Adverse Effects of RBC Transfusions: A Unifying Hypothesis (INOBA)
Transfusion of red blood cells is often used in critically ill patients with low red blood cell counts to prevent disease progression and death. Recent studies suggest that the use of "aged" versus "fresh" red blood cells are associated with worse clinical outcomes. There is evidence that red blood cells work with the cells lining our blood vessels to produce a variety of substances that normally cause arteries to relax and increase blood supply. Two of these substances are called nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). We are trying to determine the nature of these substances in human beings when they are transfused "aged" versus "fresh" red blood cells. It is our thought that "aged" red blood cells have less of the substances (NO and EDHF) that naturally relax our arteries and further changes the blood supply. One way to determine this is to transfuse a subject's own "aged" and "fresh" red blood cells and inject substances such as L-NMMA (L-NG monomethyl arginine) and TEA (tetraethylammonium chloride), which block the production of NO and EDHF respectively, and then, study what happens to the blood flow. This study is also designed to test the effects of transfusing "aged" versus "fresh" red blood cells in volunteers with traditional cardiovascular risk factors (high blood pressure, diabetes, high cholesterol, and tobacco use) on 1) the degree of relaxation in the arteries and subsequent changes in blood flow, 2) blood levels of oxidant molecules, 3) inflammation, and 4) stem cells.
There is evidence that red blood cells produce NO, which normally causes arteries to relax and increase blood supply. We will try to determine the nature of NO in red blood cells and whether the amount of this substance is altered because of different blood processing and storage techniques. It is our thought that "aged" red blood cells have less NO that naturally relaxes our arteries and further changes the blood supply. This study is designed to determine the most ideal way of storing and processing blood.
Biological: Fresh blood
Biological: Aged blood
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Adverse Effects of RBC Transfusions: A Unifying Hypothesis|
- To investigate the effects of blood processing and storage (using standard FDA-approved conditions) on NO production and scavenging by human RBCs/Hb in vitro. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
- To transfuse healthy volunteers and investigate the effects of storage-related RBC changes on blood flow, tissue oxygenation, and biomarkers of cardiovascular function. [ Time Frame: 4 years ] [ Designated as safety issue: No ]
- To determine the effects of transfused RBCs in patients with endothelial dysfunction due to cardiovascular disease. [ Time Frame: 4 years ] [ Designated as safety issue: No ]
|Study Start Date:||April 2009|
|Estimated Study Completion Date:||October 2013|
|Estimated Primary Completion Date:||October 2013 (Final data collection date for primary outcome measure)|
|Experimental: Fresh blood||
Biological: Fresh blood
For fresh transfusions, a whole blood unit will be drawn from volunteers, processed, and then reinfused on the same day during the study. For impaired and repaired transfusions, the volunteers will be brought to the blood bank to donate; then, after processing and the appropriate length of storage (eg, 28 days), they will return for the FBF studies. Since recipients of fresh transfusions are relatively anemic after donation and before reinfusion, recipients of impaired/repaired transfusions should also be mildly anemic for the study. Thus, they will donate another whole blood unit prior to beginning the study course, they will be transfused with their stored unit during the study, and then the autologous unit collected at the beginning of the day will be reinfused at the end of the day after the study is complete.
|Experimental: Aged blood||
Biological: Aged blood
In a separate aim, the FMD assay will be used to investigate NO-mediated vasodilation in patients with CVD who are receiving transfusions. Over 60% of blood orders for cardiology patients at Emory are for 2 units or more. Therefore, when a 2-unit order is placed on a consented patient, they will be issued both fresh (< 7 days) and impaired (> 28 days) compatible units from inventory. Prior to starting transfusions, the patient will be randomized to either receive the fresh or the older unit first. All RBC units will be ACD/AS1. Units will also be leukoreduced and/or irradiated, if either of those modifications were found to impair NO bioavailability in prior studies. If washing or rejuvenation were found to be successful in significantly "repairing" NO bioavailability in previous aims, some patients may also receive impaired and repaired (> 28 days; washed or rejuvenated) RBC transfusions.
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Transfusion of red blood cells (RBCs) is often effective at preventing morbidity and mortality in anemic patients. In contrast, recent studies indicate that some RBC components may have functional defects ("RBC storage lesions") that actually cause morbidity and mortality when transfused. For example, patients transfused with RBCs stored >14 days have statistically worse outcomes than those receiving "fresher" RBC units. In addition to the age of stored RBCs, the volume transfused may be important. The TRICC study showed that specific patients whose transfusions were limited by a restrictive trigger (RBCs transfusions only when hemoglobin [Hb] < 7 g/dL) had significantly better outcomes than those transfused with a more liberal trigger ([Hb] < 10 g/dL Hb). This finding has been particularly difficult to understand since conventional wisdom suggests that an elevated [Hb] should be beneficial because it supports increased O2 delivery. Recipient-specific factors may also contribute to the occurrence of these adverse events. Unfortunately, these events have been difficult to investigate because up to now they have existed only as "statistical occurrences" of increased morbidity and mortality in large data sets. There are currently no clinical or laboratory methods to detect or study them in individual patients.
The microcirculation is composed of a continuum of small vessels including small arterioles, capillaries, and post-capillary venules. The microcirculation represents an actively-adjusting vascular circuit that matches blood flow (and O2 delivery) to local tissue oxygen demands. While the physiologic mechanisms that match O2 delivery to local requirements are incompletely understood, endothelium-derived nitric oxide (NO) clearly plays an important role. Interestingly, recent work has revealed that in addition to transporting O2 and CO2, the RBC also controls local NO concentrations and thus may also play a surprisingly important role in regulating blood flow in the microcirculation.
Herein, we bring together previously unconnected data to propose a unifying hypothesis, centered on insufficient NO bioavailability (INOBA), to explain the increased morbidity and mortality observed in some patients following RBC transfusion. In this model, variables associated with RBC units (storage time; 2,3-DPG concentration) and transfusion recipients (endothelial dysfunction; hematocrit [Hct]) collectively lead to changes in NO levels in vascular beds. Under certain circumstances, these variables are "aligned" such that NO concentrations are markedly reduced, leading to vasoconstriction, decreased local blood flow and insufficient O2 delivery to end organs. Under these circumstances, the likelihood of morbidity and mortality escalates. The INOBA hypothesis is attractive because of its explanatory power and because it leads to a number of readily testable predictions, which will be investigated in the following 3 Aims:
Aim 1: To investigate the effects of blood processing and storage (using standard FDA-approved conditions) on NO production and scavenging by human RBCs/Hb in vitro. Using sensitive biochemical assays (electron spin resonance [ESR]) and a rat aortic ring in vitro bioassay, we will test the effects of RBC storage time, leukoreduction, and irradiation on NO synthesis and/or scavenging by intact RBCs and free Hb. Modifications such as washing and rejuvenation will be investigated as possible approaches to correct abnormalities in NO bioavailability.
Aim 2: To transfuse healthy volunteers and investigate the effects of storage-related RBC changes on blood flow, tissue oxygenation, and biomarkers of cardiovascular function. We will determine whether RBCs prepared and stored under conditions that alter NO bioavailability in vitro (Aim 1) inhibit NO-mediated vasodilation, reduce tissue perfusion, and decrease tissue O2 delivery in healthy transfusion recipients in vivo. The role of 2,3-DPG depletion as well as exercise-induced O2 demand will also be investigated with these specialized experimental systems.
Aim 3: To determine the effects of transfused RBCs in patients with endothelial dysfunction due to cardiovascular disease. A non-invasive ultrasound assay will be used to test whether patients with cardiovascular disease and endothelial dysfunction (who have intrinsic defects in NO synthesis) are more susceptible to adverse effects from stored/processed RBCs (impaired in NO bioavailability) than fresh RBC units. Vasodilation and tissue oxygenation in response to transfusion will be monitored, and Framingham risk scores and cardiovascular disease biomarkers will be tested as potential predictive factors to identify patients most at risk from adverse effects of RBC transfusions.
The proposed studies will not only carefully evaluate each tenet of this unifying hypothesis of the RBC storage lesion, but will also lead to potential remediations including altered RBC storage/processing conditions and media, novel transfusion recipient screening, and improved RBC/recipient matching.
|United States, Georgia|
|Atlanta, Georgia, United States|
|Principal Investigator:||Arshed A Quyyumi, MD||Emory University|
|Principal Investigator:||John Roback, MD, PhD||Emory University|