Blood Conservation Strategies In Cardiac Surgery
H. Levy, MD
Professor of Anesthesiology
Emory University School of Medicine
Division of Cardiothoracic Anesthesiology and Critical Care
(CPB) is associated with defective hemostasias that results in bleeding
and the requirement for allogenic blood product transfusions in
many patients undergoing cardiac surgery and/or coronary artery
bypass graft surgery (CABG). Conservation of blood has become a
priority during surgery because of shortages of donor blood, the
risks associated with the use of allogenic blood products, and the
costs of these products. Further, transfusions expose patients to
a variety of potential cellular and humoral antigens, pose risks
of disease transmission and immunomodulation, and may alone represent
proinflammatory stimuli in the perioperative period. Multiple approaches
are important when considering strategies to limit blood transfusions.
Strategies to reduce bleeding and transfusion requirements include
recognizing risk factors, developing transfusion practices, conservation
of red blood cells, new alternatives to red blood cells, altering
inflammatory responses, and also potentially improving anticoagulation/reversal.
Pharmacologic approaches to reduce bleeding and transfusion requirements
in cardiac surgical patients are based on either preventing or reversing
the defects associated with the CPB induced coagulopathy, and represent
one of the mainstay approaches in cardiac surgery. Strategies to
reduce the need for allogeneic blood requirements will be reviewed.
Certain risk factors
clearly are important when evaluating patients for bleeding potential.
The patient who comes to surgery anemic or with a low preoperative
red blood cell mass based on low weight (ie, children) all pose
important risk factors for the need of transfused red blood cells.
Also, associated diseases and preoperative pharmacologic strategies
are important because hemostasis is involved with platelet and coagulation
factor interaction, the pre-existing use of antiplatelet agents,
especially IIb/IIIa receptor antagonists and clopidogrel (Plavix)
are important to consider. Current studies suggest more patients
with atherosclerotic vascular disease will be receiving antiplatelet
strategies. Further, pre-existing liver disease is important to
consider because these patients have complex multifactorial coagulopathies.
Also, although widely thought that warfarin pre-exposed the patient
to bleeding, more recent data suggests this may not be true. Finally,
redo cardiac surgical procedures requiring repeat sternotomies,
multiple valve replacements, and other procedures providing long
CPB times, may also pose potential risk factors for bleeding.
Coagulation factor administration
in patients with excessive post-CPB bleeding is generally empiric
related to turnaround times of laboratory tests and empiric factor
administration . Optimal administration of pharmacologic and transfusion-based
therapy in patients who exhibit excessive bleeding after cardiac
surgery should be considered, unfortunately there are few validated
tests to asses platelet function. Point-of-care coagulation monitoring
using thromboelastography resulted in fewer transfusions in the
postoperative period. The reduction in transfusions may have been
due to improved hemostasis in these patients who had earlier and
specific identification of the hemostasis abnormality and thus received
more appropriate intraoperative transfusion therapy. These data
support the use of thromboelastography and/or an algorithm to guide
transfusion therapy in complex cardiac surgery, and further support
the concept that transfusion algorithms are effective in reducing
RED CELL CONSERVATION
Because the pre-existing
red blood mass is important, conserving red blood cells is equally
important. The use of red blood cell saver techniques for high risk
patients is important to consider especially by reprocessing shed
blood. Whether in low risk patients this is effective or not still
remains to be seen. The use of autologous normovolemic hemodilution
is an interesting concept that allows the removal of both red cells
and coagulation factors prior to bleeding. This is also done at
the time of surgery, and often cannot be preformed in a hemodynamically
unstable patient. The role of erythropoietin is interesting, but
erythropoietin requires several weeks of pre-existing therapy, requires
the need to replete iron, and should be considered in a Jehovah's
Witness or other patient who can be operated on electively with
the potential for autologous predonation.
RED CELL SUBSTITUTES
Blood substitutes are
solutions that can be used in resuscitation emergencies or during
surgery when rapid intravascular volume expansion is needed in view
of acquired red cell losses. The three main types of products in
development are primarily based on cell-free hemoglobin solutions
called hemoglobin-based oxygen carrying solutions (HBOCs) or perfluorocarbon
emulsions. None of the agents are currently approved for clinical
use, but are in different stages of clinical development. Free hemoglobin
solutions are subject to more rapid degradation when packaged outside
of the red blood cell membrane. Further, the iron moiety of free
hemoglobin readily diffuses in the plasma space and effectively
scavenges nitric oxide from pulmonary and systemic vascular endothelia,
altering both pulmonary and systemic vascular tone.
Four different stroma-free
hemoglobin solutions are under development including intramolecularly
cross-linked hemoglobin, polymerized hemoglobin, conjugated hemoglobin,
and hemoglobin microbubbles, all modified to increase molecular
size and decrease renal filtration, prolong intravascular persistence,
and to ensure a normal P50 of hemoglobin. Animal, human, or recombinant
sources of hemoglobin are used. To stabilize the smaller hemoglobin
units obtained from animal or human red cells, these hemoglobin
dimers and monomers are modified by either cross-linking, polymerization,
or conjugation. Human hemoglobin derived from outdated banked blood
is a problematic source due to a shrinking donor pool, better inventory
control, and it is unlikely that outdated banked blood could provide
enough hemoglobin for commercial purposes. Unfortunately, the half-life
of most human-derived hemoglobin solutions is short thus, the need
for red cell transfusion may merely be delayed and not eliminated
by its use.
Bovine hemoglobin represents
an interesting alternative that is currently under development.
The P50 of bovine hemoglobin is similar to human hemoglobin and
is not controlled by 2,3-DPG but instead by chloride ion which is
present in large concentrations of the plasma. The major advantage
of bovine hemoglobin is its availability and large quantity. A 500-kg
steer has approximately 35 L of blood containing approximately 12
g/dL of hemoglobin for an approximate total body hemoglobin content
of 4.2 kg. Further, cow blood is a byproduct of most slaughterhouses
and is available as almost an unlimited supply. Despite potential
concerns about the possibility of interspecies transmission of infectious
disease, hemoglobin can be successfully purified from human RBC
units containing the viruses.
Recombinant DNA technology
has been used to produce modified human hemoglobin molecules. Unfortunately,
it is unclear whether the yield of hemoglobin per unit of microorganism
is sufficient to make large scale commercial production of hemoglobin
possible. There are also concerns about complete separation of bacterial
components from the hemoglobin and waste management of the byproducts
of its production 6. Another biotechnologic approach to producing
large amounts of hemoglobin involves transgenic manipulation of
animals to produce RBCs that contain a substantial proportion of
(1-deamino-8-D-arginine vasopressin- DDAVP), is a synthetic analogue
of vasopressin decreased vasopressor activity. Desmopressin therapy
causes a two to twenty fold increase in plasma levels of factor
VIII, and stimulates vascular endothelium to release the larger
multimers of von Willebrand factor (vWF). Desmopressin also releases
tissue plasminogen activator (t-PA), and prostacyclin from vascular
endothelium. Although definitive studies are lacking supporting
its routine use, patients who might benefit from its use include
mild to moderate forms of hemophilia or von Willebrand disease undergoing
surgery and uremic platelet dysfunction. Despite initial enthusiasm
for desmopressin, only recently has data suggested it may be useful
to treat platelet dysfunction after cardiac surgery. Despotis reported
a new point-of-care test (hemoSTATUS) to identify patients at risk
of excessive bleeding.
acid (EACA, Amicar) and its analogue, tranexamic acid (TA) are derivatives
of the amino acid lysine and have been reported in clinical studies
of cardiac surgical patients. Both of these drugs inhibit the proteolytic
activity of plasmin and the conversion of plasminogen to plasmin
by plasminogen activators. Plasmin cleaves fibrinogen and a series
of other proteins involved in coagulation. Tranexamic acid is 6-10
times more potent than epsilon-aminocaproic acid. Most of the early
studies using antifibrinolytic agents showed decreased mediastinal
drainage in patients treated with EACA. However, many of these studies
lacked controls, were retrospective, and not blinded. In the literature
there have been a small number of thrombotic complications between
patients receiving lysine analogs, but the studies were not designed
to prospectively capture many of these complications . Although
the design of these studies have not been routinely prospective,
the incidence of these complications in routine CABG is low, and
a small number of patients have been studied. Prospective studies
evaluating safety issues including the risk of perioperative MI,
graft patency, and renal dysfunction still need to be studied. TA
is approved for use in the US to prevent bleeding in patients with
hereditary angioedema undergoing teeth extraction. Most studies
report lysine analogues in first-time CABG where the risk of bleeding
is low, and not in complex cases.
Aprotinin is a serine
protease inhibitor isolated from bovine lung that produces antifibrinolytic
effects, inhibits contact activation, reduces platelet dysfunction
and attenuates the inflammatory response to CPB It is used to reduce
blood loss and transfusion requirements in patients with a risk
of hemorrhage. Data from clinical trials indicate that aprotinin
is generally well tolerated, and the adverse events seen are those
expected in patients undergoing OHS and/or CABG with CPB. Hypersensitivity
reactions occur in <0.6% of patients receiving aprotinin for
the first time, and seem to be greatest within 6 months of reexposure.
The results of original reports indicating that aprotinin therapy
may increase myocardial infarction rates or mortality have not been
supported by more recent studies specifically designed to investigate
this outcome. There is little comparative tolerability data between
aprotinin and the lysine analogues, aminocaproic acid and tranexamic
acid, are available. Aprotinin is often used in patients at high
risk of hemorrhage, in those for whom transfusion is unavailable
or in patients who refuse allogenic transfusions.
Multiple studies support
aprotinin's efficacy and include approximately 45 studies involving
7,000 patients. In redo CABG patients, Cosgrove reported 171 patients
who received either high dose aprotinin (Hammersmith dose), low
dose aprotinin (half Hammersmith dose), or placebo. They found that
low dose aprotinin was as effective as high dose aprotinin in decreasing
blood loss and blood transfusion requirements. Despite the efficacy
of reducing both the need for allogeneic blood and chest tube drainage,
retrospective analysis of the data suggested a higher risk for myocardial
infarction and graft closure that was not statistically significant.
Despite the question about adequacy of anticoagulation, the study
created safety concerns that were addressed to two additional prospective
studies reported by Levy in repeat CABG patients, and by Alderman
in primary CABG patients.
In patients undergoing
repeat coronary artery bypass graft (CABG) surgery, the safety and
dose-related efficacy of aprotinin in high risk patients was studied
in a prospective, multicenter, placebo-controlled trial in 287 patients
were randomly assigned to receive high-dose, low-dose, pump-prime,
or placebo. Drug efficacy was determined by the reduction in donor-blood
transfusion up to postoperative day 12 and in postoperative thoracic-drainage
volume. The percentage of patients requiring donor-red-blood-cell
(RBC) transfusions in the high- and low-dose aprotinin groups was
reduced compared with the pump-prime-only and placebo groups (high-dose
aprotinin, 54%; low-dose aprotinin, 46%; pump-prime only, 72%; and
placebo, 75%). There was also a significant difference in total
blood-product exposures among treatment groups (high-dose aprotinin,
2.2 +/- 0.4 U; low-dose aprotinin, 3.4 +/- 0.9 U; pump-prime-only,
5.1 +/- 0.9 U; placebo, 10.3 +/- 1.4 U). There were no differences
among treatment groups for the incidence of perioperative myocardial
infarction (MI). Both high- and low-dose aprotinin significantly
reduces the requirement for donor-blood transfusion in repeat CABG
patients without increasing the risk for perioperative MI. There
was also a statistically significant reduction in strokes in the
aprotinin treated patients.
To assess the effects
of aprotinin on graft patency, prevalence of myocardial infarction,
and blood loss in patients undergoing primary coronary surgery with
cardiopulmonary bypass, patients from 13 international sites were
randomized to receive intraoperative aprotinin (n = 436) or placebo
(n = 434). Graft angiography was obtained a mean of 10.8 days after
the operation. Electrocardiograms, cardiac enzymes, and blood loss
and replacement were evaluated. In 796 assessable patients, aprotinin
reduced thoracic drainage volume by 43% and requirement for red
blood cell administration by 49%. Among 703 patients with assessable
saphenous vein grafts, occlusions occurred in 15.4% of aprotinin-treated
patients and 10.9% of patients receiving placebo. After adjusting
risk factors associated with vein graft occlusion, the aprotinin
versus placebo risk ratio decreased from 1.7 to 1.05 (90% confidence
interval, 0.6 to 1.8). These factors included female gender, lack
of prior aspirin therapy, small and poor distal vessel quality,
and possibly use of aprotinin-treated blood as excised vein perfusate.
At United States sites, patients had characteristics more favorable
for graft patency, and occlusions occurred in 9.4% of the aprotinin
group and 9.5% of the placebo group (P = .72). At Danish and Israeli
sites, where patients had more adverse characteristics, occlusions
occurred in 23.0% of aprotinin- and 12.4% of placebo-treated patients
(P = .01). Aprotinin did not affect the occurrence of myocardial
infarction (aprotinin: 2.9%; placebo: 3.8%) or mortality (aprotinin:
1.4%; placebo: 1.6%). In this study, the probability of early vein
graft occlusion was increased by aprotinin, but this outcome was
promoted by multiple risk factors for graft occlusion.
STUDIES IN CHILDREN
reduces blood loss and transfusion requirements in adults during
and after cardiac surgical procedures, but its effectiveness in
children is debated. Miller evaluated the hemostatic and economic
effects of aprotinin in children undergoing reoperative cardiac
procedures with cardiopulmonary bypass. Control, low-dose aprotinin,
and high-dose aprotinin groups were established with 15 children
per group. Platelet counts, fibrinogen levels, and thromboelastographic
values at baseline and after protamine sulfate administration, number
of blood product transfusions, and 6-hour and 24-hour chest tube
drainage were used to evaluate the effects of aprotinin on postbypass
coagulopathies. Time needed for skin closure after protamine administration
and lengths of stay in the intensive care unit and the hospital
were recorded prospectively to determine the economic impact of
aprotinin. Coagulation tests performed after protamine administration
rarely demonstrated fibrinolysis but did show significant decreases
in platelet and fibrinogen levels and function. The thromboelastographic
variables indicated a preservation of platelet function by aprotinin.
Decreased blood product transfusions, shortened skin closure times,
and shortened durations of intensive care unit and hospital stays
were found in the aprotinin groups, most significantly in the high-dose
group with a subsequent average reduction of nearly $3,000 in patient
charges. In children undergoing reoperative cardiac surgical procedures,
aprotinin is effective in attenuating postbypass
DEEP HYPOTHERMIC CIRCULATORY
Early experience with
aprotinin in deep hypothermic circulatory arrest (DHCA) raised concerns
about hazards associated with its use. Based on what little is known
about possible mechanistic interactions between hypothermia, stasis,
and aprotinin, there is no evidence that aprotinin becomes unusually
hazardous in DHCA. Excessive mortality and complication rates have
only been reported in clinical series in which the adequacy of heparinization
is questionable. Benefits associated with use of aprotinin in DHCA
have been inconsistently demonstrated. The only prospective, randomized
series showed significant reduction in blood loss and transfusion
requirements. Use of aprotinin in DHCA should be based on the same
considerations applied in other cardiothoracic procedures.
There is little data
to compare the efficacy and safety of pharmacological agents available
for reducing allogeneic blood administration in cardiac surgical
patients. Levi reported a meta-analysis of all randomized, controlled
trials of the three most frequently used pharmacological strategies
to decrease perioperative blood loss (aprotinin, lysine analogues
[aminocaproic acid and tranexamic acid], and desmopressin). Studies
were included if they reported at least one clinically relevant
outcome (mortality, rethoracotomy, proportion of patients receiving
a transfusion, or perioperative MI) in addition to perioperative
blood loss. In addition, a separate meta-analysis was done for studies
concerning complicated cardiac surgery. A total of 72 trials (8409
patients) met the inclusion criteria. Treatment with aprotinin decreased
mortality almost two-fold (odds ratio 0.55) compared with placebo.
Treatment with aprotinin and with lysine analogues decreased the
frequency of surgical re-exploration (0.37, and 0.44, respectively).
These two treatments also significantly decreased the proportion
of patients receiving any allogeneic blood transfusion. By contrast,
the use of desmopressin resulted in a small decrease in perioperative
blood loss, but was not associated with a beneficial effect on other
clinical outcomes. Aprotinin and lysine analogues did not increase
the risk of perioperative myocardial infarction; however, desmopressin
was associated with a 2.4-fold increase in the risk of this complication.
Studies in patients undergoing complicated cardiac surgery showed
Blood conservation for
cardiac surgery requires multiple strategies for reducing bleeding
and the need for donor blood products. Of all the strategies, aprotinin
has been demonstrated to be highly effective in reducing bleeding
and transfusion requirements in high risk patients undergoing repeat
median sternotomy or in high risk patients. Results from multicenter
studies of aprotinin show there is no greater risk of early graft
thrombosis, MI, or renal failure in aprotinin treated patients.
Antiinflammatory strategies on the horizon may further add to our
pharmacologic armamentarium for cardiac surgery and CPB.
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