Randomized trial of red cell washing for the prevention of transfusion-associated organ injury in cardiac surgery

Abstract

Background. Experimental studies suggest that mechanical cell washing to remove pro-inflammatory components that accumulate in the supernatant of stored donor red blood cells (RBCs) might reduce inflammation and organ injury in transfused patients. Methods. Cardiac surgery patients at increased risk of large-volume RBC transfusion were eligible. Participants were randomized to receive either mechanically washed allogenic RBCs or standard care RBCs. The primary outcome was serum interleukin-8 measured at baseline and at four postsurgery time points. A mechanism substudy evaluated the effects of washing on stored RBCs in vitro and on markers of platelet, leucocyte, and endothelial activation in trial subjects. Results. Sixty adult cardiac surgery patients at three UK cardiac centres were enrolled between September 2013 and March 2015. Subjects received a median of 3.5 (interquartile range 2–5.5) RBC units, stored for a mean of 21 (sd 5.2) days, within 48 h of surgery. Mechanical washing reduced concentrations of RBC-derived microvesicles but increased cell-free haemoglobin concentrations in RBC supernatant relative to standard care RBC supernatant. There was no difference between groups with respect to perioperative serum interleukin-8 values [adjusted mean difference 0.239 (95% confidence intervals −0.231, 0.709), P=0.318] or concentrations of plasma RBC microvesicles, platelet and leucocyte activation, plasma cell-free haemoglobin, endothelial activation, or biomarkers of heart, lung, or kidney injury. Conclusions. These results do not support a hypothesis that allogenic red blood cell washing has clinical benefits in cardiac surgery. Clinical trial registration. ISRCTN 27076315.

Transfusion-related immunomodulation: a reappraisal

“…Although relatively little plasma remains in modern units of packed RBCs, it is not absent, unless washed or frozen-thawed RBCs are prepared [19]. Thus, various plasma-induced adverse effects can occur, with immunological consequences, although these are not classically considered to represent TRIM.…”

Diagnostic and therapeutic medical devices for safer blood management in cardiac surgery: systematic reviews, observational studies and randomised controlled trials

“…Conversely, free haemoglobin increased expression of activated integrin-β1 and connecting segment-1 (CS-1) fibronectin on the surface of human umbilical vein endothelial cells, indicating an alternative activation pathway for haemoglobin in endothelial cells. 263 In the porcine model we observed that recipients of washed 14-day stored red cells developed significantly higher plasma free haemoglobin levels than other groups. Transfusion of washed 14-day stored cells also resulted in increased pulmonary levels of tumour necrosis factor-α (TNF-α), pulmonary vascular endothelial dysfunction and increased haemoxygenase-1 expression in porcine lungs, renal vascular endothelial dysfunction, an acute increase in serum creatinine levels and increased haemoxygenase-1 expression in kidney.…”

“…263 Mechanical washing of red cells significantly reduced concentrations of CD235a/annexin V microvesicles as well as total microvesicle concentrations at day 41 and day 21, the median storage time of red cells transfused in the REDWASH trial. In further (unpublished) work we have shown that oxidised lipids on the surface of microvesicles directly activate monocytes and phosphatidylserine on the surface of microvesicles directly activates platelets.…”

“…263 Mechanical washing did not reduce levels of free haemoglobin in 35-day stored human red cells and doubled free haemoglobin levels in 21-day stored red cells. In human umbilical vein endothelial cell static culture experiments we demonstrated that free RANDOMISED CONTROLLED TRIAL: REDWASH NIHR Journals Library www.journalslibrary.nihr.ac.uk haemoglobin (1 mg/ml) directly increased endothelial permeability, whereas microvesicles, or phosphatebuffered saline (PBS) (negative control), did not.…”

“…These changes were not attributable to differences in haematocrit, red cell survival, tissue hypoxia-inducible factor-1α expression, nitric oxide bioavailability or plasma iron levels. 263 On the basis of these results we concluded that mechanical red cell washing resulted in the accelerated release of cell-free haemoglobin and that this causes endothelial activation, dysfunction and pulmonary and kidney injury in experimental models in vivo. We considered whether there was evidence of similar haemoglobin-mediated endothelial injury in a post hoc exploratory analysis of the first 60 participants recruited to the REDWASH trial.…”