Adverse Effects of Red Blood Cell Transfusions: A Unifying Hypothesis (Aim 3)
| Status: | Completed |
|---|---|
| Conditions: | Peripheral Vascular Disease |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 18 - 80 |
| Updated: | 4/21/2016 |
| Start Date: | April 2009 |
| End Date: | October 2013 |
Adverse Effects of Red Blood Cell Transfusions: A Unifying Hypothesis
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.
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.
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.
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.
Inclusion Criteria:
- Inpatient or outpatient at Emory University Hospital who's physicians have ordered a
transfusion of packed red blood cells (pRBCs) of 1 or more units
- Cardiovascular risk factors (hypercholesterolemia, diabetes, hypertension, and
tobacco smoking) or known cardiovascular disease) will be carefully documented for
each subject
Cardiac risk factors are defined as follows:
- Hypercholesterolemia: Defined as serum low density lipoprotein cholesterol > 140
mg/dL if not currently on lipid-lowering therapy or > 100 mg/dL if on lipid-lowering
therapy
- Diabetes: Defined as having fasting blood glucose sample of > 126 mg/dL or a
hemoglobin A1c of > 7% or being treated with diabetes medications such as oral
hypoglycemic agents, insulin sensitizing agents, or subcutaneous insulin
- Smoking: active tobacco use, 20 cigarettes per day for the past year
- Hypertension: Blood pressure of > 140/90 or currently on anti-hypertensive
medications
- Cardiovascular disease: known coronary artery disease by angiogram or documented
myocardial infarction
Exclusion Criteria:
- Pregnancy
- Previous transfusion within one week.
- Inability to give informed consent
- On oral or IV nitrate therapy
- On vasopressor agents
- Active illicit drug use
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