Multiple cohort studies in patients undergoing liver transplantation have found an association between the amount of intra-operative transfusion and worse outcomes (16
). Postoperative infections are well known complications of transfusion in patients undergoing orthotopic liver transplantation, but the incidence of Transfusion Related Acute Lung Injury (TRALI) has been poorly defined (4
). The results of this study demonstrate that patients undergoing liver transplantation have less risk of TRALI than that of bleeding critically ill patients with chronic liver disease not undergoing liver transplantation (18
). Despite a low incidence, TRALI resulted in a 10 fold increase in hospital mortality and therefore is of clinical importance. In our cohort, only plasma containing blood products (platelets and plasma) were associated with TRALI, consistent with other reports in liver transplant and critically ill patients with chronic liver disease (16
). In addition, transfused RBCs were associated in a dose-dependent fashion with post-operative infection which resulted in a five-fold increase in mortality. Prestorage leukoreduction did not influence this risk.
The risk of TRALI in this liver transplant cohort is 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 receiving similar amounts of all blood products who were admitted to the ICU for a variceal bleed (20
). The two-event model of TRALI may explain this epidemiologic difference. In this model an underlying pro-inflammatory state activates pulmonary endothelial cells, resulting in the adherence and sequestration of neutrophils in the lung (43
). These primed, hyperactive neutrophils are vulnerable to activation from antibodies, lipids and other biologic mediators found in blood products. These mediators cause release of the microbicidal arsenal from these adherent neutrophils leading to endothelial cell damage, capillary leak and ALI (44
). Active sepsis is a pro-inflammatory condition that generally precludes patients from undergoing liver transplantation, but is very common in patients admitted with a variceal bleed (46
). Also, patients undergoing transplantation generally receive high dose intra-operative glucocorticoids with potent immunosuppressive effects that may modulate the systemic inflammatory effect of the surgery. Lastly, transplant patients receive a new liver which may somehow change TRALI risk due to immunomodulatory effects of this unique event.
One third of 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 or TACO is utilized. The one third of patients with circulatory overload had significantly prolonged ICU and hospital length of stay as well as an increased post-operative infection risk. It is unknown whether this association is causal, but circulatory overload increases time on the mechanical ventilator, thereby leading to increased ICU length of stay and increasing the risk for post-operative infection. The amount of intra-operative albumin administration and not blood product transfusion was an independent risk factor for circulatory overload. Albumin has previously been shown to be associated with cardiopulmonary complications and 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 so it is unclear of how many of these patients would actually be given the diagnosis of TACO. Nevertheless, a low intra-operative central venous pressure strategy achieved by using diuretics and avoiding intravascular volume expansion with colloid and plasma has been shown to be safe and effective and thus should be considered (50
The overall post-operative infection risk of 14% in our cohort and the incidence of pneumonia, surgical site infection and line sepsis are much lower than reported in previous clinical cohort studies (2
). 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 out of the ICU or direct admission to the floor from the post-anesthesia care unit, resulting in 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 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 post-operative infection in this cohort of patients undergoing liver transplantation (55
). Each unit of RBCs transfused increases the risk of post-operative infection by 7%. Transfusion-related immunomodulation (TRIM) and its association with post-transfusion infection is a well known phenomenon, but the mechanisms are still uncertain. The are many immunomodulatory constituents some of which accumulate during storage including, but not limited to human leukocyte antigen peptides, bioactive lipids and soluble biologic response modifiers (63
). Prestorage leukoreduction did not reduce this infectious risk which is consistent with studies in other surgical and critically ill patient populations; thus prestorage leukoreduction does not appear to protect against the known risks of transfused red blood cells (57
). Because leukocytes contaminating stored red blood cells theoretically potentiate TRIM and subsequent infectious risk by increasing the amount of lipids and inflammatory cytokines (IL-6. IL-8, TNF-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
). Moving forward, the issue of leukoreduction is of less clinical importance as most blood centers in industrialized nations have developed a policy of universal leukoreduction.
Strategies to decrease total use of RBCs during liver transplantation should be studied clinically in a bundled approach. Some of these strategies include avoiding intravascular volume expansion (maintain low central venous pressure). Elevated hydrostatic pressures in the vascular beds have been associated with increased blood loss (50
). Selective use of pharmacologic therapies may offer hemostatic benefit in certain patient populations though timing and validated clotting studies that accurately predict which agents will clinically benefit particular subgroups of patients are lacking (68
). Use of cell savers and improved surgical techniques may also decrease transfusion needs (75
). Though these techniques, some transplant centers have been able to eliminate transfusion of any blood products in >80% of patients undergoing transplantation (76
The main limitation of our study is 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 which could have underestimated the incidence of TRALI. This would likely bias any transfusion effect toward the null hypothesis strengthening the association found between plasma transfusion and TRALI, but falsely lowering the reported incidence. In addition, using CXR reports to diagnose circulatory overload has poor sensitivity though specificity when using a pre-operative to post-operative approach is likely quite high. For this reason, our definition of circulatory overload may have also 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 result in a greater number of transfusions and may increase infection risk unrelated to transfusion. We did include 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 severity of illness post-transfusion we adjusted for the incidence of re-operation. Though re-operation was associated with infection it may not be causal, but may instead identify patients who stay longer in the hospital and therefore are at higher risk to develop infection. Due to the observational study design we can only prove association and temporal relationship between blood transfusion and post-operative complications, but we cannot be sure 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 post-operative infection (77
). Lastly, we were unable to evaluate the effects of qualitative parameters of liver dysfunction such as ascites and encephalopathy on our outcome measures.
Post-operative infection is common in patients undergoing orthotopic liver transplantation and is associated with the number of red blood cell units transfused. 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.