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BleedingWeb.com
- the Bleeding Information Source, is an internet site designed
for physicians and other health care personnel who want information
about bleeding, coagulation, and hemostasis, including therapeutic
approaches.
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| Blood
Conservation Strategies in Cardiac Surgery Jerrold
H. Levy, MD
Professor of Anesthesiology
Emory University School of Medicine
Division of Cardiothoracic Anesthesiology and Critical Care
Emory Healthcare
Atlanta, Georgia |
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Introduction
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Cardiopulmonary
bypass (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.
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RISK
FACTORS
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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.
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DEVELOPING
TRANSFUSION PRACTICES
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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 transfusion requirements. |
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RED
CELL CONSERVATION
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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. |
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RED
CELL SUBSTITUTES
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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 human hemoglobin.
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DESMOPRESSIN
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Desmopressin
acetate (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. |
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LYSINE
ANALOGS
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Epsilon-aminocaproic
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. |
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APROTININ
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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.
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STUDIES
IN CHILDREN
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Aprotinin
consistently 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. |
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DEEP
HYPOTHERMIC CIRCULATORY ARREST (DHCA)
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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. |
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COMPARISON
STUDIES AND META-ANLYSIS
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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
similar results. |
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SUMMARY
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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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SELECTED
REFERENCES |
| 1. |
Alderman EL, Levy JH, Rich J, Nile M, Vidne B, Schaff H, Uretzky
G, Pettersson G, Thiis JJ, Hantler CB, Chaitman B; Nadel A: International
multi-center aprotinin graft patency experience (IMAGE). J Thorac
Cardiovasc Surg 1998;116:716-730. |
| 2. |
Benesch RE, Benesch R, Renthal RD, Maeda N. Affinity labeling
of the polyphosphate binding site of hemoglobin. Biochemistry 1972;11:3576-82.
|
| 3. |
Bennett-Guerrero E, Sorohan JG, Gurevich, et al: Cost-effectiveness
and efficacy of aprotinin as compared with aminocaproic acid in
patients undergoing cardiac operation: a randomized, blinded, clinical
trial. Anesthesiology, 1998. |
| 4. |
Berger PB, Alderman EL, Schaff HV: Frequency of early occlusion
and stenosis in the left internal mammary artery among patients
undergoing CABG through a median sternotomy on conventional bypass:
benchmark for the MIDCAB. Circulation 1997;96:3808 (Suppl). |
| 5. |
Bidstrup BP, Underwood SR, Sapsford RN, Streets EM. Effect of
aprotinin (Trasylol) on aorta-coronary bypass graft patency. J Thorac
Cardiovasc Surg 1993;105:147-153. |
| 6. |
Blauhut B, Gross C, Necek S. Effects of high-dose aprotinin on
blood loss, platelet function, fibrinolysis, complement, and renal
function after cardiopulmonary bypass. J Thorac Cardiovasc Surg
1991;101:958-967. |
| 7. |
Blauhut B, Harringer W, Bettelheim P, et al: Comparison of the
effects of aprotinin and tranexamic acid on blood loss and related
variables after cardiopulmonary bypass. J Thorac Cardiovasc Surg
1994;108:1083-91.
|
| 8. |
Bunn HF. Differences in the interaction of 2,3-diphosphoglycerate
with certain mammalian hemoglobins. Science 1971;172:1049-50. |
| 9. |
Cosgrove DM, Heric B, Lytle BW, et al. Aprotinin therapy for reoperative
myocardial revascularization: A placebo-controlled study. Ann Thorac
Surg 1992;54:1031-1038. |
| 10. |
DelRossi AJ, Cernaianu AC, Botros S. Prophylactic treatment of
postperfusion bleeding using EACA. Chest 1989;96:27-30. |
| 11. |
Despotis GJ. Joist JH. Goodnough LT. Monitoring of hemostasis
in cardiac surgical patients: impact of point-of-care testing on
blood loss and transfusion outcomes. Clinical Chemistry. 43(9):1684-96,
1997. |
| 12. |
Despotis GJ. Levine V. Saleem R. Spitznagel E. Joist JH. Use of
point-of-care test in identification of patients who can benefit
from desmopressin during cardiac surgery: a randomised controlled
trial. Lancet. 354(9173):106-10, 1999. |
| 13. |
Dietrich W, Spannagl M, Jochum M, et al. Influence of high-dose
aprotinin treatment on blood loss and coagulation patterns in patients
undergoing myocardial revascularization. Anesthesiology 1990; 73:1119-1126. |
| 14. |
Dietz N, Joyner MJ, Warner M: Blood Substitutes: Fluids, Drugs,
or Miracle Solutions? Anesth Analg 82:390-405, 1996. |
| 15. |
Fronticelli C, Bucci E, Orth C. Solvent regulation of oxygen affinity
in hemoglobin. J Biol Chem 1984;259:10841-4. |
| 16. |
Havel M, Grabenwoger F, Schneider J. Aprotinin does not decrease
early graft patency after coronary artery bypass grafting despite
reducing postoperative bleeding and use of donated blood. J Thorac
Cardiovasc Surg 1994;107:807-810. |
| 17. |
Havel M, Teufelsbauer H, Knobl P, et al. Effect of intraoperative
aprotinin administration on postoperative bleeding in patients undergoing
cardiopulmonary bypass operation. J Thorac Cardiovasc Surg 1991;101:968-972. |
| 18. |
Hess JR, Fadare SO, Tolentino LSL, et al. The intravascular persistence
of crosslinked human hemoglobin. Prog Clin Biol Res 1989;319:351-7. |
| 19. |
Hess JR, MacDonald VW, Brinkley WW. Systemic and pulmonary hypertension
after resuscitation with cell-free hemoglobin. J Appl Physiol 1993;74:1769-78. |
| 20. |
Horrow J, Hlavacek J, Strong M, et al. Prophylactic tranexamic
acid decreases bleeding after cardiac operations. J Thorac Cardiovasc
Surg 1990;99:70-74. |
21. |
Horrow JC, Van Riper DF, Strong MD, Grunewald KE, Parmet JL. The
dose-response relationship of tranexamic acid. Anesthesiology 1995;82:383-92. |
22. |
Lemmer JH, Stanford W, Bonney SL et al. Aprotinin
for coronary artery bypass grafting; effect on postoperative renal
function. Ann Thorac Surg 1995;59:132-6.
|
23. |
Lemmer JH, Stanford W, Bonney SL, et al. Aprotinin
for coronary bypass surgery: efficacy, safety, and influence on
early saphenous vein graft patency. J Thorac Cardiovasc Surg 1994;107:543-553. |
24. |
Levi M, Cromheecke ME, de Jonge E et al:Pharmacological
strategies to decrease excessive blood loss in cardiac surgery:
a meta-analysis of clinically relevant endpoints. Lancet. 1999
354(9194):1940-7.
|
25. |
Levy JH, Bailey JM, Salmenpera M. Pharmacokinetics
of aprotinin in preoperative cardiac surgical patients. Anesthesiology
1994;80:1013-1018. |
26. |
Levy JH, Murkin J, Ramsay JG: Aprotinin reduces
the incidence of strokes following cardiac surgery. Circulation
94: I-535, 1996. |
27. |
Levy JH, Pifarre R, Schaff H, et al. A multicenter,
placebo-controlled, double-blind trial of aprotinin for repeat
coronary artery bypass grafting. Circulation 1995; 92: 2236-2244. |
28. |
Levy JH: Anaphylactic Reactions in Anesthesia
and Intensive Care. (Second Edition) Stoneham: Butterworth-Heinemann,
1992.
|
29. |
Levy JH: The human inflammatory response. J
Cardiovasc Pharmacol 1996; 27 (Suppl. 1):S31-S37.
|
30. |
Levy JH: Hemoglobin-based oxygen-carrying solutions:
close but still so far. Anesthesiology. 2000;92:639-41 |
31. |
Levy JH: Novel intravenous antithrombins. Am
Heart J. 2001 141:1043-7. |
32. |
Looker D, Abbott-Brown D, Cozart P, et al: A
human recombinant haemoglobin designed for use as a "blood
substitute". Nature 356:258-260, 1992. |
33. |
Loscalzo J: Nitric oxide binding and the adverse
effects of cell-free hemoglobins: What makes us different from
earthworms. J Lab Clin Med 129:580-583, 1997.
|
34. |
Marcus, AJ Thrombosis and inflammation as multicellular
processes: significance of cell-cell interactions. Semin Hematol
1994;31:261-269.
|
35. |
Marx G, Pokar H, Reuter H, Doering V, Tilsner
V. The effects of aprotinin on hemostatic function during cardiac
surgery. J Cardiothor Vasc Anesth 1991;5:467-474. |
36. |
Miller BE, Tosone SR, Tam VKH, Kanter KR, Guzzetta
NA, Mochizuki T, Levy JH: Hematologic and economic impact of aprotinin
in reoperative pediatric cardiac surgery. Ann Thorac Surg 1998;
66:535-540. |
37. |
Miller BE, Tosone SR, Tam VKH, Kanter KR, Guzzetta
NA, Mochizuki T, Levy JH*: Hematologic and economic impact of
aprotinin in reoperative pediatric cardiac surgery. Ann Thorac
Surg 1998; 66:535-540. |
38. |
Mok W, Chen D-E, Mazur A. Cross-linked hemoglobins
as potential plasma protein extenders. Fed Proc 1975;34:1458. |
39. |
Munoz JJ. Birkmeyer NJ. Birkmeyer JD. O'Connor
GT. Dacey LJ. Is epsilon-aminocaproic acid as effective as aprotinin
in reducing bleeding with cardiac surgery?: a meta-analysis. Circulation.
99:81-9, 1999.
|
40. |
Peters DC. Noble S. Aprotinin: an update of
its pharmacology and therapeutic use in open heart surgery and
coronary artery bypass surgery. Drugs. 57:233-60, 1999. |
41. |
Peters DC. Noble S. Aprotinin: an update of
its pharmacology and therapeutic use in open heart surgery and
coronary artery bypass surgery. Drugs. 57(2):233-60, 1999.
|
42. |
Shore-Lesserson L. Manspeizer HE. DePerio M.
Francis S. Vela-Cantos F. Ergin MA. Thromboelastography-guided
transfusion algorithm reduces transfusions in complex cardiac
surgery. Anesth Analg. 88(2):312-9, 1999. |
43. |
Smith CR. Spanier TB. Aprotinin in deep hypothermic
circulatory arrest. Ann Thor Surg. 68:278-86, 1999. |
44. |
Van Norman G, Ju J, Spiess B, Soltow L, Gillies
G. Aprotinin versus EACA in moderate-to-high-risk cardiac surgery;
relative efficacy and costs. Anesth Analg 1995;80:SCA19.
|
45. |
Vander Salm TJ, Ansell JE, Okike ON. The role
of epsilon-aminocaproic acid in reducing bleeding after cardiac
operation: A double-blind randomized study. J Thorac Cardiovasc
Surg 1988;95:538-542. |
46. |
Vander Salm TJ, Kaur S, Lancey RA et al: Reduction
of bleeding after heart operation through the prophylactic use
of EACA. J Thorac Cardiovasc Surg 1996;112:1098-1107. |
47. |
Vlahakes GJ, Lee R, Jacobs EE Jr, et al. Hemodynamic
effects and oxygen transport properties of a new blood substitute
in a model of massive blood replacement. J Thorac Cardiovasc Surg
1990;100:379-88.
|
48. |
Wong M, Suslick KS. Sonochemically produced
hemoglobin microbubbles. Proceedings: Materials Research Society
Symposium W2, Boston, MA, Fall 1994. |
. |
|
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