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Fincher SH, Butt W. Red blood cell transfusion in veno-arterial extracorporeal membrane oxygenation - the disconnect between oxygen delivery and tissue oxygenation. Perfusion 2025; 40:15S-28S. [PMID: 40263905 DOI: 10.1177/02676591241239569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/24/2025]
Abstract
BackgroundRed cell transufion in veno-arterial membrane oxygenation (VA ECMO) has been widely debated.PurposeThis narrative review aims to examine the historical and current approaches of red cell transfusion in veno-arterial extracorporeal membrane oxygenation (VA ECMO) to enhance oxygen delivery. It will explore the potential benefits and pitfalls of red blood cell (RBC) transfusion in VA ECMO, including relationship between haemoglobin (Hb) concentration, tissue oxygenation and patient outcomes associated with transfusion. Following it will review the impact of cardiogenic shock on the microcirculation, performance of transfused RBC and effects of the ECMO circuit on RBC function. It will conclude with an introduction to potential mechanisms by which we might manipulate red cells to improve tissue oxygenation, without augmentation of Hb concentration.ConclusionFurther research is needed to provide insight into optimal RBC transfusion thresholds and strategies to augment red cell function to optimise tissue oxygenation in VA ECMO.
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Affiliation(s)
- Sophie H Fincher
- Cardiology Department, The Royal Children's Hospital, Melbourne, VIC, Australia
- Intensive Care Unit, The Alfred Hospital, Melbourne, VIC, Australia
- Department of Critical Care, The University of Melbourne, Melbourne, VIC, Australia
| | - Warwick Butt
- Cardiology Department, The Royal Children's Hospital, Melbourne, VIC, Australia
- Department of Critical Care, The University of Melbourne, Melbourne, VIC, Australia
- Murdoch Children's Research Institute, Division of Clinical Sciences, Melbourne, VIC, Australia
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2
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Nemkov T, Isiksacan Z, William N, Senturk R, Boudreau LE, Yarmush ML, Acker JP, D'Alessandro A, Usta OB. Supercooled storage of red blood cells slows down the metabolic storage lesion. RESEARCH SQUARE 2025:rs.3.rs-5256734. [PMID: 40060052 PMCID: PMC11888543 DOI: 10.21203/rs.3.rs-5256734/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/21/2025]
Abstract
Red blood cell (RBC) transfusion, a life-saving intervention, is limited by reduced RBC potency over time. Cold storage at +4 °C for up to 42 days can reduce transfusion efficacy due to alterations termed the "storage lesion." Strategies to mitigate the storage lesion include alkaline additive solutions and supercooled storage to extend storage by reducing metabolic stresses. However, RBC metabolism during supercooled storage in standard or alkaline additives remains unstudied. This study, thus, investigated the impact of storage additives (alkaline E-Sol5 and standard SAGM) and temperatures (+4 °C, -4 °C, -8 °C) on RBC metabolism during 21- and 42-days storage using high-throughput metabolomics. RBCs stored with E-Sol5 showed increased glycolysis and higher ratios of reduced to oxidized glutathione compared to SAGM. Supercooled storage at -4 °C showed markedly lower hemolysis than -8°C, preserved adenylate pools, decreased glucose consumption, and reduced lactate accumulation and pentose phosphate pathway activation. The combination of supercooled storage and E-Sol5 helped to preserve ATP and 2,3-DPG reservoirs, while preventing catabolism and free fatty acid accumulation. While supercooled storage with E-Sol5 offers a promising alternative to standard storage, preserving RBC metabolic and functional quality, further research is necessary to validate and improve on these foundational findings.
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Affiliation(s)
- Travis Nemkov
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA 80045
| | - Ziya Isiksacan
- Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
- Shriners Children's, Boston, MA 02114
| | - Nishaka William
- Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2R8, Canada
| | - Rahime Senturk
- Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
- Shriners Children's, Boston, MA 02114
- Department of Chemical Engineering and Chemistry, Eindhoven University of Technology, Eindhoven, The Netherlands, 5612 AZ
| | - Luke E Boudreau
- Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
- Shriners Children's, Boston, MA 02114
| | - Martin L Yarmush
- Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
- Shriners Children's, Boston, MA 02114
- Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, USA, 08854
| | - Jason P Acker
- Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2R8, Canada
- Innovation and Portfolio Management, Canadian Blood Services, Edmonton, AB T6G 2R8, Canada
| | - Angelo D'Alessandro
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA 80045
| | - O Berk Usta
- Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
- Shriners Children's, Boston, MA 02114
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3
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Willie-Permor D, Real M, Zarrintan S, Gaffey AC, Malas MB. Perioperative Blood Transfusion Is Associated with Worse 30-Day Mortality and Complications After Thoracic Endovascular Aortic Repair. Ann Vasc Surg 2024; 101:15-22. [PMID: 38154494 DOI: 10.1016/j.avsg.2023.10.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 08/23/2023] [Accepted: 10/22/2023] [Indexed: 12/30/2023]
Abstract
BACKGROUND It is not uncommon for patients requiring vascular surgery, and in particular aortic surgery, to have increased requirements for blood transfusion. However, studies examining the effects of perioperative transfusion for thoracic endovascular aortic repair (TEVAR) are limited. Using large multicenter data, we aimed to study the impact of perioperative blood transfusion on 30-day mortality and complications after TEVAR. METHODS A total of 9,263 patients who underwent TEVAR were included in this retrospective study from the multicenter Vascular Quality Initiative cohort spanning 2010-2022. We excluded patients who were post-traumatic, anemic (World Health Organization criteria: hemoglobin < 12 g/dl and < 13 g/dl for females and males respectively), who underwent open conversions or presented with ruptured aneurysms. Primary outcomes were 30-day mortality and stroke. Secondary outcomes were postop congestive heart failure (CHF), respiratory complications, spinal cord ischemia (SCI), myocardial infarction (MI) and any postop complications (composite variable). Poisson regression with robust variance was performed to determine the risk of post op outcomes comparing patients who received red blood cells (RBCs) to those who did not. RESULTS Comparing patients without any transfusion (n = 8,223), perioperative transfusion of 1-3 units (n = 735) was associated with 3-fold increased risk of 30-day mortality (adjusted relative risk [aRR] 3.30, 95% confidence interval [CI] 2.39,4.57, P < 0.001), almost 2-fold increased risk of stroke (aRR 1.98, 95% CI 1.24,3.15, P = 0.004), 2.7-fold increased risk of SCI (aRR 2.66, 95% CI 1.87-3.77, P < 0.001), 3-fold increased risk of MI (aRR 3.40, 95% CI 2.30, 5.03, P < 0.001), 2-fold increased risk of CHF (aRR 2.04, 95% CI 1.09, 3.83, P = 0.03), 3.5-fold increased risk of respiratory complications (aRR 3.49, 95% CI 2.67, 4.56, P < 0.001), and 2-fold increased risk of any postop complication (aRR 2.36, 95% CI 2.04, 2.73, P < 0.001). These effects were even higher in patients transfused 4 or more units (n = 305) than seen in the effects seen in those transfused 1-3 units; comparing each group to patients who received none. CONCLUSIONS In hemodynamically stable patients undergoing TEVAR for nonemergent/emergent and nontraumatic indications, transfusion of any amount perioperatively is associated with worse 30-day mortality, stroke, SCI, MI, CHF, and respiratory complications. A conservative transfusion approach and multidisciplinary care to identify complications and rescue TEVAR patients who receive any amount of RBCs perioperatively might help improve outcomes. Future studies to understand the mechanisms of outcomes for transfused patients are needed.
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Affiliation(s)
- Daniel Willie-Permor
- Division of Vascular and Endovascular Surgery, Department of Surgery, Center for Learning and Excellence in Vascular & Endovascular Research (CLEVER), University of California San Diego (UCSD), La Jolla, CA
| | - Marcos Real
- Division of Vascular and Endovascular Surgery, Department of Surgery, Center for Learning and Excellence in Vascular & Endovascular Research (CLEVER), University of California San Diego (UCSD), La Jolla, CA
| | - Sina Zarrintan
- Division of Vascular and Endovascular Surgery, Department of Surgery, Center for Learning and Excellence in Vascular & Endovascular Research (CLEVER), University of California San Diego (UCSD), La Jolla, CA
| | - Ann C Gaffey
- Division of Vascular and Endovascular Surgery, Department of Surgery, Center for Learning and Excellence in Vascular & Endovascular Research (CLEVER), University of California San Diego (UCSD), La Jolla, CA
| | - Mahmoud B Malas
- Division of Vascular and Endovascular Surgery, Department of Surgery, Center for Learning and Excellence in Vascular & Endovascular Research (CLEVER), University of California San Diego (UCSD), La Jolla, CA.
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4
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Reikvam H, Hetland G, Ezligini F, Dorsch K, Omert L, Dunham A, Almeland SK. Safety of hypoxic red blood cell administration in patients with transfusion-dependent hematological malignancies: An interim analysis. Transfus Apher Sci 2023; 62:103755. [PMID: 37423867 DOI: 10.1016/j.transci.2023.103755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 06/07/2023] [Accepted: 06/20/2023] [Indexed: 07/11/2023]
Abstract
Anemia is a common symptom of hematological malignancies and red blood cell (RBC) transfusion is the primary supportive treatment, with many patients becoming transfusion dependent. Hemanext Inc. (Lexington, MA, United States) has developed a CE mark certified device to process and store RBCs hypoxically - citrate-phosphatedextrose (CPD)/phosphate-adenine-glucose-guanosine-saline-mannitol (PAGGSM) RBCs, leukocytes-reduced (LR), O2/CO2 reduced - with the aim of improving RBC quality for transfusion. This interim analysis describes the first patients to receive hypoxic RBCs, administered as part of a pilot post-marketing study in Norway. The primary outcome was adverse events (AEs) within 24 h of transfusion initiation and overall up to 7 days ( ± 1 day) post-transfusion. Secondary outcomes included changes in hemoglobin levels post-transfusion. Five patients with hematological malignancies were included (80 % male, mean age 69.8 [SD ± 19.3] years). Prior to the study, patients had been receiving conventional RBC transfusions every two weeks. Patients received 2 units of hypoxic RBCs over 2 h without complication. One mild AE (rhinovirus) was reported two days post-treatment and was deemed unrelated to treatment. The mean ± SD pre-transfusion hemoglobin level was 7.7 ± 0.5 g/dL, evolving to 9.0 ± 0.9 g/dL following administration of hypoxic RBCs; an increase of 17 %. This interim analysis showed that transfusion with hypoxic RBCs processed with the CPD/PAGGSM LR, O2/CO2 reduced system was effective and well tolerated in patients with hematologic malignancies. The overall clinical program will assess whether the use of hypoxic RBCs can reduce transfusion interval versus conventional RBCs in patients requiring acute and chronic transfusions.
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Affiliation(s)
- Håkon Reikvam
- Department of Clinical Science, University of Bergen, 5007 Bergen, Norway; Department of Clinical Medicine, University of Bergen, 5007 Bergen, Norway.
| | - Geir Hetland
- Oslo University Hospital, P. O. Box 4950 Nydalen, N-0424 Oslo, Norway; Institute of Clinical Medicine, University of Oslo, N-0424 Oslo, Norway
| | - Farshid Ezligini
- Oslo University Hospital, P. O. Box 4950 Nydalen, N-0424 Oslo, Norway
| | - Kim Dorsch
- Hemanext Inc., 99 Hayden Ave building b suite 620, Lexington, MA 02421, USA
| | - Laurel Omert
- Hemanext Inc., 99 Hayden Ave building b suite 620, Lexington, MA 02421, USA
| | - Andrew Dunham
- Hemanext Inc., 99 Hayden Ave building b suite 620, Lexington, MA 02421, USA
| | - Stian K Almeland
- Department of Clinical Medicine, University of Bergen, 5007 Bergen, Norway; Haukeland University Hospital, Jonas Lies vei 65, 5021 Bergen, Norway
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Isiksacan Z, D’Alessandro A, Wolf SM, McKenna DH, Tessier SN, Kucukal E, Gokaltun AA, William N, Sandlin RD, Bischof J, Mohandas N, Busch MP, Elbuken C, Gurkan UA, Toner M, Acker JP, Yarmush ML, Usta OB. Assessment of stored red blood cells through lab-on-a-chip technologies for precision transfusion medicine. Proc Natl Acad Sci U S A 2023; 120:e2115616120. [PMID: 37494421 PMCID: PMC10410732 DOI: 10.1073/pnas.2115616120] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/28/2023] Open
Abstract
Transfusion of red blood cells (RBCs) is one of the most valuable and widespread treatments in modern medicine. Lifesaving RBC transfusions are facilitated by the cold storage of RBC units in blood banks worldwide. Currently, RBC storage and subsequent transfusion practices are performed using simplistic workflows. More specifically, most blood banks follow the "first-in-first-out" principle to avoid wastage, whereas most healthcare providers prefer the "last-in-first-out" approach simply favoring chronologically younger RBCs. Neither approach addresses recent advances through -omics showing that stored RBC quality is highly variable depending on donor-, time-, and processing-specific factors. Thus, it is time to rethink our workflows in transfusion medicine taking advantage of novel technologies to perform RBC quality assessment. We imagine a future where lab-on-a-chip technologies utilize novel predictive markers of RBC quality identified by -omics and machine learning to usher in a new era of safer and precise transfusion medicine.
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Affiliation(s)
- Ziya Isiksacan
- Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA02114
- Shriners Children’s, Boston, MA02114
| | - Angelo D’Alessandro
- Department of Biochemistry and Molecular Genetics, University of Colorado Denver – Anschutz Medical Campus, Aurora, CO80045
| | - Susan M. Wolf
- Law School, Medical School, Consortium on Law and Values in Health, Environment & the Life Sciences, University of Minnesota, Minneapolis, MN55455
| | - David H. McKenna
- Division of Transfusion Medicine, Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN55455
| | - Shannon N. Tessier
- Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA02114
- Shriners Children’s, Boston, MA02114
| | | | - A. Aslihan Gokaltun
- Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA02114
- Shriners Children’s, Boston, MA02114
- Department of Chemical Engineering, Hacettepe University, Ankara06532, Turkey
| | - Nishaka William
- Laboratory Medicine and Pathology, University of Alberta, Edmonton, ABT6G 2R8, Canada
| | - Rebecca D. Sandlin
- Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA02114
| | - John Bischof
- Department of Mechanical Engineering, University of Minnesota, Minneapolis, MN55455
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN55455
| | | | - Michael P. Busch
- Vitalant Research Institute, San Francisco, CA94105
- Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA94105
| | - Caglar Elbuken
- Institute of Materials Science and Nanotechnology, National Nanotechnology Research Center, Bilkent University, Ankara06800, Turkey
- Faculty of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Oulu, 90014Oulu, Finland
- Valtion Teknillinen Tutkimuskeskus Technical Research Centre of Finland Ltd., 90570Oulu, Finland
| | - Umut A. Gurkan
- Department of Mechanical and Aerospace Engineering, Case Western Reserve University, Cleveland, OH44106
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH44106
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH44106
| | - Mehmet Toner
- Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA02114
- Shriners Children’s, Boston, MA02114
| | - Jason P. Acker
- Laboratory Medicine and Pathology, University of Alberta, Edmonton, ABT6G 2R8, Canada
- Innovation and Portfolio Management, Canadian Blood Services, Edmonton, ABT6G 2R8, Canada
| | - Martin L. Yarmush
- Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA02114
- Shriners Children’s, Boston, MA02114
- Department of Biomedical Engineering, Rutgers University, Piscataway, NJ08854
| | - O. Berk Usta
- Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA02114
- Shriners Children’s, Boston, MA02114
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6
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Does the age of packed red blood cells, donor sex or sex mismatch affect the sublingual microcirculation in critically ill intensive care unit patients? A secondary interpretation of a retrospective analysis. J Clin Monit Comput 2023; 37:179-188. [PMID: 35665876 PMCID: PMC9852146 DOI: 10.1007/s10877-022-00877-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Accepted: 05/05/2022] [Indexed: 01/24/2023]
Abstract
In vitro studies have thoroughly documented age-dependent impact of storage lesions in packed red blood cells (pRBC) on erythrocyte oxygen carrying capacity. While studies have examined the effect of pRBC age on patient outcome only few data exist on the microcirculation as their primary site of action. In this secondary analysis we examined the relationship between age of pRBC and changes of microcirculatory flow (MCF) in 54 patients based on data from the Basel Bedside assessment Microcirculation Transfusion Limit study (Ba2MiTraL) on effects of pRBC on sublingual MCF. Mean change from pre- to post-transfusion proportion of perfused vessels (∆PPV) was + 8.8% (IQR - 0.5 to 22.5), 5.5% (IQR 0.1 to 10.1), and + 4.7% (IQR - 2.1 to 6.5) after transfusion of fresh (≤ 14 days old), medium (15 to 34 days old), and old (≥ 35 days old) pRBC, respectively. Values for the microcirculatory flow index (MFI) were + 0.22 (IQR - 0.1 to 0.6), + 0.22 (IQR 0.0 to 0.3), and + 0.06 (IQR - 0.1 to 0.3) for the fresh, medium, and old pRBC age groups, respectively. Lower ∆PPV and transfusion of older blood correlated with a higher Sequential Organ Failure Assessment (SOFA) score of patients upon admission to the intensive care unit (ICU) (p = 0.01). However, regression models showed no overall significant correlation between pRBC age and ∆PPV (p = 0.2). Donor or recipient sex had no influence. We detected no significant effect of pRBC on microcirculation. Patients with a higher SOFA score upon ICU admission might experience a negative effect on the ∆PPV after transfusion of older blood.
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Premont RT, Singel DJ, Stamler JS. The enzymatic function of the honorary enzyme: S-nitrosylation of hemoglobin in physiology and medicine. Mol Aspects Med 2022; 84:101056. [PMID: 34852941 PMCID: PMC8821404 DOI: 10.1016/j.mam.2021.101056] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 11/22/2021] [Accepted: 11/24/2021] [Indexed: 11/16/2022]
Abstract
The allosteric transition within tetrameric hemoglobin (Hb) that allows both full binding to four oxygen molecules in the lung and full release of four oxygens in hypoxic tissues would earn Hb the moniker of 'honorary enzyme'. However, the allosteric model for oxygen binding in hemoglobin overlooked the essential role of blood flow in tissue oxygenation that is essential for life (aka autoregulation of blood flow). That is, blood flow, not oxygen content of blood, is the principal determinant of oxygen delivery under most conditions. With the discovery that hemoglobin carries a third biologic gas, nitric oxide (NO) in the form of S-nitrosothiol (SNO) at β-globin Cys93 (βCys93), and that formation and export of SNO to dilate blood vessels are linked to hemoglobin allostery through enzymatic activity, this title is honorary no more. This chapter reviews evidence that hemoglobin formation and release of SNO is a critical mediator of hypoxic autoregulation of blood flow in tissues leading to oxygen delivery, considers the physiological implications of a 3-gas respiratory cycle (O2/NO/CO2) and the pathophysiological consequences of its dysfunction. Opportunities for therapeutic intervention to optimize oxygen delivery at the level of tissue blood flow are highlighted.
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Affiliation(s)
- Richard T Premont
- Institute for Transformative Molecular Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA; Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, 44106, USA
| | - David J Singel
- Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT, 59717, USA
| | - Jonathan S Stamler
- Institute for Transformative Molecular Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA; Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, 44106, USA.
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8
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Yoshida T, McMahon E, Croxon H, Dunham A, Gaccione P, Abbasi B, Beckman N, Omert L, Field S, Waters A. The oxygen saturation of red blood cell concentrates: The basis for a novel index of red cell oxidative stress. Transfusion 2021; 62:183-193. [PMID: 34761414 DOI: 10.1111/trf.16715] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 09/10/2021] [Accepted: 10/14/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND Oxidative stress is a major driving force in the development of storage lesions in red cell concentrates (RCCs). Unlike manufactured pharmaceuticals, differences in component preparation methods and genetic/physiological status of donors result in nonuniform biochemical characteristics of RCCs. Various characteristics of donated blood on oxygen saturation (SO2 ) distribution were investigated, and a model to estimate potential oxidative stress burden of stored RCC at transfusion is proposed. STUDY DESIGN AND METHODS The oxygen content of freshly prepared RCCs (770) was quantified noninvasively as fractional hemoglobin saturation (SO2 ) with visible reflectance spectrometry. Using separate RCCs and mimicking typical handling of RCCs during routine storage, evolution of SO2 was followed for construction of an empirical model. Based on this model, the oxygen exposure index (OEI) was formulated to estimate the accumulated oxygen exposure burden of RCC at the time of transfusion. RESULTS The SO2 of RCCs varied widely at donation (mean 43% ± 1.3%; range 20%-93%). Multivariate regression model showed that sex and processing method had small effects on SO2 (R2 = 0.12), indicating that variability was mainly attributed to other individual donor characteristics. Storage simulation model indicated that median SO2 increased gradually over 6 weeks (approx. 1.3 fold), while OEI increased at a faster rate (approx. eight-fold). CONCLUSION In addition to storage age, the OEI provides a potential new metric to assess the quality of RCCs at the time of transfusion in terms of their oxidative stress. In future studies, a single noninvasive measurement during storage could link OEI to clinical outcomes in transfusion recipients.
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Affiliation(s)
| | - Emma McMahon
- Irish Blood Transfusion Service, Dublin, Ireland
| | - Harry Croxon
- Irish Blood Transfusion Service, Dublin, Ireland
| | | | | | - Babak Abbasi
- Information Systems and Supply Chain, RMIT University, Melbourne, Victoria, Australia
| | | | | | - Stephen Field
- Irish Blood Transfusion Service, Dublin, Ireland.,School of Medicine, Trinity College Dublin, Dublin, Ireland
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9
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Turgeman A, McRae HL, Cahill C, Blumberg N, Refaai MA. Impact of RBC Transfusion on Peripheral Capillary Oxygen Saturation and Partial Pressure of Arterial Oxygen. Am J Clin Pathol 2021; 156:149-154. [PMID: 33347534 DOI: 10.1093/ajcp/aqaa219] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
OBJECTIVES RBCs are known to undergo deleterious changes during storage, known as storage lesions, which have been shown to result in decreased oxygen-carrying capacity. However, there is inadequate literature describing the effects of stored RBC allogeneic transfusion on oxygen parameters in vivo. The oxygen standard parameters were retrospectively assessed before and after RBC transfusion. METHODS Patients who received 1 RBC transfusion were assessed for hemoglobin (Hb) levels, peripheral capillary oxygen saturation (Spo2), and partial pressure of arterial oxygen (Pao2) from 12 hours before and 24 hours after transfusion. RESULTS In total, 78 patients who were monitored by Spo2 and 28 patients monitored by Pao2 were included in this analysis. Following RBC transfusion, Hb levels increased significantly (P < .001); however, there was a significant decrease in both Spo2 and Pao2 within 24 hours after transfusion (P = .04 and P = .003, respectively), indicating lower tissue oxygenation and lower soluble oxygen level. CONCLUSIONS This single-center, retrospective study revealed evidence of significantly decreased oxygenation and tissue perfusion after single-unit RBC transfusion, despite corrected Hb levels.
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Affiliation(s)
- Alexa Turgeman
- Department of Pathology and Laboratory Medicine, Transfusion Medicine Division, University of Rochester Medical Center, Rochester, NY
| | - Hannah L McRae
- Department of Pathology and Laboratory Medicine, Transfusion Medicine Division, University of Rochester Medical Center, Rochester, NY
| | - Christine Cahill
- Department of Pathology and Laboratory Medicine, Transfusion Medicine Division, University of Rochester Medical Center, Rochester, NY
| | - Neil Blumberg
- Department of Pathology and Laboratory Medicine, Transfusion Medicine Division, University of Rochester Medical Center, Rochester, NY
| | - Majed A Refaai
- Department of Pathology and Laboratory Medicine, Transfusion Medicine Division, University of Rochester Medical Center, Rochester, NY
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10
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Liu W, He H, Ince C, Long Y. The effect of blood transfusion on sublingual microcirculation in critically ill patients: A scoping review. Microcirculation 2021; 28:e12666. [PMID: 33091957 DOI: 10.1111/micc.12666] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 10/10/2020] [Accepted: 10/14/2020] [Indexed: 11/30/2022]
Abstract
PURPOSE To investigate the effects of red blood cell (RBC) transfusion on sublingual microcirculation in critically ill patients. METHODS Systematic strategy was conducted to search studies that measured sublingual microcirculation before and after transfusion in critically ill patients. This review was reported according to the Preferred Reporting Items for Systematic Review and Meta-Analyses Scoping Review Extension. RESULTS The literature search yielded 114 articles. A total of 11 studies met the inclusion criteria. Observational evidence showed diffusive capacity of the microcirculation significantly improved in intraoperative and anemic hematologic patients after transfusion, while the convective parameters significantly improved in traumatic patients. RBC transfusion improved both diffusive and convective microcirculatory parameters in hypovolemic hemorrhagic shock patients. Most of the studies enrolled septic patients showed no microcirculatory improvements after transfusion. The positive effects of the leukoreduction were insufficiently supported. The effects of the storage time of the RBCs were not conclusive. The majority of the evidence supported a negative correlation between baseline proportion of perfused vessels (PPV) and changes in PPV. CONCLUSIONS This scoping review has catalogued evidence that RBC transfusion differently improves sublingual microcirculation in different populations. The existing evidence is not sufficient to conclude the effects of the leukoreduction and storage time of RBCs.
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Affiliation(s)
- Wanglin Liu
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Beijing, China
| | - Huaiwu He
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Beijing, China
| | - Can Ince
- Department of Intensive Care, Laboratory of Translational Intensive Care, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Yun Long
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Beijing, China
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11
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Chng KZ, Ng YC, Namgung B, Tan JKS, Park S, Tien SL, Leo HL, Kim S. Assessment of transient changes in oxygen diffusion of single red blood cells using a microfluidic analytical platform. Commun Biol 2021; 4:271. [PMID: 33654170 PMCID: PMC7925684 DOI: 10.1038/s42003-021-01793-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 01/26/2021] [Indexed: 02/07/2023] Open
Abstract
Red blood cells (RBCs) capability to deliver oxygen (O2) has been routinely measured by P50. Although this defines the ability of RBCs to carry O2 under equilibrium states, it cannot determine the efficacy of O2 delivery in dynamic blood flow. Here, we developed a microfluidic analytical platform (MAP) that isolates single RBCs for assessing transient changes in their O2 release rate. We found that in vivo (biological) and in vitro (blood storage) aging of RBC could lead to an increase in the O2 release rate, despite a decrease in P50. Rejuvenation of stored RBCs (Day 42), though increased the P50, failed to restore the O2 release rate to basal level (Day 0). The temporal dimension provided at the single-cell level by MAP could shed new insights into the dynamics of O2 delivery in both physiological and pathological conditions.
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Affiliation(s)
- Kevin Ziyang Chng
- Department of Biomedical Engineering, National University of Singapore, Singapore, Singapore
| | - Yan Cheng Ng
- Department of Biomedical Engineering, National University of Singapore, Singapore, Singapore.,NUS Graduate School for Integrative Sciences and Efngineering, National University of Singapore, Singapore, Singapore
| | - Bumseok Namgung
- Department of Biomedical Engineering, National University of Singapore, Singapore, Singapore
| | - Justin Kok Soon Tan
- Department of Biomedical Engineering, National University of Singapore, Singapore, Singapore
| | - Soyeon Park
- Department of Biomedical Engineering, National University of Singapore, Singapore, Singapore.,Institute for Health Innovation & Technology, National University of Singapore, Singapore, Singapore
| | - Sim Leng Tien
- Department of Hematology, Singapore General Hospital, Singapore, Singapore
| | - Hwa Liang Leo
- Department of Biomedical Engineering, National University of Singapore, Singapore, Singapore.,NUS Graduate School for Integrative Sciences and Efngineering, National University of Singapore, Singapore, Singapore
| | - Sangho Kim
- Department of Biomedical Engineering, National University of Singapore, Singapore, Singapore. .,NUS Graduate School for Integrative Sciences and Efngineering, National University of Singapore, Singapore, Singapore. .,Institute for Health Innovation & Technology, National University of Singapore, Singapore, Singapore.
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12
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Robidoux J, Laforce-Lavoie A, Charette SJ, Shevkoplyas SS, Yoshida T, Lewin A, Brouard D. Development of a flow standard to enable highly reproducible measurements of deformability of stored red blood cells in a microfluidic device. Transfusion 2020; 60:1032-1041. [PMID: 32237236 PMCID: PMC9701565 DOI: 10.1111/trf.15770] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 02/17/2020] [Accepted: 02/18/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND Great deformability allows red blood cells (RBCs) to flow through narrow capillaries in tissues. A number of microfluidic devices with capillary-like microchannels have been developed to monitor storage-related impairment of RBC deformability during blood banking operations. This proof-of-concept study describes a new method to standardize and improve reproducibility of the RBC deformability measurements using one of these devices. STUDY DESIGN AND METHODS The rate of RBC flow through the microfluidic capillary network of the microvascular analyzer (MVA) device made of polydimethylsiloxane was measured to assess RBC deformability. A suspension of microbeads in a solution of glycerol in phosphate-buffered saline was developed to be used as an internal flow rate reference alongside RBC samples in the same device. RBC deformability and other in vitro quality markers were assessed weekly in six leukoreduced RBC concentrates (RCCs) dispersed in saline-adenine-glucose-mannitol additive solution and stored over 42 days at 4°C. RESULTS The use of flow reference reduced device-to-device measurement variability from 10% to 2%. Repeated-measure analysis using the generalized estimating equation (GEE) method showed a significant monotonic decrease in relative RBC flow rate with storage from Week 0. By the end of storage, relative RBC flow rate decreased by 22 ± 6% on average. CONCLUSIONS The suspension of microbeads was successfully used as a flow reference to increase reproducibility of RBC deformability measurements using the MVA. Deformability results suggest an early and late aging phase for stored RCCs, with significant decreases between successive weeks suggesting a highly sensitive measurement method.
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Affiliation(s)
| | | | - Steve J. Charette
- Biochemistry, Microbiology and Bioinformatics Department, Université Laval, Montreal, Quebec, Canada
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13
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Guyette FX, Yealy DM. Old and New: What Blood Is PROPPR in Trauma Resuscitation? Ann Emerg Med 2019; 73:662-664. [DOI: 10.1016/j.annemergmed.2019.01.041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Indexed: 01/28/2023]
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14
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Cullison M, Mahon R, McGwin G, McCarron R, Browning R, Auker C. Blood transfusions, blood storage, and correlation with elevated pulmonary arterial pressures. Transfusion 2019; 59:1259-1266. [PMID: 30681152 DOI: 10.1111/trf.15122] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 12/01/2018] [Accepted: 12/03/2018] [Indexed: 01/08/2023]
Abstract
BACKGROUND The aim of this study was to determine if transfusion with RBCs is associated with a rise in mean pulmonary artery pressure (MPAP) and whether such a rise is influenced by the duration of RBC storage. STUDY DESIGN AND METHODS A retrospective chart review of intensive care unit patients with pulmonary artery catheters was conducted at two military medical centers. RESULTS RBC transfusion is associated with a sustained (≥4 hours) statistically significant 2- to 3-mm Hg rise in MPAP relative to both pretransfusion levels (p < 0.05) and compared to asanguinous fluid infusions (p < 0.05). The magnitude of the rise (all infusions, RBCs, and asanguinous) correlates positively with in-hospital mortality (p < 0.01) and hospital length of stay (p < 0.01). The duration of RBC storage was not statistically correlated with the magnitude of rise in the population studied. Mean infusion volume was greater for RBC (vs. asanguinous) infusions, but volume adjustment of MPAP values did not alter the pattern or statistical significance of the results. CONCLUSIONS Analysis of retrospectively collected data suggests that transfusion of RBC-containing fluids results in a sustained elevation of MPAP. In the patient population studied, the duration of RBC storage did not correlate with the magnitude of MPAP rise. Future prospective studies of transfusion effects should consider including assessment of MPAP and subpopulation analyses.
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Affiliation(s)
- Marilynn Cullison
- Operational and Undersea Medicine Directorate, Naval Medical Research Center, Silver Spring, Maryland.,The Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland
| | - Richard Mahon
- Operational and Undersea Medicine Directorate, Naval Medical Research Center, Silver Spring, Maryland.,The Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland
| | - Gerald McGwin
- Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama
| | - Richard McCarron
- Operational and Undersea Medicine Directorate, Naval Medical Research Center, Silver Spring, Maryland
| | - Robert Browning
- Department of Internal Medicine, Walter Reed National Military Medical Center, Bethesda, Maryland
| | - Charles Auker
- Operational and Undersea Medicine Directorate, Naval Medical Research Center, Silver Spring, Maryland.,The Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland
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15
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Yoshida T, Prudent M, D’Alessandro A. Red blood cell storage lesion: causes and potential clinical consequences. BLOOD TRANSFUSION = TRASFUSIONE DEL SANGUE 2019; 17:27-52. [PMID: 30653459 PMCID: PMC6343598 DOI: 10.2450/2019.0217-18] [Citation(s) in RCA: 149] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 12/06/2018] [Indexed: 11/21/2022]
Abstract
Red blood cells (RBCs) are a specialised organ that enabled the evolution of multicellular organisms by supplying a sufficient quantity of oxygen to cells that cannot obtain oxygen directly from ambient air via diffusion, thereby fueling oxidative phosphorylation for highly efficient energy production. RBCs have evolved to optimally serve this purpose by packing high concentrations of haemoglobin in their cytosol and shedding nuclei and other organelles. During their circulatory lifetimes in humans of approximately 120 days, RBCs are poised to transport oxygen by metabolic/redox enzymes until they accumulate damage and are promptly removed by the reticuloendothelial system. These elaborate evolutionary adaptions, however, are no longer effective when RBCs are removed from the circulation and stored hypothermically in blood banks, where they develop storage-induced damages ("storage lesions") that accumulate over the shelf life of stored RBCs. This review attempts to provide a comprehensive view of the literature on the subject of RBC storage lesions and their purported clinical consequences by incorporating the recent exponential growth in available data obtained from "omics" technologies in addition to that published in more traditional literature. To summarise this vast amount of information, the subject is organised in figures with four panels: i) root causes; ii) RBC storage lesions; iii) physiological effects; and iv) reported outcomes. The driving forces for the development of the storage lesions can be roughly classified into two root causes: i) metabolite accumulation/depletion, the target of various interventions (additive solutions) developed since the inception of blood banking; and ii) oxidative damages, which have been reported for decades but not addressed systemically until recently. Downstream physiological consequences of these storage lesions, derived mainly by in vitro studies, are described, and further potential links to clinical consequences are discussed. Interventions to postpone the onset and mitigate the extent of the storage lesion development are briefly reviewed. In addition, we briefly discuss the results from recent randomised controlled trials on the age of stored blood and clinical outcomes of transfusion.
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Affiliation(s)
| | - Michel Prudent
- Laboratoire de Recherche sur les Produits Sanguins, Transfusion Interrégionale CRS, Epalinges, Switzerland
- Faculté de Biologie et de Médicine, Université de Lausanne, Lausanne, Switzerland
| | - Angelo D’Alessandro
- Department of Biochemistry and Molecular Genetics University of Colorado, Denver, CO, United States of America
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16
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Wagener BM, Hu PJ, Oh JY, Evans CA, Richter JR, Honavar J, Brandon AP, Creighton J, Stephens SW, Morgan C, Dull RO, Marques MB, Kerby JD, Pittet JF, Patel RP. Role of heme in lung bacterial infection after trauma hemorrhage and stored red blood cell transfusion: A preclinical experimental study. PLoS Med 2018; 15:e1002522. [PMID: 29522519 PMCID: PMC5844517 DOI: 10.1371/journal.pmed.1002522] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND Trauma is the leading cause of death and disability in patients aged 1-46 y. Severely injured patients experience considerable blood loss and hemorrhagic shock requiring treatment with massive transfusion of red blood cells (RBCs). Preclinical and retrospective human studies in trauma patients have suggested that poorer therapeutic efficacy, increased severity of organ injury, and increased bacterial infection are associated with transfusion of large volumes of stored RBCs, although the mechanisms are not fully understood. METHODS AND FINDINGS We developed a murine model of trauma hemorrhage (TH) followed by resuscitation with plasma and leukoreduced RBCs (in a 1:1 ratio) that were banked for 0 (fresh) or 14 (stored) days. Two days later, lungs were infected with Pseudomonas aeruginosa K-strain (PAK). Resuscitation with stored RBCs significantly increased the severity of lung injury caused by P. aeruginosa, as demonstrated by higher mortality (median survival 35 h for fresh RBC group and 8 h for stored RBC group; p < 0.001), increased pulmonary edema (mean [95% CI] 106.4 μl [88.5-124.3] for fresh RBCs and 192.5 μl [140.9-244.0] for stored RBCs; p = 0.003), and higher bacterial numbers in the lung (mean [95% CI] 1.2 × 10(7) [-1.0 × 10(7) to 2.5 × 10(7)] for fresh RBCs and 3.6 × 10(7) [2.5 × 10(7) to 4.7 × 10(7)] for stored RBCs; p = 0.014). The mechanism underlying this increased infection susceptibility and severity was free-heme-dependent, as recombinant hemopexin or pharmacological inhibition or genetic deletion of toll-like receptor 4 (TLR4) during TH and resuscitation completely prevented P. aeruginosa-induced mortality after stored RBC transfusion (p < 0.001 for all groups relative to stored RBC group). Evidence from studies transfusing fresh and stored RBCs mixed with stored and fresh RBC supernatants, respectively, indicated that heme arising both during storage and from RBC hemolysis post-resuscitation plays a role in increased mortality after PAK (p < 0.001). Heme also increased endothelial permeability and inhibited macrophage-dependent phagocytosis in cultured cells. Stored RBCs also increased circulating high mobility group box 1 (HMGB1; mean [95% CI] 15.4 ng/ml [6.7-24.0] for fresh RBCs and 50.3 ng/ml [12.3-88.2] for stored RBCs), and anti-HMGB1 blocking antibody protected against PAK-induced mortality in vivo (p = 0.001) and restored macrophage-dependent phagocytosis of P. aeruginosa in vitro. Finally, we showed that TH patients, admitted to the University of Alabama at Birmingham ER between 1 January 2015 and 30 April 2016 (n = 50), received high micromolar-millimolar levels of heme proportional to the number of units transfused, sufficient to overwhelm endogenous hemopexin levels early after TH and resuscitation. Limitations of the study include lack of assessment of temporal changes in different products of hemolysis after resuscitation and the small sample size precluding testing of associations between heme levels and adverse outcomes in resuscitated TH patients. CONCLUSIONS We provide evidence that large volume resuscitation with stored blood, compared to fresh blood, in mice increases mortality from subsequent pneumonia, which occurs via mechanisms sensitive to hemopexin and TLR4 and HMGB1 inhibition.
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Affiliation(s)
- Brant M. Wagener
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Parker J. Hu
- Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Joo-Yeun Oh
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Cilina A. Evans
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Jillian R. Richter
- Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Jaideep Honavar
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Angela P. Brandon
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Judy Creighton
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Shannon W. Stephens
- Department of Emergency Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Charity Morgan
- Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Randal O. Dull
- Department of Anesthesiology, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Marisa B. Marques
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Jeffrey D. Kerby
- Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Jean-Francois Pittet
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
- * E-mail: (J-FP); (RPP)
| | - Rakesh P. Patel
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
- Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
- * E-mail: (J-FP); (RPP)
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17
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Barshtein G, Arbell D, Yedgar S. Hemodynamic Functionality of Transfused Red Blood Cells in the Microcirculation of Blood Recipients. Front Physiol 2018; 9:41. [PMID: 29441026 PMCID: PMC5797635 DOI: 10.3389/fphys.2018.00041] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Accepted: 01/11/2018] [Indexed: 01/23/2023] Open
Abstract
The primary goal of red blood cell (RBC) transfusion is to supply oxygen to tissues and organs. However, due to a growing number of studies that have reported negative transfusion outcomes, including reduced blood perfusion, there is rising concern about the risks in blood transfusion. RBC are characterized by unique flow-affecting properties, specifically adherence to blood vessel wall endothelium, cell deformability, and self-aggregability, which define their hemodynamic functionality (HF), namely their potential to affect blood circulation. The role of the HF of RBC in blood circulation, particularly the microcirculation, has been documented in numerous studies with animal models. These studies indicate that the HF of transfused RBC (TRBC) plays an important role in the transfusion outcome. However, studies with animal models must be interpreted with reservations, as animal physiology may not reflect human physiology. To test this concept in humans, we have directly examined the effect of the HF of TRBC, as expressed by their deformability and adherence to vascular endothelium, on the transfusion-induced effect on the skin blood flow and hemoglobin increment in β-thalassemia major patients. The results demonstrated, for the first time in humans, that the TRBC HF is a potent effector of the transfusion outcome, expressed by the transfusion-induced increase in the recipients' hemoglobin level, and the change in the skin blood flow, indicating a link between the microcirculation and the survival of TRBC in the recipients' vascular system. The implication of these findings for blood transfusion practice and to vascular function in blood recipients is discussed.
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Affiliation(s)
- Gregory Barshtein
- Department of Biochemistry, Faculty of Medicine, Hebrew University, Jerusalem, Israel
| | - Dan Arbell
- Department of Pediatric Surgery, Hadassah University Hospital, Jerusalem, Israel
| | - Saul Yedgar
- Department of Biochemistry, Faculty of Medicine, Hebrew University, Jerusalem, Israel
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18
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Nielsen ND, Martin-Loeches I, Wentowski C. The Effects of red Blood Cell Transfusion on Tissue Oxygenation and the Microcirculation in the Intensive Care Unit: A Systematic Review. Transfus Med Rev 2017; 31:205-222. [PMID: 28800876 DOI: 10.1016/j.tmrv.2017.07.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Revised: 05/12/2017] [Accepted: 07/11/2017] [Indexed: 01/15/2023]
Abstract
The transfusion of red blood cells (RBCs) is a common intervention in intensive care unit (ICU) patients, yet the benefits are far from clear in patients with moderate anemia (eg, hemoglobin (Hb) levels of 7-10 g/dL). Determining which of these patients benefit, and how to even define benefit, from transfusion is challenging. As the intended physiological benefit underpinning RBC transfusion is to improve tissue oxygenation, several studies utilizing a wide range of assessment techniques have attempted to study the effects of transfusion on tissue oxygenation and microcirculatory function. The objective of this systematic review was to determine whether RBC transfusion improves tissue oxygenation/microcirculatory indices in the ICU population, and to provide an introduction to the techniques used in these studies. Eligible studies published between January 1996 and February 2017 were identified from searches of PubMed, Embase, Cinahl, ScienceDirect, Web of Science, and The Cochrane Library. Seventeen studies met inclusion criteria, though there was significant heterogeneity in study design, patient population, assessment techniques and outcomes reported. Overall, the majority of studies (11 of 17) concluded that transfusion did not generally improve tissue oxygenation or microcirculation. Inter-individual effects were highly variable, however, and closer review of sub-groups available in 9 studies revealed that patients with abnormal tissue oxygenation or microcirculatory indices prior to transfusion had improvement in these indices with transfusion, irrespective of assessment method. This finding suggests a new strategy for future trials in the ICU: utilizing tissue oxygenation/microcirculatory parameters to determine the need for transfusion rather than largely arbitrary hemoglobin concentrations.
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Affiliation(s)
- Nathan D Nielsen
- Section of Pulmonary Diseases, Critical Care and Environmental Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
| | - Ignacio Martin-Loeches
- Multidisciplinary Intensive Care Research Organization (MICRO), St James's University Hospital, Department of Clinical Medicine, Trinity College, Dublin, Ireland
| | - Catherine Wentowski
- Division of Pulmonary and Critical Care Medicine, Ochsner Clinic Foundation, New Orleans, LA, USA
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19
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Walz JM, Stundner O, Girardi FP, Barton BA, Koll-Desrosiers AR, Heard SO, Memtsoudis SG. Microvascular response to transfusion in elective spine surgery. World J Orthop 2017; 8:49-56. [PMID: 28144579 PMCID: PMC5241545 DOI: 10.5312/wjo.v8.i1.49] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2016] [Revised: 08/19/2016] [Accepted: 10/27/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the microvascular (skeletal muscle tissue oxygenation; SmO2) response to transfusion in patients undergoing elective complex spine surgery.
METHODS After IRB approval and written informed consent, 20 patients aged 18 to 85 years of age undergoing > 3 level anterior and posterior spine fusion surgery were enrolled in the study. Patients were followed throughout the operative procedure, and for 12 h postoperatively. In addition to standard American Society of Anesthesiologists monitors, invasive measurements including central venous pressure, continual analysis of stroke volume (SV), cardiac output (CO), cardiac index (CI), and stroke volume variability (SVV) was performed. To measure skeletal muscle oxygen saturation (SmO2) during the study period, a non-invasive adhesive skin sensor based on Near Infrared Spectroscopy was placed over the deltoid muscle for continuous recording of optical spectra. All administration of fluids and blood products followed standard procedures at the Hospital for Special Surgery, without deviation from usual standards of care at the discretion of the Attending Anesthesiologist based on individual patient comorbidities, hemodynamic status, and laboratory data. Time stamps were collected for administration of colloids and blood products, to allow for analysis of SmO2 immediately before, during, and after administration of these fluids, and to allow for analysis of hemodynamic data around the same time points. Hemodynamic and oxygenation variables were collected continuously throughout the surgery, including heart rate, blood pressure, mean arterial pressure, SV, CO, CI, SVV, and SmO2. Bivariate analyses were conducted to examine the potential associations between the outcome of interest, SmO2, and each hemodynamic parameter measured using Pearson’s correlation coefficient, both for the overall cohort and within-patients individually. The association between receipt of packed red blood cells and SmO2 was performed by running an interrupted time series model, with SmO2 as our outcome, controlling for the amount of time spent in surgery before and after receipt of PRBC and for the inherent correlation between observations. Our model was fit using PROC AUTOREG in SAS version 9.2. All other analyses were also conducted in SAS version 9.2 (SAS Institute Inc., Cary, NC, United States).
RESULTS Pearson correlation coefficients varied widely between SmO2 and each hemodynamic parameter examined. The strongest positive correlations existed between ScvO2 (P = 0.41) and SV (P = 0.31) and SmO2; the strongest negative correlations were seen between albumin (P = -0.43) and cell saver (P = -0.37) and SmO2. Correlations for other laboratory parameters studied were weak and only based on a few observations. In the final model we found a small, but significant increase in SmO2 at the time of PRBC administration by 1.29 units (P = 0.0002). SmO2 values did not change over time prior to PRBC administration (P = 0.6658) but following PRBC administration, SmO2 values declined significantly by 0.015 units (P < 0.0001).
CONCLUSION Intra-operative measurement of SmO2 during large volume, yet controlled hemorrhage, does not show a statistically significant correlation with either invasive hemodynamic, or laboratory parameters in patients undergoing elective complex spine surgery.
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20
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Stowell CP, Whitman G, Granger S, Gomez H, Assmann SF, Massey MJ, Shapiro NI, Steiner ME, Bennett-Guerrero E. The impact of red blood cell storage duration on tissue oxygenation in cardiac surgery. J Thorac Cardiovasc Surg 2016; 153:610-619.e2. [PMID: 28027790 DOI: 10.1016/j.jtcvs.2016.11.029] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2016] [Revised: 10/07/2016] [Accepted: 11/05/2016] [Indexed: 11/18/2022]
Abstract
OBJECTIVE Although storage alters red blood cells, several recent, randomized trials found no differences in clinical outcomes between patients transfused with red blood cells stored for shorter versus longer periods of time. The objective of this study was to see whether storage impairs the in vivo ability of erythrocytes to traverse the microcirculation and deliver oxygen at the tissue level. METHODS A subset of subjects from a clinical trial of cardiac surgery patients randomized to receive transfusions of red blood cells stored ≤10 days or ≥21 days were assessed for thenar eminence and cerebral tissue hemoglobin oxygen saturation (StO2) via the use of near-infrared spectroscopy and sublingual microvascular blood flow via side-stream darkfield videomicroscopy. RESULTS Among 55 subjects, there was little change in the primary endpoint (thenar eminence StO2 from before to after transfusion of one unit) and the change was similar in the 2 groups: +1.7% (95% confidence interval, -0.3, 3.8) for shorter-storage and +0.8% (95% confidence interval, -1.1, 2.9) for longer-storage; P = .61). Similarly, no significant differences were observed for cerebral StO2 or sublingual microvascular blood flow. These parameters also were not different from preoperatively to 1 day postoperatively, reflecting the absence of a cumulative effect of all red blood cell units transfused during this period. CONCLUSIONS There were no differences in thenar eminence or cerebral StO2, or sublingual microcirculatory blood flow, in cardiac surgery patients transfused with red blood cells stored ≤10 days or ≥21 days. These results are consistent with the clinical outcomes in the parent study, which also did not differ, indicating that storage may not impair oxygen delivery by red blood cells in this setting.
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Affiliation(s)
- Christopher P Stowell
- Blood Transfusion Service, Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
| | - Glenn Whitman
- Division of Cardiac Surgery, Department of Surgery, Johns Hopkins Hospital, Baltimore, Md
| | | | - Hernando Gomez
- Department of Critical Care Medicine, Center for Critical Care Nephrology, University of Pittsburgh, Pittsburgh, Pa
| | | | - Michael J Massey
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, Mass
| | - Nathan I Shapiro
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, Mass; Harvard Medical School, Boston, Mass
| | - Marie E Steiner
- Department of Pediatrics, University of Minnesota, Minneapolis, Minn
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21
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Podbregar M, Gavric AU, Podbregar E, Mozina H, Stefanovic S. Red blood cell transfusion and skeletal muscle tissue oxygenation in anaemic haematologic outpatients. Radiol Oncol 2016; 50:449-455. [PMID: 27904454 PMCID: PMC5120575 DOI: 10.1515/raon-2015-0046] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2015] [Accepted: 08/06/2015] [Indexed: 12/15/2022] Open
Abstract
Background Stored red blood cells (RBCs) accumulate biochemical and biophysical changes, known as storage lesion. The aim of this study was to re-challenge current data that anaemia in chronically anaemic haematology patients is not associated with low skeletal muscle tissue oxygen (StO2), and that RBC storage age does not influence the tissue response after ischaemic provocation, using near-infrared spectroscopy. Patients and methods Twenty-four chronic anaemic haematology patients were included. Thenar skeletal muscle StO2 was measured at rest (basal StO2), with vascular occlusion testing (upslope StO2, maximum StO2) before and after transfusion. Results Basal StO2 was low (53% ± 7%). Average RBC storage time was 10.5 ± 3.9 days. Effects of RBC transfusions were as follows: basal StO2 and upslope StO2 did not change significantly; maximum StO2 increased compared to baseline (64 ± 14% vs. 59 ± 10%, p = 0.049). Change of basal StO2, upslope StO2 and maximum StO2 was negatively related to age of RBCs. The decrease of maximum StO2 was predicted (sensitivity 70%, specificity 100%), after receiving RBCs ≥ 10days old. Discussion Resting skeletal muscle StO2 in chronic anaemic patients is low. RBC storage time affects skeletal muscle StO2 in the resting period and after ischaemic provocation.
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Affiliation(s)
- Matej Podbregar
- Clinical Department for Anaesthesiology and Surgical Intensive Care, University Medical Centre Ljubljana, Slovenia; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | | | - Eva Podbregar
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Hugon Mozina
- Emergency Department, University Medical Centre Ljubljana, Ljubljana, Slovenia
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Weinberg JA, Patel RP. Red blood cell transfusion and its effect on microvascular dysfunction in shock states. Best Pract Res Clin Anaesthesiol 2016; 30:491-498. [PMID: 27931652 DOI: 10.1016/j.bpa.2016.10.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2016] [Revised: 10/23/2016] [Accepted: 10/27/2016] [Indexed: 01/03/2023]
Abstract
Among critically ill patients, red blood cell (RBC) transfusion is often prescribed for anemia in the absence of active or recent bleeding. The failure of RBC transfusion to improve physiological parameters and clinical outcomes in this setting may be explained by current understanding of the relationship between the RBCs and the microcirculation. It is now evident that the circulating RBCs contribute to microcirculatory hypoxic vasodilation by regulated nitric oxide (NO)-dependent vasodilation, thereby facilitating delivery of oxygen to oxygen-deprived tissue. The structural and functional changes in RBCs during storage, collectively known as the storage lesion, result in circulating RBCs that may not function as expected after transfusion. In recent years, there has been a significant focus on the dysfunctional interaction between stored RBCs and the microcirculation, with emphasis on understanding the mechanisms that drive erythrocyte NO-mediated vasodilation. The development of technology that allows noninvasive observation of the microcirculation in humans has allowed for direct observation of the microcirculation immediately before and after RBC transfusion. The current understanding of RBC NO-mediated vasodilation and the results of direct observation of the microcirculation in the setting of RBC transfusion are reviewed.
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Affiliation(s)
- Jordan A Weinberg
- Creighton University School of Medicine Phoenix Campus, St. Joseph's Hospital and Medical Center, Trauma Administration, 350 W. Thomas Road, Phoenix, AZ 85013, USA.
| | - Rakesh P Patel
- University of Alabama at Birmingham, Birmingham, AL, USA.
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23
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Barshtein G, Pries AR, Goldschmidt N, Zukerman A, Orbach A, Zelig O, Arbell D, Yedgar S. Deformability of transfused red blood cells is a potent determinant of transfusion-induced change in recipient's blood flow. Microcirculation 2016; 23:479-486. [DOI: 10.1111/micc.12296] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Accepted: 07/06/2016] [Indexed: 12/16/2022]
Affiliation(s)
- Gregory Barshtein
- Department of Biochemistry; Hebrew University Faculty of Medicine; Jerusalem Israel
| | | | - Neta Goldschmidt
- Department of Hematology; Hadassah University Hospital; Jerusalem Israel
| | - Ayelet Zukerman
- Department of Biochemistry; Hebrew University Faculty of Medicine; Jerusalem Israel
| | - Ariel Orbach
- Department of Biochemistry; Hebrew University Faculty of Medicine; Jerusalem Israel
| | - Orly Zelig
- Blood Bank; Hadassah-Hebrew University Hospital; Jerusalem Israel
| | - Dan Arbell
- Department of Pediatric Surgery; Hadassah- Hebrew University Hospital; Jerusalem Israel
| | - Saul Yedgar
- Department of Biochemistry; Hebrew University Faculty of Medicine; Jerusalem Israel
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24
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Benedik PS, Hamlin SK. The physiologic role of erythrocytes in oxygen delivery and implications for blood storage. Crit Care Nurs Clin North Am 2016; 26:325-35. [PMID: 25169686 DOI: 10.1016/j.ccell.2014.04.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Erythrocytes are not just oxygen delivery devices but play an active metabolic role in modulating microvascular blood flow. Hemoglobin and red blood cell morphology change as local oxygen levels fall, eliciting the release of adenosine triphosphate and nitric oxide to initiate local vasodilation. Aged erythrocytes undergo physical and functional changes such that some of the red cell's most physiologically helpful attributes are diminished. This article reviews the functional anatomy and applied physiology of the erythrocyte and the microcirculation with an emphasis on how erythrocytes modulate microvascular function. The effects of cell storage on the metabolic functions of the erythrocyte are also briefly discussed.
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Affiliation(s)
- Penelope S Benedik
- Department of Acute and Continuing Care, School of Nursing, University of Texas Health Science Center at Houston, 6901 Bertner Street, SON 682, Houston, TX 77030, USA.
| | - Shannan K Hamlin
- Nursing Research and Evidence-Based Practice, Houston Methodist Hospital, 6565 Fannin, MGJ 11-017, Houston, TX 77030, USA
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25
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Abstract
BACKGROUND Well-characterized biochemical, structural, and physiological changes occur when red blood cells (RBCs) are stored for a period of time and are collectively called the storage lesion. METHODS Key study results are summarized and contrasted and new data from recently completed randomized controlled trials will be discussed. RESULTS It is unclear whether in vitro changes to RBCs that occur during storage are clinically relevant. The clinical effects of RBC storage have been the focus of observational studies in recent years. However, these studies lack any consensus, possibly because of methodological limitations. CONCLUSIONS The clinical significance of storing RBCs is controversial, although new data from randomized controlled trials of neonates and patients undergoing cardiac surgery suggest that the duration of RBC storage is not associated with adverse clinical outcomes in these patient populations.
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Affiliation(s)
- Lirong Qu
- Department of Pathology, Institute for Transfusion Medicine, Pittsburgh, PA 15213, USA.
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26
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Stapley R, Rodriguez C, Oh JY, Honavar J, Brandon A, Wagener BM, Marques MB, Weinberg JA, Kerby JD, Pittet JF, Patel RP. Red blood cell washing, nitrite therapy, and antiheme therapies prevent stored red blood cell toxicity after trauma-hemorrhage. Free Radic Biol Med 2015; 85:207-18. [PMID: 25933588 PMCID: PMC4508223 DOI: 10.1016/j.freeradbiomed.2015.04.025] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2014] [Revised: 04/02/2015] [Accepted: 04/20/2015] [Indexed: 12/29/2022]
Abstract
Transfusion of stored red blood cells (RBCs) is associated with increased morbidity and mortality in trauma patients. Pro-oxidant, pro-inflammatory, and nitric oxide (NO) scavenging properties of stored RBCs are thought to underlie this association. In this study we determined the effects of RBC washing and nitrite and antiheme therapy on stored RBC-dependent toxicity in the setting of trauma-induced hemorrhage. A murine (C57BL/6) model of trauma-hemorrhage and resuscitation with 1 or 3 units of RBCs stored for 0-10 days was used. Tested variables included washing RBCs to remove lower MW components that scavenge NO, NO-repletion therapy using nitrite, or mitigation of free heme toxicity by heme scavenging or preventing TLR4 activation. Stored RBC toxicity was determined by assessment of acute lung injury indices (airway edema and inflammation) and survival. Transfusion with 5 day RBCs increased acute lung injury indexed by BAL protein and neutrophil accumulation. Washing 5 day RBCs prior to transfusion did not decrease this injury, whereas nitrite therapy did. Transfusion with 10 day RBCs elicited a more severe injury resulting in ~90% lethality, compared to <15% with 5 day RBCs. Both washing and nitrite therapy significantly protected against 10 day RBC-induced lethality, suggesting that washing may be protective when the injury stimulus is more severe. Finally, a spectral deconvolution assay was developed to simultaneously measure free heme and hemoglobin in stored RBC supernatants, which demonstrated significant increases of both in stored human and mouse RBCs. Transfusion with free heme partially recapitulated the toxicity mediated by stored RBCs. Furthermore, inhibition of TLR4 signaling, which is stimulated by heme, using TAK-242, or hemopexin-dependent sequestration of free heme significantly protected against both 5 day and 10 day mouse RBC-dependent toxicity. These data suggest that RBC washing, nitrite therapy, and/or antiheme and TLR4 strategies may prevent stored RBC toxicities.
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Affiliation(s)
- Ryan Stapley
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Cilina Rodriguez
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Joo-Yeun Oh
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Jaideep Honavar
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Angela Brandon
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Brant M Wagener
- Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Marisa B Marques
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Jordan A Weinberg
- Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Jeffrey D Kerby
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Jean-Francois Pittet
- Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Center for Free Radical Biology and Pulmonary Injury Repair Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Rakesh P Patel
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Center for Free Radical Biology and Pulmonary Injury Repair Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
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27
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Martí‐Carvajal AJ, Simancas‐Racines D, Peña‐González BS. Prolonged storage of packed red blood cells for blood transfusion. Cochrane Database Syst Rev 2015; 2015:CD009330. [PMID: 26171902 PMCID: PMC11055608 DOI: 10.1002/14651858.cd009330.pub2] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
BACKGROUND A blood transfusion is an acute intervention, used to address life- and health-threatening conditions on a short-term basis. Packed red blood cells are most often used for blood transfusion. Sometimes blood is transfused after prolonged storage but there is continuing debate as to whether transfusion of 'older' blood is as beneficial as transfusion of 'fresher' blood. OBJECTIVES To assess the clinical benefits and harms of prolonged storage of packed red blood cells, in comparison with fresh, on recipients of blood transfusion. SEARCH METHODS We ran the search on 1st May 2014. We searched the Cochrane Injuries Group Specialized Register, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE (OvidSP), Embase (OvidSP), CINAHL (EBSCO Host) and two other databases. We also searched clinical trials registers and screened reference lists of the retrieved publications and reviews. We updated this search in June 2015 but these results have not yet been incorporated. SELECTION CRITERIA Randomised clinical trials including participants assessed as requiring red blood cell transfusion were eligible for inclusion. Prolonged storage was defined as red blood cells stored for ≥ 21 days in a blood bank. We did not apply limits regarding the duration of follow-up, or country where the study took place. We excluded trials where patients received a combination of short- and long-stored blood products, and also trials without a clear definition of prolonged storage. DATA COLLECTION AND ANALYSIS We independently performed study selection, risk of bias assessment and data extraction by at least two review authors. The major outcomes were death from any cause, transfusion-related acute lung injury, and adverse events. We estimated relative risk for dichotomous outcomes. We measured statistical heterogeneity using I(2). We used a random-effects model to synthesise the findings. MAIN RESULTS We identified three randomised clinical trials, involving a total of 120 participants, comparing packed red blood cells with ≥ 21 days storage ('prolonged' or 'older') versus packed red blood cells with < 21 days storage ('fresh'). We pooled data to assess the effect of prolonged storage on death from any cause. The confidence in the results from these trials was very low, due to the bias in their design and their limited sample sizes.The estimated effect of packed red blood cells with ≥ 21 days storage versus packed red blood cells with < 21 days storage for the outcome death from any cause was imprecise (5/45 [11.11%] versus 2/46 [4.34%]; RR 2.36; 95% CI 0.65 to 8.52; I(2): 0%, P = 0.26, very low quality of evidence). Trial sequential analysis, with only two trials, shows that we do not yet have convincing evidence that older packed red blood cells induce a 20% relative risk reduction of death from any cause compared with fresher packed red blood cells. No trial included other outcomes of interest specified in this review, namely transfusion-related acute lung injury, postoperative infections, and adverse events. The safety profile is unknown. AUTHORS' CONCLUSIONS Recognising the limitations of the review, relating to the size and nature of the included trials, this Cochrane Review provides no evidence to support or reject the use of packed red blood cells for blood transfusion which have been stored for ≥ 21 days ('prolonged' or 'older') compared with those stored for < 21 days ('fresh'). These results are based on three small single centre trials with high risks of bias. There is insufficient evidence to determine the effects of fresh or older packed red blood cells for blood transfusion. Therefore, we urge readers to interpret the trial results with caution. The results from four large ongoing trials will help to inform future updates of this review.
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Affiliation(s)
| | - Daniel Simancas‐Racines
- Universidad Tecnológica EquinoccialFacultad de Ciencias de la Salud Eugenio EspejoAvenida República de El Salvador 733 y PortugalEdificio Gabriela 3. Of. 403Quito (Pichincha)PichinchaEcuadorCasilla Postal 17‐17‐525
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28
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Clinical Outcomes Associated With RBC Transfusions in Critically Ill Children: A 1-Year Prospective Study. Pediatr Crit Care Med 2015; 16:505-14. [PMID: 25905491 DOI: 10.1097/pcc.0000000000000423] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE To identify the potential complications associated with RBC transfusions. DESIGN Prospective observational study. SETTING PICU in a tertiary children's hospital. PATIENTS All children consecutively admitted to our PICU during a 1-year period. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Data were abstracted from medical charts prospectively. Outcomes possibly attributable to RBC transfusions were looked for daily. In transfused cases, it was considered that an outcome was associated with a transfusion only if it was observed after the first RBC transfusion. During the 1-year study period, 913 consecutive admissions were documented, 842 of which were included. Among them, 144 (17%) were transfused at least once. When comparing transfused cases with nontransfused cases, the odds ratio for new or progressive multiple organ dysfunction syndrome was 5.14 (95% CI, 3.28-8.06; p < 0.001). This association remained statistically significant in the multivariable analysis (odds ratio, 3.85; 95% CI, 2.38-6.24; p < 0.001). Transfused cases were ventilated longer than nontransfused cases (14.1 ± 32.6 vs 4.3 ± 9.6 d, p < 0.001), even after adjustment in a Cox model. The PICU length of stay was significantly increased for transfused cases (12.4 ± 26.2 vs 4.9 ± 10.2 d, p < 0.001), even after controlling for potential confounders. The paired analysis for comparison of pretransfusion and posttransfusion values showed that the arterial partial pressure in oxygen was significantly reduced within the 6 hours after the first RBC transfusion (mean difference, 25.6 torr, 95% CI, 5.7-45.4; p = 0.029). The paired analysis also showed an increased proportion of renal replacement therapy. CONCLUSIONS RBC transfusions in critically ill children were associated with prolonged mechanical ventilation and prolonged PICU stay. The risk of new or progressive multiple organ dysfunction syndrome was also increased in some transfused children. Furthermore, our study questions the ability of stored RBCs to improve oxygenation in critically ill children. Practitioners should take into account these data when prescribing an RBC transfusion to PICU patients.
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29
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Damiani E, Adrario E, Luchetti MM, Scorcella C, Carsetti A, Mininno N, Pierantozzi S, Principi T, Strovegli D, Bencivenga R, Gabrielli A, Romano R, Pelaia P, Ince C, Donati A. Plasma free hemoglobin and microcirculatory response to fresh or old blood transfusions in sepsis. PLoS One 2015; 10:e0122655. [PMID: 25932999 PMCID: PMC4416810 DOI: 10.1371/journal.pone.0122655] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 02/10/2015] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Free hemoglobin (fHb) may induce vasoconstriction by scavenging nitric oxide. It may increase in older blood units due to storage lesions. This study evaluated whether old red blood cell transfusion increases plasma fHb in sepsis and how the microvascular response may be affected. METHODS This is a secondary analysis of a randomized study. Twenty adult septic patients received either fresh or old (<10 or >15 days storage, respectively) RBC transfusions. fHb was measured in RBC units and in the plasma before and 1 hour after transfusion. Simultaneously, the sublingual microcirculation was assessed with sidestream-dark field imaging. The perfused boundary region was calculated as an index of glycocalyx damage. Tissue oxygen saturation (StO2) and Hb index (THI) were measured with near-infrared spectroscopy and a vascular occlusion test was performed. RESULTS Similar fHb levels were found in the supernatant of fresh and old RBC units. Despite this, plasma fHb increased in the old RBC group after transfusion (from 0.125 [0.098-0.219] mg/mL to 0.238 [0.163-0.369] mg/mL, p = 0.006). The sublingual microcirculation was unaltered in both groups, while THI increased. The change in plasma fHb was inversely correlated with the changes in total vessel density (r = -0.57 [95% confidence interval -0.82, -0.16], p = 0.008), De Backer score (r = -0.63 [95% confidence interval -0.84, -0.25], p = 0.003) and THI (r = -0.72 [95% confidence interval -0.88, -0.39], p = 0.0003). CONCLUSIONS Old RBC transfusion was associated with an increase in plasma fHb in septic patients. Increasing plasma fHb levels were associated with decreased microvascular density. TRIAL REGISTRATION ClinicalTrials.gov NCT01584999.
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Affiliation(s)
- Elisa Damiani
- Department of Biomedical Sciences and Public Health, Università Politecnica delle Marche, Torrette di Ancona, Italy
| | - Erica Adrario
- Department of Biomedical Sciences and Public Health, Università Politecnica delle Marche, Torrette di Ancona, Italy
- Anesthesia and Intensive Care Unit, Azienda Ospedaliera Universitaria “Ospedali Riuniti”, Torrette di Ancona, Italy
| | - Michele Maria Luchetti
- Department of Clinical and Molecular Sciences, Clinica Medica, Università Politecnica delle Marche, Torrette di Ancona, Italy
| | - Claudia Scorcella
- Department of Biomedical Sciences and Public Health, Università Politecnica delle Marche, Torrette di Ancona, Italy
| | - Andrea Carsetti
- Department of Biomedical Sciences and Public Health, Università Politecnica delle Marche, Torrette di Ancona, Italy
| | - Nicoletta Mininno
- Department of Biomedical Sciences and Public Health, Università Politecnica delle Marche, Torrette di Ancona, Italy
| | - Silvia Pierantozzi
- Department of Biomedical Sciences and Public Health, Università Politecnica delle Marche, Torrette di Ancona, Italy
| | - Tiziana Principi
- Anesthesia and Intensive Care Unit, Azienda Ospedaliera Universitaria “Ospedali Riuniti”, Torrette di Ancona, Italy
| | - Daniele Strovegli
- Anesthesia and Intensive Care Unit, Azienda Ospedaliera Universitaria “Ospedali Riuniti”, Torrette di Ancona, Italy
| | - Rosella Bencivenga
- Immunohematology and Transfusional Medicine, AOU Ospedali Riuniti, Torrette di Ancona, Italy
| | - Armando Gabrielli
- Department of Clinical and Molecular Sciences, Clinica Medica, Università Politecnica delle Marche, Torrette di Ancona, Italy
| | - Rocco Romano
- Department of Biomedical Sciences and Public Health, Università Politecnica delle Marche, Torrette di Ancona, Italy
| | - Paolo Pelaia
- Department of Biomedical Sciences and Public Health, Università Politecnica delle Marche, Torrette di Ancona, Italy
- Anesthesia and Intensive Care Unit, Azienda Ospedaliera Universitaria “Ospedali Riuniti”, Torrette di Ancona, Italy
| | - Can Ince
- Department of Translational Physiology, Academic Medical Center, Amsterdam, The Netherlands
| | - Abele Donati
- Department of Biomedical Sciences and Public Health, Università Politecnica delle Marche, Torrette di Ancona, Italy
- Anesthesia and Intensive Care Unit, Azienda Ospedaliera Universitaria “Ospedali Riuniti”, Torrette di Ancona, Italy
- Department of Translational Physiology, Academic Medical Center, Amsterdam, The Netherlands
- * E-mail:
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Klein H, Natanson C, Flegel W. Transfusion of fresh vs. older red blood cells in the context of infection. ACTA ACUST UNITED AC 2015; 10:275-285. [PMID: 29805474 DOI: 10.1111/voxs.12109] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
The red blood cell (RBC) storage interval has been extended from less than a week to the current storage interval of 6-8 weeks. Regulatory criteria for extending storage rely upon a minimal degree of hemolysis and acceptable in vivo 24-h post transfusion recovery. Clinical studies of safety and efficacy have never been required. Concerns have arisen that RBC toward the end of storage develop a 'storage lesion' with previously unrecognized toxicity. Of the several mechanisms proposed, the bolus of iron delivered to macrophages as a result of hemolysis of stored RBC might pose a particular risk to patients with existing infections. We developed a canine model of pneumonia to compare the toxicity of stored RBC transfusion. We described increased mortality after transfusion of old RBC. We found that transfused older RBC increased mortality, in vivo hemolysis, circulating cell-free hemoglobin that scavenges nitric oxide, and elevations of non-transferrin bound and plasma labile iron. Disappearance of circulating iron correlated with increased mortality, worsening pulmonary function, and bacterial proliferation. Washing decreased the mortality associated with transfusing older RBC, but had the opposite effect on fresher blood. With low doses of bacteria, survival was unaffected by the age of blood, whereas high bacteria doses masked any effect of RBC age on mortality. Older RBC may have adverse effects, but the patient's clinical status, the age, volume and method of preparation of the RBC may be critical variables. Several mechanisms may account for this toxicity, but in the presence of bacterial infection, availability of iron likely plays a major role.
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Affiliation(s)
- H Klein
- CC/DTM, NIH, Bethesda, MD, USA
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31
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Zimring JC. Established and theoretical factors to consider in assessing the red cell storage lesion. Blood 2015; 125:2185-90. [PMID: 25651844 PMCID: PMC4383795 DOI: 10.1182/blood-2014-11-567750] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2014] [Accepted: 01/29/2015] [Indexed: 12/14/2022] Open
Abstract
The collection and storage of red blood cells (RBCs) is a logistical necessity to provide sufficient blood products. However, RBC storage is an unnatural state, resulting in complicated biological changes, referred to collectively as the "storage lesion." Specifics of the storage lesion have been studied for decades, including alterations to cellular properties, morphology, molecular biology of carbohydrates, proteins and lipids, and basic metabolism. Recently, mass spectrometry-based "omics" technology has been applied to the RBC storage lesion, resulting in many new observations, the initial effects of which are more information than understanding. Meanwhile, clinical research on RBC transfusion is considering both the efficacy and also the potential untoward effects of transfusing stored RBCs of different ages and storage conditions. The myriad biological changes that have now been observed during the storage lesion have been extensively reviewed elsewhere. This article focuses rather on an analysis of our current understanding of the biological effects of different elements of the storage lesion, in the context of evolving new clinical understanding. A synopsis is presented of both established and theoretical considerations of the RBC storage lesion and ongoing efforts to create a safer and more efficacious product.
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Affiliation(s)
- James C Zimring
- Puget Sound Blood Center Research Institute, Seattle, WA; and Department of Laboratory Medicine and Department of Internal Medicine, Division of Hematology, University of Washington, Seattle, WA
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32
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Longer RBC storage duration is associated with increased postoperative infections in pediatric cardiac surgery. Pediatr Crit Care Med 2015; 16:227-35. [PMID: 25607740 PMCID: PMC4351137 DOI: 10.1097/pcc.0000000000000320] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
OBJECTIVES Infants and children undergoing open heart surgery routinely require multiple RBC transfusions. Children receiving greater numbers of RBC transfusions have increased postoperative complications and mortality. Longer RBC storage age is also associated with increased morbidity and mortality in critically ill children. Whether the association of increased transfusions and worse outcomes can be ameliorated by use of fresh RBCs in pediatric cardiac surgery for congenital heart disease is unknown. INTERVENTIONS One hundred and twenty-eight consecutively transfused children undergoing repair or palliation of congenital heart disease with cardiopulmonary bypass who were participating in a randomized trial of washed versus standard RBC transfusions were evaluated for an association of RBC storage age and clinical outcomes. To avoid confounding with dose of transfusions and timing of infection versus timing of transfusion, a subgroup analysis of patients only transfused 1-2 units on the day of surgery was performed. MEASUREMENTS AND MAIN RESULTS Mortality was low (4.9%) with no association between RBC storage duration and survival. The postoperative infection rate was significantly higher in children receiving the oldest blood (25-38 d) compared with those receiving the freshest RBCs (7-15 d) (34% vs 7%; p = 0.004). Subgroup analysis of subjects receiving only 1-2 RBC transfusions on the day of surgery (n = 74) also demonstrates a greater prevalence of infections in subjects receiving the oldest RBC units (0/33 [0%] with 7- to 15-day storage; 1/21 [5%] with 16- to 24-day storage; and 4/20 [20%] with 25- to 38-day storage; p = 0.01). In multivariate analysis, RBC storage age and corticosteroid administration were the only predictors of postoperative infection. Washing the oldest RBCs (> 27 d) was associated with a higher infection rate and increased morbidity compared with unwashed RBCs. DISCUSSION Longer RBC storage duration was associated with increased postoperative nosocomial infections. This association may be secondary in part, to the large doses of stored RBCs transfused, from single-donor units. Washing the oldest RBCs was associated with increased morbidity, possibly from increased destruction of older, more fragile erythrocytes incurred by washing procedures. Additional studies examining the effect of RBC storage age on postoperative infection rate in pediatric cardiac surgery are warranted.
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33
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Red blood cell storage duration and trauma. Transfus Med Rev 2014; 29:120-6. [PMID: 25573415 DOI: 10.1016/j.tmrv.2014.09.007] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Revised: 09/01/2014] [Accepted: 09/25/2014] [Indexed: 12/28/2022]
Abstract
Numerous retrospective clinical studies suggest that transfusion of longer stored red blood cells (RBCs) is associated with an independent risk of poorer outcomes for certain groups of patients, including trauma, intensive care, and cardiac surgery patients. Large multicenter randomized controlled trials are currently underway to address the concern about RBC storage duration. However, none of these randomized controlled trials focus specifically on trauma patients with hemorrhage. Major trauma, particularly due to road accidents, is the leading cause of critical injury in the younger-than-40-year-old age group. Severe bleeding associated with major trauma induces hemodynamic dysregulation that increases the risk of hypoxia, coagulopathy, and potentially multiorgan failure, which can be fatal. In major trauma, a multitude of stress-associated changes occur to the patient's RBCs, including morphological changes that increase cell rigidity and thereby alter blood flow hemodynamics, particularly in the microvascular vessels, and reduce RBC survival. Initial inflammatory responses induce deleterious cellular interactions, including endothelial activation, RBC adhesion, and erythrophagocytosis that are quickly followed by profound immunosuppressive responses. Stored RBCs exhibit similar biophysical characteristics to those of trauma-stressed RBCs. Whether transfusion of RBCs that exhibit storage lesion changes exacerbates the hemodynamic perturbations already active in the trauma patient is not known. This article reviews findings from several recent nonrandomized studies examining RBC storage duration and clinical outcomes in trauma patients. The rationale for further research on RBC storage duration in the trauma setting is provided.
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34
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Neuman R, Hayek S, Rahman A, Poole JC, Menon V, Sher S, Newman JL, Karatela S, Polhemus D, Lefer DJ, De Staercke C, Hooper C, Quyyumi AA, Roback JD. Effects of storage-aged red blood cell transfusions on endothelial function in hospitalized patients. Transfusion 2014; 55:782-90. [PMID: 25393772 DOI: 10.1111/trf.12919] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Revised: 09/08/2014] [Accepted: 09/10/2014] [Indexed: 12/30/2022]
Abstract
BACKGROUND Clinical and animal studies indicate that transfusions of older stored red blood cells (RBCs) impair clinical outcomes as compared to fresh RBC transfusions. It has been suggested that this effect is due to inhibition of nitric oxide (NO)-mediated vasodilation after transfusion of older RBC units. However, to date this effect has not been identified in human transfusion recipients. STUDY DESIGN AND METHODS Forty-three hospitalized patients with transfusion orders were randomly assigned to receive either fresh (<14 days) or older stored (>21 days) RBC units. Before transfusion, and at selected time points after the start of transfusion, endothelial function was assessed using noninvasive flow-mediated dilation assays. RESULTS After transfusion of older RBC units, there was a significant reduction in NO-mediated vasodilation at 24 hours after transfusion (p = 0.045), while fresh RBC transfusions had no effect (p = 0.231). CONCLUSIONS This study suggests for the first time a significant inhibitory effect of transfused RBC units stored more than 21 days on NO-mediated vasodilation in anemic hospitalized patients. This finding lends further support to the hypothesis that deranged NO signaling mediates adverse clinical effects of older RBC transfusions. Future investigations will be necessary to address possible confounding factors and confirm these results.
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Affiliation(s)
- Robert Neuman
- Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia
| | - Salim Hayek
- Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia
| | - Ayaz Rahman
- Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia
| | - Joseph C Poole
- Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia
| | - Vivek Menon
- Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia
| | - Salman Sher
- Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia
| | - James L Newman
- Department of Pathology and Laboratory Medicine, Center for Transfusion and Cellular Therapies, Emory University School of Medicine, Atlanta, Georgia
| | - Sulaiman Karatela
- Department of Pathology and Laboratory Medicine, Center for Transfusion and Cellular Therapies, Emory University School of Medicine, Atlanta, Georgia
| | - David Polhemus
- Department of Pharmacology, Louisiana State University Health Sciences Center, New Orleans, Louisiana
| | - David J Lefer
- Department of Pharmacology, Louisiana State University Health Sciences Center, New Orleans, Louisiana
| | - Christine De Staercke
- National Center on Birth Defects and Developmental Disabilities, Division of Blood Disorders, Centers for Disease Control and Prevention, Atlanta, Georgia
| | - Craig Hooper
- National Center on Birth Defects and Developmental Disabilities, Division of Blood Disorders, Centers for Disease Control and Prevention, Atlanta, Georgia
| | - Arshed A Quyyumi
- Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia
| | - John D Roback
- Department of Pathology and Laboratory Medicine, Center for Transfusion and Cellular Therapies, Emory University School of Medicine, Atlanta, Georgia
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35
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van 't Erve TJ, Doskey CM, Wagner BA, Hess JR, Darbro BW, Ryckman KK, Murray JC, Raife TJ, Buettner GR. Heritability of glutathione and related metabolites in stored red blood cells. Free Radic Biol Med 2014; 76:107-13. [PMID: 25108189 PMCID: PMC4252477 DOI: 10.1016/j.freeradbiomed.2014.07.040] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Revised: 07/15/2014] [Accepted: 07/29/2014] [Indexed: 12/27/2022]
Abstract
Red blood cells (RBCs) collected for transfusion deteriorate during storage. This deterioration is termed the "RBC storage lesion." There is increasing concern over the safety, therapeutic efficacy, and toxicity of transfusing longer-stored units of blood. The severity of the RBC storage lesion is dependent on storage time and varies markedly between individuals. Oxidative damage is considered a significant factor in the development of the RBC storage lesion. In this study, the variability during storage and heritability of antioxidants and metabolites central to RBC integrity and function were investigated. In a classic twin study, we determined the heritability of glutathione (GSH), glutathione disulfide (GSSG), the status of the GSSG,2H(+)/2GSH couple (Ehc), and total glutathione (tGSH) in donated RBCs over 56 days of storage. Intracellular GSH and GSSG concentrations both decrease during storage (median net loss of 0.52 ± 0.63 mM (median ± SD) and 0.032 ± 0.107 mM, respectively, over 42 days). Taking into account the decline in pH, Ehc became more positive (oxidized) during storage (median net increase of 35 ± 16 mV). In our study population heritability estimates for GSH, GSSG, tGSH, and Ehc measured over 56 days of storage are 79, 60, 67, and, 75%, respectively. We conclude that susceptibility of stored RBCs to oxidative injury due to variations in the GSH redox buffer is highly variable among individual donors and strongly heritable. Identifying the genes that regulate the storage-related changes in this redox buffer could lead to the development of new methods to minimize the RBC storage lesion.
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Affiliation(s)
- Thomas J van 't Erve
- Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA 52242, USA
| | - Claire M Doskey
- Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA 52242, USA
| | - Brett A Wagner
- Free Radical and Radiation Biology Program, Radiation Oncology, The University of Iowa, Iowa City, IA 52242, USA
| | - John R Hess
- Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA
| | - Benjamin W Darbro
- Department of Pediatrics, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Kelli K Ryckman
- Department of Epidemiology, College of Public Health, The University of Iowa, Iowa City, IA 52242, USA
| | - Jeffrey C Murray
- Department of Pathology, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Thomas J Raife
- Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
| | - Garry R Buettner
- Free Radical and Radiation Biology Program, Radiation Oncology, The University of Iowa, Iowa City, IA 52242, USA; Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
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