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Introduction
Although the term "bloodless medicine and surgery" is relatively new,
the desire to restrict blood loss and transfusion need is not. In
fact, medicine has searched for alternatives to allogeneic blood ever
since transfusion became a practical reality. The history of transfusion
can be followed by tracking the convergence of the growth of knowledge
in anatomy and physiology with the development of technology and the
maturation of our rationale for using blood. Underlying and anchoring
these themes is the persistent bass note of risk, that prompted the
search for alternatives. This brief review highlights the reasons
for and the results of the changes in transfusion medicine that ultimately
led to the current state of bloodless medicine and surgery. Although
the focus may seem weighted toward the United States, particularly
in recent developments, I have attempted to include worldwide milestones,
especially those of true pioneers in the field.
A Definition of Bloodless Medicine and Surgery
To most people, the term bloodless medicine and surgery (BM&S) is
defined as the avoidance of allogeneic blood transfusion. However,
the practice of bloodless medicine and surgery entails more than this.
As understood by both practitioners and advocates, BM&S requires a
balance of transfusion risks and benefits, a knowledge of a broad
spectrum of techniques and methods to minimize blood loss, and the
employment of autologous alternatives to allogeneic blood as dictated
by the individual patient's condition and needs. At the heart of BM&S
is a philosophy of transfusion avoidance based on a desire to provide
the best possible outcomes for our patients while minimizing any potential
harm. These very concepts also form the basis for the development
of blood transfusion as a therapy over the ages. It should not be
a surprise to find that they also prompted physicians to seek alternatives
to blood, beginning soon after transfusion became practical.
Development of Allogeneic Transfusion
It is generally accepted that the first human transfusions were performed
in France and England in 1667. Although there are apocryphal reports
of blood being transfused to Pope Innocent VIII in the 15th
century, the lack of means to transfuse blood makes this unlikely.
As is true in much of medicine, 17th century transfusions
were the direct result of the development of technology coinciding
with a knowledge of anatomy and physiology, no matter how crude, that
made an idea a reality. The sentinel events were the description of
the venous circulation in De Motu Cordis by William Harvey in 1628
and Sir Christopher Wren's creation in 1658 of the first "syringe"
made by fastening an animal bladder to a sharpened goose quill. Wren
was actually preceded in 1652 in the use of this device by Francis
Potter, a British rector, whose choice of pullets as an experimental
animal doomed his experiments to failure. Using larger animals, Wren
was able to inject a variety of substances into veins. Building on
these early experiments, Richard Lower performed the first animal
to animal blood transfusions in a dog in 1665 in London. Similar experiments
were conducted by Jean Baptiste Denis and a group of collaborators
in Paris at the same time. This group is credited as the first to
transfuse animal blood into a human subject when they gave lamb's
blood to a young man "possessed of an incredible stupidity" on June
15, 1667. [1]. Lower quickly
followed with a similar transfusion given to Arthur Coga in London
on November 23, 1967.
The transfusions were technically successful, but no clinical benefit
was achieved. The latter is not unexpected since the physicians' goal
was to treat the patient's mental problems through the infusion of
animal humors from the blood. This medical fad continued for only
a short period of time until a French patient, Antoine Mauroy, died
after two transfusions of calf's blood given by Denis in December,
1667. In the investigation that ensued, Dr. Denis and colleagues were
acquitted of the patient's death when the French courts determined
that Mauroy had been poisoned by his wife. However, the civil action
dealt a death blow to transfusion experimentation. The procedure was
quickly banned as dangerous by medical and legislative bodies throughout
Europe and it disappeared from sight expect for sporadic cases. Since
transfusion had not been shown to have any measurable benefit, there
was no movement to find a replacement.
Only sporadic reports of transfusion can be found from the 1660's
until the early 1800's, a period of 150 years. During this time medical
science had made significant advances with the further elucidation
of oxygen physiology and red cell function. In 1774, Priestley described
the function of red blood cells as oxygen carriers. In same year,
Lavoisier clarified the role of oxygen in respiration. The stage was
set for a new era of transfusion medicine. The credit for the rebirth
of interest in transfusion belongs to James Blundell, a physician-surgeon
practicing in London in the early 19th century. Alarmed by the unacceptably
high number of deaths in his practice caused by post-partum hemorrhage,
Blundell looked for a means to replace this shed blood. Blundell's
interest prompted him to experiment first in the animal laboratory
with interspecies transfusion, which led him to the conclusion that
transfusing animal blood into humans was inherently unsafe. [2]
When faced with the daunting task of obtaining human blood for transfusion,
he developed two approaches: 1) obtaining capillary blood from volunteer
donors with a rather monstrous device, and 2) salvaging shed blood.
He stirred or agitated the blood to "defibrinate" it, then infused
it through an impeller device that included one of the first uses
of a three-way stopcock. Four of his first eight attempts at human
to human transfusion were successful.
Blundell is considered to be the Father of Autotransfusion for his
work in this field. [3] He justly deserves credit as the
first to use autologous blood for transfusion. However, I believe
he warrants even greater recognition as the Father of Modern Surgical
Transfusion Science for being the first to make the connection between
the potential benefit of transfusion in preventing death from hemorrhage.
This philosophy was a departure from the traditional view of blood
transfusion based on Galenic principles of blood as a humor rather
than as a physiological substance. Remember that Blundell practiced
medicine at a time when blood letting to the extreme was widely accepted
as appropriate therapy for most illnesses. Little regard was paid
to the deaths caused by this iatrogenic hemorrhage. Battlefield approaches
to bleeding were based on quick action and vessel ligation. Surgeons
had made the connection between blood loss and death, but Blundell
was the first to show that transfusion could be therapeutic. [4]
In addition, Blundell's rejection of animal blood as incompatible
with human's predated Landsteiner's discovery of blood groups by almost
100 years.
Blundell's pioneering work reawakened the medical world to the therapeutic
potential of transfused blood. Others modified and improved on his
clinical experiments, to the extent that Jennings was able to compile
and publish a bibliography and review of 243 transfusions performed
before 1873.[5] Figure 1 His findings pointed out the problems
with transfusion that prompted the search for an alternative. Although
114 patients (46.9%) were reported to have had a "complete recovery"
following transfusion, others did not fare so well. During this period,
our understanding of physiology and the effects of blood loss advanced
rapidly. Claude Bernard established the concept of an internal milieu
of checks and balances in the body and the need to maintain a steady
intravascular volume to prevent death. In 1854, Le Dran defined metabolic
derangement as the clinical entity of shock. The use of blood transfusion
now had a firmer physiological foundation for use in clinical practice
as a means of restoring blood volume.
However, multiple problems with blood hindered its regular use. Lethal
transfusion reactions were not understood. Blood was difficult to
handle because of its rapid clotting time, which effectively eliminated
even temporary storage and indirect transfusion. As a result, the
field of clinical transfusion medicine was dominated by surgical specialists
who created direct, surgical communications between donor and recipient
by connecting artery to vein. Figures 2 & 3 Unfortunately, this approach
required considerable skill, was cumbersome, and permitted only one-time
transfusions. Early syringe and roller devices using two syringes
improved direct transfusion practices, but the problems of reactions,
sterility, and volume overload remained. These problems prompted physicians
to look for easier more universal solutions.
As early as 1876, Barnes and Little described the use of saline solutions
in the restoration of "equilibrium in the circulatory system." [1]
Further experiments with this first "blood substitute" established
a firm role for crystalloid infusions in the treatment of hemorrhage.
Hamlin tried infusions of milk as a blood replacement, reasoning that
the white corpuscles of blood came from the same source as milk. (Hamlin
ref) Fortunately, this approach was short-lived. Saline provided some
advantages and was used in conjunction with the newly developed general
anesthesia that permitted more involved surgery. Evidence produced
by Rudolph Virchow that malignancies traveled via the lymphatic system
led to the radical excision of cancers and their lymph node groups,
e.g., radical mastectomy and abdominoperineal resection. Excessive
hemorrhage as a cause of death now moved from the battlefield into
the elective surgical suite. Halsted's description of uncontrolled
bleeding as the only defense of the unconscious patient against the
incompetent surgeon epitomized the new era of surgical training aimed
at controlling blood loss. [6] Figure 4 Surgeons trained
by Halsted at Johns Hopkins spread the bible of gentle tissue handling,
anatomic surgical approaches and meticulous hemostasis that remain
with us today as a mainstay of bloodless medicine and surgery. Halsted
was a true innovator in bloodless medicine and surgery both in his
insistence on careful technique but also in his introduction of the
"German hemostat", an instrument used today by surgeons around the
world. His refusal to accept preventable blood loss in the operating
theater is a major tenet of modern transfusion alternative philosophy.
He also understood that the use of patient and procedure-directed
anesthesia permitted the surgeon the time necessary to perform surgery
without hemorrhage. Even with these advances, blood loss remained
an obstacle to the further development of surgery.
As the 20th century approached, some investigators tackled the problem
of transfusion reactions, some searched for ways to store blood, while
others improved our knowledge of when to transfuse. Landsteiner's
description of the ABO red cell antigen system led to early forms
of testing that dramatically reduced the risk of death from transfusion
reactions.[7] Weil added citrate salts to blood, proving
that this would retard coagulation. Lewisohn was the first to devise
a safe combination of citrate that permitted blood to be stored temporarily.
Rous and Turner, working at the Rockefeller Institute in New York,
added dextrose to the citrated blood, thereby allowing storage for
up to 21 days.[8] Crile consolidated our understanding
of anemia, hemorrhage and transfusion as a means of restoring blood
loss. [1]
This landmark work was completed just in time for blood to be used
at the front in World War I. However, it created a whole, new set
of problems of the need for a donor supply and how, where and for
how long to store blood. Figure 5 Russian physicians, led by Filatov,
Depp and Yudin pioneered the collection and storage of cadaver blood.
[9] This approach met with great disfavor in the West,
but it formed the basis for the development in 1934 of the first blood
bank in Chicago by Seed and Fantus. [10] Their unique contribution
was twofold: development of a facility to store blood and the use
of live human donors.
The onset of World War II created the need for modernization in transfusion
delivery as well the need for a suitable substitute. Figure 6 British
blood services responded with both direct and indirect battlefield
transfusions. Work presented at the American Human Serum Association
meeting in 1941 focused on the need for the United States and Canada
to prepare a wartime supply of blood and blood products. This work
is summarized in the monograph entitled Blood Substitutes and Blood
Transfusion edited by Stuart Mudd and William Thalhimer. [11]
The book contains state of the art chapters on preparation of dried
human plasma, early work on hemoglobin-saline solutions by Amberson,
and the use of casein infusions by Whipple. Substitutes saw little
use during the war. 13 million units of blood and blood products were
contributed by United States citizens for use by the Armed Forces
between 1941 and 1945. The realization that the United States now
collects the same number of units in one year reflects how much the
business of blood banking has grown.
Lessons learned in World War II were described by White and Weinstein
in their book on current transfusion practices. [12] Topics
in the book included the use of human plasma in treating shock on
the battlefield and plans for the adaptation of its use to civilian
settings. A variety of gelatin-based and animal derivative substitutes
that were under investigation were described as well as protein hydrolysates,
the clinical precursors of hyperalimentation solutions. None of these
were ready for extensive clinical use. For example, Amberson's hemoglobin
solutions produced significant renal damage and were rapidly eliminated
from the circulation. [13] .
The general opinion based on this huge wartime experience was that
blood and blood products were safe for widespread human use. No one
wished to return to the "bad old days" of animal products for transfusion
when human plasma and albumin were readily available, effective and
safe. Physicians returning home after the war demanded that blood
transfusion be available, so transfusion medicine entered an era of
rapid growth secure in the belief that the benefits of transfused
blood far outweighed the risks.
The Rise of Alternatives to Allogeneic Blood
Several major forces played pivotal roles in the development of transfusion
alternatives and bloodless medicine and surgery, including our increasing
knowledge of the risks of allogeneic blood, the desire of Jehovah's
Witnesses to have advanced medical care without transfusion, explosions
in medical technology and steady progress in our understanding of
oxygen transport physiology. The problem of lethal transfusion reactions
had been solved with the introduction of routine typing and crossmatching.
The ability to identify the Rh complex and multiple, isolated red
cell antigens reduced the incidence of hemolytic and antibody-based
reactions. It had been known for some time that blood transfusion
transmitted syphilis, malaria, smallpox and what was known as passive
anaphylaxis. The only disease thought to be a public health concern
in the United States was syphilis. Transmission could be prevented
by mandatory testing for spirochetes using the Venereal Disease Research
Laboratory, or VDRL, test. As a result, physicians were complacent
about the use of blood.
Water began to seep through the dam as early as 1943 with reports
of jaundice following the administration of blood products. [14,
15] These isolated reports raised little concern among the surgeons,
most frequent users of blood, primarily because they rarely saw the
consequences of transfusion-transmitted hepatitis. Patients who developed
this disease after surgical transfusion were long gone from the surgeon's
practice. Milles, Langston and D'Alessandro raised concerns about
this problem in their visionary monograph on autologous transfusion
published in 1971. [9] They reported not only on the relationship
between transfusion and hepatitis but also on their experience with
the use of both predonated autologous blood and autotransfusion to
avoid allogeneic transfusion.
Predonation of the patient's own blood was not a new phenomenon when
Milles and Langston considered its use. As we have seen, Blundell
used a form of predonation without storage as early as 1812. Grant
was the first in 1921 to phlebotomize his polycythemic patient before
a craniotomy, storing his blood for later transfusion. [16]
Fantus had also recommended that patients serve as their own donors.
[10] The credit goes to Milles and Langston for proving
the value of autologous blood as a an alternative to allogeneic red
cell transfusion. Using as combination of autotransfusion and predonation,
they eliminated transfusion in 53.8% of all patients who underwent
thoracic surgery at the Chicago state Tuberculosis Sanatorium during
the 1960's. They collected 534 units of blood from 458 patients who
had preoperative hemoglobin levels of 11 gm/dL or higher. 522, or
98%, of these units were transfused during surgery or within 48 hours.
They extended this work to both general surgical and urological patients,
accruing data on approximately 1000 patients treated with alternatives.
These early investigators were able to provide 90% of the surgical
blood needs through autologous sources.
Milles and Langston's pioneering work in autologous predonation and
autotransfusion was prompted by their concerns about transfusion-transmitted
hepatitis and medicine's inability to prevent its spread. Unfortunately,
their work fell on deaf ears in most operating rooms in the United
States, in part because of the need for allogeneic blood to support
advances in surgical technology and treatment. Some others saw the
wisdom of using the patient's own blood. Investigation of another
approach to using autologous blood through hemodilution has been part
of the life's work of Konrad Messmer of Germany, who has provided
us with the understanding of hemodilution and the physiologic basis
for its current clinical use.
The ready availability of blood in the 1950's and 1960's led to the
development of what I have chosen to call transfusion-based surgical
technologies and operations. These include cardiac, vascular, oncologic
and joint replacement surgery amongst others. Gibbon's invention of
the first heart-lung machine in 1953 provided the means for surgery
on the heart and great vessels. Blood was used to prime the pump in
early machines. I personally remember routinely typing and crossmatching
25 units of blood for single-vessel cardiac bypass operations in the
1970's. This extensive use of blood prompted surgeons and anesthesiologists
to find ways of salvaging any left over cells. (Tawes ref)
Autotransfusion, or salvage and reinfusion of shed blood, had been
used sporadically since 1914 when Theis, a German obstetrician, successfully
returned blood lost from ruptured ectopic pregnancies through a gauze
filter in three women.[17] Loyal Davis and Harvey Cushing
reported on its usefulness in neurosurgery in 1925.[18]
Stager's review of the literature in 1951 showed that autotransfusion
had been used close to 500 patients with great success.[19]
Although Cohn had conceived of the idea of a cell separation device
for autotransfusion as early as 1953, the first prototype was built
by Taswell and Wilson at the Mayo Clinic in 1968. At the same time,
Dyer and Klebanoff developed a cell salvage device through Bentley
Laboratories. Blood collected by this first "Bentley" machine was
contaminated with impurities that often lead to coagulopathy and it
was known to produce lethal air embolism. Improvements in separation
technology and circuit design helped combat these problems. Latham
at Haemonetics Corporation devised a differential centrifugation bowl
coupled with a collection reservoir containing anticoagulant that
created a practical means for recovery of shed blood in the operating
room during a variety of surgical procedures.[20] Improvements
in these devices over the years have led to the current range of cell
salvage devices that are used in both the operative and postoperative
periods.
One group of patients, the Jehovah's Witnesses, were unable to take
advantage of these transfusion-based surgical technologies and operations,
because of their religious beliefs that forbade them from accepting
blood transfusions. [21] Their desire to obtain the best
possible medical care without the use of blood was met with scorn
and derision by many in the medical community. Most physicians misunderstood
the Witnesses position and labeled them as nuts who refused all medical
treatment for themselves and their children. Few surgeons who did
understand were willing to take on the problems of major surgery without
transfusion. One of these few, Denton Cooley, was the earliest of
the modern pioneers in bloodless medicine and surgery. His demonstration
that open heart surgery could be safely performed without blood, first
published in 1977, encompassed a twenty year experience including
542 patients ranging in age from one day to 89 years. [22]
This work provided a stimulus for others to provide surgical treatment
to Jehovah's Witnesses. The most notable among these was Ron Lapin,
a California surgeon, who operated on several thousand Witness patients
during his surgical career. Moreover, he was the first to recognize
bloodless medicine and surgery as a "speciality" or discipline. Based
on this belief, he created the first bloodless medicine and surgery
center in Bellflower Hospital in California in the late 1970's - early
1980's in response to the demand for his services. He also published
the first journal in the field and made the first efforts at training
and credentialing physicians. The Watchtower Bible and Tract Society,
the parent organization of the Jehovah's Witness religion, recognized
the importance of providing educational assistance to physicians who
were willing to treat their members. Early. Informal efforts at education
and communication were given structure in 1988 with the introduction
of the Hospital Information Services branch of the watchtower in Brooklyn.
This group of individuals has become one of the primary sources of
information regarding transfusion alternatives to the medical community.
Technological developments also played a significant role during this
time, particularly in the field of blood substitutes. Gerald Moss
and Stephen Gould in Chicago and Tom Chang were among those who worked
diligently on the production of a safe, human hemoglobin-derived substitute
for blood. [23, 24] Moss and Gould's systematic approach
to solving the toxicity problems of these products has led to their
polymerized hemoglobin, Polyheme", which is in clinical trials today.
[25] Tom Chang's continued quest for a liposome encapsulated
hemoglobin substitute has produced two, significant side benefits.
He has provided us with much needed information on oxygen transport
physiology as well as a venue for discussion of blood substitute through
both his biannual conferences and the journal Artificial Cells, Blood
Substitutes and Immobilization Biotechnology. Perfluorocarbon-based
blood substitutes saw the light of day in the early 1980's in the
form of Fluosol DA 20%, a product produced by Green Cross of Osaka,
Japan. It was the genius of Ryochi Naito, the company's founder, that
coupled Leland Clark's work with raw perflourocarbons with Robert
Geyer's development of intravenous lipid emulsions to produce this
first artificial blood substitute. [26]
Clinical trials of Fluosol in the anemic Jehovah's Witness patient
in the early 1980's lead to a myriad of advances in bloodless medicine
and surgery. Although Fluosol was not proven to be of significant
benefit in treating surgical anemia, its failings helped us to redefine
the role of temporary oxygen carriers and to focus on their correct
potential use as transfusion alternatives. Duane Roth, Peter Keipert
and Simon Faithfull of Alliance Pharmaceuticals have built on this
early experience to produce Oxygent", the modern perfluorocarbon oxygen
carrier now in clinical trials. [27] Experiences with Fluosol
had a much greater impact on those involved in the 1980's clinical
trials, myself included.[28] These were the stimulus for
many to question longstanding teachings about the transfusion trigger
and to begin to reassess our use of allogeneic blood. Experience with
treating Jehovah's Witnesses prompted us to develop one of the first
bloodless medicine and surgery centers at Cooper Hospital in Camden,
New Jersey. Others sprang up in Chicago, Cleveland and in Europe as
time progressed. To date there are close to 200 such centers throughout
the world. A look at the world's literature on bloodless medicine
and surgery top0ics shows how much work has been published in this
field. Figure
Without question, the realization in the early 1980's that the HIV
virus was transmissible by blood transfusion opened the eyes of both
physicians and the public to the inherent risks of allogeneic blood.
This reawakening coincided with many of the technological and scientific
advances that allowed us not only to analyze blood in a more sophisticated
and complete way but also to take measures to ensure increased safety.
The reader is undoubtedly familiar with the worldwide efforts and
successes in this area. Physicians and scientists throughout the world
have modified surgical procedures, investigated and improved autologous
strategies, explored the role of drugs, blood substitutes and sealants
in minimizing blood loss and the need for transfusion. Alternatives
are widely accepted as typified by predonation, which has become a
standard in joint replacement surgery. Arguments have shifted from
whether or not these alternatives reduce allogeneic blood use concerns
over appropriate and cost-effective use. Consensus conferences transfusion
policies have been held in a variety of countries and by all major
societies. Organizations such as NATA, the Network for Advancement
of Transfusion Alternatives, and the driving force behind this textbook
are now in place.
Although bloodless medicine and surgery has come a long way, there
is still much to be done. Our understanding of the benefit of allogeneic
blood in a clinical settings is now under scrutiny and will help redefine
when and whom we transfuse. Although most physicians understand the
risks of blood, education is still needed in the correct use of alternatives.
Blood substitutes, or oxygen carriers, are finally on the clinical
horizon and will revolutionize the way we understand and treat oxygen
transport. The future is bright for the field of transfusion alternatives.
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References
1. Diamond, L., A History of Blood Transfusion, in Blood, Pure and
Eloquent, W. MM, Editor. 1980, McGraw-Hill: New York, New York. p.
659-683.
2. Blundell, J., Experiments on the Transfusion of Blood by the Syringe.
Medicochirurgical Transactions, 1818. IX: p. 56-92.
3. Tawes, R. and T. Duvall, Autotransfusion in Cardiac and Vascular
Surgery: Overview of a 25 - Year Experience with Intraoperative Autotransfusion,
in Autotransfusion. Therapeutic Principles and Trends, R. Tawes, Editor.
1997, Gregory Appleton: Detroit. p. 147-8.
4. Bell, J., The Principles of Surgery. 1810, Philadelphia, PA.
5. Jennings, C., Transfusion: It's History, Indications, and Modes
of Application. 1883, New York: Leonard & Co. 108.
6. Surgical Papers by William Stewart Halsted. 1924, Baltimore, MD:
Johns Hopkins Press,.
7. Landsteiner, K., Wein Klin Wschr, 1901. 14: p. 1132-6.
8. Rous, P. and J. Turner, Preservation of living RBC in vitro. J
Exp Med, 1916. 232(219-25).
9. Milles, G., H. Langston, and W. D'Allessandro, Autologous Transfusion.
The John Alexander Monograph series, ed. H. Maier. 1971, Springfield,
IL: C.C. Thomas. 127.
10. Fantus, B., Therapy of the Cook County Hospital (blood preservation).
JAMA, 1937. 109: p. 128-32.
11. Mudd, S. and W. Thalhimer, Blood Substitutes and Blood Transfusion.
Vol. 1. 1942, Springfield, IL: C.C. Thomas. 407.
12. White, C. and J. Weinstein, Blood Derivatives and Substitutes.
Preparation, Storage, Adminsitration and Clinical Results including
a Discussion of Shock. Etiology, Physiology, Pathology and Treatment.
Vol. 1. 1947, Baltimore: Williams and Wilkins. 484.
13. Amberson, W., J. Jacobs, and A. Hisey, Hemoglobin Solutions as
Transfusion Media, in Blood Substitutes and Blood Transfusion, S.
Mudd and W. Thalheimer, Editors. 1942, Chas. C. Thomas: Springfield,
IL. p. 156-172.
14. Morgan, H. and D. Williamson, Jaundice following administration
of human blood products. Brit Med Journal, 1943. 1: p. 750-2.
15. Lehane, D. and e. al, Homologous Serum Jaundice. BMJ, 1949. 2:
p. 572-4.
16. Grant, F., Autotransfusion. Ann Surg, 1921. 74(253-5).
17. Theis, J., Zur Behandling der extrauterine Gravidataet. Zbl Gynaek,
1914. 38: p. 1191-4.
18. Davis, L. and L. Cushing, Experiences with blood replacement during
and after major intracranial operations. Surg Gynec Onstet, 1925.
40: p. 310-6.
19. Stager, W., Blood conservation by autotransfusion. Arch Surg,
1951. 63: p. 78-83.
20. Tawes, R., Jr. and T.B. DuVall, The basic concepts of an autotransfusor:
the Cell-Saver. Semin Vasc Surg, 1994. 7(2): p. 93-4.
21. Jehovah's Witnesses and the Question of Blood. 1977, New York,
New York: Watchtower Bible and Tract Society. 38-49.
22. Ott, D.A. and D.A. Cooley, Cardiovascular surgery in Jehovah's
Witnesses. JAMA, 1977. 238: p. 1256-8.
23. Moss, G., S. Gould, and L. Sehgal, Polyhemoglobin and Flurocarbon
as Blood Substitutes. Biomat Art Cells Art Org, 1981. 15(2): p. 333-6.
24. Chang, T.M., Blood substitutes based on modified hemoglobin prepared
by encapsulation or crosslinking: an overview. Biomater Artif Cells
Immobilization Biotechnol, 1992. 20(2-4): p. 159-79.
25. Gould, S.A., et al., The first randomized trial of human polymerized
hemoglobin as a blood substitute in acute trauma and emergent surgery
[see comments]. J Am Coll Surg, 1998. 187(2): p. 113-20; discussion
120-2.
26. Spence, R.K., Perfluorocarbons in the twenty-first century: clinical
applications as transfusion alternatives. Artif Cells Blood Substit
Immobil Biotechnol, 1995. 23(3): p. 367-80.
27. Keipert, P., Perfluorochemical Emulsions: Future Alternatives
for Transfusion, in Blood Substitutes: Principles, Methods, Products
and Clinical Trials, T. Chang, Editor. 1998: Montreal. p. 127-156.
28. Spence, R.K., et al., Fluosol DA-20 in the treatment of severe
anemia: randomized controlled study of 46 patients. Crit Care Med,
1990. 18(11): p. 1227-30.
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