Differential effects of plasma and red blood cell transfusions on acute lung injury and infection risk following liver transplantation †‡
This research was performed at the Anschutz Medical Campus of the University of Colorado (Denver, CO).
This study was supported by the National Heart, Lung, and Blood Institute (grant K24 HLO89223 to Christopher C. Silliman), the National Institute of General Medical Science (grant GM49222), the American Gastroenterological Association (through a Research Scholar Award), and the National Institute of Diabetes and Digestive and Kidney Diseases (grant DK076565 to Scott W. Biggins).
Abstract
Patients with chronic liver disease have an increased risk of developing transfusion-related acute lung injury (TRALI) from plasma-containing blood products. Similarly, red blood cell transfusions have been associated with postoperative and nosocomial infections in surgical and critical care populations. Patients undergoing liver transplantation receive large amounts of cellular and plasma-containing blood components, but it is presently unclear which blood components are associated with these postoperative complications. A retrospective cohort study of 525 consecutive liver transplant patients revealed a perioperative TRALI rate of 1.3% (7/525, 95% confidence interval = 0.6%-2.7%), which was associated with increases in the hospital mortality rate [28.6% (2/7) versus 2.9% (15/518), P = 0.02] and the intensive care unit length of stay [2 (1-11 days) versus 0 days (0-2 days), P = 0.03]. Only high-plasma-containing blood products (plasma and platelets) were associated with the development of TRALI. Seventy-four of 525 patients (14.1%) developed a postoperative infection, and this was also associated with increased in-hospital mortality [10.8% (8/74) versus 2.0% (9/451), P < 0.01] and a prolonged length of stay. Multivariate logistic regression determined that the number of transfused red blood cell units (adjusted odds ratio = 1.08, 95% confidence interval = 1.02-1.14, P < 0.01), the presence of perioperative renal dysfunction, and reoperation were significantly associated with postoperative infection. In conclusion, patients undergoing liver transplantation have a high risk of developing postoperative complications from blood transfusion. Plasma-containing blood products were associated with the development of TRALI, whereas red blood cells were associated with the development of postoperative infections in a dose-dependent manner. Liver Transpl 17:149–158, 2011. © 2011 AASLD.
Infectious complications are among the most common causes of early death after liver transplantation.1-5 Both postoperative pneumonia and surgical site infections have been linked to intraoperative red blood cell (RBC) and plasma transfusions in liver transplant patients and other postoperative patient populations.4, 6-12 However, the incidence and distribution of all postoperative infections as well as the type and prestorage characteristics of the blood products associated with these infections in the liver transplant population are not clearly defined.
Postoperative respiratory complications following liver transplantation also carry a poor prognosis and have been previously reported to be associated with intraoperative transfusions.9, 13-16 One of the most serious postoperative respiratory complications is the development of acute lung injury (ALI). Transfusion-related acute lung injury (TRALI) is diagnosed when ALI develops within 6 hours of the receipt of blood products and is considered to be mechanistically related to transfusion.17 Epidemiological studies in critically ill medical patients suggest that patients with chronic liver disease have the greatest individual risk of TRALI in comparison with other populations.18-20 Although the incidence of ALI has been reported in smaller series, the incidence of TRALI and the types of blood products associated with perioperative TRALI in patients undergoing orthotopic liver transplantation have not been described.13, 16, 21
Currently, there is no consensus about what laboratory values should be used as trigger points for the transfusion of blood products during liver transplantation, and as a result, transfusion strategies vary dramatically within and between transplant centers.22-25 Recently, the difference in overall mortality between transplant centers has been attributed to center-specific approaches to transfusion.26 The aim of this study was to describe both the incidence of postoperative infections and TRALI and the association between specific blood products and these complications in patients undergoing liver transplantation.
Abbreviations:
ALI, acute lung injury; CI, confidence interval; CXR, chest X-ray; DRI, donor risk index; ICU, intensive care unit; MELD, Model for End-Stage Liver Disease; OR, odds ratio; RBC, red blood cell; RR, relative risk; TEG, thromboelastogram; TRALI, transfusion-related acute lung injury.
PATIENTS AND METHODS
This protocol was approved by the Colorado Multiple Institutional Review Board before our secondary analyses of existing databases. We used a patient database from the Division of Hepatology and Liver Transplantation at the University of Colorado to identify a cohort of 525 consecutive patients who underwent liver transplantation between 2002 and 2009. We did not collect data before 2002 to minimize differences in practices that may have resulted from the introduction of organ allocation using the Model for End-Stage Liver Disease (MELD) in 2002. Data on perioperative blood transfusion were extracted from both hepatology and anesthesia databases and the medical records. There were 2 primary outcome measures: the development of postoperative infectious complications and the development of postoperative respiratory complications. These are defined later. Secondary outcome measures included the in-hospital mortality rate, the length of primary hospitalization, and the length of stay in the intensive care unit (ICU).
Intraoperative Management
Our liver transplantation program has a team of 4 anesthesiologists who provide care for all recipients. This anesthesia team has established distinct criteria for the use of perioperative blood products. Therefore, transfusion practices at our institution are relatively uniform between physicians. Furthermore, all patients receive methylprednisolone (500 mg) and prophylactic antibiotics at the start of surgery.
In the immediate preoperative period, patients are transfused with platelets if the count is less than 30/μL, and they are given RBCs if the hemoglobin level is less than 9 g/dL. No plasma is given before surgery. During surgery, RBCs are given to maintain a hemoglobin value of 10 g/dL. Intraoperative plasma and platelet transfusions are considered only if there is evidence of decreased clot formation. This is determined by an evaluation of the thromboelastogram (TEG). When there is continued blood loss, evidence of decreased clot formation, and a platelet count lower than 50/μL and the maximal amplitude (clot strength) of the TEG is less than 50 mm, apheresed platelets are transfused. Fresh frozen plasma is given when the TEG clotting time is greater than 20 seconds. Cryoprecipitate is given when the alpha angle (rapidity of crosslinking fibrin) is less than 40 degrees and the fibrinogen level is less than 100 mg/dL. Prohemostatic agents are used only as rescue drugs for bleeding that has not responded to a transfusion. Aminocaproic acid (10 g) is given when there is fibrinolysis present on the TEG. Recombinant factor VII (40 μg/kg) is given when the TEG fails to deflect (straight line) or when 2 consecutive TEG readings show a prolongation of the clotting time and coagulation time with suboptimal clot formation despite adequate transfusion therapy according to the aforementioned criteria.
Patients are managed by aggressive diuresis during surgery to maintain a low central venous pressure (6-10 mm Hg). Patients with renal failure undergo intraoperative hemodialysis with volume removal. All patients who meet the standard criteria are extubated in the operating room at the conclusion of surgery with a protocol previously described by our institution.27 Perioperative management is designed to maintain a low central venous pressure by fluid restriction and diuresis, and the majority of patients leave the operating room with a negative fluid balance. In general, patients undergo a preoperative chest X-ray (CXR) examination to confirm central line placement and a postoperative CXR examination to assess for intraoperative changes in their pulmonary status.
There are no prespecified criteria with respect to prestorage leukoreduction or male-donor plasma, but all units of RBCs are required to be ≤10 days old, and all platelets are allogenic and are isolated via apheresis. At present, all RBCs from our main blood supplier are leukoreduced, and plasma is prepared from male or never-pregnant donors in conjunction with the American Association of Blood Bank recommendations.
A postoperative operation was defined as a return to the operating room after transplantation but before the development of a nosocomial infection during the hospitalization that included the initial transplant. Kidney dysfunction was determined by the need for perioperative dialysis, which was defined as the need for dialysis within 48 hours of liver transplantation (before or after). Patients who received only 1 cycle of intraoperative dialysis but no pretransplant or posttransplant dialysis were not included in this total because at our institution dialysis is frequently used for volume control intraoperatively and is less reflective of ongoing kidney dysfunction. The dialysis data and pretransplant location (ie, ICU, floor, or home) were obtained from our transplant database.
Definitions
The MELD score was retrospectively and prospectively shown to be highly predictive of short-term mortality (<90 days) in patients with any cause of end-stage liver disease (including those on the liver transplant waiting list).28, 29 This scoring system is currently used to rank patients on the liver transplant waiting list. The donor risk index (DRI) is a quantitative risk score for graft failure based on 9 variables related to the characteristics of the donor and graft.30 Our calculation of the DRI was based on 8 of 9 variables because the donor height was not available in our database.
Definitions of Outcome Variables
Postoperative Infection
Initial screening for the diagnosis of postoperative infections was performed with our hospital diagnostic coding database. Subsequently, the medical records of all patients identified as having any in-hospital infection were reviewed. Infections that developed before or within 48 hours of transplantation, after discharge from the initial hospitalization, or more than 60 days after transplantation were not considered. With the Centers for Disease Control and Prevention definitions for postoperative and nosocomial infections, patients were reclassified or excluded on the basis of the results of a formal chart review.31, 32 Infections that were considered to be viral in origin were not included in the analysis.
TRALI
Patients were considered to have TRALI if they met the 2004 consensus conference definition, which requires the development of ALI within 6 hours of the initiation of an infusion of a transfused blood product.17 TRALI was defined by the development of hypoxemia and new bilateral infiltrates (see the definition of ALI in the next sentence) on the postoperative CXR that were temporally associated (within 6 hours) with an intraoperative transfusion. We used the American-European Consensus Conference definition to define ALI: bilateral infiltrates on a chest radiograph, a partial pressure of arterial oxygen/fraction of inspired oxygen ratio less than 248 (adjusted for the altitude in Denver, CO), and no clinical evidence of left atrial hypertension.33
Circulatory Overload
Patients were diagnosed with circulatory overload and not TRALI if there was new evidence on the postoperative CXR of intravascular volume overload (large vascular pedicle, large azygos vein, cephalization of vessels, or vascular indistinctness) or if the patients met TRALI criteria but had rapid CXR resolution of their diffuse infiltrates over the next 48 hours in association with a negative fluid balance. CXR abnormalities were determined by a review of the formal dictated report on the immediate postoperative CXR.
Transfusion Data
We used an internal diagnostic coding database and nurse-completed transfusion slips in the medical record to identify the type, date, and time of each unit of blood product transfused during hospitalization. We were able to extract transfusion totals for each type of blood product for the intraoperative, 24-hour, and 48-hour intervals after the initiation of the transplant operation. Only intraoperative transfusion totals were analyzed for an association with perioperative TRALI, whereas the 24- and 48-hour totals were analyzed for an association with postoperative infections. We determined whether each unit of RBCs had been leukoreduced or nonleukoreduced. Per protocol, none of the transfused RBC units were older than 10 days. All platelet preparations either were apheresed or were autologous. The thawing time and sex or parity of the donors with respect to plasma could not be obtained, but our main blood supplier began TRALI mitigation for plasma with both male-only and never-pregnant females in December, 2007. In addition, our main blood supplier adopted universal leukoreduction for RBCs in 2005.
Statistical Analysis
The chi-square test of independence was used to examine categorical variables at the baseline, and independent sample t tests were used to compare continuous characteristics of the 2 groups. Univariate and multivariate logistic regression were used to evaluate associations between transfusion variables and other potential predictors of both primary and secondary outcome measures. P < 0.1 on univariate analysis was required for inclusion in the multivariate analysis. P < 0.05 was used elsewhere as the threshold for statistical significance. Continuous variables are reported as medians and 25% to 75% quantiles.
RESULTS
Data on 525 consecutive liver transplant patients were analyzed. Only 2% of the surgeries (11/525) were retransplants. The most common reason for transplantation was cirrhosis due to hepatitis C virus [49% (259/525)]. Additionally, 42% of the hepatitis C–positive patients had a coexistent history of previous alcohol abuse. The median patient age was 52 years (46-57 years), and 67% were male. The majority of patients were of Caucasian [71% (375/525)] or Latino descent [21% (108/525)]. The median preoperative MELD score was 25 (21-29). Kidney dysfunction was present (ie, dialysis was performed perioperatively) in 10% of patients (55/525) before and/or after transplantation. Preoperative dialysis was performed in 8% of all patients (44/525), and postoperative dialysis was performed in 9% (49/525). A posttransplant reoperation was performed in 16% of patients (83/525) for a variety of reasons, the most common of which were clot evacuation and cleanout (n = 56) and anastomotic leaks (n = 12). Diabetes was present in 16% (85/525) of patients. For 44% of these patients (232/525), the preoperative location was home; 44% (231/525) were non-ICU inpatients; and 12% (62/525) were in the ICU immediately before transplantation.
Intraoperative Transfusion Characteristics
Eighty-six percent of all patients received an intraoperative RBC transfusion. Nonleukoreduced RBCs accounted for 45% of all transfused RBCs. The median amount of transfused RBCs was 8 U (3-15 U). At least 1 U of plasma was transfused intraoperatively in 82% of patients. For those patients who received a transfusion of plasma, the median amount was 7 U (2-12 U). In addition, 64% of patients received an intraoperative platelet transfusion of at least 1 U. In those patients who received a transfusion of platelets, the median amount was 1 U (0-2 U). Only 14% of patients received cryoprecipitate. When transfusion trends were analyzed over time, there was a significant trend toward an increase in the use of both plasma (P < 0.01) and RBCs (P = 0.03), but statistically less albumin (P < 0.01) was used when we analyzed for differences in each 2-year interval from 2002 to 2009. There was no statistical difference in the laboratory MELD scores of the patients who underwent transplantation in each corresponding 2-year interval. The proportion of patients receiving nonleukoreduced RBCs also decreased significantly in the final 3 years of the study.
Characteristics of Patients Developing Postoperative Nosocomial Infections
The incidence of postoperative infection in our cohort was 14% [74/525, 95% confidence interval (CI) = 11.4%-17.3%]. Surgical site infections were most common [39% (29/74)], and they were followed by nosocomial pneumonia [30% (22/74)], bloodstream infections [27% (20/74)], urinary tract infections [7% (5/74)], and other sources [14% (10/74)]. In addition, 14% of patients (10/74) developed 2 or more postoperative infections. Sixty-two of these 74 infected patients (84%) had positive culture results. The most common infecting organism was Enterococcus (26%), which was followed by Staphylococcus [coagulase-negative species (12%), methicillin-resistant Staphylococcus aureus (11%), and methicillin-sensitive S. aureus (7%)]. Fungal infections made up 7% of infections. Pseudomonas aeruginosa accounted for 8% of infections (all pneumonia).
Risk Factors for the Development of Nosocomial Infections
A comparison of the demographics, transfusion characteristics, and outcomes of the patients who did develop postoperative infections and those who did not is detailed in Table 1. Patients who eventually developed a postoperative infection more commonly had evidence of circulatory overload on their immediate postoperative CXR [47% versus 27%, relative risk (RR) = 2.08 (1.37-3.16), P < 0.01]. Multiple variables were evaluated in univariate analysis for an association with postoperative infection; these included age, gender, etiology of liver disease, retransplantation, reoperation, presence of kidney dysfunction, dialysis, preoperative serum albumin, MELD and DRI scores, operation time, and transfusion factors. The DRI score was available for 86% of patient grafts (453/525) and was not associated with postoperative infections (P = 0.42). The only statistically significant non–transfusion-related risk factors associated with the development of postoperative infection on univariate analysis were the median operation length [342 (283-428 minutes) versus 305 minutes (263-358 minutes), P < 0.01], the reoperation rate [31% (23/74) versus 11% (50/451), P < 0.01], and the presence of kidney dysfunction [23% (17/74) versus 8% (38/451), P < 0.01]. All types of transfused blood products (RBCs, plasma, and platelets) showed a significant association with the development of a postoperative infection when they were analyzed on a per-unit basis for intraoperative, 24-hour, and 48-hour totals from the initiation of the transplant operation (Table 2). We chose to use transfusion totals for the 24-hour interval from the start of the transplant operation for all blood products in our multivariate analysis, but similar analyses using intraoperative and 48-hour totals resulted in similar odds ratios (ORs) and P values. A multivariate logistic regression model, which included the operation time (minutes), reoperation (yes or no), presence of kidney dysfunction in need of dialysis (yes or no), and 24-hour totals for plasma, platelets, and RBCs (all analyzed as continuous variables on a per-unit basis), revealed RBCs (adjusted OR per unit = 1.08, 95% CI = 1.02-1.14, P < 0.01) to be the only statistically significant transfusion-specific risk factor for the development of postoperative infections (Table 3). The presence or absence of leukoreduction did not significantly alter the presence or strength of the association. The presence of kidney dysfunction (adjusted OR = 2.74, 95% CI = 1.34-5.46, P < 0.01) and the need for reoperation post-transplant (adjusted OR = 2.28, 95% CI = 1.23-4.14, P < 0.01) were also significantly associated with postoperative infections.
| Characteristic (n = 525) | No Postoperative Infection (n = 451) | Postoperative Infection (n = 74) | P Value |
|---|---|---|---|
| Age, years | 52 (46-57) | 52 (47-57) | 0.66 |
| Male gender, % (n/N) | 66 (300/451) | 72 (53/74) | 0.80 |
| Race, % (n/N) | 0.11 | ||
| Caucasian | 72 (326/451) | 64 (47/74) | |
| African American | 4 (17/451) | 5 (4/74) | |
| Hispanic | 20 (88/451) | 27 (20/74) | |
| Other | 4 (20/451) | 4 (3/74) | |
| Etiology, % (n/N) | 0.24 | ||
| Hepatitis C virus | 28 (128/451) | 31 (23/74) | |
| Hepatitis C virus and alcohol | 21 (93/451) | 20 (15/74) | |
| Alcohol | 10 (44/451) | 8 (6/74) | |
| Hepatitis B virus | 4 (19/451) | 7 (5/74) | |
| Nonalcoholic steatohepatitis | 2 (10/451) | 7 (5/74) | |
| Primary biliary sclerosis | 4 (19/451) | 0 (0/74) | |
| Primary sclerosing cholangitis | 10 (46/451) | 11 (8/74) | |
| Acute liver failure | 3 (13/451) | 3 (2/74) | |
| Cryptogenic cirrhosis | 4 (16/451) | 4 (3/74) | |
| Other | 14 (63/451) | 9 (7/74) | |
| MELD score | 25 (21-29) | 27 (22-31) | 0.17 |
| DRI score (n = 453) | 1.47 (1.34-1.61) | 1.49 (1.36-1.65) | 0.42 |
| Albumin, g/dL (n = 457) | 3.1 (2.6-3.5) | 3.2 (2.6-3.6) | 0.53 |
| Operation time, minutes | 305 (263-358) | 342 (283-428) | <0.01 |
| Retransplantation, % (n/N) | 2.2 (10/451) | 1.4 (1/74) | 0.61 |
| Reoperation, % (n/N) | 11 (50/451) | 31 (23/74) | <0.01 |
| Kidney dysfunction: preoperative or postoperative dialysis, % (n/N) | 8 (38/451) | 23 (17/74) | <0.01 |
| Preoperative dialysis, % (n/N) | 8 (34/451) | 14 (10/74) | 0.10 |
| Postoperative dialysis, % (n/N) | 7 (33/451) | 22 (16/74) | <0.01 |
| Diabetes, % (n/N) | 17 (75/451) | 14 (10/74) | 0.50 |
| Pretransplant location, % (n/N) | 0.42 | ||
| ICU | 11 (49/451) | 18 (13/74) | |
| Hospital floor | 44 (200/451) | 42 (31/74) | |
| Home | 45 (202/451) | 41 (30/74) | |
| Outcomes | |||
| CXR findings, % (n/N) | |||
| Circulatory overload | 27 (123/451) | 47 (35/74) | <0.01 |
| Pleural effusion | 20 (91/451) | 42 (31/74) | <0.01 |
| Atelectasis | 52 (236/451) | 69 (51/74) | <0.01 |
| TRALI, % (n/N) | 1 (5/451) | 3 (2/74) | 0.31 |
| Mortality, % (n/N) | 2 (9/451) | 11 (8/74) | <0.01 |
| ICU length of stay, days | 0 (0-2) | 2 (1-5) | <0.01 |
| Postoperative length of stay, days | 9 (7-13) | 18 (14-30) | <0.01 |
| Transfused Product and Interval | No Postoperative Infection | Postoperative Infection | P Value |
|---|---|---|---|
| Any plasma in 24 hours, % | 80 | 97 | <0.01 |
| Plasma in first 24 hours, U | 6 (2-11) | 10 (6-17.5) | <0.01 |
| Plasma in first 48 hours, U | 6 (2-12) | 12 (8-21) | <0.01 |
| Platelets in 24 hours, % | 61 | 85 | <0.01 |
| Platelets in 24 hours, U | 1 (0-2) | 2 (1-3) | <0.01 |
| Platelets in 48 hours, U | 1 (0-3) | 3 (1-5) | <0.01 |
| Any RBCs in 24 hours, % | 84 | 100 | <0.01 |
| Nonleukoreduced RBCs in 24 hours, U | 0 (0-6) | 3.5 (0-12) | <0.01 |
| Nonleukoreduced RBCs in 48 hours, U | 0 (0-8) | 4 (0-16) | <0.01 |
| Leukoreduced RBCs in 24 hours, U | 1 (0-8) | 6.5 (0-16) | <0.01 |
| Leukoreduced RBCs in 48 hours, U | 2 (0-10) | 9.5 (0-19) | <0.01 |
| Total albumin volume, L | 1.5 (1.0-2.5) | 1.5 (0.5-2.5) | 0.24 |
| Transfusion- or Patient-Specific Risk Factor | Adjusted OR | 95% CI | P Value |
|---|---|---|---|
| Operation time, minutes | 1.00 | 0.99-1.00 | 0.33 |
| Plasma (per unit) in 24 hours | 0.95 | 0.89-1.02 | 0.18 |
| Platelets (per 10 pack) in 24 hours | 1.11 | 0.92-1.34 | 0.28 |
| RBCs (per unit) in 24 hours | 1.08 | 1.02-1.14 | <0.01 |
| Preoperative and/or postoperative dialysis, yes or no | 2.74 | 1.34-5.46 | <0.01 |
| Reoperation between transplant and infection, yes or no | 2.28 | 1.23-4.14 | <0.01 |
Incidence and Transfusion-Specific Risk Factors for TRALI
Overall, 2.1% of patients (11/525) had evidence of new postoperative bilateral infiltrates on CXR, but 4 of these patients were judged to have hydrostatic edema because of 48-hour resolution of hypoxemia and CXR abnormalities associated with fluid removal. Therefore, the incidence of TRALI was 1.3% (7/525, 95% CI = 0.6%-2.7%). In univariate analysis, only transfusions of plasma (OR per unit of plasma = 1.06, 95% CI = 1.00-1.11, P = 0.05) and platelets (OR per unit of platelets = 1.44, 95% CI = 1.12-1.87, P < 0.01) were significant risk factors for TRALI on a per-unit analysis. The DRI score was not associated with the risk of TRALI (P = 0.59). Other variables showing no statistical association with postoperative TRALI included age, gender, etiology of liver disease, retransplantation, serum albumin, MELD and DRI scores, operation time, preoperative or perioperative dialysis, and intraoperative tidal volume. Neither the volume of intraoperative albumin nor the number of RBC transfusions (leukoreduced or nonleukoreduced) was associated with the development of TRALI.
CXR Characteristics and Circulatory Overload
Postoperative CXR abnormalities were common. Atelectasis or consolidation was present in 55% of patients (287/525), and 23% (122/525) had evidence of a pleural effusion or a chest tube placed to drain a pleural effusion. Thirty percent (158/525) had evidence of intravascular volume overload (large vascular pedicle, enlarged azygos vein, cephalization of vessels, or vascular indistinctness). In multivariate logistic regression analysis, the amount of intraoperative albumin was associated with CXR evidence of intravascular volume overload (adjusted OR = 1.23, 95% CI = 1.08-1.39, P < 0.01).
TRALI and Postoperative Infection Increase Both the Length of Stay and In-Hospital Mortality
The development of TRALI was associated with worse in-hospital mortality [29% (2/7) versus 3% (15/518), RR = 9.9 (2.8-35.2), P = 0.01] and with an increased ICU length of stay [2 (1-11 days) versus 0 days (0-2 days), P = 0.03] but not with the postoperative hospital length of stay. CXR evidence of circulatory overload was associated with an increase in the postoperative length of stay [10 (8-16 days) versus 9 days (7-14 days)] and the ICU length of stay [1 (0-2 days) versus 0 days (0-2 days), P < 0.01 for both]. Postoperative infection was also a significant risk factor for in-hospital mortality [RR = 5.4 (2.2-13.6), 11% (8/74) versus 2% (9/451), P < 0.01], hospital length of stay [18 (14-29 days) versus 9 days (7-13 days), P < 0.01], and ICU length of stay [1.5 (0-3 days) versus 0 days (0-1 day), P < 0.01; Table 1].
DISCUSSION
Multiple cohort studies of patients undergoing liver transplantation have found an association between the amount of intraoperative transfusions and worse outcomes.16, 22, 23, 34-38 Postoperative infections are well-known complications of transfusions in patients undergoing orthotopic liver transplantation, but the incidence of TRALI has been poorly defined.4, 6, 8, 12, 14, 15, 39-42 The results of this study demonstrate that patients undergoing liver transplantation have less risk of TRALI than bleeding, critically ill patients with chronic liver disease who are not undergoing liver transplantation.18, 20 Despite the low incidence, TRALI resulted in a 10-fold increase in hospital mortality and, therefore, is clinically important. In our cohort, only plasma-containing blood products (platelets and plasma) were associated with TRALI, and this is consistent with other reports of liver transplant patients and critically ill patients with chronic liver disease.16, 18, 19, 21 In addition, transfused RBCs were associated in a dose-dependent fashion with postoperative infections, which resulted in a 5-fold increase in mortality. Prestorage leukoreduction did not influence this risk.
The risk of TRALI in this liver transplant cohort was much lower (1.3%) than the incidence (29.3%) seen at the same center over a similar time period (2002-2008) in patients with a similar severity of liver disease who received similar amounts of all blood products and were admitted to the ICU for a variceal bleed.20 The 2-event model of TRALI may explain this epidemiological difference. In this model, an underlying proinflammatory state activates pulmonary endothelial cells, and this results in the adherence and sequestration of neutrophils in the lungs.43 These primed, hyperactive neutrophils are vulnerable to activation by antibodies, lipids, and other biological mediators found in blood products. These mediators cause the release of the microbicidal arsenal from these adherent neutrophils, and this leads to endothelial cell damage, capillary leaks, and ALI.44, 45 Active sepsis is a proinflammatory condition that generally precludes patients from undergoing liver transplantation, but it is very common in patients admitted with a variceal bleed.46-48 Also, patients undergoing transplantation generally receive high-dose intraoperative glucocorticoids with potent immunosuppressive effects that may modulate the systemic inflammatory effect of the surgery. Lastly, transplant patients receive a new liver that may somehow change their TRALI risk because of the immunomodulatory effects of this unique event.
One-third of our patients had evidence of intravascular volume overload on postoperative CXR. When this circulatory overload progresses to pulmonary edema and is related to transfused blood products, the term transfusion-associated circulatory overload is used. The one-third of our patients with circulatory overload had significantly prolonged ICU and hospital lengths of stay as well as an increased postoperative infection risk. It is unknown whether this association is causal, but circulatory overload increases a patient's time on the mechanical ventilator and thereby leads to an increased ICU length of stay and increases the risk for postoperative infection. The amount of intraoperative albumin administration (not blood product transfusion) was an independent risk factor for circulatory overload. Albumin has previously been shown to be associated with cardiopulmonary complications and an increased length of stay in patients undergoing liver transplantation, and its use requires re-examination.49 It should be noted that only 4 patients had frank pulmonary edema attributed to a hydrostatic mechanism. The other patients in this subset had evidence of circulatory overload, but because this syndrome exists on a spectrum, it is unclear how many of these patients would actually have been given the diagnosis of transfusion-associated circulatory overload. Nevertheless, a low intraoperative central venous pressure strategy, which is achieved by the use of diuretics and the avoidance of intravascular volume expansion with colloid and plasma, has been shown to be safe and effective and thus should be considered.50-52
The overall postoperative infection risk of 14% in our cohort and the incidence of pneumonia, surgical site infections, and line sepsis were much lower than those reported in previous clinical cohort studies.2, 4, 9, 12, 53 The reasons for this observation may be related to the fact that our transplant team has a very aggressive early extubation strategy.27 This strategy allows for rapid transfer from the ICU or direct admission to the floor from the postanesthesia care unit and results in the early withdrawal of indwelling vascular and urinary catheters and mobilization of patients. In addition, only relatively fresh RBCs (≤10 days old) are transfused into this patient population, and the age of blood has been shown to be a risk factor for infection.54
As shown in other surgical populations, RBCs were an independent risk factor in a dose-dependent fashion for postoperative infections in this cohort of patients undergoing liver transplantation.55-62 Each unit of transfused RBCs increased the risk of postoperative infection by 7%. Transfusion-related immunomodulation and its association with posttransfusion infection are well known, but the mechanisms are still uncertain. There are many immunomodulatory constituents, some of which accumulate during storage; these include but are not limited to human leukocyte antigen peptides, bioactive lipids, and soluble biological response modifiers.63 Prestorage leukoreduction did not reduce this infectious risk, and this is consistent with studies of other surgical and critically ill patient populations; thus, prestorage leukoreduction does not appear to protect against the known risks of transfused RBCs.57, 60, 64, 65 Because leukocytes contaminating stored RBCs theoretically potentiate transfusion-related immunomodulation and subsequent infectious risk by increasing the amounts of lipids and inflammatory cytokines (interleukin-6, interleukin-8, and tumor necrosis factor α) that accumulate during storage, we must consider the possibility that because our patients received only relatively fresh blood, the effect of leukoreduction may have been mitigated.66, 67 In the future, the issue of leukoreduction will be of less clinical importance because most blood centers in industrialized nations have developed a policy of universal leukoreduction.
Strategies to decrease the total use of RBCs during liver transplantation should be studied clinically with a bundled approach. Some of these strategies include avoidance of intravascular volume expansion (maintenance of a low central venous pressure). Elevated hydrostatic pressures in the vascular beds have been associated with increased blood loss.50-52 Selective use of pharmacological therapies may offer hemostatic benefit in certain patient populations, although timing and validated clotting studies that accurately predict which agents will clinically benefit particular subgroups of patients are lacking.68-74 Use of cell savers and improved surgical techniques may also decrease transfusion needs.75 With these techniques, some transplant centers have been able to eliminate the transfusion of any blood products in more than 80% of patients undergoing transplantation.76
The main limitation of our study was an inability to accurately differentiate TRALI from hydrostatic pulmonary edema and circulatory overload. We were stringent in our TRALI criteria, in that we did not include any patients who improved with fluid removal even if they met TRALI consensus criteria; this could have underestimated the incidence of TRALI. This likely would have biased any transfusion effect toward the null hypothesis and strengthened the association found between plasma transfusions and TRALI but falsely lowered the reported incidence. In addition, the use of CXR reports to diagnose circulatory overload has poor sensitivity, but the specificity with a preoperative-to-postoperative approach is likely quite high. For this reason, our definition of circulatory overload may also have resulted in a falsely low reported incidence. Another limitation was our inability to adequately control for the amount of tissue damage, technical difficulties, and complications during the surgical procedure. These factors likely resulted in a greater number of transfusions and may have increased infection risk unrelated to transfusion. We did include the total operative time as a surrogate for these factors in our logistic regression model with transfusion variables and found that it was not an independent risk factor. To attempt to control for the severity of illness post-transfusion, we adjusted for the incidence of reoperation. Although reoperation was associated with infection, this factor may not be causal but may instead identify patients who stay longer in the hospital and therefore are at higher risk of developing infection. Because of the observational study design, we can prove only an association and temporal relationship between blood transfusions and postoperative complications, but we cannot be sure that the association is causal. There are also potentially unmeasured confounding variables that we were unable to adjust for or identify. In addition, we were unfortunately not able to report on the sex or parity of the plasma donors, which may be transfusion-specific risk factors for TRALI and postoperative infections.77, 78 Lastly, we were unable to evaluate the effects of qualitative parameters of liver dysfunction such as ascites and encephalopathy on our outcome measures.
Postoperative infections are common in patients undergoing orthotopic liver transplantation and are associated with the number of transfused RBC units. In contrast, plasma-containing blood products (plasma and platelets) but not red cells are associated with the development of TRALI in this patient population. Future clinical trials in liver transplant patients should now focus on mitigating the use or preparation of a specific blood product while analyzing the effect on the appropriate clinical complication.
