EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Our goal was to evaluate the predictors of coagulopathic hemorrhage after living-donor liver transplant.

Materials and Methods: We retrospectively evaluated 161 patients who had undergone living-donor liver transplant from July 2005 to April 2014 at a single medical institution. Of these patients, 32 developed hemorrhage after transplant. Patients were separated into those with coagulopathy-related hemorrhage (n=15) or noncoagulopathy-related hemorrhage (n=17) based on the results of computed tomography images. Predictors of hemorrhage after living-donor liver transplant evaluated in this study included preoperative, perioperative, and posttransplant factors and hemodynamic status.

Results: Patients who developed coagulopathy-related hemorrhage had significantly lower pretransplant platelet counts (P = .040), a longer cold-ischemia time (P = .045), more blood loss (P = .040), and earlier onset of hemorrhage (P = .048) than patients who had noncoagulopathy-related hemorrhage after transplant. Results of the generalized estimating equation analysis showed that heart rate and central venous pressure differed significantly between the 2 groups of patients. Heart rates increased significantly during hemorrhage (P < .010). Central venous pressure was higher in the coagulopathic group (P = .005) than in the noncoagulopathic group.

Conclusions: Lower pretransplant platelet counts, longer cold ischemia time, more blood loss, earlier onset of hemorrhage, and higher central venous pressure level are indicators of coagulopathic hemorrhage after living-donor liver transplant.

Key words : Central venous pressure, Cold ischemia time, Computed tomography

Hemorrhage is one of the most common complications after liver transplant, especially during the first postoperative week.^1,2 There are many factors that contribute to postoperative hemorrhage, including the recipient’s preoperative condition (for example, coagulopathy, thrombocytopenia), liver graft condition (donors > 60 years, steatosis), surgical technique (inadequate hemostasis of the cut surface of the remnant liver, blood loss from vascular anastomosis, and prolonged cold ischemia time), and recipient’s postoperative condition (early graft dysfunction or primary nonfunction, use of heparin, vascular complications).^3-6 Regardless of the underlying causes of hemorrhage, hemorrhage after liver transplant can be classified as coagulopathic bleeding (bleeding related to poor graft function and coagulopathy, resulting in continuous oozing of blood) or noncoagulopathic bleeding (bleeding in patients with normal coagulation function).

Computed tomography (CT) has been reported to be a sensitive modality for detecting active bleeding in patients with major trauma.^7,8 However, CT is contraindicated for some patients who have recently undergone major surgery, such as liver transplant. Therefore, we investigated whether certain clinical parameters could be used to distinguish between patients with postoperative hemorrhage due to coagulopathy and patients with postoperative noncoagulopathy-related hemorrhage after living-donor liver transplant (LDLT).

Materials and Methods

Patients and definitions of hemorrhage after living-donor liver transplant
In this retrospective study, we included 161 patients who underwent LDLT at our center from July 2005 to April 2014. For donor eligibility, our original legislative proposal confined donors to those within 5th-degree consanguinity of the patient and spouses (per our Regulation on Human Organ Transplantation). Liver transplant is an important treatment option for recipients with acute liver failure, end-stage liver disease, and primary hepatic malignancies.

Of 161 patients included, 32 developed postoperative hemorrhage. Postoperative hemorrhage was defined as persistent drainage of blood from drainage tubes in association with a hemoglobin drop ≥ 2 g/dL9 or packed red blood cell transfusion with or without fresh frozen plasma (FFP) transfusion, due to a decrease in hemoglobin concentration to < 7 g/dL. Indication for blood transfusion was massive hemorrhage (> 1500 mL) within 24 to 48 hours after surgery.^10,11

All patients who developed postoperative hemorrhage underwent abdominal CT scans and were divided into 2 groups based on the CT findings. Patients who did not have contrast material extravasation were considered to have coagulopathic hemorrhage (n = 15), and patients who presented with extravasation of contrast material were considered to have noncoagulopathic hemorrhage (n = 17). Clinical parameters of the 32 patients (pretransplant, operative, and posttransplant factors, as well as hemodynamic parameters) were analyzed to find associations between clinical parameters and type of hemorrhage. This protocol was approved by our ethics committee (Changhua Christian Hospital Institutional Review Board; number CCH 140708).

Clinical data
Clinical data were obtained through medical record review. Donor-related factors such as age and steatosis were collected. Recipient-related factors were categorized as a pretransplant factor, an intraoperative factor, or a posttransplant factor. The pretransplant factors included Model for End-Stage Liver Disease score, coagulation function using International Normalized Ratio (INR), platelet count, and fibrinogen levels, and graft-to-recipient weight ratio. Intraoperative factors included anhepatic phase time, cold ischemia time, operative time, estimated blood loss, and intraoperative blood transfusion, including units of packed red blood cells, units of FFP, and units of transfused platelets. Posttransplant factors included acute physiology and chronic health evaluation (APACHE) II score, onset of hemorrhage, the lowest hemoglobin level, platelet count, and INR value. Hemodynamic status results, including mean arterial pressure (MAP), heart rate (HR), and central venous pressure (CVP) level, were recorded every hour in the intensive care unit. Posttransplant hemoglobin levels were routinely monitored every 4 hours during the first 2 days after LDLT. If the patient had no hemorrhage, hemoglobin levels were routinely followed every 12 hours or once per day. If the patient displayed hemorrhage, the patient was followed every 4 hours. Hemodynamic parameters (MAP, HR, and CVP) at 0, 2, 4, and 6 hours before the time of lowest hemoglobin level and at 2 hours after the time of lowest hemoglobin level were collected and compared between the 2 groups.

Statistical analyses
All data were recorded in a computer database. The patients were classified into 2 subgroups based on the presence of contrast extravasation on CT images. Possible predictors of post-LDLT coagulopathy-related hemorrhage included donor age, Model for End-Stage Liver Disease score, graft-to-recipient weight ratio, coagulation function (INR, platelets, fibrinogen), anhepatic phase, cold ischemia time, operative time, blood loss, blood transfusion during transplant procedure (packed red blood cells, FFP, or platelets), APACHE II score, onset of hemorrhage, hemoglobin, platelet, INR, and fibrinogen levels at the time of hemorrhage. Differences in continuous variables were analyzed by the Mann-Whitney U test. The Fisher exact test was used to measure differences in categorical variables. Hemodynamic status (MAP, HR, CVP) were 5 data of distinguished time. We used the categorical comparisons of data and the generalized estimating equation (GEE) to determine differences in the means of continuous variables. P < .05 was considered to represent statistical significance. Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 17.0, IBM Corporation, Armonk, NY, USA).

During the study period, 32 of 161 patients (19.9%) developed posttransplant hemorrhage, but only 22 (13.7%) required relaparotomy for bleeding control of or removal of hematoma due to intra-abdominal hypertension, or abdominal compartment syndrome.

On average, posttransplant hemorrhage occurred 3.5 days (mean, 3.47 d; range, 0-14 d) after the liver transplant procedure. In patients with coagulopathy-related hemorrhage, bleeding occurred approximately 2 days after liver transplant (mean, 2.33 d; range, 0-11 d); in patients with noncoagulopathic-related hemorrhage, bleeding occurred approximately 4.5 days after surgery (mean, 4.47 d; range, 1-14 d).

Table 1 shows the demographic and clinical features of the patients in the 2 groups. In comparison with patients with noncoagulopathy-related hemorrhage, patients with coagulopathic-related hemorrhage had significantly lower platelet count (mean of 60.93 ± 32.65 × 103/μL, range of 19-131 × 103/μL vs 94.88 ± 52.14 × 103/μL, range of 24-256 × 103/μL; P = .04), longer cold ischemia time (mean of 166.33 ± 45.02 min, range of 75-428 min vs mean of 119.82 ± 30.30 min, range of 70-119 min; P = .045), greater estimated blood loss (mean of 8694.67 ± 6912.65 mL, range of 700-23 000 mL vs 4452.94 ± 4884.81 mL, range of 200-20 700 mL; P = .04), and earlier onset of hemorrhage (mean of 2.33 ± 2.80 d, range of 0-15 d vs 4.47 ± 3.71 d, range of 1-14 d; P = .048).

Hemodynamic parameter results (MAP, HR, CVP at 0, 2, 4, 6 h before the time of lowest hemoglobin level and at 2 h after the time of lowest hemoglobin level), which were analyzed by GEE, are shown in Figure 1. There were no significant differences in MAP or HR between the 2 groups. However, HR was significantly higher at 6 hours (β = -16.65, 95% confidence interval, -26.34 to -6.95; P = .001), 4 hours (β = -17.00, 95% confidence interval, -24.20 to -9.80; P < .001), and 2 hours (β = -10.53, 95% confidence interval, -16.71 to -4.35; P = .001) before the time of lowest hemoglobin level. We found that HR increased in the 2 groups after hemorrhage and at the lowest hemoglobin level. Heart rate then significantly decreased at 2 hours after the time of lowest hemoglobin level (β = -11.24, 95% confidence interval, -19.47 to -3.00; P = .008). After blood transfusion, patient showed decreased HR levels.

Our GEE analyses revealed that CVP levels were significantly higher in the coagulopathic group (β = 4.49, 95% confidence interval, 1.32 to 7.66; P = .005) than in the noncoagulopathic group(Figure 1).

Studies have shown that massive blood loss, prolonged cold ischemia time, and reperfusion injury are associated with poor graft function and poor patient outcomes.^2,9,12-16 Transient liver dysfunction after liver transplant can potentially cause bleeding , thereby increasing the chance of coagulopathic hemorrhage. Our data show that patients who developed coagulopathic-related hemorrhage had significantly lower preoperative platelet counts, a longer cold ischemia time, and greater estimated blood loss than patients with noncoagulopathic-related hemorrhage. Our results also show that the onset of hemorrhage was significantly earlier in patients with coagulopathic-related hemorrhage than in patients with noncoagulopathic-related hemorrhage. In situations such as LDLT when the liver’s raw surface is larger or transient liver dysfunction occurs after liver transplant, there is a possibility of earlier coagulopathic hemorrhage. Possible explanations for delayed hemorrhage in patients with noncoagulopathic-related hemorrhage include lysis of the thrombus in the bleeding artery or rupture of a pseudoaneurym.¹⁷

Patients with postoperative hemorrhage typically present with signs of shock (eg, hypotension, tachycardia), abdominal distension, oliguria, elevated intra-abdominal pressure (> 20 cm H₂O), and peak airway pressure.^1,18,19 We found that MAP did not differ significantly between patients with coagulopathic-related hemorrhage and patients with noncoagulopathic-related hemorrhage. This is because compensatory mechanisms (eg, tachycardia and vasoconstriction) were activated to keep a relatively stable MAP, regardless of the cause of hemorrhage.^20-22

We found that patients with coagulopathic-related hemorrhage had significantly higher CVP levels than patients with noncoagulopathic-related hemorrhage. We think this is because the speed with which hemorrhage develops after LDLT is lower in patients with evidence of coagulopathic-related bleeding. Those patients, therefore, benefit from fluid therapy and transfusion of blood products such as FFP, platelets, and cryoprecipitate. Another possible explanation for higher CVP levels in patients who have coagulopathic-related hemorrhage is that, after transfusion of blood products and improvement of coagulation functions, the slow oozing of blood gradually stops, resulting in an accumulation of blood clots in the abdominal cavity. Blood clots are not easily drained by drainage tubes and often result in an increase in intra-abdominal pressure and CVP level. However, surgical removal of intra-abdominal hematoma should be considered when patients present with symptoms and signs of abdominal compartment syndrome.^18,19

Hemorrhage due to noncoagulopathic causes is essentially due to vascular defects, which explains why the speed and magnitude of blood loss are usually higher in those patients than in patients with coagulopathic-related hemorrhage. In our study, we found that the estimated blood loss during the operation was significantly lower in patients in the noncoagulopathic group. The reason for this is probably due, at least in part, to the fact that they received less fluid replacement during the operation. Therefore, CVP levels tend to be lower in patients with noncoagulopathic-related hemorrhage than in patients with coagulopathic-related hemorrhage after LDLT.

High pretransplant platelet counts, shorter cold ischemia time, lower estimated blood loss, late onset of hemorrhage, and lower CVP levels are predictors of noncoagulopathic hemorrhage after LDLT.

Volume: 15 Issue: 6 December 2017

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