Adverse Effects of Red Blood Cell Transfusions: A Unifying Hypothesis (Aim 3)
Condition: Cardiovascular Diseases
MeSH terms: Cardiovascular Diseases
Study type: Interventional
Phase: Phase 2

Summary: 
      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). The investigators are trying to determine the nature of these substances in human
      beings when they are transfused "aged" versus "fresh" red blood cells. The purpose of the
      study is 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.

      A similar study with healthy volunteers are further described in NCT00838331.
    

Detailed description: 
      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 Transfusion Requirements in
      Critical Care (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
      oxygen (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 carbon
      dioxide (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, the investigators 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-diphosphoglycerate (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 t 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.
    

Intervention name(s): Storage-aged red blood cells (saRBCs) units; Fresh red blood cells units
Intervention type(s): Biological; Biological
Intervention description(s): Packed RBCs units stored for greater than 21 days, with a mean storage duration of 29.6 ± 4.9 days (mean ± SD); Packed RBCs units stored for less than 14 days, with a mean storage duration of 9.6 ± 3.9 days (mean ± SD)
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Blood Transfusions