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Transfusion of Aged Red Blood Cells in Liver Transplantation: Et tu, Brute?

Tanaka, Kenichi A. MD, MSc; Mazzeffi, Michael A. MD, MPH; Chow, Jonathan H. MD

doi: 10.1213/ANE.0000000000002811
Editorials: Editorial
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From the Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, Maryland.

Accepted for publication December 8, 2017.

Funding: None.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Kenichi A. Tanaka, MD, MSc, Department of Anesthesiology, University of Maryland School of Medicine, 22 S Greene St, Suite S8D12, Baltimore, MD 21201. Address e-mail to ktanaka@som.umaryland.edu.

After the first successful orthotopic liver transplantation (OLT) at the University of Colorado by Dr Thomas E. Starzl (1926–2017) in 1967, surgical techniques and perioperative management were steadily improved by his team during the 1980s at the University of Pittsburgh. Major blood loss and the need for massive transfusion (MT) were not uncommon in the early days of OLT,1 and, subsequently, the rapid infusion system was developed to manage MT.2 With advanced surgical techniques and effective transfusion protocols, allogeneic blood transfusion changed from an absolute necessity to a viable option in the past 10 years.3,4 Transfusion practice remains widely variable among transplant centers. The average transfusion rate of red blood cells (RBCs) may be as low as 0.5 units,3–5 but it can increase to 25 units in high-risk OLT cases.6 It is of clinical interest to know if newer versus older RBCs make any difference in clinical outcomes after transfusion because it is common practice for many blood banks to dispense the oldest compatible RBCs before newer ones.

A multitude of changes occurs during RBC storage, including the depletion of 2,3-diphosphoglycerate, loss of RBC integrity/deformability, hemolysis, and hyperkalemia. This so-called storage lesion of RBCs is associated with the release of cell-free hemoglobin and microparticles.7,8 Many clinicians thus became interested in testing the hypothesis that transfusion of aged RBCs worsens clinical outcomes compared to the newer ones after the publication of 1 large observational study in cardiac surgery (n = 6002).9 In the study, both cohorts received median 2 RBCs, but older RBCs (median, 20-day old) were associated with higher incidences of renal failure (2.7% vs 1.6%; P = .003) and in-hospital mortality (2.8% vs 1.7%; P = .004) when compared to newer RBCs (median, 11-day old). However, despite propensity score–matched statistical modeling, clinical features of 2 cohorts were statistically different at baseline, and older units were preferentially used in MT, a known factor that worsens mortality.10,11 Indeed, the Red-Cell Storage Duration Study (RECESS) study which randomized 1098 cardiac surgery patients to receive newer RBCs (mean, 7.8-day old) or older RBCs (mean, 28.3-day old) found no difference in renal dysfunction or multiple organ dysfunction after transfusion of median 3 RBCs through postoperative day 7.12 Notably, 13.2% of patients (n = 145) were transfused 8 or more RBC units, and these patients incurred more multiorgan dysfunctions regardless of RBC age.

In this issue of Anesthesia& Analgesia, Wang et al13 report their findings from a retrospective cohort study comparing the ages of transfused RBCs on postoperative acute kidney injury (AKI) in consecutive OLT patients (n = 156). Two cohorts were separated by the mean RBC age of 9.2-day (newer) and 18.7-day (older). The older RBC cohort had more severe disease than did the newer RBC cohort (mean Model for End-stage Liver Disease [MELD] score 14 vs 10; P = .003), and had more MT (median RBCs 16 vs 12 units; P = .104; median plasma volume 2200 vs 1600 mL; P = .003). Using propensity score matching and inverse probability of treatment weighting, the authors achieved reasonable parity except for blood type distribution. Inverse probability of treatment weighting–adjusted transfusion data still show that large amounts of RBCs (14–16 units) and plasma (1.8–2.0 L) were transfused in 2 cohorts, which might have resulted in a high overall incidence of AKI at 51.8%. The authors found that the adjusted odds ratios (ORs) for primary end points were higher in the older RBC versus newer RBC groups; AKI 61.3% vs 42.7% (OR, 2.13; P = .03) and severe AKI 36.5% vs 14.7% (OR, 3.34; P = .003).

Given the large number of conflicting studies on aged RBCs, one must consider the unique aspect of OLT patients as pertinent to the Wang et al’s13 hypothesis. Abnormal RBCs are typically cleared from circulation by splenic and hepatic marcrophages via a process called erythrophagocytosis.14,15 Assuming that the liver has a major role in erythrophagocytosis, OLT patients potentially suffer from increased risks associated with abnormal RBCs and microparticles due to the anhepatic phase and ischemia/reperfusion injury of the donor liver. As mentioned by Wang et al,13 2 previously published retrospective studies on the age of RBCs in OLT showed conflicting results. Dunn et al16 failed to demonstrate any effect for RBC age in 500 OLT cases, but showed that higher RBC requirement (≥10 units; n = 45) increased the risk of death. Conversely, Cywinski et al17 reported a higher hazard ratio (1.65; P = .004) for the composite of mortality and graft failure in the patients who received older RBCs (median, 19-day old) versus newer ones (median, 12-day old) among 637 OLT recipients. Unfortunately, different end points in these studies (ie, lack of AKI data) hinder direct comparisons with this study.13

AKI after OLT surgery is multifactorial with factors such as older age, poor baseline kidney function, hemodynamic instability, massive hemorrhage and transfusion, and immunosuppression contributing to lower glomerular filtration. RBC and plasma requirements were considerably high in Wang et al’s13 study for relatively low MELD scores in comparison with the recent American data by Nicolau-Raducu et al18 (Table). In the latter data, patients with a higher MELD score tend to receive antifibrinolytic therapy and increased amounts of RBCs and plasma, ultimately suffering from more severe AKIs.18 Although statistical techniques by Wang et al13 numerically controlled MELD scores and numbers of RBC and plasma between 2 cohorts, it is possible that unmeasured confounders such as hemodynamic instability associated with MT might have influenced the incidence of AKIs.16 Use of antifibrinolytics and the impact of MT were not specifically discussed by Wang et al’s13 study. Heterogeneity of OLT practice thus limits the generalizability of their findings on the use of aged RBCs.

Table.

Table.

To answer the storage age question, mechanistic and translational approaches are needed in future studies. For example, poststorage rejuvenation treatment of RBCs may represent a potential way to mitigate potential harms of RBC storage lesion in MT.19 For non-RBC components, ABO nonidentical minor incompatibility should be investigated as a potential modifier of clinical outcomes in MT.20 More comprehensive analyses of donor units beyond their storage time and recipients’ characteristics are also necessary to better establish a causal relationship.

In the time of an aging society and emerging pathogens, allogeneic blood products are a scarce resource, and inventory management is complex. A multidisciplinary effort to reduce allogeneic transfusion should be encouraged even in complex OLT. We congratulate Wang et al13 for entering the coliseum of old versus new RBCs, but it seems that old Caesar is not yet taken over by young Brute.

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DISCLOSURES

Name: Kenichi A. Tanaka, MD, MSc.

Contribution: This author came up with the concept and wrote the editorial.

Name: Michael A. Mazzeffi, MD, MPH.

Contribution: This author helped write the editorial.

Name: Jonathan H. Chow, MD.

Contribution: This author helped write the editorial.

This manuscript was handled by: Marisa B. Marques, MD.

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