|OFFICE OF MEDICAL HISTORY AMEDD REGIMENT AMEDD MUSEUM|
HISTORY OF THE OFFICE OF MEDICAL HISTORY
The Blood, Plasma, and Related Programs in the Korean War
Part I. Administrative Background
When the Korean War broke out on 25 June 1950,1 less than 10 years after the United States had entered World War II and less than 5 years after that war had ended, the situation was improved over the situation in December 1941 in only one respect: No well-organized blood bank system was in operation, but a plan for the supply of whole blood and plasma did exist. The plan had not been implemented, however, because it had been prepared only a short time before the outbreak of hostilities. It is extremely unfortunate that planning had not begun earlier, for the need for whole blood arises whenever combat commences; the Korean War proved again that whole blood cannot be provided promptly and efficiently unless supplies, equipment, trained personnel, and a detailed plan for its collection, processing, transportation, and distribution have already been set up.
When the Korean War broke out, the course of events in respect to the blood program was as follows:
1. Blood collecting teams were immediately utilized in Japan, to meet the first need for blood in the field.
2. These supplies proved inadequate as action became more intense, and requests for whole blood were sent to the Zone of Interior.
3. The American Red Cross was asked, as in World War II, to become the collecting agency for blood for the oversea airlift. Fortunately, this agency already had in operation a blood collecting program to supply blood to civilian hospitals in the United States, and could build upon it.
4. Later, when the initial program proved inadequate, an Armed Forces Blood Program and a National Blood Program were established and remained in operation until the end of active fighting in Korea.
5. A plasma program was also developed which later had to be discontinued because of the risk of serum hepatitis associated with plasma infusions (p. 776). The production of human serum albumin was substituted for the production of plasma and was supplemented by the production of plasma expanders (the so-called blood substitutes of World War II).
1 That date should be borne in mind. Unless the dates of the various activities to be described are borne in mind and are related to the dates of the Korean War (25 June 1950, when the invasion of South Korea occurred, and 27 July 1953, when the armistice was signed), it will not be realized that, in many instances, the actions were almost too late.
In spite of the expedient nature of the blood program, casualties in Korea never lacked the blood they needed, but the comment is justified concerning this war, as it was concerning World War II, that the efficient way to provide blood for combat casualties is not to wait for the need for it to arise and then to provide it, at least initially, by a series of improvisations.
It is interesting, and somewhat depressing, to note in various reports of conferences concerning the blood and blood-derivatives program in the Korean War how quickly the World War II experience seemed to have been forgotten and how the tendency was again evident to concentrate on agents other than whole blood in the management of combat and other casualties. At a meeting of the Subcommittee on Shock, Committee on Surgery, NRC (National Research Council), on 14 November 1951 (1), Dr. Walter L. Bloom rather impatiently called the attention of the members to the fact that the entire philosophy of plasma expanders was questionable. Military and surgical groups, he said, should define the limitations of these substitutes, and they should be considered as suitable for emergency use only. The first need of combat casualties was for whole blood.
THE INTERIM BETWEEN THE WARS
A knowledge of certain background facts is essential to the story of the blood, plasma, and plasma-expanders program in the Korean War, beginning with one major difference between this program and the similar program in World War II: In the Korean War, the program covered civilian defense as well as military needs. In World War II, the two responsibilities were entirely separate. The development of the program that provided blood and plasma in the Korean War is best described chronologically.2
In September 1945, with the end of hostilities in World War II, the whole blood program was discontinued immediately, and the plasma program was terminated as promptly as contracts could be ended. The research that had been a part of both programs also came to an end except for the plasma-fractionation studies, which were continued in Dr. Edwin J. Cohn's laboratory at Harvard.
During the interim between the wars, needs for whole blood in Army hospitals were met within the hospitals. There were no plans, militarily or otherwise, to stockpile reserves of plasma for a national emergency. Indeed, had such a disaster occurred, there would have been no program to put into effect. The whole blood program would have died between the wars except for the stimulus provided by the activities of the American Red Cross.
2 Unless otherwise indicated, the data in this section of this chapter are derived from the excellent and well-documented account of the blood, blood derivatives, and plasma-expanders program in the first 2 years of the Korean War prepared by Col. Patrick H. Hoey, MC, USAF, Chairman of the blood and blood derivatives group (2), and the convenient account of the historical development of the Office of Assistant Secretary of Defense (Health and Medical) prepared by Miss Elsie LaMantia (3).
Postwar activities in respect to blood began on 26 July 1947, with the passage of the National Security Act (Public Law No. 253, 80th Congress), which established the Department of Defense (2). This act provided for the establishment of NSRB (National Security Resources Board) to advise President Harry S. Truman on policies relating to industrial and civilian mobilization. It also provided for the policy just mentioned, the integration of civilian and military health resources. Finally, it authorized steps leading toward a more unified control of national medical services.
On 1 January 1948, the then Secretary of Defense, Mr. James V. Forrestal, appointed a Committee on Medical and Hospital Services of the Armed Forces, to study all questions of common interest to the three medical services, with a view to obtaining maximum efficiency and economy in all their operations. Secretary Forrestal's committee consisted of Maj. Gen. Paul R. Hawley (Ret.), chairman (hence, the Hawley Committee); the Surgeons General of the Army, the Navy, and the Air Force; and Rear Adm. Joel T. Boone, MC, USN, who served as executive secretary.
In the meantime, the President had appointed a Commission on Reorganization of the Executive Branch of Government under Ex-President Herbert Hoover (the Hoover Commission), which, by the middle of 1948, had two task forces working on the coordination of health and medical matters in the National Military Establishment:
On 9 November 1948, still another committee was appointed, the Armed Forces Medical Advisory Committee. Its chairman, Mr. Charles P. Cooper (hence, the Cooper Committee), also served as Deputy to the Secretary of Defense in the fields of medicine and health. The committee consisted of the Surgeons General of the three services, General Hawley, and a number of distinguished civilian physicians.
The recommendations of this committee immediately identified a structural weakness in the Office of the Secretary of Defense: There was no agency or personnel in it to implement committee recommendations after the Secretary had approved them. The Surgeons General, who were members of the committee, were in the untenable position of making recommendations to the Secretary and then receiving these same recommendations from him for comment. This phase of the problem was solved by removing the Surgeons General from membership on the Cooper Committee.
In February 1949, the Joint Chiefs of Staff asked that the Cooper Committee consider the entire question of "unification or coordination" of the Armed Forces medical services, including the possible development of a single medical service. At the end of 2 months of intensive study, the committee recommended against a single Tri-Force medical service. Instead, it recommended that the recommendations of the Eberstadt, Voorhees, and Hawley Committees should be implemented and that an organization be established in the Office of the Secretary of Defense, with authority to act on committee and other recommendations.
In accordance with this recommendation, the Medical Service Division was set up in the Office of the Secretary of Defense in May 1949, with a director who had authority to
establish general policies for the medical services of all three Armed Forces. The Hawley Committee was then dissolved and its subcommittees were transferred to the Medical Service Division. The Cooper Committee continued to function.
On 29 September 1949, the Medical Service Division was renamed the Office of Medical Services. Its current director, Dr. Richard L. Meiling, was named Director of Medical Services and Assistant to the Secretary of Defense for Medical Affairs. Dr. Meiling established a Medical Advisory Council consisting of the three Surgeons General, who met weekly in his office. After the Korean War broke out, the Surgeon General of the U.S. Public Health Service and the Medical Director of the Veterans' Administration were added to the membership of the Council.
The Cooper Committee continued to function throughout 1950, as did the Office of Medical Services. On 2 January 1951, the Cooper Committee and the Office of Medical Services were replaced by an Armed Forces Medical Policy Council, whose director was named Assistant to the Secretary of Defense for Health Affairs. The Council consisted of the three Surgeons General; a dental surgeon; and two other civilians, Dr. Isidor S. Ravdin and Dr. W. Randolph Lovelace III, both of whom had had wide medicomilitary experience. With the establishment of this council, there was now fully carried out, for the first time, the intent of Congress as expressed in the National Security Act of 1947 (p. 715). Also for tile first time:
1. There existed in the DOD (Department of Defense) an organization with authority to coordinate medical policy within the department as well as between the department and other governmental agencies and civilian medical and allied health organizations.
2. The three Surgeons General had authority to represent their respective departments in the formulation of medical and health policies at the level of the Department of Defense.
There were no further changes of consequence in the medical structure of the Department of Defense until 1 April 1953, when DOD Directive 5136.4 established the position of Assistant to the Secretary of Defense (Health and Medical) in the Office of the Secretary of Defense. This was a considerable forward step. All medical and health policies, plans, standards, criteria, and other aspects of medical service could now be reviewed in the Office of the Assistant to the Secretary of Defense (Health and Medical), who also maintained liaison, on both a national and an international basis, with all other governmental and civilian health and medical agencies and associations. The advice of the Surgeons General was made available to the Assistant to the Secretary of Defense as necessary.
On 30 June 1953, Congress approved Reorganization Plan No. 6 for the Department of Defense. This plan authorized, among nine Assistant Secretaries of Defense, an Assistant Secretary of Defense (Health and Medical); thus, in effect, regularizing and giving authority to the plan adopted in the Office of the Secretary of Defense in April 1953. On 2 September 1953, the Secretary of Defense, by DOD Directive 5136.4, established a Health and Medical Advisory Council composed of civilians.
Meantime, the NSRB chairman, former Secretary of the Air Force W. Stuart Symington, had set up a Health Resources Office, which reported directly to him and which was responsible for the development of plans and recommendations relative to mobilization and allocation of health resources and for the medical aspects of civilian defense. Dr. Howard A. Rusk was appointed chairman of the special committee to advise Mr. Symington on broad policies relating to health resources. When these last actions were taken, the armistice of 27 July 1953 had already ended the fighting in the Korean War.
The organizational steps just outlined were all extremely important and are entirely relevant to the blood program in the Korean War. They meant that, for the first time, the Department of Defense would coordinate and integrate all phases of its health program, including the blood program, to with broad policies established at the presidential level. It also meant that recommendations of task groups concerning coordination with other agencies would no longer be conflicting, since both military and civilian national health agencies would now act jointly, to meet the overall requirements of national mobilization.
INITIAL STEPS IN THE NATIONAL BLOOD PROCUREMENT PROGRAM
One of the joint problems that came to the attention of the Director of Medical Services, Office of the Secretary of Defense, in 1949, soon after the establishment of his position, concerned military and civilian requirements for whole blood and blood derivatives. An inventory of existing stocks of plasma and other derivatives, early in October of that year, indicated that they were very low (p. 772); that there was no coordinated plan to expand them; and that, if an emergency should arise, there were no facilities for their augmentation. Only four laboratories were producing plasma commercially. Their combined annual production was about 300,000 units, and they had no incentive to expand it, for plasma was a nonprofit item.
This situation was viewed with the seriousness it deserved, and, on 26 October 1949 the Director of Medical Services, acting for the Secretary of Defense, appointed a task group to study the whole problem of providing blood, blood derivatives, and plasma substitutes (expanders) for the Armed Forces in peacetime and in war. The investigation was to cover such related matters as supplies and equipment for transfusion; training of personnel in the technical aspects of procurement, control, storage, transportation, and use of blood and blood derivatives to meet expanded requirements of an emergency program; and the development of a system of logistics capable of meeting requirements on a global scale (4).
The members of this Task Group included Capt. Hilton W. Rose, MC, USN; Capt. Lloyd R. Newhouser, MC, USN; Col. William S. Stone, MC, USA; and Lt. Col. (later Col.) Alonzo A. Towner, Jr., MC, USAF. The comprehensive report which they submitted to the Secretary of Defense on 15 March 1950 (4) had been approved by the Military Medical Advisory Council (the predecessor of the Armed Forces Medical Policy Council) on 14 February 1950. On 5 May 1950, the report was approved by the Secretary of Defense, in a memorandum addressed to the three Service secretaries, and thus became official DOD policy (5).
As of this date, the retrenchment that had characterized all activities relating to blood in the postwar period began to be reversed, but it was almost too late: It was less than 2 months later that the outbreak of hostilities in Korea required the immediate translation of still theoretical concepts of a national emergency into a stern reality, though, fortunately, several additional weeks were to elapse before a request for whole blood carne to the Zone of Interior from the combat area.
REPORT OF TASK GROUP
The report by the Task Group to the Director of Medical Services on "A Suggested Program of Whole Blood and Blood Derivatives for the Armed Forces" in March 1950 analyzed the problem; summarized the commercial potential for dried plasma; and outlined the requirements for stockpiling plasma and for the collection, distribution, and use of whole blood. In substance, the report was as follows:
Whole human blood, required in modern therapy, cannot be stockpiled because it is extremely labile; it requires constant refrigeration and precise technical control and handling; and, under present procedures, it cannot be stockpiled for more than 30 days.
The Armed Forces can operate blood banks to meet peacetime requirements but cannot supply wartime necessities. It is not desirable to use combat troops as donors. Neither in peacetime nor in war can the Armed Forces provide blood derivatives.
The reserves of blood derivatives left from World War II will largely be outdated by the end of 1950, though some can be reprocessed, at about a third of the cost of new products. The total amount that has been reprocessed, however, will provide only a third to a half of the required war reserve (set at a million units) for the Armed Forces. Reprocessing and handling can be carried out only by specially trained personnel, with considerable technical background.
The present civilian program for blood and blood derivatives is not adequately organized or planned to meet the requirements of the Armed Forces, the civil defense program, and other civilian needs in time of war.
The wartime needs can therefore be met only by a national program, which must be organized in peacetime.
The Present Situation
At this time (March 1950), the blood procurement situation in tile United States is as follows:
1. Twenty-one blood banks are in operation in Armed Forces installations. All have standardized equipment and supplies, are centrally controlled, and would be capable of
operating under wartime conditions. Four of these banks are each collecting 300 pints a month. The others are collecting from 50 to 250 pints each.
2. Some two or three thousand nonprofit blood banks are in operation, most of which belong to the American Association of Blood Banks.3 About half of these banks actually draw and process blood. The remainder, whose chief function is to serve their own hospitals and adjacent rural communities, act merely as storage and issue points for blood drawn elsewhere. When the operations of these banks are entirely intrastate, they are under no control and their equipment, supplies, and procedures are not standardized. If, however, these hospital banks would adopt NIH (National Institutes of Health) standards and could produce significant surpluses above their own needs, they could contribute to the national blood program.
3. Four commercial blood banks are in operation in New York. Others are in operation in Dallas, San Francisco, and Chicago, and there are a few smaller banks in other locations. They lack trained personnel and uniform standards, and it is doubtful that they could expand significantly in time of war.
4. Only three commercial biologic laboratories are now collecting blood for plasma: Cutter Laboratories, 100,000 pints per year; Hyland Laboratories, 40,000 pints per year; and Sharp & Dohme, 150,000 pints per year. All these laboratories produced plasma during World War II, and Sharp & Dohme also produced plasma fractions, which only Cutter Laboratories is now producing.
Equipment can be manufactured by a number of larger firms as well as some smaller firms, on reasonably short notice, with certain exceptions. There would be difficulty, for instance, supplying 15- to 20-gage needles for intravenous and donor sets if they should be required at once, though within 6 months, well over a million could easily be produced.
The Task Group, on the basis of the World War II experience factor, set the replacement requirements for each combat casualty who survived to be hospitalized at one 500-cc. unit of whole blood and the same amount of plasma or other blood-derivative. Only group 0 blood would be used, preserved in ACD (acid-citrate-dextrose) solution; typed for the Rh factor; and refrigerated at 4° to 10° C. from collection until administration.
The Task Group did not think that the Department of Defense of itself could procure such amounts of blood and blood derivatives and therefore recommended immediate coordination with other interested governmental and non-governmental agencies in the development of a program that would meet the standards and fulfill the requirements of the Department of Defense, as well as civilian requirements, in peacetime and in wartime.
The Task Group also recommended that the Department of Defense assume responsibility for the direction and implementation of the whole blood program and its coordination with other agencies, including the American Red Cross; Armed Forces blood banks; commercial biologic agencies; and nonprofit and commercial blood banks. It was noted that, if these various separate groups were to serve as an integrated national blood group, they must be tightly controlled because of the multiple risks attending the use of blood, including its perishability; incompatibility; possible errors in grouping, typing, and cross-
3 Although this is the figure used by the Task Group, it seems high unless every hospital laboratory storing a few pints of blood is considered a blood bank.
matching; contamination from unsound techniques; unsatisfactory conditions of storage; and possible transmission of such diseases as malaria, syphilis, and hepatitis.
Finally, the Task Group recommended that the Director of Medical Services should be responsible for, and direct, the continued study and implementation of the Department of Defense blood program and till coordination of tile activities of tile department with those of other agencies.
In addition to these basic recommendations, the Task Group made tile following specific recommendations:
1. That transfusion supplies, equipment and procedures as standardized for the Armed Forces be standardized by all participating agencies, with the Director of Medical Services, DOD, taking the necessary steps to accomplish this objective.
2. That biologic standards for blood and blood derivatives be uniform throughout the country, with necessary legislation to assure the adoption of the desired criteria.
3. That all military combat plans include logistic requirements for blood.
4. That all blood donations be voluntary.
5. That a war reserve be established for plasma, plasma substitutes (expanders), and transfusion supplies and equipment, with economical maintenance of estimated requirements, and that a system be devised for replacing deteriorated supplies, so as to maintain a satisfactory and economical reserve.
6. That research on blood preservation and on improvement of transfusion equipment be emphasized by the Department of Defense. It was suggested that the sum of $100,000 be allocated annually for the next 2 or 3 years to provide for additional research in these fields.
It was essential, the report of the Task Group concluded, that the agency for civilian and military whole blood requirements that was developed in peacetime should be of such a character that it could be expanded in time of war to meet logistic requirements and organization, training, and operating procedures. Such an agency should have ramifications down to the community level, so that, in an emergency, all potential sources of blood could be tapped. Also, the personnel of such an agency should be so organized and trained that, in time of war, its existing operational activities would simply have to be expanded.
Continuing misconception of requirements for whole blood.- Another depressing phase of the development of the blood program after World War II was the position taken by the Director of Military Supply and the Acting Chief, Requirements Coordination, Munitions Board, in April 1950, in connection with the recommendations of the Task Force (6).
Both granted the necessity for a national blood program, the importance of its prompt development, and the wisdom of correlating military and civilian requirements, policies, standards, and procedures. These officers, however, could not agree with the recommendation that the Director of Medical Services, Department of Defense, be responsible for, and direct continued study and implementation of, the DOD blood program and its coordination with other agencies. Nor could they agree that the director should take steps to accomplish standardization of related military and civilian supplies, equipment, and procedures, for the following reasons:
1. Blood and blood derivatives are considered a supply commodity or munition.
2. The Munitions Board is legally responsible for developing coordinated policies relating to military supplies.
3. The blood program is no different from other programs and must be handled in the same manner as other programs.
It would be hard to imagine a more total misconception of the requirements and implications of a whole blood program. The position of these officers, obviously taken in complete ignorance of how whole blood must be procured, handled, and administered, represented everything the Subcommittee on Blood Substitutes, NRC, the Blood Transfusion Branch, Office of The Surgeon General and other agencies and personnel had fought against during World War II. Had these ideas been permitted to prevail, the entire whole blood program for Korea would have foundered and many lives would probably have been lost from the use of incorrectly handled blood. The controversy had no chance to develop, however, for the Secretary of Defense, in August 1950, gave the operational responsibility of the blood program to the Directorate, Armed Services Medical Procurement Agency, and directed the Director of Medical Services, DOD, to prescribe the policies and standards for the implementation of the program (7).
IMPLEMENTATION OF TASK GROUP PROPOSALS
In May 1950, Dr. Meiling assumed the chairmanship of a Blood and Blood Derivatives Committee in the Department of Defense, which had the function of determining the need of the Armed Services for plasma and whole blood. He at once appointed an ad hoc committee on blood and blood derivatives to serve in an advisory capacity to him.
At its meeting on 28 July 1950- a month after the outbreak of the Korean War- the Military Medical Advisory Group, in a full discussion of the Blood and Blood Derivatives Program, decided that the American Red Cross should be the coordinating blood procurement agency for the Department of Defense and that the Armed Services Medical Procurement Agency should be assigned operational responsibility for the program in the Department of Defense.
A week later, when the Secretary of Defense formally assigned operational and technical responsibility for the program to the Directorate of the Armed Services Medical Procurement Agency, the directorate at once requested the chief of this agency to establish a blood and blood derivatives division within the agency. At the same time, the directorate requested that the director of Medical Services, Office of the Secretary of Defense, grant membership in the Task Group studying the Whole Blood and Blood Derivatives Program to the chief of the Procurement Agency and the chief of its Blood and Blood Derivatives Division.
All of these requests were granted. Col. Douglas B. Kendrick, MC, who had been in charge of the Army blood program in World War II from its inception until November 1944, was named chairman of the Blood and Blood Derivatives Group, which position he held for the next 2 years. On 1 May 1952, he was succeeded by Col. Patrick H. Hoey, MC, USAF, who held this position
until the end of the war. Lt. Col. Arthur J. Carbonnell, MC, was the Army member of the group from 15 February 1951 to 18 February 1952.
On 12 September 1950, the Armed Services Blood and Blood Derivatives Division (which became the Armed Services Blood and Blood Derivatives Group a few days later) was officially established. It consisted of a professional staff and of administrative, field, laboratory, and liaison branches. Its mission was as follows:
1. To provide whole blood for FECOM (Far East Command).
2. To provide whole blood for the production of dried plasma for the DOD War Reserve stockpile.
3. To reprocess outdated stocks of plasma produced in World War II.
4. To investigate developments in the field of plasma-expanders.
The actual division of responsibility for the blood and plasma program was that the Committee on Blood and Blood Derivatives recommended policy and the Blood and Blood Derivatives Group had the operational responsibility for its implementation.
The structural evolution of the blood and blood derivatives program in the Department of Defense between 1949 and 1953 is shown in charts 11, 12, and 13.
NATIONAL RESEARCH COUNCIL
Organization and Functions
The Subcommittee on Blood Substitutes, Committee on Shock, Division of Medical Sciences, NRC, had done such important work on the collection and distribution of whole blood and its derivatives, and had supervised so much valuable research, in World War II, that it was reactivated in 1948 as the Committee on Blood and Blood Derivatives. The work of the subcommittee had lapsed at the end of World War II, but in the interim before its reconstitution, the American Red Cross, which was entrusted with returning surplus
blood derivatives to the people of the United States who had contributed them, used many of the same physicians who had served on the subcommittee on its own Committee on Blood and Blood Derivatives, thus maintaining their contacts with the blood program. The reason for the reactivation of the World War II subcommittee was the realization that a national emergency would demand huge amounts of blood and blood derivatives for civilian as well as military uses, and the subcommittee was promptly enlarged because of the complexity of the problems to be solved.
As soon as it was activated, the Committee on Blood and Blood Derivatives went actively to work. At its first meetings, the stage of existing knowledge in the special fields of blood and blood derivatives was assessed. Ad hoc responsibilities were delegated to particular members, who were directed to investigate equipment, preservatives, and sterilization of blood and blood derivatives. Contracts for research in the field of blood and blood derivatives were reviewed for the National Military Establishment and the Veterans' Administration.
At the meeting of the Committee on Blood and Blood Derivatives on 3 December 1949, much of the agenda concerned general principles and policies (8). Dr. Charles A. Janeway, chairman of the committee, pointed out that the blood program was an integral part of national defense and that the counterpart of this committee during World War II had sat as an advisory group to all agencies and organizations concerned in any way with blood. Its successor committee would perform the same functions.
Dr. Meiling, Director of Medical Services, Office of the Secretary of Defense, explained the functions of his office. Dr. Cohn spoke of the importance of the cooperation of all agencies concerned in the blood program. During World War II, he noted, no decision regarding blood products was ever made without the approval of the Laboratory of Biologics Control, National Institutes of Health. Many of these matters were within the province of the Food and Drug Administration. The World War II subcommittee had been careful never to recommend any action or procedure on the basis of research alone; the practicability of all recommendations was tested by pilot operations. It was possible that blood might be collected by some agency other than the Red Cross, which was now operating with no obligations to turn over any material to the Armed Forces in an emergency. The important consideration was that there must be a single blood program, cooperative and not competitive. In conclusion, said Dr. Cohn, "Failure to act until an emergency entails accepting the responsibility for being unprepared."
By this time (December 1949), a great many problems had already been referred to the Committee on Blood and Blood Derivatives, NRC, and many more were to be referred to it before and during the Korean War. The recommendations made concerning them are discussed under appropriate headings. The contribution of the committee was incalculable. There were, however, many perfectionists on it, and, at intervals, the more practical-minded members felt constrained to remind them of current needs. If, for
instance, excessive and unnecessary standards of accuracy were required, the volume of production would be impractically small. The point at issue was the quick determination of what agents were safe to put into people's veins from the standpoint of immediate or delayed antigenicity and toxicity.
At the December 1949 meeting, an ad hoc committee was appointed to consider all phases of the blood program, talk with civilian defense planning groups and other agencies, and then make recommendations to the Committee. The membership of this committee included Dr. Janeway, Dr. Cohn, Dr. Ravdin, Dr. Carl V. Moore, and Dr. Charles A. Doan.
At this same meeting, a number of changes were recommended in the 13 May 1943 agreement with the American Red Cross, both to bring the text into agreement with the current organizational situation and to indicate that collections of blood were for civilian needs as well as for needs of the Armed Forces. It was also recommended that a committee be formed to serve in an advisory capacity to the American Red Cross, Department of Defense, National Institutes of Health, Veterans' Administration, Atomic Energy Commission, and whatever agency would be responsible for civilian defense.
Some of the problems referred to the Committee on Blood and Blood Substitutes, NRC, might be mentioned here, to indicate their range and importance:
1. Could not a preservative solution be devised in which
blood for transfusion and blood intended for plasma could both be collected?
THE AMERICAN RED CROSS PARTICIPATION
The Committee on Blood and Blood Derivatives, DOD, recommended to the Secretary of Defense on 2 October 1948 and 10 January, and 13 February 1949 that the American Red Cross be officially designated as the agency to collect blood for the National Military Establishment. The Subcommittee on Burns, Committee on Surgery, NRC, also recommended, in November 1949, that some large-scale machinery for the collection of blood be set up.
On 20 July 1950, the Secretary of Defense, then Mr. Louis Johnson, recommended to the Chairman of the American Red Cross, then Gen. George C. Marshall, that the relation which had existed during World War II between that organization and the War and Navy Departments be reestablished between it and the Department of Defense to meet the needs of the Armed Forces for blood and blood derivatives (9). On 22 July, General Marshall replied that the Red Cross would at once increase its blood collections and that Adm.
Ross T McIntire, MC, USN (Ret.), who was assigned to the Red Cross National Blood Program, would be assigned to work with Dr. Meiling on the necessary plans (10).
On 30 August 1950, Mr. Symington, as Chairman, NSRB, formally requested, through General Marshall, that the American Red Cross accept the responsibility for coordinating a nationwide civil defense blood program for recruitment of donors and for the collection, storage, processing, and preparation for shipment of blood and blood derivatives collected under the program (11). On 7 September 1950, General Marshall replied that the Red Cross would accept the specified responsibilities, on the assumption that local civil defense units would coordinate their planning with the national program (12).
The Boston Agreement.- Meantime, on 11 and 12 July 1950, the Committee on Blood and Blood Derivatives, American Red Cross, and the Red Cross Medical Advisory Committee on the National Blood Program met in Boston with representatives of the American Medical Association, the American Association of Blood Banks, and the American Hospital Association, to determine their relations with each other. The so-called Boston Agreement provided that these four agencies would cooperate with each other in peacetime and with the National Security Resources Board in time of war (13). In peacetime, there would be a free exchange of blood on a unit-for-unit basis, as would best serve community needs. As a matter of principle, surplus blood would be given to the Red Cross or other designated agencies for conversion into blood derivatives. In time of war, procurement agencies would be set up in communities not already served by Red Cross regional blood centers.
It was recognized at this conference that standardization of equipment for the blood program was desirable in peacetime and imperative in a national emergency. It was also recommended that all blood banks cooperating in the joint program should meet the minimum standards of the National Institutes of Health.
Part II. The Whole Blood Program
Section I. Blood Procurement in Japan
INITIATION OF PROGRAM
The blood program for the Korean War began in Japan. Here, in the interim between the wars, a few Army hospitals, all of which were authorized to provide definitive surgical care, collected blood from donor lists in accordance with Army Regulations No. 40-1715. These hospitals, located mainly in the Tokyo and Osaka areas, operated small banks, sufficient for their own needs.
Within 10 days after the outbreak of the Korean War (then considered only a police action), it became apparent that the Armed Forces in combat would
FIGURE 167.-Blood donors (Flag allowance personnel, Commander, U.S. Naval Forces, Far East) lined up outside 406th Medical General Laboratory blood bank, Tokyo, July 1950, ready to donate blood for fighting forces in Korea.
require blood in large amounts, and plans were at once made for a centrally controlled blood procurement program in Japan (2, 14). Three initial steps were taken:
1. A special blood bank unit was formed from personnel of the 406th Medical General Laboratory to operate a blood bank there. As the bank was first set up, it consisted of a collecting and processing center in Tokyo, a transportation and courier center (later called the Blood Bank Storage Depot and Shipping Section) in Tokyo, and an advance blood bank depot at the 118th Station Hospital in Fukuoka.
2. 8090th Blood Bank Laboratory Detachment was organized as a temporary duty unit in August 1950 and was assigned to the 406th Medical General Laboratory. The detachment consisted of two mobile bleeding units and a laboratory unit. It functioned until 5 November 1951, when it was replaced by the 48th Blood Bank Laboratory Detachment.
3. Blood bank sections were activated in Korea, as organic parts of medical supply depots.
The necessary organizational steps were taken quickly, donors were recruited (fig. 167), and the first shipment of blood from Japan (69 bottles) was sent to the 8054th Evacuation Hospital in Pusan, Korea, on the night of 7 July 1950.
For the first 5 weeks, the blood bank operated on an emergency basis, as troop strength built up rapidly and field medical installations were sent to Korea to care for casualties. It then became evident that the combat in which the U.S. troops were engaged would be considerably more than a local engagement, rapidly terminated, and that blood bank operations must be put on a firmer basis.
The first step was to determine a working ratio between anticipated casualties and future needs for whole blood. By the use of figures supplied by the Assistant Chief of Staff, G-1 (personnel), which were available daily and were regarded as accurate, a ratio was developed of 0.82 pint of blood to each casualty wounded in action and surviving to be hospitalized.
At this time, the donor panels in the Tokyo-Yokohama areas could supply, at the most, 100 pints of blood per day. Official approval had not yet been obtained for the use of Japanese donors, and, until the end of 1950, blood was secured only from noncombatant Army, Navy, and Air Force personnel; Allied Forces personnel; civilian employees of the U.S. Armed Forces; foreign nationals other than Japanese; and adult dependents of these groups.
When the needs of anticipated casualties were surveyed realistically, it was at once clear that available local donors could not possibly meet their requirements, and a request for blood was made on 15 August 1950 to the Zone of Interior (15) and promptly acceded to (p. 713). It was hoped, however, that local sources could continue to meet emergency needs and could also supply group-specific and Rh-specific bloods, which, as in World War II, would not be sent from the Zone of Interior.
After 6 months of combat, and after blood from the Zone of Interior had been reaching Korea for over 4 months, it was found that the ratio of blood to casualties had undergone a change. The factor then used, 3.32 pints of blood for each combat casualty who was hospitalized, was based on an experience factor for logistic blood requirements that included not only the blood actually used but the blood wasted in storage and distribution, a wastage that was then considered unavoidable in such a perishable product as blood in such combat circumstances as Korea.
The first bloods collected in Japan were transported from the bank at the 406th Medical General Laboratory to the advance depot at the 118th Station Hospital in Fukuoka in railway baggage cars, three of which had been equipped with reach-in reefers (refrigerators) for this purpose. Later, air transport was used almost exclusively (p. 752).
Techniques of collection of blood in Japan generally followed those employed in Red Cross bleeding centers in World War II until donations from Japanese began to be accepted, at the end of 1950. Then, certain changes in
procedure were necessary. For one thing, language difficulties made it necessary to employ a small Japanese staff, as well as to use nurses and volunteers supplied by the Japanese Red Cross (fig. 168). For another, Japanese medical authorities were at first reluctant to depart from their standard practice of limiting donations to 200 cc. Some concessions, naturally, had to be made to the small size of the Japanese, who could not routinely give 500 cc. of blood as did U.S. donors, and tables of maximum collections for bleeding them and others of similar stature were therefore worked out (table 34). When these standards were adhered to, there was never any evidence of immediate or delayed harmful effects from the donations.
Publicity for the blood program in, Japan was provided by the U.S. and the Japanese Red Cross, the Armed Forces radio station in Tokyo, the Pacific edition of the Stars and Stripes, and similar sources. Documentary films showing blood bank operations were made by the Army Signal Corps and by Japanese photographers for use locally as well as in the United States. Posters, pictures, and stories were provided for both local and stateside release by General Headquarters and Joint Logistical Command Public Information Offices.
On one occasion, a spectacular air rendezvous was made with the U.S.S. Boxer, then in Korean waters; her crew donated 2,407 pints of blood in 4 days. On another occasion, Gen. Douglas MacArthur publicly received a token
FIGURE 168.-Japanese mothers, representing the United Nations Educational, Scientific and Cultural Organization, giving blood for forces in Korea at 406th Medical General Laboratory, Tokyo, February 1952, as their children watch.
shipment of blood from the German employees of a commercial airline. On 4 July 1951, the medical section of the Joint Logistical Command, at a carnival at Meiji Park, staged a complete demonstration of blood bank operations; the processing of the blood was carried out in full view of the spectators. The Gallon Club, instituted in August 1951, had almost 150 members within a few weeks.
During fiscal year 1951, a total of 43,479 donors were interviewed at the blood bank in Japan and more than 39,000 pints of blood were collected from them through the efforts of the central bank and its mobile teams. The chief reason for refusing donors was a history of disease, including malaria and infectious hepatitis, and of hypertension. Only 175 positive serologies were encountered, 0.4 percent.
The low incidence of Rh-negative blood (table 35), a Japanese racial characteristic, limited to a considerable degree any extensive use of Japanese donors if Rh-compatible blood was to be given to a recipient population composed chiefly of Americans and Europeans. In the first 2,784 Japanese
bloods collected, there were only 19 Rh-negative bloods, 0.68 percent. The distribution according to type in 39,100 units of Japanese blood collected in 1951 is shown in table 35. Statistics for 1952 and 1953 were of the same order.
In 1951, almost 25 percent of the blood received in Japan by the blood bank was procured in that country (table 36). Something over a third of this amount was collected in Tokyo. The remainder was collected by mobile teams at various stations in the vicinity, including 6,456 pints from the U.S. Naval Hospital in Yokosuka and 3,308 pints from the U.S. Army Hospital in Yokohama.
TABLE 36. - Receipts of blood, Tokyo Blood Depot, 1951-52
Section II. The Development of the Whole Blood Program in the Zone of Interior
THE FIRST YEAR
Collections of blood by the American Red Cross for the Department of Defense began in August 1950. By the middle of 1951, those responsible for the blood and plasma program in the Department of Defense were increasingly concerned because procurement was lagging far behind requirements and commitments (2). Whole blood requirements for the Armed Forces were being met, but reserves of plasma were in alarmingly short supply because of lack of blood to process.
On 20 July 1951, the chairman of the Armed Forces Medical Policy Council, Dr. Lovelace, projecting present trends into the future, reported to the Secretary of Defense that the blood procurement program of the Department was in serious need of revision. On the basis of a report made to the Policy Council on 16 July 1951 by an ad hoc committee,4 Dr. Lovelace recommended that the program be referred to the newly established Health Resources Advisory Committee of the Office of Defense Mobilization for information and assistance. He also recommended that the American Red Cross Blood Donor
4 This committee consisted of Colonel Kendrick, Chairman; Captain Newhouser, Department of Defense; Maj. Gen. David N. W. Grant, USAF (Ret.), and Mr. Richard Swigart, American Red Cross; and Dr. F. Douglas Lawrason NRC.
Program be stimulated with the assistance and cooperation of the Department of Defense, as follows:
1. There should be a continuously active advertising campaign
In addition to these steps, which should be taken jointly with the American Red Cross, Dr. Lovelace recommended that the Department of Defense:
1. Should establish a military blood collection program
to reach military personnel and civilian employees on military bases.
THE ARMED FORCES BLOOD DONOR PROGRAM
On 2 August 1951, in a DOD directive, the Acting Secretary of Defense, Mr. Robert D. Lovett, announced the establishment of an Armed Forces Blood Donor Program, "to provide a continuous and vigorous campaign, in conjunction with the Red Cross, to persuade the civilian and military population to contribute whole blood to the Armed Forces" (16). The program would be launched on 10 September 1951.
The Director of Information, Office of the Secretary of Defense, would be responsible for directing publicity and information concerning the program. Policy guidance would be provided by the Armed Forces Medical Policy Council, Office of the Secretary of Defense. All programs would be coordinated through the Armed Services Medical Procurement Agency.5
The success of the military program was immediate (figs. 169-172). Within a few months there were more donors than facilities to handle them. The attitude of the Air Force was typical of all the Services. On 6 September 1951, the Air Adjutant General directed that "every level of command of the Air Force give its whole-hearted cooperation to insure the success of the program." Effective on 10 September, the date of initiation of the program, or as soon thereafter as possible, Air Force collection centers would be established at Lowry Air Force Base, Denver, Colo., Lackland Air Force Base, San Antonio, Tex., and Sheppard Air Force Base, Wichita Falls, Tex. Tentative sites were also selected for other collection centers, to be activated as necessary later.
5 The National Advertising Council worked closely with the Director of Information, DOD, and deserves much of the credit for the outstanding success of the program.
THE NATIONAL BLOOD PROGRAM
One of the major problems of blood procurement was the necessity of providing blood for civil defense as well as for combat needs. It was studied by Dr. Rusk, Chairman, Health Resources Advisory Committee, and his staff; on their recommendation, on 10 December 1951, President Truman issued an Executive order to the effect that the Director of the Office of Defense Mobilization would provide, within his office, "a mechanism for the authoritative coordination of an integrated and effective program to meet the nation's requirements for blood, blood derivatives and related substances" (17). In this order, it was pointed out that a subcommittee on blood had been appointed within the Health Resources Advisory Committee, to develop "a single National Blood Program encompassing all phases of the problem." It was the President's desire that the activities of all departments and agencies in the field be coordinated "through this mechanism."
FIGURE 170.-Shipments of blood for processing centers secured from military installations in Zone of Interior. A. From Fort Bragg, N.C., October 1951, by train. B. From Camp Rucker, Ala., October 1951, by plane. C. From Fort Leonard Wood, Mo., November 1951, by truck.
FIGURE 171.-Mr. William J. Richards, Red Cross representative, Capt. Ray Jones, and Copilot Wilson Byerhoff inspecting shipment of blood as it arrived via American Air Lines at San Francisco Airport for transshipment to Japan, 26 August 1950.
On 18 February 1952, the Subcommittee on Blood (the Cummings Committee) submitted a statement of basic principles upon which the reorganized program should be based. The substance of this report, which was immediately transmitted to the Secretary of Defense, Mr. Lovett, was as follows (18):
1. The program created to meet the blood needs of the nation in the
time of national emergency and to be known as the National Blood Program
would represent a coordination of the blood programs already in existence.
FIGURE 172.-Representatives of Swiss and British Armies watching as nurse takes blood from representative of Iranian Army during visit of mobile blood unit from Louisville Regional Blood Donor Center to Fort Knox, Ky., July 1950.On this visit, 189 donations were secured.
6. Priorities for allocation of blood would be as follows:
a. The Armed Services, for whole blood transfusions.
7. In the event of enemy action, the total reserves of plasma, blood
derivatives, and plasma expanders would be allocated as necessary by Executive
These recommendations were put into effect and the national blood program was successfully operated according to them for the remaining years of the war.
Section III. The Oversea Airlift to Korea
The Korean War began on 25 June 1950, and active fighting ended on 27 July 1953, with the signing of an armistice. The formal Zone of Interior blood supply program for Korea began on 15 August 1950, with a radio request from the Far East Command for shipments of blood from the Zone of Interior to augment the quantities collected and distributed by the 406th Medical General Laboratory in Tokyo (15). The first blood shipped in response to this message, which had been requested for 30 August, left the temporary laboratory at the U.S. Naval Hospital in Oakland, Calif., for Japan on 26 August 1950. On 8 February 1954, a dispatch from the Far East Command recommended that the service be terminated, and the last blood was flown to Japan on 13 February 1954 from the Armed Services Whole Blood Processing Laboratory, Travis Air Force Base, Calif. Between the dates of the first and last shipments, this laboratory had received and handled 397,711 pints of whole blood, of which 340,427 pints had been shipped to Japan for transshipment to Korea for distribution to the various medical units of the United Nations there. The Travis laboratory was placed on a standby basis on 13 February 1954 and was deactivated a month later. This program was the largest operation of its kind in the history of military medicine in the United States.
The important steps in the development of the administrative background of the airlift of blood in the Korean War have been described in detail elsewhere (p. 713). Many of the most important actions, it will be remembered, were taken after fighting had commenced.
PROCESSING LABORATORY, TRAVIS AIR FORCE BASE
In order that the military might have a central processing facility in which to receive blood collected by the American Red Cross, perform necessary laboratory tests on it, package it, and ship it to Japan for transshipment to Korea, a processing laboratory was established at Travis Air Force Base (then Fairfield-Suisun Air Force Base), Calif., where a Military Air Transport Service group of the Pacific Division was located. The building selected had to be renovated and converted for this purpose, and until it was ready, on 25 September 1950, a temporary laboratory was set up and operated in the U.S. Naval Hospital at Oakland, Calif., about 50 miles away.
6 Unless otherwise specified, the material concerning the airlift is derived from the history of the Armed Services Whole Blood Processing Laboratory, Travis Air Force Base, Calif., 25 August 1950-15 March 1954 (19).
During the war, a number of attempts were made to establish a blood processing laboratory on the east coast, but no definitive action was ever taken, though supplies and personnel were earmarked for an emergency standby facility at the U.S. Naval Hospital, Chelsea, Mass. This facility was not called upon, but it was expected that, if it had been, it could have begun to ship blood to Japan within 24 hours after activation.
The Armed Services Whole Blood Processing Laboratory at Travis Air Force Base performed the following functions:
1. It received whole blood from the American Red Cross, performed appropriate
laboratory tests on it, and shipped it to the Far East Command for use
Facilities and Equipment
Structures of the permanent laboratory included a building of 3,400 sq. ft. and two warehouses, respectively 2,786 and 800 square feet. All buildings, office equipment and supplies, housekeeping items, heat, electricity, gas, communication services, and motor vehicle transportation were furnished to the laboratory and maintained by the Travis Air Force Base. Billeting and messing facilities for laboratory personnel were also furnished by Travis Air Force Base. A Navy panel truck, on loan from Oakland Naval Hospital, was assigned to the laboratory for general use.
The building at Travis Air Force Base that was converted into a laboratory was an old hospital messhall. The conversion required the installation of lighting fixtures, water-distilling apparatus, refrigerators, sinks, laboratory counters and workbenches, and natural gas fixtures. The precooling room and warehouses were not completed until about 8 months after the laboratory was occupied. When the converted building was taken over, however, on 25 September 1950, everything else was in such good order that a shipment of blood could be sent to Japan the same day.
Initial medical supplies and equipment were procured directly from the Oakland Naval Medical Supply Depot. Later, by agreement among the three Services, the requirements and stock control section of the Supply
Division, Office of The Surgeon General, U.S. Army, was given the responsibility of furnishing medical supplies and equipment to the laboratory. All requisitions went through the Travis Air Force Base medical supply section to the Alameda Army Medical Supply Depot.
The operational cost of this laboratory was estimated at over $1 million a year. It cost approximately $17.83 to procure and process a pint of blood and transport it from the United States to the Far East Command in Japan, this sum including $6.56 paid to the Red Cross for processing services, $9.40 for laboratory expenses, and $1.87 for transportation costs.
Four Navy blood bank technicians arrived from the east coast at the laboratory on 23 August 1950. Office, laboratory, and cold storage spaces were made available to them at once, and supplies and equipment were procured from the hospital and from the U.S. Naval Medical Supply Depot in Oakland. As a result, 48 hours after these technicians had arrived, the first whole blood shipment (1,488 pints) was received, processed, and delivered to the Military Air Transport Service at Travis Air Force Base for transshipment to Japan.
Requests for additional laboratory personnel were at first handled very slowly, and, by the middle of September 1950, the staff working in the Oakland laboratory included, in addition to the four original technicians, only one Navy Medical Service Corps officer and three laboratory technicians. Laboratory technicians were borrowed from Oakland and Mare Island Naval Hospitals and from Letterman General Hospital, San Francisco, Calif. Clerical and some general duty helpers were borrowed from Travis Air Force Base and the Oakland Naval Hospital. Additional duty corpsmen and convalescent patients aided on a day-to-day basis. All of these men were returned to their duty stations when additional permanent personnel began to arrive about the middle of October. In spite of its personnel difficulties, the laboratory handled over 7,000 pints of whole blood during the weeks of its operation at the U.S. Naval Hospital in Oakland.
In the approximately 42 months of its operation, an average of 35 persons were regularly attached to the laboratory, including an average of 11 from the Army, 10 from the Navy, and 14 from the Air Force (fig. 173).
Training.-A quick, efficient blood bank technique can be acquired only by experience, and most of the personnel assigned to the Travis laboratory were inexperienced. All therefore worked long hours while they were receiving individual instruction. A formal training program was set up a few months after the laboratory was activated, and 59 persons completed the course of instruction, including 14 Air Force Medical Service Corps officers, 34 Army enlisted men, and 11 Air Force enlisted men.
FIGURE 173.-Personnel of Travis Air Force Base Whole Blood Processing Center. Seated, left to right, M. Sgt. John F. Firmani, USA, NCOIC (Noncommissioned Officer in Charge) of Blood Processing Department and head of Section III; M. Sgt. Marvin C. Lynn, USAF, leader, Laboratory Section III; Lt. James H. Parker, MSC, USN, officer in charge; 1st Lt. William R. Bonnington, MSC, USAF, assistant officer in charge; M. Sgt. Joseph F. Firmani, USA, NCOIC of Supply Section; M. Sgt. Milton L. Burgeson, USAF, administrative assistant to OIC and NCOIC, Records Section. Standing, Sgt. Henry M. Sottnek, USA, leader, Receiving-Storage-Shipping Section II; T. Sgt. Alvis E. Hotchkiss, USAF, leader, laboratory Section II; M. Sgt. Leon C. Branum, USA, NCOIC of Blood Processing Department and head of Section II; HM1 Sherwood J. Syverson, USN, blood bank technician; and S. Sgt. John E. Ahearn, USAF, leader, Receiving-Storage-Shipping Section III.
Because of its short life, 21 days at best, expeditious as well as expert handling of blood is necessary, and the work schedule at the Travis laboratory was geared to that consideration. Blood from the collection centers was shipped by air, rail, or motor transport, as most convenient. Centers near the laboratory delivered their blood by motor transport. Blood from distant collection centers arrived by air. The shipments were offloaded at airports in San Francisco or Oakland, where they were picked up by the Railway Express Agency and transshipped by train to Fairfield-Suisun, about 7 miles from Travis. Here, they were offloaded and trucked to the laboratory by the agency. Blood from centers nearer the laboratory was sent by train and delivered to the laboratory by the Railway Express Agency. Because the agency worked on a 5-day workweek schedule, arrangements were made with the motor pool at Travis Air Force Base to meet trains on Saturdays, Sundays, and holidays, pick up the blood and deliver it to the laboratory.
The Red Cross blood donor centers also worked on a 5-day week, usually Monday through Friday. Few collections were made on Saturdays, Sundays, and holidays.
Each Friday, and oftener if requirements changed, the officer in charge of the laboratory at Travis Air Force Base notified the central office of the Red Cross of the quotas of blood desired for the following week. The Red Cross, in turn, designated the donor centers which would collect, process, and ship these quotas. A number of attempts were made, all unsuccessful, to have the weekly quotas collected in equal amounts on each of the 5 days weekly that the centers operated. Few bloods were received from Monday through Wednesday, often not the equivalent of the amounts shipped to Japan. Most bloods were processed from Thursday through Sunday. By Sunday night, the refrigerators were filled, and there was sufficient blood on hand for the Monday-through-Wednesday shipments.
Although bloods arrived in the laboratory at all hours of the day and night, most of them arrived twice daily, at 1000 and 1800 hours. On Sundays and holidays, the bulk of the blood usually arrived at 1800 hours.
Because of these various circumstances, the Travis laboratory had to operate 7 days a week, day and night. After additional personnel arrived at the laboratory in October 1950, separate day- and night-working sections were established to receive, process, and ship blood. The two sections, each composed of equal numbers of clerical, laboratory, and general duty personnel, alternated day- and night-working hours at weekly intervals. A third section, composed of administrative and supply personnel, carried on the administrative and supply duties of the laboratory. This section worked a regular day shift, but its personnel were subject to night call as necessary.
Collection and Initial Processing
Only proved group-O blood, of low titer and Rh-verified, was sent to Korea. As in World War II, about 45 percent of random donors proved to be group O, and about a quarter of this group had agglutinin titers above 1:64.
The technique of collection was essentially that employed in World War II (p. 145). Donors were screened to make sure that they were group O. Whole blood intended for oversea use was collected in ACD solution (blood intended for plasma was collected in sodium citrate solution). The blood was collected in 500-cc. amounts in sterile, pyrogen-free bottles; samples for serologic testing and crossmatching were collected into pilot tubes. The collection bottles were not entered again until the recipient sets were attached just before the transfusions were to be given. With this precaution, there was no possibility of contamination and there is no record that any occurred.
After the blood had been collected, two technicians performed two separate tests for specificity. With this doublecheck, the percentage of error did not exceed 0.5 percent, and there was not a single report of incompatibility during the course of the war. This was a remarkable record, for the blood that arrived at the processing center at Travis Air Force Base came from donor centers all over the United States.
Serologic tests were also performed, even though by this time there was valid evidence that syphilis could not be transmitted by blood that had been stored longer than 3 days (p. 143).7
After the collected blood had been chilled to 39.2º to 42.8º F. (4º to 6° C.), it was shipped by truck, rail, or air to the processing center in insulated Church shipping cases, refrigerated with wet ice (p. 204). Blood usually arrived within 48 hours after it had been collected. At the base, it was taken to the receiving, storage, and shipping section; logged in; placed in a walk-in refrigerator maintained in the temperature range just mentioned; and there unpacked, inventoried, and stored. Two such refrigerators were available, each capable of holding 2,500 pints of blood. The empty insulated blood shipping container was readdressed to the blood donor center whence it had come, and was returned to the center by Railway Express.
The pilot tube containing 6-8 cc. of whole blood was detached from the bottle and taken to the laboratory section, where the sample was regrouped, retyped, and retitered (fig. 174). The repetition of these tests served two purposes: (1) It eliminated units of blood that were not group 0. (2) It served, to a degree, as a crossmatch; it was not always possible for medical units in Korea to type and crossmatch their patients before transfusing them.
Each year the Travis laboratory used approximately 9,600 cc. of anti-A and anti-B, and 5,800 cc. of anti-Rh, blood typing sera. During the last month the laboratory operated, the sera were used in dried form. The liquid form, which had been used up to this time, was thought more satisfactory, for several reasons: It contained fewer artifacts. It saved time because it did not have to be reconstituted. It was packaged in smaller units, and less warehouse space was required to maintain an adequate supply. On the other hand, the dried form cost a little less and had a longer useful life, 60 months, against 12 months for the liquid form. There was no significant difference in the number of bloods that could be tested with given amounts of each form.
After testing, a label was securely glued to each bottle, containing the unit blood number, blood group, Rh-factor, point of origin, and original blood donor center number. Although the expiration date did not ordinarily exceed
7 At the meeting of the Committee on Blood and Blood Derivatives on 23 September 1953 (after the armistice bad been signed), it was proposed by Dr. William G. Workman that serologically positive bloods be used for the preparation of dried plasma, and that bloods intended for these purposes should not be tested serologically (20). These proposals were concurred in by Dr. Thomas B. Turner, Dean, Johns Hopkins University School of Public Health, and were recommended for action by the committee.
FIGURE 174.-Laboratories at blood processing center, Travis Air Force Base. A and B. Typing, titration, and Rh-testing laboratory. C. Typing laboratory. Note slides with wells, a post-World-War-II development.
21 days, an expiration date of 22 days from the date of collection was placed on each bottle because this blood would be shipped across the international date line for use in a later time zone. If the serum agglutinin titer of a unit exceeded 1:256, the label read, High Titer Group "O" Blood-For Group "O" Recipient Only. If the titer was less than 1:256, the label simply read Low Titer.
During the Korean War, the processing laboratory at Travis Air Force Base maintained in store two or three times the estimated daily requirement of blood, so that emergency requests could be met without delay. When such a request was received, the blood was given a No. 1 priority and sent to Japan immediately on a cargo or passenger plane.
If circumstances permitted, the blood was held in the refrigerator for 8 to 12 hours, so that it could be examined grossly for hemolysis, clots, or excessive fat content. Frequently, however, because of the heavy demands, bloods were processed and shipped out on the same day that they were received. They were packed for shipment in the walk-in refrigerators.
Except in emergencies as just noted, all whole blood shipped from the United States to the Far East Command was transported in aircraft of the Military Air Transport Service (figs. 175 and 176). It was flown from Travis Air Force Base to Haneda Air Force Base near Tokyo, with stops at Honolulu and Wake Island (map 7). It was reiced at these stops if necessary. As soon as the blood arrived in Japan (fig. 177), it was removed from the plane, trucked to the blood storage section of the 406th Medical General Laboratory, and stored there until it was shipped to Tokyo and thence to Korea (fig. 178). All blood moved in Korea was transported by plane or helicopter (fig. 179).
The largest number of bloods received, tested, and labeled in the Travis laboratory in a single day was 1,881 pints. The overall daily average was 319 pints, based on a 7-day week for the almost 42 months during which the laboratory operated.
The largest number of bloods handled in a single day by the receiving and shipping section was 2,500 pints, this number including both units received and units shipped. The largest shipment placed in a single plane for shipment to Japan was 1,488 pints. The average daily shipment was 273 pints.
The total weight of the blood and recipient sets shipped to Japan was 1,782,434 pounds (891 tons) and the total space required for the shipments, 426,379 cubic feet.
Of the 397,711 pints of whole blood received in the processing laboratory, 340,427 (about 85 percent), were shipped to the Far East Command for use in Korea. The remaining 15 percent included surplus bloods and bloods which for other reasons (hemolysis, clots, breakage, excessive fat content, volume less than 500 cc.) could not be used for transfusions. Most of it (56,809 pints) was sent to the Cutter Laboratories, Berkeley, Calif., for plasma fractionation, but 347 pints were used in local military hospitals. Breakage involved only 128 bottles; 94 were received broken, and 34 were broken during processing.
Only 144 of the bloods received in the laboratory were not group O; 116 were group A, 24 group B, and 4 group AB. These units had been either mistyped or mislabeled at the original blood donor centers, and the errors were caught when they were retyped in the laboratory. The remarkably low percentage of misgrouped blood indicates the skill and care of the technicians who did the initial grouping and labeling. Theirs was a most responsible task, for, as already mentioned, most group-O blood used in Korea, as in World War II, was not crossmatched before it was used.
About 10 percent of all the blood received had an agglutinin titer of 1:256 or higher. During the first 18 months the laboratory operated, less than 9 percent of the bloods received were Rh-negative. During the last 2 years, because of repeated requests for such bloods, the proportion rose to 12 percent. Rh-negative blood was not sent to Korea but was used in the fixed installations in Japan, since it was in them that Rh-negative casualties might receive repeated transfusions 10 to 14 days after they had received Rh-positive blood in forward hospitals.
FIGURE 177.-Blood flown from blood processing center, Travis Air Force Base, to Japan. A. One of first shipments of blood from United States, stored in medical depot in Yokohama, August, 1950. B. Boxes of blood just received at Haneda Air Force Base, Tokyo, November 1950.
FIGURE 178.-Blood, flown from United States via Tokyo, on arrival in Korea. Blood being unloaded by native labor at Seoul Air Field, Korea, whence it will be transshipped to 11th Evacuation Hospital, February 1952.
Losses.- As has just been indicated, most of the blood rejected for oversea shipment for various reasons was made into albumin and immune serum globulin, so that the overall loss was very slight.
Losses remained at about the same level during most of the war. The heaviest losses occurred in the winter of 1950-51, when, because of inadequate processing facilities in the East, bloods intended for plasma, which had to be shipped to a laboratory on the west coast, froze en route. Otherwise, losses remained at about the same level during most of the war. In March 1952, losses amounted to 4.4 percent (2 percent hemolysis, 2 percent short amounts, 0.004 percent lipemia, and 0.4 percent other causes).
FIGURE 179.-Transportation of blood by helicopter, in Korea. A. Blood being loaded for emergency shipment to frontlines. Note that ports of this model of helicopter admit only marmite cans. On return trip, a casualty will be brought back. B. Blood for emergency use in forward mobile army surgical hospital being placed aboard helicopter, Chunchon, Korea, December 1951. C. Helicopter, loaded with whole blood, ready for takeoff, June 1953.
Section IV. The Whole Blood Oversea Experience
ESTIMATE OF NEEDS
Experience in the European theater in World War II showed that an army in action, meeting stiff resistance would require about 500 pints of blood a day, the requirement varying with the type of fighting (p. 557). As would be expected, it was found that the faster an army moved, as in a breakthrough, the less blood would be required. During conventional fighting, in order to keep units supplied with their daily requirements, theater inventories of blood had to be maintained at two to three times normal daily requirements.
These rules of thumb proved quite acceptable for conventional military requirements in Korea (table 37). Estimates for total blood needs were predicated on estimated casualty rates. Requirements usually worked out at 1½ to 2 pints for each hospitalized casualty.
Since delivery of blood from the Zone of Interior could not immediately reflect increased demands from Korea, the policy was to maintain a rather constant demand upon Zone of Interior sources and adjust collections of blood as necessary in Japan.
At the beginning of the oversea blood program, all blood received in Japan from the Zone of Interior was sent to Korea, while blood collected at the 406th Medical General Laboratory blood bank was used only at fixed hospitals in Japan. Within a short time this policy was changed and all blood was handled at the bank on an integrated basis.
When requisitions from Korea were received, the blood was flown to a distribution point in Korea (chart 14), where a distribution team received it from the courier who had accompanied it. Early in the war, when the fighting was highly fluid, two blood depots were maintained, both in the southern part of the peninsula. Later, as the front stabilized, several subdepots were established farther north. By the end of 1951, three depots were in close support of the front, and two supplied rear areas. Helicopters proved the most efficient way of distributing blood to forward units (fig. 179) as they could evacuate casualties on the return trip.
During 1952, reserve blood depots were maintained in Korea at Pusan and Seoul, and three advanced depots were maintained in Eighth U.S. Army areas. In addition, many hospitals stored reserves of blood to meet possible emergencies.
In Korea, although whole blood was considered a special item, it was handled in medical supply channels. The Supply Service deserves great credit for its cooperation and competence, but personnel intimately connected with the blood program could not accept this concept of handling whole blood. The operation of a blood bank system, including distribution,
1U.S. and U.N. forces, without ROK forces.
these personnel argued, is not a supply problem but a professional logistic project requiring the highest degree of coordination on the part of skilled professional personnel. In their opinion, later concurred in by the investigating officer who made a special survey of the blood program in Korea (p. 755), there should be in every theater a transfusion officer with the responsibility of supplying blood to the armies. By supply standards, the multiple supply points just listed were entirely reasonable. By standards of trained transfusion officers, this policy was inefficient and wasteful because it permitted blood to age in storage.
It was almost impossible to collect precise data concerning the age of blood received and used in Eighth U.S. Army installations in Korea after it had left the base depot. In 1951, it was estimated that when blood reached the Haneda Air Force Base in Japan from the Zone of Interior, it was 6 days old, which meant that it had an average usable remaining life of 15 days
(table 38). When the blood was received in Korea, the average remaining life was 9.4 usable days. Fragmentary reports from forward hospitals indicated that when it was used, it was from 9 to 20 days old.
TABLE 38. - Remaining usable days of blood received from Zone of Interior and shipped to Korea, 1951
Medical officers and trained blood bank workers realize the importance of issuing blood that is as fresh as possible, knowing that the older the blood, the faster will red cells break down after transfusion, the less effective is the transfusion, and the more blood must eventually be used. Since supply personnel did not realize this, their policy in Korea in respect to blood was, as with other supplies, to issue the oldest blood first, to get rid of it.
A number of studies by the fragility test were made daily for 10 days on blood that was 8 to 10 days outdated, in the hope that some safe extension of the expiration date could be determined. Although cell fragility was not notably increased over the testing period, no evidence was adduced to encourage the idea that overage blood should be used deliberately.
SURVEY OF WHOLE BLOOD EXPERIENCE, FAR EAST COMMAND
On 11 March 1953, Lt. Col. Arthur Steer, MC, submitted a report to the Chief Surgeon, U.S. Army Forces, Far East, on a 14-day survey made in October 1952 and dealing with the use and supply of whole blood in this command (21). During October, both U.S. and ROK (Republic of Korea) troops sustained higher casualties than at any other time in 1952. The survey was confined to the Eighth U.S. Army area.
Use factor.-Colonel Steer noted that the data he had collected were somewhat difficult to interpret because no policy had been established for the
issuance of blood to ROK units. ROK units were not supposed to be evacuated through Eighth U.S. Army installations, but a significant, though unknown, number, particularly in troops attached to U.S. units, had thus been evacuated and so had been transfused by U.S. Army standards.
During the period of the survey, approximately 20 percent of all U.S. and U.N. (United Nations) casualties, other than ROK wounded, were transfused, at an average rate of 4.4 bottles per casualty or 0.9 bottles per U.S. wounded who reached a medical treatment facility. On the basis of U.S. casualties only, 5.54 bottles were issued per each soldier wounded in action. If all casualties, including ROK casualties, are considered, 1.95 bottles were issued per each soldier wounded in action. The true issue factor thus lay somewhere between 1.95 and 5.54 bottles per U.S. and other U.N. casualties except ROK casualties.
Reserves.-All medical installations and depots surveyed were found to maintain reserves of blood which provided, in toto, an average stock on hand of 7.87 times the average daily amount used and 3.1 times the maximum ever used on any single day. In a sense, this blood was not wasted because aging blood was sent to ROK installations, which were given it at an average age of 16.1 days. The figures, however, "illustrate the compounding effect of reserve levels resulting from the maintenance of multiple depots." Furthermore, the existence of these multiple depots and the maintenance of reserve stocks inevitably resulted in the aging of blood on the shelves. This policy also made the control of reserve levels, as well as flexibility in the use of reserves, extremely difficult. When activity was increased in one portion of the line, for instance, increased needs should have been met by transferring blood to it from a hospital or depot supporting an inactive portion of the front. Instead, they were met by requisitioning more blood from rear areas, where it was supplied without question because there was no single medical officer in charge of the blood supply and with authority to question the requisitions.
Reactions.-During the survey period, there were only 19 reactions (2.5 percent) in the 757 identified patients who received blood. Most of the reactions were mild and of the urticarial type. One hospital, which gave transfusions to 57 patients, reported 11 of the 19 reactions.
Colonel Steer's most important recommendation was that a continuing study be made of the use of whole blood and blood substitutes in Korea, with particular reference to the establishment of a separate medical unit, commanded by a medical officer, whose sole responsibility would be the procurement, storage, and distribution of blood and blood substitutes. For two reasons, such a study should be made by a team sent from the Zone of Interior to the Far East Command by the Department of the Army: (1) Numerically, there were no personnel in the theater who could be detached for the purpose and (2) more important, there were no experienced blood bank operators in the
command. Colonel Steer also considered it important that the group which made the study should have had no previous experience with the control of blood in supply channels and thus would be entirely free from bias.
Another recommendation in Colonel Steer's March 1953 report was that general hospitals outside the Tokyo-Yokohama area in Japan establish small blood banks, subject to frequent supervisory inspections. In the event of emergency, these banks would be provided with blood from the Tokyo bank.
In a later communication to Colonel Kendrick on 15 December 1953, Colonel Steer again emphasized the need for a medical officer in a theater of combat, under the theater surgeon, able to travel in all zones, and to be totally responsible for this blood program (22). This would involve the setting up of minimum standards for local blood collection practices and for shipping and storage procedures, control of the flow and distribution of blood, establishment of minimum bank levels, advice to the surgeon on policies and publicity concerning blood, and constant inspection of all agencies involved in the handling or using of blood. When this recommendation was made, the armistice had been signed, and, within another 2 months, the oversea airlift would be discontinued.
TABLE 39. - Distribution of blood by Tokyo Blood Depot, 1951-52
Section V. Equipment and Refrigeration for Airlift
Development of Criteria
Plastic equipment came under discussion at the Symposium on Blood Preservation held under the auspices of the Committee on Blood and Blood Derivatives, NRC, on 2 December 1949 (28). Dr. Carl W. Walter, who had been working on its development for some time for the American Red Cross, laid down the criteria for it as follows:
1. Simple, one-piece equipment that would permit hermetic sealing during
processing, storage, and transportation of the blood and that could be
employed with a bacteriological safe technique.
It was additionally specified, in view of the logistic difficulties which the use of blood presents in times of war and disaster, that plastic equipment recommended must be lightweight, nonbreakable, collapsible, and sized to accommodate the volume of liquid it was intended to contain. Also, it must be inexpensive enough to warrant discarding after a single using but, at the same time, it must be so designed that, in emergencies, it could be cleaned and reused without risk of pyrogenic reactions.
Dr. Walter's studies had been carried out with equipment fabricated from elastic thermoplastic vinylite resin that incorporated an ion-exchange column (p. 770) of sulfonated polystyrene copolymer. It was sealed by dielectrically induced heat and was sufficiently elastic to yield a hermetic seal if a single throw knot in it were stretched tightly and then released. It was tough and flexible and provoked minimal tissue reaction. The tubing for both donor and recipient sets was extruded with a lumen 3 min. in diameter and a wall 0.5 mm. thick.
The bag was available in any desired capacity and could be so compartmentalized that a single donation of blood could be subdivided into multiple isolated amounts, each with its own delivery tube for use in multiple small transfusions.
The bag, together with tile filled exchange column, fitted with a needle and cannula, was sterilized at 250° F. (121° C.) for 30 minutes. Compressed air was then admitted to the sterilizing chamber to maintain a pressure of 1.4 kg. per square centimeter until the bag had cooled to 194° F. (90° C.). The assembly was ready for use as soon as the pressure had vented.
The cost of the equipment described by Dr. Walter was then $1.48 per unit, but, when the bags were in mass production, it was expected that the unit cost would be reduced to 45 to 50 cents.
Operation.-Blood was collected in this apparatus essentially as in regular collecting bottles. After the bag had been filled by gravity, the tourniquet was released and a spring clip was placed across the tube distal to the exchange column. Samples for testing were collected in pilot tubes before the needle was removed from the vein. The tube was sealed or knotted close to the bag, and the bag of blood, after being hermetically sealed, was refrigerated.
The transfusion could be given by suspending the bag from a gravity pole by the grommet provided, or the blood could be squeezed into the recipient's vein by placing the bag under his shoulder or buttock. If rapid transfusion was desired, the intra-arterial technique was used, or the operator could stand on the bag.
Comment.-The bag described by Dr. Walter had obvious advantages. Although it took slightly longer to collect the blood than when collecting bottles were used, the quality and yield of blood collected was equal, if not superior, to the quality and yield of blood collected in bottles. Moreover, blood collected in plastic bags practically never had to be discarded because of hemolysis. The bags did not require refrigeration before the blood was collected. A plastic bag containing 500 cc. of blood occupied in the refrigerator only half the space of a bottle holding the same amount. Finally, the insulated containers developed toward the end of the war for the transportation of blood held 48 bags instead of 24 bottles.
Testing and Adoption
By March 1950, the Walter apparatus was in commercial production, by the Fenwal Co., and comparable equipment had been developed by the Abbott Laboratories.
When the ad hoc committee on plastic bag collecting equipment reported on 8 October 1951, plastic equipment had received sufficiently extensive testing in various military and civilian hospitals to establish its desirability and efficiency (24). Further testing was planned for civilian hospitals and Red Cross blood donor centers, and field trials were planned for the Army under what was termed extreme conditions. Figures 180 and 181 illustrate the final type of plastic equipment developed in the Korean War and demonstrate its use. These bags were never formally used in the blood program in Korea because of objections raised to them by
the American Red Cross. They came into general use in military hospitals, though only after some indoctrination. Medical officers at first did not like the plastic equipment, particularly the resin column, and there was some resistance to the use of the bags, even when the blood was collected in ACD solution. At Walter Reed General Hospital, Washington, D.C., where a large-scale test was conducted, it was found worthwhile to have an experienced nurse indoctrinate all personnel in their use.
REFRIGERATED SHIPPING CONTAINERS
Up to the spring of 1951, blood was shipped from the Whole Blood Processing Laboratory at Travis Air Force Base in the Navy (fig. 139, p. 611) and the Army (fig. 182, p. 762) insulated containers developed for use in World War II. The Army boxes did not hold up too well (fig. 183), and when the supply was exhausted, other models were tested (19).
Bailey container.-The first shipping container procured from the Bailey Co. was designed on the principle of the Army box. It had an outside measurement of 8 cu. ft., held 24 pints of blood, and weighed 115 pounds when fully packed and iced.
The outer shell of the Bailey box was made of fiberboard or V-board, which was supposed to be water-resistant. The insulating mechanism moisture-vapor barrier, lid, and ice cans were similar to those used in the Army container.
FIGURE 181.-Demonstration of use of plastic equipment. A. Collection of blood, Fort Sam Houston, April 1952. B. Demonstration of transfusion by gravity by personnel of Walter Reed General Hospital in field tests, June 1952. C. Accelerating rate of blood flow during transfusion by placing bag, which is break-resistant, beneath patient's body.
Sufficient space was allotted for recipient sets, but, in the first model, the wire racks were so close together that the larger type of blood bottle did not fit between the separators.
When the box was closed, it was secured by wingnuts on each side, and handles of sashcord were attached on the same sides. This arrangement made it impossible for personnel to lift the container by the cord handles without scraping their hands on the nuts. As long as the first Bailey container was used, shipping and receiving personnel at the Travis laboratory could be identified by their bruised hands.
FIGURE 182.-Army insulated box, developed late in World War II and used in early airlift to Korea. Boxes are being moved into air-conditioned receiving and shipping room, Travis Air Force Base processing laboratory.
In spite of its defects, this container maintained the proper temperature for blood during its transportation to Japan, and about 2,000 were used. In the meantime, a new model was devised, with a number of improvements, including the attachment of the cord handles and the nuts on different sides. This model, 1,200 of which were delivered, had, like the first model, an outside measurement of 8 cu. ft., held 24 pints of blood, and, when packed, weighed 132 pounds.
The wire racks were so designed that the larger bottles could easily be inserted. This container was, like the first Bailey model, too bulky for one man to handle, and, like the first, it did not withstand adverse weather conditions.
Hollinger container.-Containers made by the Hollinger Corp. were put into use in October 1951, after the supply of Bailey containers was exhausted. This container (fig. 184) was built like a trunk. Its outside measurement was 6.4 cu. ft. and it weighed 115 pounds when fully packed. The exterior shell was of plywood covered with laminated fiber to make it waterproof. Insulation was provided by 2-inch slabs of Styrofoam, which were snugly fitted and attached to the inside of the plywood shell by cement. Each of the two wire racks held twelve 500-cc. bottles of blood, and the tin container in the center held about 20 pounds of wet ice. Between the insulation and the wire racks was a moisture-vapor barrier of corrugated paper.
The insulated lid of the Hollinger container was attached by hinges, and the box could be closed and latched like a trunk or footlocker. A strip of rubber around the rim of the box increased its insulating properties. Metal handles
FIGURE 183.-Whole blood shipments arriving in Korea in insulated cardboard Army box originally used for airlift. Note that boxes are beginning to show signs of deterioration after transportation and exposure. A. Arrival of blood at 6th Medical Depot, Taegu. B. Arrival of blood at 4th Field Hospital, Taegu.
attached to the sides facilitated handling. Although it could not be handled by one man, this box was easier to move than the containers previously used.
The original Hollinger model was very sturdy, withstood rough handling and bad weather conditions, and maintained the correct temperature en route. Approximately 600 were employed, and each made an average of 10 to 12 round trips from the Travis laboratory to Japan.
While the original Hollinger container was still in use, another container was obtained from this manufacturer. It was also a trunk type, but larger (8.1 cu. ft.), heavier (133 pounds), and better insulated than the first model. The insulating layer, which consisted of 3 inches of Styrofoam instead of the 2 inches used in the smaller container, was supplemented by an aluminum moisture-vapor barrier instead of the corrugated paper barrier used in the original model. The strip of rubber around the rim of the box was wider.
The improvement in insulation, which amounted to less than 0.5° F. over 36 to 40 hours, was not considered enough to compensate for the increased size And weight of this second model. Nonetheless, about 900 were used, each making an average of four round trips from the Travis laboratory to Japan.
Of all the insulated shipping containers used at the Travis processing laboratory, the Navy plywood container and the 6.4-cu. ft. Hollinger trunk-type container were considered the most practical, though the Navy container
FIGURE 184.-Trunk type of insulated container developed for Army by Hollinger Corp. during Korean War. A. Closed. B. Open, loaded with ice and blood and ready for shipment. Note that bottles are upside-down, so that blood cells will settle in the top.
could be used for only two or three round trips against the 12 or more trips the Hollinger container could make.
Fiberboard or V-board containers did not prove practical for field use. They did not lend themselves to long-distance shipping, rough handling, and adverse weather conditions, and they were good for only a single trip. They made difficulties in FECOM, and personnel were understandably reluctant to ship blood to forward areas in them because they sometimes fell apart. The
blood distribution center of the 406th Medical General Laboratory in Tokyo had the Navy plywood container (16-pint capacity) duplicated; most of the whole blood shipped from Japan to Korea during the last 2 years of the war went in these boxes.
In all, about 15,000 containers were shipped from Travis Air Force Base to Japan during the course of the war. Of the reusable Hollinger trunk type, 1,500 were the only ones used between October 1951 and February 1954. Though some of them made as many as 12 round trips, they were still in good condition when the program was terminated.
One disadvantage of the Hollinger containers was that they had no space for recipient sets. During the time they were in use, therefore, the sets had to be packed in separate crates, which were shipped with the containers. In all, over 350,000 recipient sets were shipped to the Far East.
The price of insulated shipping containers ranged from $25-$30 for the Navy plywood type to $40-$50 for the Hollinger container.
Shortly after the war in Korea ended, another refrigerated container, which is still in use (1962), was developed at Fort Totten. This box (fig. 185) has
space for 24 bottles of blood, weighs only 20 pounds loaded, and costs only $4.80. The ice is in the plastic bag in the cover, and the arrangement provides better insulation: In the refrigerated container originally developed at Fort Totten, as the ice in the center melted, the tops of the bottles of blood were left unrefrigerated.
REFRIGERATION FACILITIES IN THE FAR EAST
Refrigeration facilities in Japan and Korea (figs. 186, 187, and 188) were generally satisfactory.
Section VI. Techniques of Preservation
Whole blood.-The first blood sent to the Far East from the Zone of Interior during the Korean War was collected in the ACD formula used during World War II, 25 cc. of which was used for each 100 cc. of blood (p. 227). At the 23 September 1950 meeting of the Committee on Blood and Blood Derivatives (25), on the advice of Dr. William G. Workman, Chief, Laboratory. of Biologics Control, National Institutes of Health, the amount of solution used was left unchanged but the formula was altered to 2.45 gm. of dextrose; 137 gm. of U.S.P. sodium citrate, and 5 gm. of U.S.P. citric acid per 100 cc.
of solution. The recommended change was accepted because it was expected that temperature controls would be less precise during the airlift of the blood than during its storage.
Plasma.-Blood intended for plasma was usually collected in a 4-percent trisodium citrate solution during the Korean War. When it was collected in ACD solution, the plasma was difficult to dry, and the quality of the product varied from lot to lot.
The question of using a single solution for the collection of blood, no matter for what purpose it was intended, came up a number of times in the Committee on Blood and Blood Derivatives. On 26 August 1952, the Blood Group, Department of Defense, in cooperation with the National Research Council, American Red Cross, and National Institutes of Health, agreed to enter upon a formal investigation of the use of ACD solution in the prepara-
FIGURE 188.-Refrigerator, used in field hospitals in Korea. The prototype of this box was available in World War II but was never put into production. A. Closed. B. Open, showing storage arrangement and mechanism.
tion of plasma. By the plan adopted, 240 units of blood collected in the NIH ACD formula would be shipped to each of two processing laboratories, and samples of the dried plasma produced would be sent to NIH for routine testing. The National Research Council would conduct the clinical investigations.
The investigation, which was not finished during the war, gave only inconclusive results.
RED BLOOD CELL PRESERVATION
It was the consensus of the Committee on Blood and Blood Derivatives that the crux of the problem of blood preservation was the vitality of red blood cells. On 2 December 1949, Dr. Colin, reporting to the Committee for the Formed Elements Group, stated that all the evidence indicated that intact erythrocytes were necessary if blood was to fulfill its respiratory function (23). He thought it possible that optimum preservation might be achieved only after separation of the red blood cells from all destructive enzymes for which each element served as a substrate.
As time passed, the Committee on Blood and Blood Derivatives, NRC, became more and more convinced that no very great advances could be expected in red blood cell preservation until more basic knowledge concerning these cells was available. The committee (now known as the Committee on Blood and Related Problems) therefore sponsored two symposia on the subject. The first, a Conference on the Differential Agglutination of Erythrocytes, was held on 17 September 1952 (26), and the second, a Symposium on the Structure and Cellular Dynamics of the Red Blood Cell, was held on 11-12 June 1953 (27).
In spite of all the work done on red blood cell preservation before and during the Korean War, the statement made at the 4 March 1953 meeting of the Committee on Blood and Related Problems (28) remained true until the end of the war, that the last great advance in blood preservation was the addition of glucose to the preserving medium. (p. 217). This addition marked the first time that the energy of red blood cells had been taken into consideration in attempts to preserve them. On the other hand, while the addition of glucose was an improvement, it did not prevent cellular energy from deteriorating during storage.
Space does not permit the account of several related conferences held during the Korean War under the auspices of various committees and subcommittees of the Division of Medical Sciences, National Research Council. They included, among others, several conferences on blood coagulation and a conference on fibrinolysis.
At the Symposium on Blood Preservation held on 2 December 1949 (23), Dr. John G. Gibson II, Harvard University Medical School, and Dr. Edward
S. Buckley, Jr., Peter Bent Brigham Hospital, reported their work on exchange resins in the preservation of blood as follows:
Reduction of the calcium content of the blood below the critical level will prevent blood clotting by preventing the formation of thrombin by prothrombin, a reaction for which calcium is apparently essential. When citrate is added to blood, a soluble calcium-citrate complex results which does not dissociate sufficiently to provide enough calcium for the reaction just described to occur. presumably, other divalent ions are also "complexed" by the citrate ion. The same principle is involved in the use of an ion-exchange resin except that the calcium-resin complex is insoluble, as are also the other ion complexes formed. The degree of reduction in effective concentration may therefore be quantitated.
Collecting blood directly into a flask containing the resin did not prove feasible. Best results were obtained when the blood was allowed to flow through a column of resin into the collecting vessel.
Blood collected by this technique did not clot. It showed no significant changes in pH, freezing point, or sodium concentration. The calcium concentration was reduced to less than 1 percent and the potassium to about 1 milliequivalent per liter. Zinc was not removed from either cellular or plasma components. Two in vivo canine experiments showed a post-transfusion red blood cell survival of approximately 90 percent.
At the conclusion of this report, Dr. Colin commented that the most remarkable recent advance in the preservation of blood was the introduction of an ion-exchange resin, which apparently removed not only the calcium involved in coagulation of the blood but also some of the metals utilized in enzyme activity. The collection of blood over an exchange resin into a vessel without a wetting surface, which did not contain an anticoagulant, would, however, make necessary the determination of a new baseline regarding the optimal environment for its formed elements. Except for a few small-scale experiments, blood had never been studied in the absence of citrate concentrations, which were usually quite high.
Among other reports at this same symposium was one by Dr. Charles P. Emerson, Jr., Boston University School of Medicine, which showed that the immediate decalcification of fresh blood by passing it through a resin column had no immediate discernible effect on the osmotic fragility of red blood cells. When, however, the blood thus collected was stored, there was, as in blood stored in ACD solution, a progressive increase in their fragility. Moreover, the magnitude of the changes observed was considerably greater, particularly after the 10th day, than in ACD solution. Resin-collected blood stored less than 10 days without removal of plasma but with the addition of a saline-dextrose diluent seemed comparable in stability to ACD-collected blood stored without modification for a similar length of time. Resin-collected blood stored without further modification was essentially nonviable when transfused on the 20th day; 80 percent was eliminated from the recipient's circulating
blood within 10 minutes and the remainder within 48 hours. The period of survival was essentially the same whether the pH was 7.2 or 6.8.
It was considered possibly significant that poor survival of stored citrate-free, calcium-free blood was invariably associated with the finding of a dextrose concentration below 100 mg. percent.
At a meeting of the Panel on Preservation of Whole Blood and Red Cells on 28 March 1951 (29), it was agreed that none of the studies carried out with ion-exchange resins or anything, else had produced sufficient effects on red blood cell survival to warrant changes in the preservative solution in use. It was urged that testing techniques used in the various laboratories be standardized, to facilitate comparison of results and thus aid in the evaluation of the solutions used. Particular emphasis was placed upon the temperature of collection and storage of the blood and upon the rapidity of cooling.
The preservation of whole blood at subzero temperatures, although it had been discussed before the Korean War, was not seriously considered during it.
At the 2 December 1949 Symposium on Blood Preservation (23), Dr. Max M. Strumia reported on the extensive experiments he had conducted with this technique. From them, he concluded that optimal preservation of whole blood for up to 2 months could be accomplished if it were stored at 26.6° F. (-3° C.). The temperature range, however, was relatively narrow. With a variation of more than 1.5° C., even though the physical status of the blood remained unchanged (that is, whether it were liquid or solid), the status of the red blood cells showed considerable deterioration. In all of his experiments, therefore, Dr. Strumia used the temperature of -3° C. as optimal and kept variations within plus or minus 0.2° C. If preliminary shrinkage of the red blood cells, which he considered essential, was carried out by the correct technique before the blood was frozen, the period of preservation was materially lengthened. Cells thus shrunken returned to normal size when they were immersed in plasma but not when they were immersed in physiologic salt or other isotonic solutions. When the cells were used for transfusion, they resumed their normal shape and size within an hour of the transfusion.
The concentration of glucose in the preserving fluid when the cells were frozen at -3° C. was found to be critical. If the level was below 40 mg. percent, preservation was bad. If it was greater, it was fair. If the level was below 20 mg. percent, preservation was "terrible."
At this same meeting, Dr. Walter stated that he had been able to reproduce Dr. Strumia's work; that his laboratory had repeated the work on vitrification done 10 years earlier, with the same results; namely, that approximately 50 percent of morphologically intact erythrocytes were present after thawing. He thought that the problem was one of thawing and that it might be a blind alley.
Part III. The Plasma Program
PLASMA SUPPLIES BETWEEN THE WARS
The details of the disposition of surplus plasma at the end of World War II are related elsewhere (p. 310). In substance, all the surplus, exclusive of certain amounts retained for Army use, was transferred to the American Red Cross, for use by the public which had provided it originally. The stocks transferred amounted to 960,183 250-cc. packages and 1,386,726 500-cc. packages. When the Korean War broke out, a large part of this plasma had been utilized by hospitals, clinics, private physicians, and research workers. What was left had become outdated and required reprocessing, which had been accomplished in only a small number of units.
At the end of World War II, the production facilities for plasma, which had been established by the Federal Government through the Defense Plants' Corp., were dismantled. Equipment was declared surplus. A small portion was purchased by individual laboratories, and the remainder was disposed of by public sale.
STOCKPILES AND FUTURE REQUIREMENTS
Army and Navy inventories as of September and November, 1949, respectively, were as follows:
1. No blood was on band except for day-by-day requirements.
An Army contract with Cutter Laboratories to reprocess 40,000 packages of outdated dried plasma had gone unexpectedly well. The percentage of loss, which was only 0.3 percent, was chiefly caused by subjecting the material to intense heat and by failure of proteins to go into solution when the plasma was reconstituted. The cost of reprocessing was about a third of the cost of processing fresh plasma obtained from voluntary donors. The National Institutes of Health was willing to approve reprocessed plasma for 5 years. The manufacturers thought a longer dating period was justified.
Stocks of plasma, albumin and gamma globulin on hand were considered temporarily adequate for peacetime requirements. Most of the plasma, however, would become outdated during 1950, and none of it had been irradiated
against the hepatitis virus (p. 778). Also, some plasma would not be satisfactory for reprocessing because of its fat content and because of original inadequate drying. A considerable amount of albumin and other fractions could probably be recovered from the plasma unsuitable for reprocessing, but the remaining stocks might not meet even peacetime needs, and replacements must be procured from agencies participating in the national blood program.
Although there was no substitute for whole blood, as the Task Group emphasized, it could not be stockpiled, and blood derivatives and plasma-expanders must be stockpiled for emergencies. Research must be pressed for better agents for replacement therapy than were presently available.
The March 1950 report of the Task Group (4) estimated that in the event of war, requirements for the Zone of Interior from M-day to M+12 (months) would be 290,000 units of blood and 510,000 500-cc. units of plasma. Oversea estimates were based on two units of blood and two units of plasma for each thousand troops exposed to combat, with 10 percent added for losses due to breakage and outdating. Allowances were also made for shipping losses in the first month, and for the needs of U.S. civilian casualties in the combat zone.
The Task Group estimated that for wartime, at least 120,000 units of blood would be required for shipment overseas during the first year of combat, with increasing amounts thereafter. Transportation of blood in wartime would require the highest priority. The capabilities of various types of aircraft for this purpose were estimated.
The Task Group also recommended: 1. That at least a million 500-cc. packages of plasma should be stockpiled by 1 June 1951, with additional increments procured in yearly installments over the next 4 years. Provision should also be made for rotation of stock by withdrawals to meet current military and civilian needs. 2. That equipment should be stockpiled for the collection and administration of blood and should be replaced by rotation. It was thought that there should be no difficulty in meeting this requirement if manufacturers were provided with the proper priorities.
PROCUREMENT OF PLASMA
Since at this time there was neither a civilian nor a military blood program in existence of sufficient scope to meet the needs of national defense, the Task Group recommended that, as a first step in procurement of the desired amount of plasma, existing stores of plasma and blood derivatives be reprocessed as they became outdated while additional plasma was being procured to bring the war reserve for the Armed Forces up to the desired level. Along with the re-
sponsibility of whole blood procurement for Korea, the American Red Cross accepted the responsibility of coordinating the collection of blood for plasma.
In August 1950, after it complete survey of commercial laboratories by the Industrial Mobilization Board, DOD, it tentative production schedule was established to meet the target of a million units of plasma by June 1951, a target that had become both more urgent and more difficult because of the outbreak of the war in Korea on 25 June 1950.
Government-owned plasma-processing facilities were set up at once at, Sharp & Dohme, the Upjohn Co., and Eli Lilly and Co. Litter contracts were made with Hyland Laboratories; Courtland Laboratories; Cutter Laboratories; Armour Laboratories; and E. R. Squibb and Sons. These firms, which were variously located on the west and east coasts and in the midportion of the country, were selected on the principle of locating commercial processing laboratories as near to donor collecting centers as possible, since plasma and red cells must be separated from each other within 24 to 30 hours after the blood is collected.
In October 1950, before planning had proceeded very far, it became necessary to replace the stockpiling program because of unexpectedly heavy demands for blood from the Far East Command, as well as because of processing delays. The original goal of a million units by June 1951 was halved, but even this objective could not be met, and, by the end of the fiscal year, only 87,279 units of plasma had been delivered. At this time, seven of the eight plants listed were in operation. Their joint monthly capacity was 58,600 units, and their final capacity as of April 1952 was set at 148,000 units per month.
For the first 6 months of the new plasma operation, the largest available drying capacity was in the three laboratories on the west coast. By February 1951, the east coast laboratories had a capacity of 10,000 packages per month, but it, was not until August 1951 that the laboratories in the middle of the country had completed the installation of their drying equipment. On the east coast, the opening of bleeding centers had been set far ahead of scheduled production, while on the west coast, the reverse was true. As a result, blood had to be shipped to the west coast production laboratories from the east coast bleeding centers. Shipping of blood in ACD solution long distances by air was not desirable technically or economically when the blood was to be used for plasma, and some of it froze during the bitter winter weather, but this plan had to be employed as a matter of expediency.
In January 1951, representatives of the Department of Defense and the American Red Cross were assigned to the processing laboratories to iron out difficulties as they arose and to take corrective action at once. Production at one laboratory, for instance, was held up until administrative and personnel problems were corrected by the appointment of a new laboratory director.
Another laboratory was inoperative for 2 weeks because of trouble with its shell-freezing technique.
Early in January 1952, the Department of Defense learned that the Bureau of the Budget had allocated the funds for its 1953 plasma reserve to Federal Civil Defense, for inclusion in its estimates for stockpiling (2). The situation was considered at a meeting on 18 January 1952, in the Office of the Directorate, Armed Services Medical Procurement Agency, which was attended by both military and civilian personnel. It was agreed that the Blood Donor Program must continue to operate at its present level (300,000 bleedings per month) and that plasma processing facilities be used without interruption. Two general plans were considered:
1. That a single stockpile of plasma be set up for national defense,
with both the Armed Services and Federal Civil Defense drawing from it.
Neither of these plans was desirable, but the second was considered the more undesirable of the two: It would require revision of the Current program; initiation of new contracts with the American Red Cross and the plasma processing laboratories; hiring of additional personnel; and training them in procurement, testing, inspection, and other procedures. It would also require deemphasizing the program for blood for Korea, which had been generally successful, and stressing the requirements for stockpiling for national defense, with little assurance that the new program would be completely successful or have the same general appeal.
While these plans were being debated, a new factor entered the picture, which could not be ignored by the Department of Defense. This was the "alarming" percentage of hepatitis in persons who had received plasma infusions, especially when the plasma had been prepared from large pools (p. 674). The reprocessing of World War II stocks of plasma had run into this problem, and the Department of Defense wanted no reserves of that kind.
At meetings of the Armed Forces Medical Policy Council on 17 March and 28 April 1952 (2), it was agreed that, after some satisfactory method of sterilization against the virus of hepatitis had been found, the plasma program would be divided into two phases. In the first, priority would be given to military and pipeline requirements for plasma. In the second, stockpile reserves would be accumulated. The Department of Defense wished to continue its priority until such time as the first increment of its reserves had been built up with plasma free from infection, after which stocks would be divided equally between civilian and military agencies. At a joint meeting on 16 May 1952 of the Armed Forces Medical Policy Council and the (Cummings) Subcommittee on Blood, Health Resources Advisory Board, the subcommittee agreed to accept the dual stockpile plan but not the proposal that the Department of Defense build up an increment of infection-free plasma before Federal Civil Defense secured any plasma at all. The Department of Defense, on the
other hand, was entirely unwilling to use currently available plasma, from which a comparatively large proportion of recipients might be expected to develop infectious hepatitis. The Armed Forces could not tolerate long periods of incapacity among its personnel, their corresponding delay in return to duty, and a reduction in the effective military strength of the country. All of these losses could be better tolerated by civilian personnel than by combat troops.
When the disagreement continued, with the Secretary of Defense supporting the position of his Policy Council, it was agreed, on 2 June 1952, that the decision would have to be made by the President. The allocation of plasma reserves was still undecided by the end of the year, but had become largely academic, since no satisfactory method of sterilization of plasma had been devised. A lack of funds also made it impossible to meet the desired goals.
By the end of fiscal year 1952, the Federal Civil Defense Administration had contracted for 750,000 units of plasma, none of which had been delivered. In addition, it had not received any of the 300,000 units of dextran and the 1.2 million units of polyvinylpyrrolidone that had also been ordered.
The potential problem of serum hepatitis, as mentioned elsewhere (p. 776), began to be appreciated only shortly before World War II ended. With the end of the war, the massive use of plasma ceased, and, in the absence of a central reporting agency, such cases of serum hepatitis as occurred after plasma infusion did not have the impact which they would have had in time of war and which they were to have when the outbreak of the war in Korea required a resumption of en masse plasma infusions.
Shortly before World War II ended, Dr. John W. Oliphant and his associates at the National Institute of Health (30, 31) began their work on the ultraviolet sterilization of plasma as part of its processing (fig. 189). The first results were most encouraging, a particularly desirable feature of the method being that the plasma proteins were apparently unaffected by the amount of ultraviolet energy used. Unfortunately, the belief that the problem had been solved was to prove fallacious.
There was scarcely a meeting of the Committee on Blood and Blood Derivatives (the reconstituted Subcommittee on Blood Substitutes), NRC, at which serum hepatitis and attempts at sterilization of infected plasma did not come up for discussion. Space does not permit an extended account of these matters, and the reader is referred to an excellent summary by Dr. Roderick Murray, Laboratory of Biologics Control, National Institutes of Health, who took over the work on Dr. Oliphant's death. The report which contains a comprehensive list of references, was presented at a Conference on Derivatives of Plasma Fractionation, on 28 October 1953 (32).
FIGURE 189.-Technique of plasma production during Korean War. A. Insertion of bottles of blood into large centrifuge to separate plasma from red blood cells. B. Pooling of plasma from from bleeding bottles after centrifugation. C. Transfer of plasma from pool into individual dispensing bottles. D. Shell freezing of plasma in large bottles. E. Storage of shell-frozen plasma. F. Ultraviolet light sterilization of plasma. This additional step was introduced into the processing of plasma when serum hepatitis became a serious threat.
The experience of the Armed Forces in Korea showed that, while 0.5 percent of recipients of whole blood developed hepatitis, 12 percent or more developed it after infusions of pooled plasma. In 1951, it was therefore decided to use human volunteers for testing the infectivity of plasma and plasma derivatives and evaluating the efficacy of various methods proposed for its sterilization (table 40).
1Incubation periods in parentheses refer to cases
of hepatitis without jaundice.
By the time these studies were undertaken, numerous disquieting reports had been received indicating that hepatitis was occurring after the use of irradiated plasma, which presumably had been rendered safe. One such report (33) showed an incidence of 11.9 percent in patients who had been followed for at least 6 months and most of whom had received more than one unit of plasma.
Ultraviolet irradiation.-Irradiation of plasma with ultraviolet light was usually carried out by exposing a thin film of plasma to radiation from a high intensity source (32). Various types of equipment were used. In some, the plasma was passed through a narrow-bore, usually flat, quartz tube resembling a hollow ribbon. In others, the film was formed on the inside wall of a hollow cylinder or cone which rotated at high speed and in the cavity of which the ultraviolet lamps were located. In some of these lamps, quartz envelopes transmitted most of the ultraviolet light. In others, Vycor envelopes transmitted radiation only in the 2735 A. band or higher. Apparatus of the latter type was most widely used in the plasma-processing laboratories because of
its ability to handle relatively large amounts of plasma, by the formation of films on the inner surfaces of cylinders or cones.
The NH studies on the effect of ultraviolet light on plasma were carried out with three different machines of the type just described (table 41). An attempt was made to simulate actual processing conditions. Special attention was paid to the measurement of the ultraviolet output of the lamp used, to continuous monitoring of each irradiation run, and to accurate measurement of the rate of flow of plasma through the apparatus. Each run was also checked by the Aerobacter aerogenes test.
The results of this study eliminated the hope originally raised that failure of sterilization might be due to some defect in the apparatus or to inadequate exposure to ultraviolet irradiation. As this experience (table 41) showed, the margin of safety between the sterilizing dose and the dose producing unacceptable denaturation of plasma was not sufficiently great to justify placing much reliance on this technique. Moreover, considerable changes in plasma proteins were apparent after sterilizing dosages that might actually produce inadequate exposure.
Controlled heating.-Samples of infected pooled plasma were subjected to controlled heating by complete immersion in constantly agitated water at 59.2° and 60.4° C. for 2 hours and 4 hours, respectively. Two bottles were tested for each time period, and a fifth bottle was kept at room temperature during the heating process. All bottles were then immediately shell frozen
by means of Dry Ice and alcohol and stored at -20° C. until they were administered to volunteers. Some of the Dry Ice in which the material was transported to the using hospitals was still present when the flasks were opened for the inoculations.
Two groups of 10 volunteers each, who had been carefully screened by liver function tests, were inoculated with the heated material, and 5 others were inoculated with the control plasma. Cases of hepatitis developed in each group (table 42).
Storage at room temperature.- Room storage temperature, which had been developed by Dr. J. Garrott Allen and his associates at the University of Chicago with extremely promising results (32, 34), was evaluated in three groups of volunteers. There were three instances of hepatitis in a group of five subjects inoculated with plasma stored at an almost constant temperature of 70° F. for 3 months against only one instance in 20 subjects inoculated with plasma stored at a similar temperature but for 6 months. The single case of hepatitis in these patients occurred at the end of 196 days, the longest incubation period on record, and was mild.
1Clinical signs and symptoms, no jaundice.
Dr. Allen presented his own figures on plasma stored in the liquid stage for 6 months before use: There was no instance of hepatitis in 1,546 plasma transfusions, with a careful 6-month followup, while over the same period there were 49 cases of hepatitis, 0.4 percent, in 37,026 whole blood transfusions.
At this same meeting, it was reported that beta-propiolactone had failed
in experiments involving the administration of transfusion sized (600 cc.)
doses of known infected plasma treated with 3,000 mg. per liter of this
agent. Cathode-ray irradiation had proved lethal for the laboratory virus
of hepatitis, but it had been given a relatively low priority in experiments
on human volunteers because the outlook with beta-propiolactone had then
been considered more promising.
There would be little point to citing other clinical and experimental studies with treated plasma. A great many of them were extremely hopeful
up to a point. In September 1950, a distinguished clinician was so impressed with the results apparently being obtained from ultraviolet irradiation that he declared that "the key to the control of homologous serum jaundice is now at hand." The blunt fact is that hepatitis continued to follow the use of plasma, no matter how it was treated. Complete sterilization was never achieved. All methods failed in the end.
The crux of the matter was that the Armed Forces needed some agent to use for resuscitation until the casualty could reach an installation where whole blood was available. They therefore had no choice but to take the calculated risk of using plasma, even though it might cause hepatitis. The risk was considerable. Late in 1951, the incidence of hepatitis after plasma transfusion reached 21 percent, in sharp contrast to the reported World War II incidence of 7.5 percent. Part of the explanation was that much of the plasma used in Korea in the first months of the war had not been treated at all. Moreover, different diagnostic criteria were used in the two wars. In World War II, the diagnosis was chiefly clinical. In the Korean War, any elevation of the serum bilirubin was considered an indication of hepatitis.
In January 1952, the National Institutes of Health agreed that pools of plasma should be reduced from the approximately 400 bloods then being used to not more than 50. The change could not be made immediately because the smaller pools required changes in equipment and techniques.
Hepatitis continued to occur, and at the 8 October 1952 meeting of the Subcommittee on Sterilization of Blood and Plasma, Committee on Blood and Related Problems, it was recommended that, because of the risk of hepatitis, plasma should be used only in emergencies and when no plasma-expander was available (85). Otherwise, serum albumin, which had proved to be extremely effective, or dextran, which had been tested extensively, should be used. The reduced yield from blood, as compared with the plasma yield (p. 342), would be compensated for by the other desirable byproducts secured by fractionation of plasma, and it was recommended that, as far as was practical, the present plasma program be converted to large-scale production of human serum albumin. Meantime, the search for techniques of sterilizing plasma should be continued. It was brought out, however, that when such a method was found, the sterilized plasma would be a new item, and an extensive program of testing and clinical evaluation would be required before it could be recommended and standardized. Some doubt was expressed that the blood procurement program could be sufficiently increased to provide the extra blood needed for the production of serum albumin.
At the 4 February 1953 meeting of the Subcommittee on Sterilization of Blood and Plasma, the third death from hepatitis in a volunteer was reported, and the testing program was suspended by action of the Armed Forces Epidemiological Board (36).8 It was recommended at this meeting that
packages of plasma prepared for clinical use carry a conspicuous warning to physicians that, serum hepatitis could be transmitted by plasma, in spite of ultraviolet irradiation, and also advising careful selection of blood donors.
On 20 August 1953, Circular No. 73, Department of the Army, directed that, because of the risk of serum hepatitis, the higher cost, and the need to use it for the production of specific globulins, plasma would not be used "to support blood volume" unless dextran was not available (37).
Part IV. The Plasma Fractionation Program
When the Korean War broke out, the same reasoning that made the Army choose plasma in preference to serum albumin as their agent of resuscitation in World War II led them to choose it again; that is, it took 4.2 bleedings to provide 25 gm. of serum albumin, against only 1.2 bleedings to provide 250 cc. of plasma. Also, it was usually necessary to supply water when serum albumin was used, whereas the distilled water used in the reconstitution of plasma was provided with it. Finally, the finished price of a unit of albumin was about $20, against about $4 for a unit of plasma.
When the military reverses suffered by the U.S. Army in Korea in the winter of 1951 increased the need for replacement substances, 50,000 units of outdated serum albumin were obtained from the Navy and transferred to the San Francisco medical depot for shipment to FECOM. Technically outdated serum albumin proved perfectly satisfactory. One of its advantages was that the small size of the units made it possible for corpsmen to load their pockets with it. Also, serum albumin did not freeze in the bitter winter weather encountered, as reconstituted plasma did.
When the incidence of serum hepatitis made it necessary to discontinue the use of plasma in Korea, serum albumin was the logical substitute. Extensive tests had shown that, when it was heated for 10 hours at 60° C., it carried no risk of hepatitis (28, 38). Also, it could be made from contaminated plasma, which meant that a large quantity could be obtained from the plasma on hand and no longer considered fit for use because of the risk of transmission of hepatitis; it was, of course, essential to use a therapeutic replacement agent that did not cause a second pathologic condition.
Serum albumin was readily administered in forward areas.
At the meeting of the Subcommittee on Shock, Committee on Surgery, NRC, on 11 December 1950, it was brought out that, though globin is of great nutritive value as a protein, it was lost in 18 percent of the total protein of the blood then being discarded in the form of red blood cells (39). It was
also brought out that problems connected with its clinical use, chiefly hematuria and renal complications, had not yet been overcome.
At the 5 April 1951 meeting of the Committee on Blood and Blood Derivatives (40), it was reported that a modified form of globin, prepared by Sharp & Dohme, from discarded red blood cells, had been used by some 12 investigators to date as (1) a protein supplement and (2) as a plasma-expander. In about a hundred trials, there had been 10 to 15 percent of rather serious reactions, but the processing procedure had recently been altered, and there had been no reactions in the last 60 clinical trials.
Globin was used in 8-percent solution, in doses of about 16 gm. daily, for patients with hypoproteinemia, caused by cirrhosis, nephrosis, and other conditions in which there was a negative nitrogen balance. It had been tested on only four patients in shock, and no evidence existed that it possessed sufficient osmotic activity to become a satisfactory plasma-expander. The trials had not been entirely adequate because many investigators had failed to analyze the globin per se in the bloodstream.
A Conference on the Uses of Gamma Globulin was held oil 5 August 1952, under the chairmanship of Dr. Milton C. Winternitz (41). Earlier in the war, there had been numerous meetings concerning this product at the Office of Defense Mobilization, to discuss the amount available and the anticipated needs if testing should indicate that it was effective in preventing paralytic poliomyelitis. If it was proved effective, the nationwide demand for it expected during the summer of 1953 would have a tremendous impact on the blood program, affecting every phase of it from the donation to the final product.
An ad hoc committee which had been convened by the Committee on Blood and Related Problems to assess the situation agreed in principle with proposals developed by the U.S. Public Health Service. It was recommended that the National Research Council investigate current stockpiles of gamma globulin and present production capacities; consider production for the Armed Forces and the civilian population and the equitable distribution of gamma globulin between them; assess the need for, and means of, increasing production; solicit the cooperation of both public and private groups working on this problem; conduct, or arrange for epidemiologic studies bearing on allocation; adopt such measures of allocation as might be necessary and set up priorities if it was thought that gamma globulin would be in short supply. It was also recommended that the U.S. Public Health Service and the American Medical Association arrange for publicity on the production and use of gamma globulin.
Up to this time (August 1942), three field studies had been conducted, in Provo, Utah; Houston, Tex.; and Sioux City, Iowa. It was thought that a fourth might be necessary. Followup studies were still incomplete, and both the potency and the dosage of gamma globulin remained to be established.
Whether the ad hoc committee assumed that gamma globulin would be only partially successful, or successful in only some cases, it had to postulate some measure of success to make plans for the future. It was most important to be ready to expand production capacity to the limit as soon as possible after all field tests were completed, by 15 October 1952.
In a second report of the ad hoc committee on the uses of gamma globulin on 30 September 1952 (42), it was noted that the first knowledge the National Research Council had of the possible magnitude of the problem was at a meeting held in June 1952, with the Subcommittee on Blood of the President's Health Resources Advisory Committee. The Subcommittee on Blood fully recognized its responsibility because of the possible effect a demonstration of the preventive effect of gamma globulin in poliomyelitis might have on the future of blood collections in the National Blood Program (p. 735) and on the allocation of blood and its derivatives between civilian and military claimants. The present supply of gamma globulin was inadequate. The Office of Defense Mobilization had turned to the National Research Council for help, and the council had noted that its role was to advise, not to implement advice. The Office of Defense Mobilization was investigating the legal implications connected with the situation. The provision of gamma globulin for military dependents was, of course, an Armed Forces responsibility.
At this time (September 1952), the American Red Cross which had received the bulk of the surplus gamma globulin at the end of World War II, was distributing between 700,000 and 800,000 2-cc. doses per year for the prophylaxis of poliomyelitis and was recovering 200,000. It was then producing 70 percent of the current output and commercial firms, 30 percent. The Red Cross was also distributing gamma globulin for the prophylaxis of measles and of infectious hepatitis. The Army was holding 12,000 10-cc. units and had 1,013,450 gm. in the dried state. The Federal Civil Defense Administration had no reserves at all. On an assumed loss of 5 percent of current blood collections of 3,360,000 pints per year, 191,680 gm. of gamma globulin could be recovered.
The problem was discussed at several other meetings in 1952 and 1953 (43, 44), including a conference on Epidemiology of Poliomyelitis (45). The end of active combat in June 1953 eliminated the need for further action on the part of the National Research Council and the Armed Forces.
When final action was taken by the Office of Defense Mobilization in June 1953 to terminate dried plasma contracts, in accordance with NRC recommendations, because of the proved danger of serum hepatitis (32), it was agreed by the Department of Defense and the Federal Civil Defense Administration that the program for the current fiscal year should include only fractionation of plasma, with the production of serum albumin and gamma ( globulin. All gamma globulin produced would be made available to the American Red Cross and the National Foundation for Infantile Paralysis at the cost of processing.
RED BLOOD CELLS
During the Korean War, as in World War II (p. 313), packed red blood cells were used extensively in the treatment of chronic and secondary anemias and in the preparation of anemic patients for surgery. One of the chief advantages of this technique was that large quantities could be injected within short periods without risk of overloading the circulation. No in vitro tests were developed during the Korean War to determine the viability of these cells, and no gross or microscopic characteristics proved useful for this purpose. The only valid criterion of their viability continued to be a study of their survival in normal human subjects, a test that was both difficult and cumbersome. Without a simple method for continuous quality control, rigid standards of collecting, processing, and storage were essential precautions.
At the fourth meeting of the Committee on Blood and Related Problems on 10 December 1952 (46), an inquiry was received from the Army Research and Development Board concerning the possibility of using cadaveric blood. The American Red Cross had also received numerous letters on the same subject.
In response to these inquiries, Dr. Strumia reported work he had done in this field in 1937-38. He considered only 12 of the 125 cadavers he had examined usable. He obtained much less blood than he expected, an average of 1,500 cc. per body. It was difficult to secure a free flow of blood, even shortly after death; the best flow was from patients who had died of coronary occlusion. He found it impossible to secure a satisfactory flow from the femoral vein, as the Russians had reported, and had to enter the right auricle with a ½-inch trocar. In vitro tests were normal in all respects, but the incidence of contamination was very high unless the blood was drawn within 6 hours of death.
Dr. Strumia had not used cadaveric blood clinically, and it was the consensus of the committee that there would be strong esthetic objections to it by both physicians and patients in the United States. It was also pointed out that there was no need for the use of this method for the Armed Forces at this time since the country was still far from exhausting its donor supply.
Part V. The Plasma-Expanders Program
It is not the function of this history to go beyond the important historical facts in the study of plasma expanders (the so-called blood substitutes of World War II). Attention should be called, however, to the excellent bibliog-
raphy on plasma expanders (except those derived from human blood) prepared in the reference division of the Army Medical Library (now the, National Library of Medicine) in December 1951 (47). This is a most useful list. The references under each major item are grouped according to subheadings; the number of references in each article is stated; and the substance of the article is summarized in one or more succinct sentences.
The need for such a reference list was pointed out in the preface: The treatment of shock was then (1951) the most pressing single medicomilitary emergency. It was urgent both militarily arid in the event of a thermonuclear war in which civilians would be involved. Since the prolonged storage of whole blood is not feasible, realism required that two facts be faced, (1) that it would be completely impractical to secure blood from donors in the event of a thermonuclear attack, and (2) that potential donors might well themselves be victims of the attack and therefore candidates for blood. The solution of the military and civilian problem was the development of plasma, volume expanders and their stockpiling. This collective bibliography was a useful first step in such a task.
GELATIN AND OXYPOLYGELATIN
The extensive studies made on gelatin during World War II under the auspices of the National Research Council (p. 373) were resumed early in the Korean War. Then, as in World War II, the major objection to gelatin from the military standpoint was that it gelled at about room temperature. It therefore could not be used in the field, and even in hospitals, its use furnished some problems, which would be intensified if bombing or some other catastrophe interrupted electricity and heat.
Some observers believed, in view of the nature of the emergency, that gelatin manufacturers should be encouraged to begin production at once, even if the material might not be precisely what was wanted (39). The proposal that 30 gm. of urea be added to each 500 cc. of gelatin to keep it liquid was considered ingenious, but unsafe unless there could first be assurance that the recipient's urea clearance was normal (48). Such a specification was clearly impractical. Moreover, renal function was often sharply reduced in combat casualties, and if they were given gelatin infusions in the amount of 1,000 to 1,500 cc. in the course of a few hours, they would also receive 60-90 gm. of urea, which was obviously undesirable.
At the 14 October 1950 meeting of the Committee on Shock (49), Dr. Ravdin reported on an oxypolygelatin of superior quality which had been prepared in his laboratory. It did not gel at ordinary temperatures, but it gave rise to toxic reactions closely resembling certain reactions to oxalic acid, and he was not prepared to recommend it at this time. A year later, it was still impossible to obtain production of oxypolygelatins of uniform quality. Moreover, the amounts and rates of excretion varied from laboratory to laboratory, one probable reason being the variety of analytic methods in use.
In February 1953, the outlook was even more discouraging (50). Oxvpolygelatin had proved to be antigenic. Its retention in the bloodstream in normotensive patients as well as in bled patients was poorer than that of dextrall or Periston (polyvinylpyrrolidone). If its melting point were lowered by further degradation, its molecular weight would also be so lowered that it would not remain in the circulation long enough to have any effect at all. Moreover, the high initial elevation of the plasma volume achieved by gelatin preparations, followed by the rapid loss of the osmotically active material, might, throw a patient in shock into it very dangerous state. In fact, if hemorrhage were also present, he would be in real jeopardy unless he were given blood or a more effective plasma-expander than gelatin.
It had been brought out, at one of the earlier meetings of the Committee on Blood and Related Problems (49), that gelatin, like other blood substitutes proposed up to that time, lacked the capacity, essential in the management of shock, to transport oxygen. It was also brought out at this meeting that the Armed Forces must not assume that funds were unlimited for studies in all areas. On the contrary, the field must be narrowed to agents of reasonable cost, suitable for stockpiling, whose production could be expedited. In view of these criteria, it seemed to many members of the committee that further investigation of gelatin was not warranted.
In March 1953, it was reported to the Subcommittee on Shock that fluid gelatin had been sent to Korea for a field trial, and it was believed that reports on it would be favorable, since it had been shown to restore blood volume for brief periods (51). On the other hand, the committee noted that, if not more than 35 percent of the blood volume had been lost and if hemorrhage did not continue, the normal homeostatic mechanisms of the body would tend to maintain the restoration, in which gelatin would play no part.
It was decided at this meeting that the investigation of gelatin and oxypolygelatin should be discontinued until a product could be supplied that could be characterized physicochemically; with evidence of reproducibility and stability; and of higher molecular size, so that it would not be excreted at an excessive rate, as were the products then in use. Data on tolerance and toxicity in animals were also desired.
No further reports on gelatin and gelatin products were made to NRC committees during the Korean War.
POLYVINYLPYRROLIDONE (PERISTON, PVP)
Knowledge of polyvinylpyrrolidone, the plasma-expander more commonly known as Periston or PVP, reached the United States during 1943. The Subcommittee on Blood Substitutes conducted a brief investigation on it (p. 380), but it was not used in the U.S. Army during World War II.
This agent was developed in Germany in 1940, when the need was recognized for a colloidal solution for the emergency treatment of shock (52). It was selected from some 30 compounds studied at I. G. Farben Laboratories. When the choice fell upon polyvinyl esters, polyvinyl alcohol polymers were first tested but were discarded when it was found that bone-marrow depression occurred after their repeated injection. When polyvinylpyrrolidone was synthesized from acetylene and ammonia, the polymers formed had molecular weights as high as 150,000 to 200,000.
According to the Germans, whose investigative methods were not considered entirely satisfactory, about 20 percent of Periston was excreted in the urine in the first 3 days. The remaining 80 percent was thought to be phagocytosed after 24 hours, stored in the reticuloendothelial system, and then probably slowly excreted, perhaps in the bile. Qualitative tests indicated that some Periston remained in the tissues for several weeks after injection.
Development in the United States
Periston was first considered in the Subcommittee on Shock on 14 October 1950 (49). Although it had been widely used in Germany during World War II and about half a million cases had since been followed up, not much was known about its use in recent years. Apparently, it caused no lasting damage to the tissues, but no definitive data were available on its course in the body and on the amount that could be tolerated without deposition in the tissues. Some members of the committee considered it worthless. Others took the position that if it had any deleterious effects, they would have been evident, even in the absence of expert observation, because of the large number of cases in which it had been used.
At the 11 December 1950 meeting of the Subcommittee on Shock (39), it was learned that the Schenley Corp. could then import 5,000 to 10,000 bottles of Periston per month from Germany and by July 1951 expected to import an intermediate form that could be processed further in the United States. Other manufacturers were also able to produce Periston.
The Subcommittee on Shock met with the manufacturers and potential manufacturers of Periston on 4 January 1951 (53). A research project had been approved in principle, but, up to this time, no funds had been assigned for it (54). Some companies were making Periston that very closely resembled the German product, but they stated that their progress would be faster if the Army would reach a decision concerning its use. The Food and Drug Administration was prepared to clear Periston as soon as the National Research Council furnished precise data about it and recommended it. The point was again made that the hundreds of thousands of cases in which it had been used in Germany, plus a favorable report made on it by Dr. J. A. Walker, University of Pennsylvania, furnished sufficient basis for recommending it without much further investigation. The Department of Defense, of course, was not in-
terested in putting money into material coming from a source in which resupply was not certain.
At a meeting of the Subcommittee on Shock on 26 September 1951 (55), another study that had been made in Germany was reported. It had showed no deleterious effects, but it was not adequate by United States standards: Pathologic practices were different. Records were not precisely kept. Sections were not studied carefully, and were not preserved.
Late in 1952, the Subcommittee on Shock recommended that Periston produced according to certain specifications should be stockpiled by the Federal Civil Defense Administration but should be used only in emergencies (56). Other recommendations were withheld until the long-term followup studies then in progress had been completed and a more closely fractioned product of suitable molecular weight had become available and been tested. The effectiveness of Periston had been clearly established, but it was stored in the body for undesirably long periods. Followup studies on German children showed no effect on hepatic and renal function, and post mortem studies made up to 14 months after its injection revealed no abnormalities, but the sense of the committee was that the burden of proof still rested on those who claimed that Periston was perfectly safe.
At the February 1953 meeting of the Panel on Plasma Volume Expanders (50), data were reported on 48 German children which brought the total studied to 68. All had been treated with Periston between 1944 and 1948, and none of them showed any abnormalities.
At the meeting just mentioned, Dr. Robert M. Zollinger reported a number of special studies on Periston made in his clinic. All tests were within normal range except that bone abnormalities were observed in 2 (of 18) examinations made on 14 patients. He and his associates were unwilling at this time to attribute these abnormalities to Periston.
Radioactive studies showed that from 95 to 100 percent of injected Periston was excreted via the urine within 72 hours; 40 percent was excreted within 20 minutes. Within 6 hours, virtually all circulating PVP had disappeared from the plasma. Excretion was thus too rapid for Periston to be of value, and it was recommended that general approval of it should be withheld, though again it was given limited approval for stockpiling for use in emergencies if serum albumin and dextran were not available.
On 3 March 1953, a panel discussion at a meeting of the Subcommittee on Shock brought out the following points (51):
At a meeting of the Committee on Blood and Related Problems, also in March 1953 (28), radioautographs were reported on patients who had been given K-30 Periston for 1 or 2 weeks before death. After a year's exposure, the tissues showed no concentration greater than twice what would be expected from uniform distribution in any tissues; the accuracy of this technique did not go beyond this level. Other studies showed that the goals of complete elimination of PNT from the body and adequate plasma volume expansion by its use were not mutually compatible.
At the meeting of the Subcommittee on Shock on 20 May 1953 (57), it was reported that large amounts of Periston had been stockpiled by the Government, but further studies were still considered necessary before it could be recommended for any but emergency use. The Korean War ended before further action was taken on it.
Dextran came to the attention of the Subcommittee on Blood Substitutes, NRC, shortly before World War II ended (p. 381), but no action was taken on it at that time. Some experimental work was done on it in Army hospital laboratories after the war, but it had not been used clinically in the United States when a request for information about it was received from the Food and Drug Administration at the meeting of the Committee on Blood and Blood Derivatives on 3 December 1949 (8), in connection with an application for its import from a Swedish company (Pharmacia).
Composition and Properties
Dextran was developed in Sweden during the early part of World War II and refined to the point at which it found wide clinical acceptance in Scandinavian countries (58). It was made up of a variety of polysaccharides of varying molecular sizes (59). Its production was quite simple. The only materials needed were sucrose and an organic solvent. Fermentation required only a day, and fractionation was not complicated. The chief bottleneck in production was the elimination of pyrogens and testing for sterility.
Smaller molecules of dextran were rapidly lost from the bloodstream, a matter of importance in military medicine, in which a considerable time might elapse between infusions. About half of each dose was accounted for by excretion through the kidneys or the intestinal tract. The fate of the remainder was unknown when the Committee on Blood and Blood Derivatives began to investigate dextran, but it was thought that the larger molecules were probably
deposited in the reticuloendothelial system and that they might be nephrotoxic or hepatotoxic.
The committee, remembering that periods of 5 to 15 years had elapsed before it was found that gum acacia could lead to amylold degeneration, understandably took the position that great, caution should be exercised in recommending dextran: macromolecular substances of this type were known to cause rapid sedimentation of red blood cells as well as a tendency to sludging. It was necessary to consider whether dextran might give rise to breakdown products of hemoglobin, which might be nephrotoxic or hepatotoxic. Finally, it was necessary to investigate the maximum safe dosage and over what period this dosage could safely be administered.
Because of the commercial situation in Sweden, it was difficult to obtain pertinent chemical data on dextran (49), and the British, who were also manufacturing it, did not have the desired information. The only data on molecular size were based on viscosity measurement. Moreover, the clinical studies conducted in Europe had not been carried out with the precision used in such studies in the United States.
Another reason for caution on the part of the Committee was pointed out by Col. (later Brig. Gen.) John R. Wood, MC, at the October 1950 meeting of the Subcommittee on Shock (49): The implications of the decision to use dextran for combat and other casualties would, he pointed out, be far reaching. The adoption of any new technique would commit thousands of medical officers to it, and the recommendation of the Committee would probably be followed also by the civil defense organizations.
Experimental and Clinical Studies
Up to September 1950, the British experience with dextran covered 10,000 540-ml. bottles (25). No untoward effects had been observed, but the rate of excretion via the kidneys had varied widely, from 10 to 50 percent. At the end of 9 months, no dextran had been found in the bodies of rabbits except for slight traces in the lymph nodes and bone marrow. There was no histologic evidence of tissue damage. It was believed that the chief production problem was ridding the dextran of the small molecule, to reduce the rate of excretion.
Up to December 1950, the Swedish experience with dextran had covered 200,000 cases (39). In the 10 years of its use, there had been no post mortem evidence of tissue damage, and reactions were fewer than with the use of either blood or plasma. A compilation of articles from the literature by Pharmacia showed an impressive use of dextran by reliable investigators in Denmark, Finland, and Holland as well as in Sweden.
Between 24 and 69 percent of Swedish-produced dextran was excreted within 24 hours. Its molecular weight ranged from 120,000 to 200,000, against 80,000 to 100,000 for the British product. Swedish dextran was now fairly uniform.
Clinical testing, in the United States during 1950 produced the following data:
At a meeting of the Subcommittee on Shock on 30 January 1951 (52), it was reported that another review of the literature had shown no clinically undesirable renal, hepatic, hematologic, or circulatory changes after the use of dextran. Hemodilution was maintained for at least 6 hours after injection. Between 30 and 50 percent of the injected material was excreted in the urine, but the fate of the remainder was still unknown.
At this meeting a number of clinical reports were made, all to the effect that dextran was of great temporary value. Dr. John S. Lundy, who had had some anaphylactoid reactions with dextran when the material was imported from Sweden and bottled in the United States, had had no difficulty with the total Swedish product.
The single adverse report at this meeting, and at several subsequent meetings, came from Lt. Col. Edwin J. Pulaski, MC, and his group at Brooke General Hospital, San Antonio, Tex., who reported 26 reactions in 105 patients (48, 52, 60), all after the use of Swedish and British dextran. Some of the reactions had been quite severe. A breakdown of the cases showed that four reactions had occurred in 45 anesthetized patients. Seven different lots of Swedish dextran had been used. There were no reactions in patients treated with U.S.-produced dextran, which was now available.
Thirteen ambulatory patients, chiefly Korean veterans, hospitalized at the Forest Glen Section of Walter Reed General Hospital, were given 500-cc. injections of Swedish dextran (Macrodex). All but three had reactions, three of which were moderately severe. The experiment was not considered conclusive. There were no controls, and the patients, who were an in the same ward, were watched over by too many observers amid too much commotion.
Later in the year, 10 volunteers at Brooke General Hospital were studied with fractionated material from a lot of Swedish dextran (55). The observations suggested that the reactions which occurred must be explained by factors other than high molecular weights or aggregates of molecules.
At a Conference on Radioactive Dextran held on 29 August 1951 (61), under the chairmanship of Dr. Ravdin, it was reported that the most precise chemical analyses of excreted dextran had accounted for only 50 percent of the amount injected; all excretion was via the urine. Dextran tagged with
radioactive carbon, prepared by Commercial Solvents Corp., in cooperation with the Argonne National Laboratory, had been distributed to it number of investigators, whose results suggested that 95 percent of the injected material would be either excreted or metabolized. Although the combined studies were limited both in number (three dogs, six rats, four mice) and time (10 days), it was decided to test radioactive dextran clinically without further delay.
At the 13 February 1952 meeting of the Subcommittee on Shock (62), an ad hoc committee, appointed in December 1951, reported that there was no doubt that dextran was antigenic in man and could produce precipitins and skin sensitivity, with the degree of sensitivity apparently unrelated to the occurrence of systemic reactions. All the reactions had occurred in first injections; none had been observed in a limited number of second injections. Immunization apparently played a negative role. Preparations of higher molecular weight seemed to cause more systemic reactions than those of lower weight and also precipitated more antibodies in sensitive subjects (63).
While the studies reported were still incomplete, it seemed to the conferees to be desirable, to minimize reactions, to avoid highly branched dextrans and preparations of high molecular weight. No doubt was felt that reactions to dextran could be extremely dangerous if they occurred in battalion aid stations, where medical supervision might be inadequate. Later, it was recommended that a warning be placed on bottles of dextran that if an anaphylactoid reaction developed, the infusion must be stopped at once and active treatment instituted (64).
At the 1 October 1952 meeting of the Subcommittee on Shock, it was reported that 125 units of dextran had been used in Korea, with good clinical results and no significant reactions (56). A 6-month study had been started in Air Force installations in the United States.
At an ad hoc meeting on dextran fractions on 8 December 1952 (68), it was reported that a fairly large proportion of normal, healthy adults had experienced allergic-type reactions after the use of both British and Swedish dextrans but that the rate with the United States products was very low. It was now possible to define the best possible dextran for mass production. Determination of molecular weight was now quite accurate, and refined analytic methods made it possible to detect even small quantities of dextran in plasma or urine.
Studies on dextran were conducted in Korea in July and August 1952, by members of the surgical research team, on the ground that it was not possible to duplicate total combat situations in the wards and operating rooms of civilian hospitals, or even military hospitals, in the Zone of Interior (65).
During this investigation, 200 500-cc. units of 6 percent dextran were used on 60 patients, 3 suffering from burns and the others from trauma of varying degrees. The total clinical response was excellent. The blood pressure response was most satisfactory. The hematocrit showed a decrease, which was maintained. There were no allergic reactions. One patient received 2,500 cc. of dextran solution in a single day with no ill effects. No
abnormalities were observed at autopsy in the three patients who died. The best tribute to dextran was that the medical officers who used it were uniformly eager for more.
Dextran was used in increasing amounts until the end of' the Korean War. To complete the record, one postwar matter should be mentioned: In September 1953, a hitherto undescribed consequence of dextran injections was reported, a prolongation of the bleeding time, (66, 67). It had occurred in 2 normal subjects at Walter Reed General Hospital, and in 11 other normal subjects observed elsewhere; the product of four manufacturers was involved. These observations were confirmed by a study of 121 normal subjects at Bolling Air Force Base.
The change in the bleeding time occurred within 3 to 9 hours after the dextran had been given. There was usually a return to normal level within 9-4 hours. The amount of dextran that had produced the alteration ranged from 500 cc. in a single dose to 6,500 cc. over a 5-day period. There was no correlation between the maximum prolongation of bleeding time and the maximum expansion of plasma volume.
Recommendation and Production
At one of the first meetings after the outbreak of the Korean War at which dextran was discussed (25), Dr. Ravdin emphasized that in the emergency that existed, this product must be investigated promptly as well as thoroughly. He also stated that the Armed Forces must not rely on commercial firms to provide specifications and standardization.
The first contract for the production of dextran was set up with the Commercial Solvents Corp. (54). In December 1950, this firm reported that it was negotiating with Pharmacia to manufacture dextran under its patents (39). The Schenley Corp., which was also producing dextran, had a similar agreement with a British company. Meantime, Pharmacia had already licensed Refined Syrups and Sugars Corp., whose product would probably be bottled by the Abbott and Cutter Laboratories. The American Sugar Refining Co. was working on a new fractionation method which did not require alcohol and which might prove of great value if alcohol should become in short supply. At the meeting at which these details were reported (Subcommittee on Shock, 11 December 1950), it was recommended that the Department of Defense begin to procure dextran that would meet British and Swedish specifications (39).
Encouraging reports on present and anticipated production were made at a conference on 19 December 1950, under the auspices of the Subcommittee on Shock, which was attended by manufacturers of dextran, including a representative of Pharmacia, drug firms, and other interested parties (68). At this meeting the subcommittee recommended that all dextran produced be labeled For Stocking for Emergency Use.
During the following month, arrangements were made to purchase 50,000 units of Swedish dextran for the Armed Forces, to bridge the gap while U.S. manufacturers were getting into mass production (69).
By the end of 1951, the National Research Council approved the stockpiling of U.S.-produced dextran and the Department of Defense entered into a contract for its production with Commercial Solvents Corp., Terre Haute, Ind. (2). Delivery was delayed because of the necessity of developing large-scale production facilities.
In April 1952, the Medical Policy Council directed that commitments for the procurement of Periston be canceled and the funds allocated to it be diverted to the procurement of additional quantities of dextran (2). By this time, the risk of hepatitis in the use of plasma was fully appreciated.
By the end of September 1952, Commercial Solvents Corp. had delivered 28,588 of the 810,000 units of dextran contracted for. The other three companies with which contracts had been made later had not yet produced anything, but their facilities were about completed and their potential was 3,060,000 units.
Early in 1953, dextran was approved by the Food and Drug Administration, and a larger proportion of the stockpile was set up with it, though the proportion between synthetic and natural plasma-expanders was deliberately kept in balance. Later in the year, the manufacturers made it clear that they were losing interest in the production of dextran, in the absence of definite commitments for its use by military and civilian agencies (67). The concern of the Subcommittee on Shock at this development was duly transmitted to the Office of Defense Mobilization and the Assistant Secretary of Defense for Medical Affairs.
Plastic equipment.-The first attempt to put dextran up in plastic bags was a failure (51). Vapor transfer through the plastic was so great that the dextran crystallized out in the recipient tube. A later attempt was successful (57). The bags, which were tested in Korea and in certain U.S. hospitals, could withstand sterilization temperatures, and long-term storage was apparently possible; they were tested at 60° C., considered equivalent to 2½ years' storage at room temperature. The vapor transfer problem was settled by the use of an aluminum foil barrier.
Two ad hoc Conferences on Fat Emulsions for Intravenous Administration were held during the Korean War, on 24 May 1951 (70) and 19 March 1953 (71). By the time the war broke out, these emulsions had been used extensively enough to establish their clinical value, and it was believed that there was a real need for them to maintain caloric intake in seriously ill and wounded patients. It was true that less than 5 percent of these patients would need
parenteral fat. On the other hand, their needs might be urgent. In Korea, the most imperative nutritional problems were encountered in seriously wounded patients with renal dysfunction and oliguria, in whom it was necessary to limit fluids to 500 cc. per day for about 10 days. During this period, these casualties often lost as much as 45 gm. of nitrogen per day, which was the equivalent of a total 25-pound loss of muscle weight. Wound healing was slow, edema was frequent, and the incidence of wound dehiscence was abnormally high. The desideratum, not yet achieved, was for the development of a pyrogen-free emulsion which would provide from 2,000 to 4,000 calories per day by parenteral administration, in as small a fluid volume as possible.
At the second of these ad hoc conferences, as at the first, there were two chief problems (1) the pyrogenicity of the preparations then available, and (2) their instability. Commercial preparation of consistently safe and satisfactory emulsions could not be expected until a solution was found for these problems. Some of the participants in the discussion thought that if only a fraction of the funds expended in the development of plasma extenders were allotted to this project, results would be prompt and beneficial, but no such allocation was made during the war.
Part VI. Clinical Considerations
THERAPEUTIC PRINCIPLES AND PRACTICES
The principles and practices governing the use of plasma (fig. 190) and albumin (fig. 191) were essentially the same in the Korean War as in World War II. The administration of whole blood also followed the same pattern (figs. 192, 193, 194, and 195) except that intra-arterial transfusion was given a trial.
Historical note.-According to Lewisohn (72), the first recommendation for intra-arterial transfusion, by Huerter in 1871, contained the report of eight cases in which defibrinated blood was injected by this route.. Not much more work was done on the subject until 1937, when Davis (73) showed, in a study of experimental shock, that the intra-arterial injection of sodium chloride solution elevated the blood pressure but that a similar solution, given intravenously, lowered it. Kendrick and Wakim (74) confirmed these observations in dogs in 1939. They also demonstrated that the intra-arterial administration of physiologic salt solution is not a desirable emergency treatment for secondary shock. In spite of the immediate vasopressor response and the maintenance of the elevated blood pressure for a certain period of time, the end result was always severe injury to the recipient.
FIGURE 190.-Administration of plasma in Korea. A. Company aidmen bringing in casualty from combat area forward of machinegun emplacements. Plasma has not yet been started. B. Plasma transfusion during jeep transportation of casualty to hospital, September 1950. C. Continuing administration of plasma to casualty as he is put aboard plane at Taejon Air Base, en route to Itazuke, Japan, July 1950. This particular plane was one of the last to leave the airstrip. D. Continuation of plasma transfusion as seriously wounded U.S. soldier is unloaded from observation plane (L-5), converted to use as one-casualty air ambulance, and moved to conventional ambulance, 2d Infantry Division Airstrip, Korea, August 1950.
FIGURE 191.-Administration of albumin in Korea. A. Preparation of albumin for treatment of casualty, 45th U.S. Infantry Division, near Chorwon, June 1952. B. Administration of albumin to casualty, Model Aid Station, 7th U.S. Infantry Division, preparatory to further evacuation by helicopter, Kunwha, July 1952.
Field studies.-During the Korean War, Maj. Curtis P. Artz, MC, Capt. Yoshio Sako, MC, and Capt. Alvin W. Bronwell, MC, treated eight casualties by the intra-arterial route, the largest amount given being 4,500 cc. of blood (75). The surgeon held the needle in the artery during the transfusion, which was discontinued as soon as the systolic pressure reached 100 mm. Hg.
One of the eight casualties died on the operating table, and three others died within 3½ hours of operation. Although the other four recovered, it was the impression of these observers that casualties given blood by this route showed no appreciably improved response as compared with patients who received blood at a comparable rate under pressure or in multiple veins (fig. 195). One of their patients, for instance, who was almost moribund, recovered after being given 5,500 cc. of blood into two veins through 15-gage needles in 30 minutes; 3,500 cc. of blood was pumped into one vein in 21 minutes.
Experimental studies by Major Artz and his group also failed to indicate any superiority of the intra-arterial over the intravenous route. Since the experimental data coincided with clinical impressions derived from the small groups of cases just described, this method of administration was discontinued in favor of rapid intravenous injection of blood through multiple large-gage needles or intravenous cannulas.
FIGURE 193.-Administration of blood in Korea. A. Near Uijong, April 1951. B. Before evacuation to battalion aid station behind front-lines. C. On pod of helicopter during evacuation from 44th General Hospital, October 1953.
Conclusions.-Intra-arterial transfusion was discussed in detail at a conference at Walter Reed Army Medical Center on 11 June 1953 (76). It was found, in extensive experimental studies, that there was no significant difference in survival rates in experimental and control series, and no significant difference in the effectiveness of intra-arterial and intravenous administration of blood. All studies pointed to the conclusion that it was the rate of transfusion, not the route, that was the important factor.
In the general discussion that followed this presentation, Brig. Gen. Sam F. Seeley, then Chief of Surgery, Walter Reed General Hospital, stated that, provided that an adequate amount of blood was given rapidly, the technique of transfusion probably made little difference as long as cardiac action was still present. In deep shock, it was often mechanically difficult to introduce blood
into a vein, but always quite easy to make a femoral arterial puncture. He also pointed out that a certain number of casualties could be expected to die from the severity of their injuries, even if they received preferential intra-arterial transfusion.
Other participants in the discussion took the position that intra-arterial transfusion is an extremely dangerous technique; cases were cited in which complete gangrene of the hand, requiring amputation, had followed its use (72). Others, however, in spite of the risk of ischemia, believed that in strictly qualified circumstances intra-arterial transfusion might be justified.
Surgical Research Team
The request of the World War II Subcommittee on Blood Substitutes, Division of Medical Sciences, NRC, to send a team of observers to oversea theaters was never granted (p. 79). The question of sending such a team to Korea was brought up at the second meeting of the Subcommittee on Shock, Committee on Surgery, on 2 November 1950 (54), and several times thereafter until such a team was sent to the Far East in December 1951 (65). The
9 December 1952 meeting of the subcommittee was devoted chiefly to progress reports from the team (64).
The Surgical Research Team was organized by the Army Medical Service Graduate School and the Army Medical Research and Development Board, which appointed personnel, set policies, established techniques, provided consultants, and furnished nonstandard supplies.
In Japan, the team was attached to the Far East Research Unit (406th Medical General Laboratory) in Tokyo for administrative purposes. Here, additional personnel, including consultants, were provided, and supplies available on the Japanese market were obtained. In Korea, the team was attached to the 11th Evacuation Hospital and the 8209th MASH (Mobile Army Surgical Hospital) for standard supplies, day-by-day assistance, and the provision of clinical opportunities.
The principal problems related to blood which were encountered by the team were as follows:
The special studies on blood were made by Lt. Col. William H. Crosby, MC; Capt. John M. Howard, MC; and Lt. Col. Joseph H. Akeroyd, MSC (77-79).
General considerations.-When the Surgical Research Team reached the Far East in December 1951, it found blood plentiful in U.S. Army hospitals, as it had been all during the past year. The only blood available in ROK Army hospitals was the amounts occasionally provided by U.S. units (p. 803). The O blood used was now available between 12 and 14 days after collection, instead of 21 to 28 days as originally. Massive and repeated transfusions were given with few reactions, and there were no records of deaths attributable to the use of blood.
A special investigation showed that transportation of blood over the thousands of miles between the United States and Korea had only minor effects on it. Generally, it arrived at forward hospitals in an excellent state of preservation. In 300 pints examined at random, it was found that less than a quarter of 1 percent of the red blood cells had been lost, and, when the blood was transfused, few red cells were found nonviable. The plasma hemoglobin rose from about 50 mg. percent on the 10th day after collection to 100 mg. percent on the 28th day. Harmful amounts of hemoglobin were not released into the recipient's plasma from the transfused blood. Abnormally high plasma potassium was not encountered during or after massive transfusions unless renal failure was also present. The plasma potassium level of bottled blood was apparently a straight line function of time, the concentration increasing at the
rate of approximately 1 milliequivalent per day. The osmotic fragility of the red cells showed few changes during the first 2 weeks after collection. Then it rose sharply, suggesting the desirability, whenever practical, of using blood within the first 14 days after it had been drawn. All the evidence indicated that the use of properly stored blood had only beneficial effects; few if any deleterious effects were observed even when as much as 20 to 30 pints were given in less than 6 hours.
Continuous refrigeration, at temperatures of 0° to 10° C., was absolutely essential to the safe preservation of blood. If refrigeration were omitted, even for brief periods, irreversible changes occurred in the red cells. They might not hemolyze spontaneously in the bottle, but they did not survive after transfusion.
Reactions and sequelae.-Reactions were remarkably infrequent. In 1,620 transfusions observed at the 46th Army Surgical Hospital (8209th MASH), there were only four urticarial reactions and no reactions due to incompatibility. Several hemoclastic reactions were considered as caused by gross contamination of the bloodstream from the sites of wounds or from the peritoneal cavity.
The practice of using O blood for massive transfusions of non-O recipients did not seem harmful provided that so-called dangerous universal donors were avoided. These donors, who are extremely uncommon, have plasma that contains a high titer of anti-A antibodies, which can produce an unmistakable hemolytic transfusion reaction, with all the signs associated with major incompatibility. Some of the recipient's own red blood cells might be eliminated by antibodies in plasma from these donors, though there is no clinical evidence of this phenomenon.
Casualties who received multiple transfusions over long periods of time tended to develop greater sensitivity to pyrogens. This observation, first recorded in 1951 (79), was never explained.9
These same casualties were also prone to develop hemosiderosis because of the excess iron deposited after increased erythrocytic destruction. It was suggested, with the fear of hemochromatosis in mind, that if these patients developed resistant chronic anemias, whole blood and red blood cells should be used as sparingly as the circumstances justified.
Patients who received more than 15 pints of blood often showed a tendency to ooze from cut surfaces. The condition regressed quickly, without treatment.
A patient in shock, who had been given a transfusion in excess of the normal capacity of his circulatory system, sometimes developed polycythemia. In such cases, the excess blood was apparently carried in the dilated vessels of the skeletal muscles, liver, and lungs. So-called overtransfusion, which was sometimes employed in severe shock, was surprisingly well tolerated.
Hematologic response.-A battery of hematologic studies was carried out on 37 of the casualties received at the 46th Army Surgical Hospital, located several miles behind the infantry division that it supported, between October 1952 and January 1953. Between 2 and 42 transfusions were used in each case. The plasma hemoglobin was determined in 300 of the units used. Particular attention was paid to the results of storage of blood (high plasma hemoglobin and potassium, low labile factor activity, nonviable platelets and leukocytes). As already mentioned, changes in stored blood were slight and innocuous.
The important observations made in this study were as follows:
1. At the time of resuscitation and shortly thereafter, there was a remark able loss of circulating red blood cell mass in casualties with wounds associated with considerable tissue destruction. The loss was thought to be caused by hemolysis, though the exact mechanism was not determined. The loss of red cells was sometimes so rapid that a casualty with bilateral traumatic amputation of both legs, even if hemostasis was adequate, might become severely anemic if there was any hesitation in using massive, rapid transfusions. Shock associated with wounds which involved less tissue destruction, such as lacerations of the colon, did not destroy red cells in this fashion. After moderate transfusions, these patients often became polycythemic, and transfusions had to be carried out "rather gingerly," because of the tendency for signs of congestion to appear.
2. During the early period of recuperation from severe wounds, casualties tended to become anemic, apparently as the result of hemolytic processes plus a relative inhibition of red cell formation.
3. A particularly striking observation was that in patients not in group O, massive transfusions of O blood resulted in the virtual replacement of the recipient's cells by cells of the O group. His plasma sometimes contained antibodies against red cells of his own hereditary blood group. Gradual hemolysis of native red cells by transfused antibodies was observed, but the hemolytic process was not evident clinically and did not appear to harm the patient. The presence of foreign antibodies, however, sometimes made it impossible to crossmatch the patient with blood of his hereditary group, and it was believed that transfusions with the hereditary type of blood might be dangerous. Severe reactions, in fact, sometimes occurred when type-specific blood was given after large transfusions of O blood. In the light of this new observation, it was recommended that, after transfusions of universal donor blood had been given, no change should be made to blood of another group until at least 2 weeks had elapsed.
Immunohematologic response.-Another special study by Colonel Crosby and his associates was an investigation of 25 casualties from the standpoint of the immunohematologic results of large transfusions of group O blood in recipients of other blood groups. These patients were all received by ambulance or helicopter between 1 and 3 hours after wounding. Transfusions
of plasma or whole blood had often been begun at battalion aid stations and they were continued during evacuation, and, as needed, through resuscitation and operation. Some patients received as much as 37 pints of blood within 12 hours. One or two received 20 pints within an hour. Most of the blood transfused was used before the 15th day, and none was used after the 21st day, of shelf life. All the blood was group O, all was Rh-positive, and all was used without crossmatching. It was tested for the high titer isoagglutinins active against group A and group B red blood cells.
The important observations made in this study were as follows:
1. After large transfusions of low titer group O blood into patients of groups A, B, and AB, it was not possible to demonstrate foreign isohemolysins or incomplete antibodies in the recipient serum. Cold isoagglutinins were frequently evident immediately after the transfusion, but they usually disappeared rapidly. In several patients, the titer of foreign anti-A isoagglutinins was quite high, and the antibody persisted in the circulation for several days. A possible explanation was the relatively small amount of A substance in the recipient's blood; when the transfused isoagglutinins were found persistent, the patients usually proved to be weak secretors of A substance in the saliva, or complete nonsecretors.
2. In most of these patients there was evidence of selective destruction of recipient red blood cells after the transfusion of O blood, probably as the result of activity of transfused isoantibodies in the plasma of the transfused blood. The hemolytic activity was observed in cases in which it was not possible to demonstrate the presence of foreign isoantibodies. It was postulated that forms of antibodies might exist that could not be demonstrated by available methods and that manifested themselves only by causing destruction of red blood cells.
3. Clinically, as already mentioned, the hemolytic, process originating from such transfused isoantibodies, while it caused destruction of native red cells, did not threaten the lives or impede the recovery of these patients. No reactions, in fact, were encountered or heard of in Korea that might have been ascribed to so-called dangerous universal donors. In practice, the division of group O blood into high and low titer, on the basis of dilution of 1:200 to 1:256, proved perfectly safe.
1. Minutes, meeting of Subcommittee on Shock, Committee on Surgery,
Division of Medical Sciences, NRC, 14 Nov. 1951.
6. Memorandum, Rear Adm. M. L. Ring, SC, USN, for Director for Military
Programs, Munitions Board (attention: Chief, Office of Programs Coordination),
7 Apr. 1950, subject: Proposed Program of Whole Blood and Blood Derivatives
for the Armed Forces.
31. Oliphant, J. W., and Hollander, A.: Homologous Serum Jaundice. Experimental
Irradiation of Etiologic Agent in Serum by Ultraviolet Irradiation. Pub.
Health Rep. 61: 398-602, 26 Apr. 1946.
55. Minutes, meeting of Subcommittee on Shock, Committee on Surgery,
Division of Medical Sciences, NRC, 26 Sept. 1951.
78. Crosby, Lt. Col. William H., MC, and Howard, Capt. John M., MC:
The Hematologic Response to Wounding and to Resuscitation Accomplished
by Large Transfusions of Stored Blood. A Study of Battle Casualties in