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 patients 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 Wrens 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 lambs blood to a young man possessed of an incredible stupidity on June 15, 1667 <||>. 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 physiciansgoal was to treat the patients 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 calfs blood given by Denis in December, 1667. In the investigation that ensued, Dr. Denis and colleagues were acquitted of the patients 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 1660s until the early 1800s, 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 the 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. Blundells 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 <||>. 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 <||>. 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 <||>. In addition, Blundells rejection of animal blood as incompatible with humans predated Landsteiners discovery of blood groups by almost 100 years.
Blundells 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 <||> <|(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 <|(Figure 2)|> <|(Figure 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 <||>. 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 <||>.
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. Halsteds 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 <||> <|(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 surg e r y. Halsted was a true innovator in bloodless medicine and surgery both in his insistence on careful technique and 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 s u rgery without hemorrhage. Even with these advances, blood loss remained an obstacle to the further development of surg e r y.
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. Landsteiners description of the ABO red cell antigen system led to early forms of testing that dramatically reduced the risk of death from transfusion reactions <||>. 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 <||>. Crile consolidated our understanding of anemia, hemorrhage and transfusion as 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 <||>. 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. Thirteen million units a means of restoring blood loss <||>.
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 <||>. 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 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, Ambersons hemoglobin solutions produced significant renal damage and were rapidly eliminated from the circulation <||>.
<||>. 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 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 <||>. 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
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 Jehovahs 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 cross-matching. 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 surgeons practice. Milles, Langston and DAlessandro raised concerns about this problem in their visionary monograph on autologous transfusion published in 1971 <||>. 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 patients 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 <||>. Fantus had also recommended that patients serve as their own donors <||>. The credit goes to Milles and Langston for proving the value of autologous blood as a an alternative to allogeneic red cell transfusion. Using a 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 1960s. 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 1,000 patients treated with alternatives. These early investigators were able to provide 90% of the surgical blood needs through autologous sources.
Milles and Langstons pioneering work in autologous predonation and autotransfusion was prompted by their concerns about transfusion-transmitted hepatitis and medicines 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 patients own blood. Investigation of another approach to using autologous blood through hemodilution has been part of the lifes 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 1950s and 1960s 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. Gibbons 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 1970s. This extensive use of blood prompted surgeons and anesthesiologists to find ways of salvaging any left over cells <||>.
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 <||>. Loyal Davis and Harvey Cushing reported on its usefulness in neurosurgery in 1925 <||>. Stagers review of the literature in 1951 showed that autotransfusion had been used in close to 500 patients with great success <||>. 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 <||>. 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 Jehovahs 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 <||>. 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 radicals 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 <||>. This work provided a stimulus for others to provide surgical treatment to Jehovahs 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 1970s early 1980s 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 Jehovahs 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 in Montreal were among those who worked diligently on the production of a safe, human hemoglobin-derived substitute for blood <|[23, 24]|>. Moss and Goulds systematic approach to solving the toxicity problems of these products has led to their polymerized hemoglobin, Polyheme which is in clinical trials today <||>. Tom Changs 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 1980s in the form of Fluosol DA20%, a product produced by Green Cross of Osaka, Japan. It was the genius of Ryochi Naito, the companys founder, that coupled Leland Clarks work with raw perflourocarbons with Robert Geyers development of intravenous lipid emulsions to produce this first artificial blood substitute <||>.
Clinical trials of Fluosol in the anemic Jehovahs Witness patient in the early 1980s led 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 <||>. Experiences with Fluosol had a much greater impact on those involved in the 1980s clinical trials, myself included <||>. 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 Jehovahs 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 worlds literature on bloodless medicine and surgery topics shows how much work has been published in this field.
Without question, the realization in the early 1980s 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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