transfusion; Phlebotomy; Antifibrinolytic; Cell saver; MELD score

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