Red Blood Cell Transfusion in Patients With Coronary Artery Disease (CAD)

Adverse clinical outcomes are reduced when critically ill patients are only transfused if
their hematocrit drops below 21%: Hematocrit (HCT) is a measure of the severity of anemia. A
HCT is considered normal if it ranges between 38 and 48% of total blood volume. In critically
ill patients anemia is very common; about 95% of patients admitted to the intensive care unit
have hemoglobin levels below normal by intensive care unit (ICU) day 3.{Corwin, 1995
#8809;Rodriguez, 2001 #8810} The transfusion trigger of "30/10" (HCT < 30%, hemoglobin <10
g/dl) has been suggested in a case series of trauma patients as early as 1942.{Adam, 1942
#8811} Since then these triggers have largely been a matter of faith, without prospective
data supporting an improvement in clinical outcome. Several clinical trials conducted in the
past two decades have shown at least equivalence in clinical outcomes when a more
conservative transfusion trigger of hemoglobin 7-9 g/dL is applied to a critically-ill
patient population.{Hebert, 1999 #8812;Vincent, 2002 #8814;Corwin, 2004 #8813} The
transfusion trigger in patients with acute coronary syndrome (ACS) or recent coronary artery
bypass grafting as a subset of critically ill patients is more controversial, and in most
intensive care units a more liberal approach to transfusions for these patients is typically
chosen.{Gerber, 2008 #8815} However, the efficacy of RBC transfusion appears to be
significantly more limited than empirically assumed in patients with active coronary artery
disease. The TRICC investigators performed a subset analysis and independent study of their
patient cohort of critically-ill patients with cardiovascular disease.{Hebert, 1997 #8835}
They found that a transfusion hemoglobin trigger of 7 g/dL is safe. Furthermore, greater
end-organ dysfunction was recorded in patients with a liberal transfusion trigger, and the
overall mortality was similar between the study cohorts for any time interval (intensive care
unit, over the course of hospital stay, at 30-d and 60-d follow-up).{Hebert, 1999 #8812}

ACS patients should receive a transfusion if their HCT is less than 24%: Several
retrospective studies have shown that in general, transfusion of RBC in patients with ACS and
a hematocrit > 24% is neutral or very slightly beneficial and causes harm if HCT > 30%. {Rao,
2004 #8836;Yang, 2005 #8837;Sabatine, 2005 #8827;Singla, 2007 #8838;Singla, 2007 #8838} Such
small (if any) benefit is not intuitive, in light of an increase in arterial oxygen content
by a PRBC transfusion and therefore decrease in cardiac output and oxygen consumption. Two
very beneficial effects in patients with active coronary artery disease. Indeed, increasing
arterial oxygen content by transfusion may either 1) not increase oxygen delivery to the
myocardium distal to an anatomic coronary stenosis or 2) have other deleterious biological
effects on the cardiovascular system. Despite the results that RBC transfusion in unstable
coronary artery disease has very little beneficial effects, most clinicians (standard of
care) transfuse patients with ACS to a HCT of 30% regardless of potential adverse side
effects of RBC transfusions. The guidelines for transfusion practice at the BIDMC for
instance differentiate between hemodynamically stable and bleeding patients. The HCT of
bleeding patients should be greater then 30%. In hemodynamically stable patient they further
differentiate between patients with and without signs of end-organ ischemia. In patients
without end-organ ischemia a HCT of 21% is tolerated and in patients with end-organ ischemia
such as active coronary artery disease the HCT should be > 30%.

Storage of RBC before transfusion lowers the function of the RBCs: In a retrospective study
in patients undergoing coronary artery bypass grafting (CABG) a recent study found that RBC
transfusions were associated with an increased risk of mortality and short term and long term
postoperative complications when patients were transfused with stored RBCs (older than 14
days). This association remained significant even after controlling for the assumption that
patients receiving blood transfusions are in general sicker and therefore more prone to
complications.{Koch, 2008 #8847} Since the introduction of acid-citrate-dextrose as a
preservative it was possible to store blood for several weeks currently up to 42 days. The
criteria for the decision when is blood storage too long is based arbitrarily on red blood
cell survival in the recipient after 24 hours and should be greater than 70%.{Mollison, 1942
#8848} In the past decades however it has been established that transfused and surviving red
blood cells exhibit quite different physiologic properties when compared to native RBCs. This
phenomenon is called the storage lesion. There is a rapid depletion of 2,3 diglycerophosphate
(2,3-DPG) with storage.{Bunn, 1968 #8849} This has a profound impact on hemoglobin affinity
reducing oxygen release from hemoglobin by as much as 25% at similar change in oxygen
saturation. Of note within 72h about 50% of the 2,3-DPG is restored in the transfused RBCs.
Moreover, there is a marked decrease of adenosine triphosphate (ATP), which reduces
deformability of transfused RBCs and the ability of the RBCs to navigate the
microcirculation.{Dern, 1967 #8850}

Infusion of stored RBCs causes hemolysis which in turn reduces nitric oxide bioavailability:
Significant hemolysis (a condition in which RBC burst and the contents of RBC leak outside;
in particular free hemoglobin) occurs both during storage and in particular during
transfusion.{Sowemimo-Coker, 2002 #8851} Free hemoglobin outside of RBCs scavenges nitric
oxide. Nitric oxide (NO) is a colorless gas, which is produced by the inner lining of the
vessels (endothelium). It acts as D5W lubricant for vessels. It keeps blood vessels open and
"lubricates them" so blood cell can flow through these blood vessels more easily. A decrease
in nitric oxide bioavailability causes vasoconstriction and increased RBC adhesion to
endothelium which in turn decreases microcirculatory flow.{Reiter, 2002 #6096} RBCs also
contain arginase which released into the circulation will further enhance nitric oxide
depletion by reducing its precursor arginine.{Kato, 2005 #7955}

The investigators will systematically examine the effects of RBC transfusion on systemic
oxygen delivery, whole body oxygen consumption, nitric oxide bioavailability, endothelial
function, cardiac performance, microcirculatory function, and platelet aggregation in
patients with active coronary artery disease, presenting to the BIDMC with anemia, defined as
hematocrit of < 30%. This is to test our hypothesis that depletion of the nitric oxide pool
by transfusion-associated hemolysis causes a decrease in microcirculation, endothelial, and
platelet function. To the best of our knowledge there is no study to date that explores the
physiologic effects of RBC transfusion in patients with active coronary artery disease.

Inclusion Criteria:

- ACS as defined by a patient who has cardiac chest discomfort and a troponin (cTnT)
elevation of greater than 0.1 ng/mL.

- Pt. who is s/p CABG

- Patients with chronic coronary artery disease will be recruited as defined as past
history of myocardial infarction, percutaneous coronary intervention, CABG, or history
of coronary artery disease documented in the medical record.

- Anemia as defined by HCT between 21%-30%.

Exclusion Criteria:

- Patients with stage III/IV heart failure

- Patients who are actively bleeding requiring immediate transfusion.

- Pregnant patients will be excluded.

- Patients taking sildenafil (Viagra) or other drugs like it, such as vardenafil
(Levitra), or tadalafil (Cialis) within 48 hours before the study.

- Patients on iv nitroglycerine infusion.

- Patients who present with ACS or CABG surgery and who are hemodynamically unstable or
require immediate revascularization.

- Patients who have received a blood transfusion 24 hours prior to the start of the
study.

- Patients with a HCT of < 21% and those that have chest tube drainage greater then 30
mL/h will be excluded.