Point-of-care washing of allogeneic red blood cells for the prevention of transfusion-related respiratory complications (WAR-PRC): a protocol for a multicenter randomised clinical trial in patients undergoing cardiac surgery

Matthew A Warner, Ian J Welsby, Phillip J Norris, Christopher C Silliman, Sarah Armour, Erica D Wittwer, Paula J Santrach, Laurie A Meade, Lavonne M Liedl, Chelsea M Nieuwenkamp, Brian Douthit, Camille M van Buskirk, Phillip J Schulte, Rickey E Carter, Daryl J Kor, Matthew A Warner, Ian J Welsby, Phillip J Norris, Christopher C Silliman, Sarah Armour, Erica D Wittwer, Paula J Santrach, Laurie A Meade, Lavonne M Liedl, Chelsea M Nieuwenkamp, Brian Douthit, Camille M van Buskirk, Phillip J Schulte, Rickey E Carter, Daryl J Kor

Abstract

Introduction: The transfusion-related respiratory complications, transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO), are leading causes of transfusion-related morbidity and mortality. At present, there are no effective preventive strategies with red blood cell (RBC) transfusion. Although mechanisms remain incompletely defined, soluble biological response modifiers (BRMs) within the RBC storage solution may play an important role. Point-of-care (POC) washing of allogeneic RBCs may remove these BRMs, thereby mitigating their impact on post-transfusion respiratory complications.

Methods and analysis: This is a multicenter randomised clinical trial of standard allogeneic versus washed allogeneic RBC transfusion for adult patients undergoing cardiac surgery testing the hypothesis that POC RBC washing is feasible, safe, and efficacious and will reduce recipient immune and physiologic responses associated with transfusion-related respiratory complications. Relevant clinical outcomes will also be assessed. This investigation will enrol 170 patients at two hospitals in the USA. Simon's two-stage design will be used to assess the feasibility of POC RBC washing. The primary safety outcomes will be assessed using Wilcoxon Rank-Sum tests for continuous variables and Pearson chi-square test for categorical variables. Standard mixed modelling practices will be employed to test for changes in biomarkers of lung injury following transfusion. Linear regression will assess relationships between randomised group and post-transfusion physiologic measures.

Ethics and dissemination: Safety oversight will be conducted under the direction of an independent Data and Safety Monitoring Board (DSMB). Approval of the protocol was obtained by the DSMB as well as the institutional review boards at each institution prior to enrolling the first study participant. This study aims to provide important information regarding the feasibility of POC washing of allogeneic RBCs and its potential impact on ameliorating post-transfusion respiratory complications. Additionally, it will inform the feasibility and scientific merit of pursuing a more definitive phase II/III clinical trial.

Registration: ClinicalTrials.gov registration number is NCT02094118 (Pre-results).

Keywords: Adult Anaesthesia; Anaemia.

Conflict of interest statement

Competing interests: None declared.

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Figures

Figure 1
Figure 1
Schematic of the planned study procedures. ALI, acute lung injury; CATS, Continuous Autotransfusion System; CCL5, chemokine ligand 5; CFH, cell free haemoglobin; CHF, congestive heart failure; FiO2, fraction of inspired oxygen; Hb, haemoglobin; MAP, mean arterial pressure; PAI-1, plasminogen activator inhibitor 1; PaO2, arterial partial pressure of oxygen; PCWP, pulmonary capillary wedge pressure; PEEP, positive end expiratory pressure; PO, postoperative; POD, postoperative day; RAGE, receptor of advanced glycation end-products; RBC, red blood cell; RBC-MP, red blood cell microparticle; Rxs, reactions; sCD40L, soluble CD40 ligand; SOFA, sequential organ failure assessment; SpO2, oxygen saturation by pulse oximetry; SVR, systemic vascular resistance; TACO, transfusion-associated circulatory overload; TRALI, transfusion-related acute lung injury; Trx, transfusion.

References

    1. Vlaar AP, Binnekade JM, Prins D, et al. . Risk factors and outcome of transfusion-related acute lung injury in the critically ill: a nested case-control study. Crit Care Med 2010;38:771–8. 10.1097/CCM.0b013e3181cc4d4b
    1. Gajic O, Rana R, Winters JL, et al. . Transfusion-related acute lung injury in the critically ill: prospective nested case-control study. Am J Respir Crit Care Med 2007;176:886–91. 10.1164/rccm.200702-271OC
    1. Silliman CC, Fung YL, Ball JB, et al. . Transfusion-related acute lung injury (TRALI): current concepts and misconceptions. Blood Rev 2009;23:245–55. 10.1016/j.blre.2009.07.005
    1. Popovsky MA. The Emily Cooley Lecture 2009 to breathe or not to breathe-that is the question. Transfusion 2010:2057–62. 10.1111/j.1537-2995.2010.02788.x
    1. Popovsky MA. Transfusion and the lung: circulatory overload and acute lung injury. Vox Sang 2004;87:62–5. 10.1111/j.1741-6892.2004.00453.x
    1. Li G, Kojicic M, Reriani MK, et al. . Long-term survival and quality of life after transfusion-associated pulmonary edema in critically ill medical patients. Chest 2010;137:783–9. 10.1378/chest.09-0841
    1. Bux J, Sachs UJ. The pathogenesis of transfusion-related acute lung injury (TRALI). Br J Haematol 2007;136:788–99. 10.1111/j.1365-2141.2007.06492.x
    1. Rana R, Fernández-Pérez ER, Khan SA, et al. . Transfusion-related acute lung injury and pulmonary edema in critically ill patients: a retrospective study. Transfusion 2006;46:1478–83. 10.1111/j.1537-2995.2006.00930.x
    1. Kopko PM, Popovsky MA. Pulmonary injury from transfusion-related acute lung injury. Clin Chest Med 2004;25:105–11. 10.1016/S0272-5231(03)00135-7
    1. Silliman CC, Moore EE, Kelher MR, et al. . Identification of lipids that accumulate during the routine storage of prestorage leukoreduced red blood cells and cause acute lung injury. Transfusion 2011;51:2549–54. 10.1111/j.1537-2995.2011.03186.x
    1. Silliman CC. The two-event model of transfusion-related acute lung injury. Crit Care Med 2006;34:S124–S131. 10.1097/01.CCM.0000214292.62276.8E
    1. Khan SY, Kelher MR, Heal JM, et al. . Soluble CD40 ligand accumulates in stored blood components, primes neutrophils through CD40, and is a potential cofactor in the development of transfusion-related acute lung injury. Blood 2006;108:2455–62. 10.1182/blood-2006-04-017251
    1. Bierbaum BE, Callaghan JJ, Galante JO, et al. . An analysis of blood management in patients having a total hip or knee arthroplasty. J Bone Joint Surg Am 1999;81:2–10. 10.2106/00004623-199901000-00002
    1. Popovsky MA, Audet AM, Andrzejewski C. Transfusion-associated circulatory overload in orthopedic surgery patients: a multi-institutional study. Immunohematology 1996;12:87–9.
    1. Bless NM, Huber-Lang M, Guo RF, et al. . Role of CC chemokines (macrophage inflammatory protein-1 beta, monocyte chemoattractant protein-1, RANTES) in acute lung injury in rats. J Immunol 2000;164:2650–9. 10.4049/jimmunol.164.5.2650
    1. Andrzejewski C, Popovsky MA, Stec TC, et al. . Hemotherapy bedside biovigilance involving vital sign values and characteristics of patients with suspected transfusion reactions associated with fluid challenges: can some cases of transfusion-associated circulatory overload have proinflammatory aspects? Transfusion 2012;52:2310–20. 10.1111/j.1537-2995.2012.03595.x
    1. Klein HG, Anstee DJ, Mollison's Blood Transfusion in Clinical Medicine. 11 ed Malden, MA: Oxford: Blackwell Publishing, 2006.
    1. Vermeulen Windsant IC, de Wit NC, Sertorio JT, et al. . Blood transfusions increase circulating plasma free hemoglobin levels and plasma nitric oxide consumption: a prospective observational pilot study. Crit Care 2012;16:R95 10.1186/cc11359
    1. Stapley R, Owusu BY, Brandon A, et al. . Erythrocyte storage increases rates of NO and nitrite scavenging: implications for transfusion-related toxicity. Biochem J 2012;446:499–508. 10.1042/BJ20120675
    1. Singel DJ, Stamler JS. Chemical physiology of blood flow regulation by red blood cells: the role of nitric oxide and S-nitrosohemoglobin. Annu Rev Physiol 2005;67:99–145. 10.1146/annurev.physiol.67.060603.090918
    1. Jy W, Ricci M, Shariatmadar S, et al. . Microparticles in stored red blood cells as potential mediators of transfusion complications. Transfusion 2011;51:886–93. 10.1111/j.1537-2995.2011.03099.x
    1. Gladwin MT, Kim-Shapiro DB. Storage lesion in banked blood due to hemolysis-dependent disruption of nitric oxide homeostasis. Curr Opin Hematol 2009;16:515–23. 10.1097/MOH.0b013e32833157f4
    1. Burnier L, Fontana P, Kwak BR, et al. . Cell-derived microparticles in haemostasis and vascular medicine. Thromb Haemost 2009;101:439–51. 10.1160/TH08-08-0521
    1. Westphal-Varghese B, Erren M, Westphal M, et al. . Processing of stored packed red blood cells using autotransfusion devices decreases potassium and microaggregates: a prospective, randomized, single-blinded in vitro study. Transfus Med 2007;17:89–95. 10.1111/j.1365-3148.2007.00732.x
    1. Rosolski T, Matthey T, Frick U, et al. . Blood separation with two different autotransfusion devices: effects on blood cell quality and coagulation variables. Int J Artif Organs 1998;21:820–4.
    1. Gruber M, Breu A, Frauendorf M, et al. . Washing of banked blood by three different blood salvage devices. Transfusion 2013;53:1001–9. 10.1111/j.1537-2995.2012.03853.x
    1. Booke M, Fobker M, Fingerhut D, et al. . Fat elimination during intraoperative autotransfusion: an in vitro investigation. Anesth Analg 1997;85:959–62.
    1. Blumberg N, Heal JM, Gettings KF, et al. . An association between decreased cardiopulmonary complications (transfusion-related acute lung injury and transfusion-associated circulatory overload) and implementation of universal leukoreduction of blood transfusions. Transfusion 2010;50:2738–44. 10.1111/j.1537-2995.2010.02748.x
    1. Blumberg N, Heal JM, Rowe JM. A randomized trial of washed red blood cell and platelet transfusions in adult acute leukemia [ISRCTN76536440]. BMC Blood Disord 2004;4:6 10.1186/1471-2326-4-6
    1. Biffl WL, Moore EE, Offner PJ, et al. . Plasma from aged stored red blood cells delays neutrophil apoptosis and primes for cytotoxicity: abrogation by poststorage washing but not prestorage leukoreduction. J Trauma 2001;50:426–32. discussion 32. 10.1097/00005373-200103000-00005
    1. Silliman CC, Moore EE, Johnson JL, et al. . Transfusion of the injured patient: proceed with caution. Shock 2004;21:291–9. 10.1097/00024382-200404000-00001
    1. The 2011 National blood collection and utilization survey. Washington, DC: Department of Health and Human Services, 2011.
    1. Reeves BC, Murphy GJ. Increased mortality, morbidity, and cost associated with red blood cell transfusion after cardiac surgery. Curr Opin Cardiol 2008;23:607–12. 10.1097/HCO.0b013e328310fc95
    1. Koch CG, Li L, Sessler DI, et al. . Duration of red-cell storage and complications after cardiac surgery. N Engl J Med 2008;358:1229–39. 10.1056/NEJMoa070403
    1. Koch CG, Li L, Duncan AI, et al. . Morbidity and mortality risk associated with red blood cell and blood-component transfusion in isolated coronary artery bypass grafting. Crit Care Med 2006;34:1608–16. 10.1097/01.CCM.0000217920.48559.D8
    1. Koch C, Li L, Figueroa P, et al. . Transfusion and pulmonary morbidity after cardiac surgery. Ann Thorac Surg 2009;88:1410–8. 10.1016/j.athoracsur.2009.07.020
    1. Goudie R, Sterne JA, Verheyden V, et al. . Risk scores to facilitate preoperative prediction of transfusion and large volume blood transfusion associated with adult cardiac surgery. Br J Anaesth 2015;114:757–66. 10.1093/bja/aeu483
    1. Murphy GJ, Reeves BC, Rogers CA, et al. . Increased mortality, postoperative morbidity, and cost after red blood cell transfusion in patients having cardiac surgery. Circulation 2007;116:2544–52. 10.1161/CIRCULATIONAHA.107.698977
    1. Li G, Rachmale S, Kojicic M, et al. . Incidence and transfusion risk factors for transfusion-associated circulatory overload among medical intensive care unit patients. Transfusion 2011;51:338–43. 10.1111/j.1537-2995.2010.02816.x
    1. O'Leary MF, Szklarski P, Klein TM, et al. . Hemolysis of red blood cells after cell washing with different automated technologies: clinical implications in a neonatal cardiac surgery population. Transfusion 2011;51:955–60. 10.1111/j.1537-2995.2010.02935.x
    1. Mehta RL, Kellum JA, Shah SV, et al. . Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007;11:R31 10.1186/cc5713
    1. Bakkour S, Acker JP, Chafets DM, et al. . Manufacturing method affects mitochondrial DNA release and extracellular vesicle composition in stored red blood cells. Vox Sang 2016;111:22–32. 10.1111/vox.12390
    1. Danesh A, Inglis HC, Jackman RP, et al. . Exosomes from red blood cell units bind to monocytes and induce proinflammatory cytokines, boosting T-cell responses in vitro. Blood 2014;123:687–96. 10.1182/blood-2013-10-530469
    1. Bridges EJ, Woods SL. Pulmonary artery pressure measurement: state of the art. Heart Lung 1993;22:99–111.
    1. Fremont RD, Koyama T, Calfee CS, et al. . Acute lung injury in patients with traumatic injuries: utility of a panel of biomarkers for diagnosis and pathogenesis. J Trauma 2010;68:1121–7. 10.1097/TA.0b013e3181c40728
    1. Shi Q, Pavey ES, Carter RE. Bonferroni-based correction factor for multiple, correlated endpoints. Pharm Stat 2012;11:300–9. 10.1002/pst.1514
    1. Fransen E, Maessen J, Dentener M, et al. . Impact of blood transfusions on inflammatory mediator release in patients undergoing cardiac surgery. Chest 1999;116:1233–9. 10.1378/chest.116.5.1233
    1. Hirai S. Systemic inflammatory response syndrome after cardiac surgery under cardiopulmonary bypass. Ann Thorac Cardiovasc Surg 2003;9:365–70.
    1. Allan CK, Newburger JW, McGrath E, et al. . The relationship between inflammatory activation and clinical outcome after infant cardiopulmonary bypass. Anesth Analg 2010;111:1244–51. 10.1213/ANE.0b013e3181f333aa
    1. Meduri GU, Headley S, Kohler G, et al. . Persistent elevation of inflammatory cytokines predicts a poor outcome in ARDS. plasma IL-1 beta and IL-6 levels are consistent and efficient predictors of outcome over time. Chest 1995;107:1062–73.
    1. Koch CG, Li L, Sessler DI, et al. . Duration of red-cell storage and complications after cardiac surgery. N Engl J Med 2008;358:1229–39. 10.1056/NEJMoa070403
    1. Eikelboom JW, Cook RJ, Liu Y, et al. . Duration of red cell storage before transfusion and in-hospital mortality. Am Heart J 2010;159:737–43. 10.1016/j.ahj.2009.12.045
    1. Manlhiot C, McCrindle BW, Menjak IB, et al. . Longer blood storage is associated with suboptimal outcomes in high-risk pediatric cardiac surgery. Ann Thorac Surg 2012;93:1563–9. 10.1016/j.athoracsur.2011.08.075
    1. Basran S, Frumento RJ, Cohen A, et al. . The association between duration of storage of transfused red blood cells and morbidity and mortality after reoperative cardiac surgery. Anesth Analg 2006;103:15–20. table of contents. 10.1213/01.ane.0000221167.58135.3d
    1. Silliman CC, Clay KL, Thurman GW, et al. . Partial characterization of lipids that develop during the routine storage of blood and prime the neutrophil NADPH oxidase. J Lab Clin Med 1994;124:684–94.
    1. Kristiansson M, Soop M, Saraste L, et al. . Cytokines in stored red blood cell concentrates: promoters of systemic inflammation and simulators of acute transfusion reactions? Acta Anaesthesiol Scand 1996;40:496–501. 10.1111/j.1399-6576.1996.tb04475.x
    1. Nielsen HJ, Reimert CM, Pedersen AN, et al. . Time-dependent, spontaneous release of white cell- and platelet-derived bioactive substances from stored human blood. Transfusion 1996;36:960–5. 10.1046/j.1537-2995.1996.36111297091738.x
    1. Rapido F, Brittenham GM, Bandyopadhyay S, et al. . Prolonged red cell storage before transfusion increases extravascular hemolysis. J Clin Invest 2017;127:375–82. 10.1172/JCI90837
    1. Ware LB, Koyama T, Billheimer DD, et al. . Prognostic and pathogenetic value of combining clinical and biochemical indices in patients with acute lung injury. Chest 2010;137:288–96. 10.1378/chest.09-1484
    1. Parsons PE, Eisner MD, Thompson BT, et al. . Lower tidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury. Crit Care Med 2005;33:1–6. discussion 230-2. 10.1097/01.CCM.0000149854.61192.DC
    1. McClintock D, Zhuo H, Wickersham N, et al. . Biomarkers of inflammation, coagulation and fibrinolysis predict mortality in acute lung injury. Crit Care 2008;12:R41 10.1186/cc6846
    1. Ware LB, Matthay MA, Parsons PE, et al. . Pathogenetic and prognostic significance of altered coagulation and fibrinolysis in acute lung injury/acute respiratory distress syndrome. Crit Care Med 2007;35:1821–8. 10.1097/01.CCM.0000275386.95968.5F
    1. Prabhakaran P, Ware LB, White KE, et al. . Elevated levels of plasminogen activator inhibitor-1 in pulmonary edema fluid are associated with mortality in acute lung injury. Am J Physiol Lung Cell Mol Physiol 2003;285:L20–L28. 10.1152/ajplung.00312.2002
    1. Christie JD, Robinson N, Ware LB, et al. . Association of protein C and type 1 plasminogen activator inhibitor with primary graft dysfunction. Am J Respir Crit Care Med 2007;175:69–74. 10.1164/rccm.200606-827OC
    1. Ware LB, Koyama T, Billheimer DD, et al. . Prognostic and pathogenetic value of combining clinical and biochemical indices in patients with acute lung injury. Chest 2010;137:288–96. 10.1378/chest.09-1484
    1. Fremont RD, Koyama T, Calfee CS, et al. . Acute lung injury in patients with traumatic injuries: utility of a panel of biomarkers for diagnosis and pathogenesis. J Trauma 2010;68:1121–7. 10.1097/TA.0b013e3181c40728
    1. Ware LB, Eisner MD, Thompson BT, et al. . Significance of von Willebrand factor in septic and nonseptic patients with acute lung injury. Am J Respir Crit Care Med 2004;170:766–72. 10.1164/rccm.200310-1434OC
    1. Ware LB, Conner ER, Matthay MA. Von Willebrand factor antigen is an independent marker of poor outcome in patients with early acute lung injury. Crit Care Med 2001;29:2325–31. 10.1097/00003246-200112000-00016
    1. Rubin DB, Wiener-Kronish JP, Murray JF, et al. . Elevated von Willebrand factor antigen is an early plasma predictor of acute lung injury in nonpulmonary sepsis syndrome. J Clin Invest 1990;86:474–80. 10.1172/JCI114733
    1. Moss M, Ackerson L, Gillespie MK, et al. . von Willebrand factor antigen levels are not predictive for the adult respiratory distress syndrome. Am J Respir Crit Care Med 1995;151:15–20. 10.1164/ajrccm.151.1.7812545
    1. Calfee CS, Eisner MD, Parsons PE, et al. . Soluble intercellular adhesion molecule-1 and clinical outcomes in patients with acute lung injury. Intensive Care Med 2009;35:248–57. 10.1007/s00134-008-1235-0
    1. Covarrubias M, Ware LB, Kawut SM, et al. . Plasma intercellular adhesion molecule-1 and Von Willebrand factor in primary graft dysfunction after lung transplantation. Am J Transplant 2007;7:2573–8. 10.1111/j.1600-6143.2007.01981.x
    1. Agouridakis P, Kyriakou D, Alexandrakis MG, et al. . The predictive role of serum and bronchoalveolar lavage cytokines and adhesion molecules for acute respiratory distress syndrome development and outcome. Respir Res 2002;3:25 10.1186/rr193
    1. Eisner MD, Parsons P, Matthay MA, et al. . Plasma surfactant protein levels and clinical outcomes in patients with acute lung injury. Thorax 2003;58:983–8. 10.1136/thorax.58.11.983
    1. Greene KE, Wright JR, Steinberg KP, et al. . Serial changes in surfactant-associated proteins in lung and serum before and after onset of ARDS. Am J Respir Crit Care Med 1999;160:1843–50. 10.1164/ajrccm.160.6.9901117
    1. Christie JD, Shah CV, Kawut SM, et al. . Plasma levels of receptor for advanced glycation end products, blood transfusion, and risk of primary graft dysfunction. Am J Respir Crit Care Med 2009;180:1010–5. 10.1164/rccm.200901-0118OC
    1. Calfee CS, Ware LB, Eisner MD, et al. . Plasma receptor for advanced glycation end products and clinical outcomes in acute lung injury. Thorax 2008;63:1083–9. 10.1136/thx.2008.095588
    1. Grommes J, Alard JE, Drechsler M, et al. . Disruption of platelet-derived chemokine heteromers prevents neutrophil extravasation in acute lung injury. Am J Respir Crit Care Med 2012;185:628–36. 10.1164/rccm.201108-1533OC
    1. Conti P, DiGioacchino M. MCP-1 and RANTES are mediators of acute and chronic inflammation. Allergy Asthma Proc 2001;22:133–7. 10.2500/108854101778148737
    1. Donadee C, Raat NJ, Kanias T, et al. . Nitric oxide scavenging by red blood cell microparticles and cell-free hemoglobin as a mechanism for the red cell storage lesion. Circulation 2011;124:465–76. 10.1161/CIRCULATIONAHA.110.008698
    1. Li G, Daniels CE, Kojicic M, et al. . The accuracy of natriuretic peptides (brain natriuretic peptide and N-terminal pro-brain natriuretic) in the differentiation between transfusion-related acute lung injury and transfusion-related circulatory overload in the critically ill. Transfusion 2009;49:13–20. 10.1111/j.1537-2995.2008.01941.x
    1. Tobian AA, Sokoll LJ, Tisch DJ, et al. . N-terminal pro-brain natriuretic peptide is a useful diagnostic marker for transfusion-associated circulatory overload. Transfusion 2008;48:1143–50. 10.1111/j.1537-2995.2008.01656.x
    1. Zhou L, Giacherio D, Cooling L, et al. . Use of B-natriuretic peptide as a diagnostic marker in the differential diagnosis of transfusion-associated circulatory overload. Transfusion 2005;45:1056–63. 10.1111/j.1537-2995.2005.04326.x

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