The historical basis of transfusion and oncologic practice

The Historical Basis of T r a n s f u s i o n and Oncologic Practice H a y d e n G. B r a i n e

ODAY, blood transfusion is a standard component of medical therapy. Most of the pubT lic are aware of its crucial role in the management

by James Blundell in the early 1800s. 2 Such early attempts at transfusion were hampered by lack of equipment to transfuse the blood, ignorance of the antigenic barriers of blood types, and lack of recognition of the effect of hypovolemia on the donor. Nonetheless, transfusions were attempted during the Crimean War and the American Civil War. Lacking a clear pattern of success, through the last half of the 19th century physicians experimented with alternate sources of transfusion, including animal blood and milk. The first successful use of normal saline transfusion was reported in 1884. These early transfusion attempts were also hampered by a poor understanding of the concept of shock. It was not until World War I that the relationship between bleeding and shock was appropriately understood. The turn of the century anticipated four events that would determine the course of modem transfusion science. These included definition of blood groups, solutions for the technical problem of indirect transfusion, development of safe anticoagulants, and understanding the role of blood and blood replacement in the pathophysiology of shock. In Table I these events are depicted chronologically relative to major milestones in the development of oncologic and nursing science.

of trauma, cancer, hemophilia, and other illnesses. The public also participate in transfusion through donation of blood. Hence, transfusion may be perceived as one of the most well-understood aspects of modem medicine. The apparent simplicity of blood transfusion, however, belies its intrinsic complexity. Generally perceived as a single fluid, blood is actually a complex mixture of salts, macromolecules, cells, and cell fragments. The collection, storage, and transfusion of each of these components is complex, as is the determination of benefits and risks of transfusion. Spurred by the concern regarding the acquired immunodeficiency syndrome (AIDS), public interest in controlling the sources of blood for transfusion, as well as determining the indication for its use, has increased. These factors have made the area of blood transfusion an increasingly challenging problem for the blood bank specialist, physician, and nurse. Like the development of oncology itself~ clinical blood transfusion has been a development of the past 100 years. From even the most primitive times, however, blood has been recognized as a life force; uncontrolled blood loss has been temporally associated with death. Reversal of this process and replenishment of life must have been a desire of the earliest men. The first written descriptions of attempts at human transfusion were recorded in 1667 when an Englishman, Richard Lower, and a Frenchman, Jean Batiste Denis, tried to transfuse sheep blood into humans. 1 These initial attempts at transfusion were, of course, unsuccessful. In Denis's case, following initial apparent success, serial transfusions were attempted with subsequent severe reactions. These problems ultimately led to the revocation of the Denis's license and his untimely and rapid departure from Pads. The first human-to-human transfusion was reported by Phillip Physic of Philadelphia. While in Edinborough in 1795, he noted the use of blood transfusion in treating obstetrical hemorrhage. This practice was further popularized in England

From the Johns Hopkins Oncology Center, Baltimore, MD. Hayden G. Braine, MD: Associate Professor of Oneology, Johns Hopkins Oncology Center. Address reprints requests to Hayden G. Braine, MD, Johns Hopkins Oncology Center, Hemapheresis Treatment Center, 550 N Broadway, Eighth Floor, Baltimore, MD 20205. © 1990 W.B. Saunders Company. 0749-2081190/0602-000255.00/0

Seminars in Oncology Nursing, Vol 6, No 2 (May), 1990: pp 91-98

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BLOOD GROUPS

Karl Lansteiner was the first to recognize, in his sentinal report in 1901, that human red blood cells were characterized by distinctive antigens subsequently identified as the A and B red cell antigens. 3 The formal ABO nomenclature, however, was not adopted until the 1920s, and characterization of the Rh blood system was not understood until after the work of Allen and Diamond in the t940s. Since then, over 15 other red cell antigen systems have been described.

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HAYDEN G. BRAINE

Table 1. Selected Milestones in the Development of Transfusion in Oncology Decade

1890

SurgicaVMedical Science

Transfusion Science

1894, Halsted radical en bloc mastectomy

1900 1902, Pusey: first irradiation of Hodgkin's disease 1904, Young: Radical prostatectomy 1908, Miles: AP resection for rectal cancer

1901, Landsteiner: ABO blood group

1908, Carrel: Artery-vein transfusion

Nursing Science 1873, Nursing schools based on Nightengale's principles opened in the US 1900, American Journal of Nursing

1909, First collegiate nursing program, University of Minnesota 1909, Red Cross Nursing Service

1910 1914, Sodium citrate anticoagulant 1918, Blood storage and indirect transfusion 1920

1930 1940

1923, Cannon: Hypovolemic shock

1925, Fresh plasma reverses hemophilia

1911, American Nurses' Association (ANA) founded

1923, Goldmark report on nursing and nursing education

1926. Flemming discovered penicillin Cushing: Neurosurgery 1933, Graham: Pneumonectomy 1942. Cadet Nurse Corps 1943, Mustard chemotherapy for Hodgkin's disease 1945, Huggis: Adrenalectomy for prostate cancer 1948. Ferber: chemotherapy for leukemia

1947, Red Cross brood program founded 1948, Brown Report: Nursing for the future 1949, Plastic blood bag Military nursing Functional nursing

1950

1960

1950, Peters: X-ray cure of Hodgkin's disease Multimodality cure of leukemia

Team Nursing

Development of platelet transfusion

1967, Devita: Chemotherapy cure of Hodgkin's disease 1969, Thomas: Bone marrow transplant Autotransfusor

1969, First clinical cell separator Development of granutocyte transfusion

1970

1952, Nursing Research 1965, ANA position paper on baccalaureate degree 1967, First cancer nursing text 1969, ANA statement on graduate education in nursing: Nursing process

1970, Jerome Lysaught: Abstract for action primary nursing theory (Continued on following page)

HISTORICAL BASIS OF TRANSFUStON IN ONCOLOGY

93

Table 1. Selected Milestones in the Development of Transfusion in Oncology (Cont'd) Decade

Surgical;Medical Science Multimodality therapy of cancer

Transfusion Science

I972, Hepatitis B test

Chemotherapy cure of testicular cancer "Lumpectomy'" for breast cancer

1980

1980, Adjuvant therapy for breast cancer

1972, Expanded definitions of nurse practice acts: Standards of practice 1974, Certification exams (geriatric) 1975, Ontology Nursing Society 1976, Association of Pediatric Oncology Nurses 1970s, Master's degrees in oncology for clinical specialist

1980, AIDS reported 1983, HIV agent discovered

1987, Rosenberg: Bioregulator therapy (LAK cell)

Nursing Science

1986, Oncology nursing certification

1988, Unrelated bone marrow donor program 1989, Hepatitis C agent discovered

Abbreviations: AP, anterior-posterior; LAK, lymphokine activated killer (cell).

MECHANICAL PROBLEMS IN TRANSFUSION

Initial attempts at blood transfusion were via direct routes; that is, blood was allowed to flow in continuity directly from the donor to the recipient. Numerous tubing systems with syringes and valves were developed to facilitate this process. At the turn of the last century, surgically constructed anastomoses between donor and recipient blood vessels were also popular. The first successful human-to-human blood transfusion in the United States was reported in 1908 by Carrel, who used surgically implanted vascular cannulas in donor and recipient. At this primitive stage, transfusion was fraught with hazard. Febrile and hemolytic transfusion reactions were common. Slowly, it became apparent that when the compatibilities suggested by Lansteiner were adhered to, transfusion could be accomplished with minimal mortality and essentially no hemoglobinuria. Development of indirect transfusion, however, was not possible until the development of effective anticoagulation. Initially, blood for indirect transfusion was drawn into glass bottles. Although effective in many respects, glass bottles presented many practical problems. They were fragile, and maintenance of sterility with the necessary rubber seals and air vents was difficult. Furthermore, glass had

poor biocompatibility characteristics. Platelets, for example, adhere to glass, thus making their collection in unmodified glass containers impossible. Finally, blood in rigid glass containers was difficult to infuse rapidly in emergency situations. Injection of air under pressure into the bottle could facilitate rapid emptying, but could give rise to fatal air embolism if not watched closely. An alternate type of container was clearly preferable. With the development of the plastics industry in the 1940s, the modem blood container became feasible. The plastic container was flexible and difficult to break. With proper selection of plastic, its surface was compatible with platelets, and fast infusion could be accomplished by external compression. A series of bags, interconnected with plastic tubing, facilitated the collection and fractionation of blood without the need to open the system to air and possible contamination during blood processing. Intermediate laboratory steps necessary for fractionation could be made with integrally connected presterilized transfer containers. This development significantly reduced the risks of contamination during manufacture and thereby improved the safety of blood transfusion. Today the transfusion bag continues to be a subject of active research. Current plastics are being modified to further improve blood storage. Intro-

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duction of plastics permeable to gas has allowed introduction of "breathable" plastics. This improvement prevents the buildup of carbon dioxide and acidification during storage, and extends the allowable storage time of platelets to five days. To be flexible, plastic must be mixed with constituents called plasticizers. The most commonly used plasticizers are known chemically as phthalates. They convert a rigid plastic into a soft, pliable material. Unfortunately, these substances can leach into blood during storage and represent at least a theoretical hazard to blood transfusion. At this time, the blood bag manufacturing industry is developing safer, more biocompatible plasticizers than those currently in use.

storage. 2,3-DPG is an intracellular chemical necessary for binding and release of oxygen to hemoglobin. Red cells with low 2,3-DPG levels do not transport oxygen efficiently. Next, further improvement in red cell 2,3-DPG was achieved by the addition of adenine to the anticoagulant solution (CDP-adenine). More recently, the storage of packed red cells with a minimum of plasma has been achieved by adding "rejuvenating" solutions containing citrate, dextrose, adenine, inosine, phosphate, and mannitol to the red cells after plasma has been removed. Whereas such second and third generation anticoagulants have improved red cell viability, the basic principle of anticoagulation has remained calcium chelation with sodium citrate.

ANTICOAGULATION AND TRANSFUSION

Anticoagulation of blood by binding (chelation) of serum calcium with sodium citrate was first reported in 1914. 4 This was a crucial step toward the development of safe blood storage and indirect transfusion. By the end of World War I, indirect transfusion in the war theater was attempted on a limited basis. However, initial trials with anticoagulated stored blood were associated with an extremely high incidence of febrile transfusion reactions. In the early 1920s it was recognized that the majority of these febrile reactions were related to contaminating pyrogens such as endotoxin, and not to the citrate itself. With the removal of these pyrogens, citrate anticoagulation became the standard, and the indirect method of transfusion became the technique of choice. By the mid-1930s, during the Spanish Civil War, the first organized attempts to develop "blood banks" for the treatment of war casualties were being undertaken. Today sodium citrate remains the anticoagulant of choice for the collection and storage of blood. By 1943, it was recognized that the addition of a sugar (dextrose) to the storage solution could improve red cell viability during storage. However, acidification of the solution was also necessary to prevent caramelization of dextrose during heat sterilization. Thus, ACD (acid-citrate-dextrose) became the anticoagulant of choice for the next 30 years. In the past 15 years, several further improvements in storage solutions have been adapted for general clinical use. In 1967 phosphates (CPD) were added to maintain red cells' 2,3-DPG during

HEMORRHAGIC SHOCK AND BLOOD TRANSFUSION

Today, the principles of hemorrhagic shock and its management are basic principles of medicine and nursing. Before World War I, however, these principles had not been integrated into a coherent theory of blood pressure and circulation. Experience with traumatic blood loss during World War I resulted in an improved understanding of the role of fluid replacement in the management of hypovolemic shock. This discovery, combined with the recently expanding knowledge of red cell antigens, serocompatibility, and anticoagulation, allowed the development and acceptance of whole blood transfusion for the management of hypovolemic shock. It was also rapidly appreciated that plasma or albumin solutions derived from whole blood were as efficacious as whole blood in reversing most cases of hypovolemia. More importantly, albumin solutions could be stored for periods of months, whereas problems with refrigeration and sterility precluded extended storage of whole blood. Thus, the collection and fractionation of plasma and albumin constituents of blood became the major focus of research in the problem of shock. Technologies first developed in the dairy industry to separate cream from raw milk in a sterile continuous manner were applied by E.J. Cohen and others to the separation of plasma from whole blood. 5 These plasma separators became the first generation of instruments that are now recognized as hemapheresis cell separators. 6

HISTORICAL BASIS OF TRANSFUSION IN ONCOLOGY

In the initial enthusiasm to obtain plasma and plasma derivatives for transfusion, large numbers of red cells were frequently discarded. In World War II the full potential for use of red cells for the treatment of anemia and shock was recognized by Mollison and his associates. 7 Thus, during the London blitz, blood fractionation was first effectively practiced. Today a single unit of whole blood can be routinely fractionated into five or more components (Fig 1). ONCOLOGIC MEDICINE AND TRANSFUSION

Surgical Oncology Like transfusion, therapeutic oncology is a science of the 20th century (Table 1). In William Osler's classic textbook of medicine, The Prhlciples and Practice of Medichze, published in 1892, fewer than 50 pages of the 1,000-page textbook relate to cancer. This is somewhat ironic as Osler's colleague, Halsted, initiated the modem era of on-

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cology in 1894 with his description of the en bloc resection of breast cancer. This procedure was based on the concept of an ordered sequence of cancer metastases. This concept, combined with effective antisepsis and anesthesia, a high degree of skill, and knowledge of anatomy facilitated the development of similar surgical approaches to other cancers. Resection of prostatic cancer was reported in 1904, resection of rectal carcinoma in 1908, and pneumonectomy for lung cancer in 1933. Transfusion science was of central importance in the development of surgical oncology, Without replacement of blood, surgical approaches would have had to be limited to tolerable degrees of anemia and hypovolemia. With transfusion, blood loss was removed as a barrier to development of surgical technique.

Radiation Oncology Radiation oncology has also developed rapidly in the 20th century (Table 1). The first successful

1 UNIT FRESH WHOLE BLOOD CENTRIFIGATION

RED CELL CONCENTRATE (180 ml)

PLATELET RICH PLASMA 320 ml CENTRIIUGATION

LIOIID FROIEN STORAGE STORAGE

FRESH PLASMA

1 UNIT PLATELETS

l

150 ml)

COD+ CENTRIFUGATION

Y

CRYOPRECIPITATE

Fig 1. Schema of current fractionation of blood.

PLASMA

FRESH FROZEN PLASMA

MANUFACTURE

• PLASMAPROTEIN FRACTION • ALBUMIN

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treatment for Hodgkin's disease with radiation therapy was described by Pusey in 1902. 8 It was not until 1950, however, that Peters described the first cure of Hodgkin's disease with radiation. 9 Today, radiation therapy is a major modality in the treatment of cancer. Understanding of the principles of radiation-induced hematopoietic toxicity has been an important development of its application. Effective transfusion support has also facilitated the development of several radiation techniques such as total body irradiation.

Medical Oncology The field of cancer chemotherapy is the youngest of the traditional approaches to cancer therapy (Table 1). The principle of drug therapy of disease was first described by Paul Ehrlich in 1890 with his description of arsenicals (Salverson) for the treatment of syphilis. ~° This discovery was followed by the introduction of sulfa drugs and penicillin in the 1920s. However, it was not until the 1940s that it was recognized that similar principles could be applied to the management of cancer. In World War I it was noted that survivors of the pulmonary effects of mustard gas frequently suffered from hypoplasia of the bone marrow and lymph nodes, thus leading to the application of intravenous mustard therapy in conditions of neoplastic hyperaplasia of the lymph nodes such as Hodgkin's disease. Publication of these observations was delayed by the War Secrecy Acts. x~ In 1948, Sidney Farber described the use of aminopterin, an antifolate similar to methotrexate, in the management of acute leukemia, and thereby initiated the modem era of cancer chemotherapy.~2 In the past 30 years, curative chemotherapeutic regimens have been developed for Hodgkin's disease, non-Hodgkin's lymphoma, and testicular cancer. In addition, successful strategies for adjuvant therapy of breast cancer, as well as intensification strategies such as bone marrow transplantation have been developed. Recently, the era of biological response modifiers was introduced. First pioneered with hormonal therapy of prostate and breast cancer, the most recent event is the application of genetically engineered molecules such as the interferons and interleukins to a variety of malignancies. Overall, the development of the oncologie sciences has depended significantly on concurrent de-

HAYDEN G. BRAINE

velopment of transfusion sciences. Effective surgical therapy is dependent on the availability of blood replacement for life-threatening hypovolemia and anemia. Likewise, the development of effective platelet transfusions in the 1960s was an essential step in the conquest of leukemia.

Transfusion Safety Relative to the acute consequences without transfusion, the frequently delayed toxicities of transfusion have been less appreciated. Periodically the medical profession, as well as the general public, has had to be reminded of the risks that must be undertaken with transfusion. In the 1940s, there was concern over transfusion-related syphilis. In the late 1960s, before recognition of the hepatitis B virus, posttransfusion hepatitis was a major concern of the public. Most recently, with the spread of the human immunodeficiency virus and non A, non B (NANB) hepatitis, safety conceres are again being reemphasized. Today, molecular biology and microbiology have made the blood supply considerably safer. The importance of the discovery of the hepatitis B virus (HBV), the hepatitis C virus (HCV) responsible for NANB hepatitis, the human immunodeficiency virus (HIV), and the type I human T-cell lymphotrophic virus (HTLV-I) cannot be overemphasized. Also important in improving transfusion safety have been techniques of autotransfusion and intraoperative red cell salvage. Before widespread application of homologous transfusion became possible, autotransfusion was commonly used. In 1926, Tiber 13 reported only 1 death in a series of 123 cases of intraoperative transfusion for ruptured ectopic pregnancy. After several periods of disfavor and acceptance, intraoperative blood salvage is again becoming accepted, particularly with surgical procedures such as liver transplantation that require massive transfusion. Expanded salvage also has been facilitated by second-generation intraoperative blood processors. 14 Autotransfusion may also be accomplished by autologous donation or intraoperative hemodilution. In the future, these techniques may be augmented by the use of recombinant human erythropoietin to increase the patient's red cell mass. Directed donations (recruitment of specific friends or relatives as donors of blood intended for a spe-

HISTORICAL BASIS OF TRANSFUSION IN ONCOLOGY

cific patient) are also currently popular with the public, but to date they have no proven role in improving safety of blood transfusion. NURSING SCIENCE AND TRANSFUSION

Although nursing principles can be traced to antiquity, the era of modem nursing is generally attributed to the work of Florence Nightingale in the Crimean War. In the subsequent 100 years, nursing has evolved to its current status as an independent science with a development that, like medicine, has been shaped by the dramatic changes that have occurred in the last 100 years (Table 1). In transfusion medicine, nursing has taken leadership in the development of the donation process. At the time of the Korean War, a national shortage of blood components was recognized. To meet this emergency, Congress empowered the American National Red Cross to coordinate a national blood donation program to ensure adequate blood reserves. At that time, national medical services were being stressed by both military and civilian requirements, and the primary responsibility for blood acquisition became a nursing function. This development was a logical step because nurses were already trained in antiseptic technique and venipuncture. Furthermore, their medical skills were essential for management of donor reactions. To this day, supervision of blood donation is largely a nursing responsibility. In the modem mobile blood donation facility, the nurse is challenged with the problem of medically screening hundreds of donors with complex decisions involving both donor and patient safety. The nurse is also responsible for safe antiseptic venipuncture, donation, and appropriate diagnosis and management of adverse reactions. This development of the nursephlebotomist as a model of nursing practice has been, perhaps, one of the most innovative and least-emphasized developments in the last 30 years of nursing history. Nursing has also taken the leadership in developing both the clinical and technical aspects of automated plateletpheresis, leukapheresis, and plasmapheresis, as well as intraoperative red cell salvage. Many hospitals now staff intraoperative transfusion teams or rely on mobile communitybased intraoperative transfusion support systems. Such intraoperative cell salvage teams are frequently staffed with nurse specialists.

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The nurse's role as a transfusionist, however, has been a much more recent development. Before the introduction of the modem blood bank, transfusion was solely a physician's responsibility. Historically, primary care physicians were responsible for selection of appropriate units of blood and were required to perform crossmatches themselves. Remnants of this practice can be seen in Europe today. To this day, in some parts of Germany a final bedside crossmatch is performed by the primary physician. With the development of oncology nursing as a discipline and of specialty care units for trauma, dialysis, leukemia, and bone marrow transplant, transfusion has become more routine. With highvolume repetitive transfusion needs in these specialty units, systemization of transfusion management has become easier and nursing has taken an increasingly important role in transfusion. Today the nurse is central to the transfusion process. The nurse is expected to educate the patient regarding the overall transfusion and transfusion process, in addition to administering the transfusion and managing adverse reactions. Specific details of these responsibilities are described in subsequent articles in this issue. PERSPECTIVE

Paul Schmidt Is has observed that retrospectively the sequence of historical events seems to take on an apparent predictability: "The end result we see now may seem to have been always inevitable.'" In fact, the development of all new concepts involves a complex combination of necessity, basic work, insight, and luck. History also tends to give the present a sense of completeness, a false sense that all the big points have been discovered. In fact, history should show us that the story of transfusion is still unfolding. It therefore behooves the transfusionist to maintain an educated and open mind. Today's problems and solutions are tommorow's "'classic principles." Our challenge is to recognize this and facilitate this evolution while at the same time delivering effective and compassionate clinical care. ACKNOWLEDGMENT

The authorgratefullyacknowledgesCindyYoungfor assistance in manuscriptpreparation.

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HAYDEN G. BRAINE REFERENCES

1. Denis J: (1667) Letter to the publishers. Philos Trans R Soc Lond 3:489, 1967 2. Blundell J: A successful case of transfusion. Lancet 1:431, 1829 3. Landsteiner K: Uber Aggilutination-Serscheinungen Normalen Menschlichen Blutes. Klin Wochenschr 14:1132, 1901 4. Hustin A: Principe d'une nouvelle methode de transfusion. J Med Brux 2:436, 1914 5. Cohn EJ, Oncley JC, Strong LE, et al: Chemical, clinical, and immunologic studies on the products of human plasma fractionation. J Clin Invest 23:417, 1944 6. Cohn EJ, Tullis JL, Surgenor DM, et al: Biochemistry and biomechanics of blood collection, processing, and analyzing of human blood and other tissues. Address before the National Academy of Science, Yale University, New Haven, CT, 1951. 7. Mollison PL: Blood Transfusion in Clinical Medicine (ed 7). London, England, Blackwell Scientific, 1983 8. Pusey WA: Cases of sarcoma and of Hodgkin's disease

treated by exposures to x-rays: A preliminary report. JAMA 38:166-170, 1902 9. Peters MV: A study of survival in Hodgkin's disease treated by irradiation. Am J Roentgenol 63:299-311, 1950 10. Marshall EK: Historical perspective in chemotherapy, in Goldin A, Hawkin IF (eds): Advances in Chemotherapy, vol 1. San Diego, CA, Academic, 1964 11. Goodman LS, Wintrobe MM, Dameshek W, et al: Nitrogen mustard therapy. JAMA 132:126-132, 1946 12. Farber S, Diamond LK, Mercer RD: Temporary remissions in acute leukemia in children produced by folic acid antagouist, 4-aminopteroylglutamic acid (aminopterin). N Engl J Med 28:787-793, 1948 13. Tiber LJ: Ruptured ectopic pregnancy. Calif West Med 41:16, 1934 14. Dale RF, Lindop MJ, Farman JV, et al: Autotransfusion, an experience of 76 Cases. Ann Coll Surg Engl 68:295-297, 1986 15. Schmidt PJ: Traasfusions, thefirst three hundred years, in Rutman RC, Miller WV (eds): Transfusion Therapy: Principles and Procedure (ed 2). Rockville, MD, Aspen, 1985, p 13