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Chapter XIV

Contents

CHAPTER XIV

Blood Substitutes and Other Intravenous Fluids

Part I. Blood Substitutes

GENERAL CONSIDERATIONS

Historical Note

A considerable amount of basic research was carried out on so-called blood substitutes1 in World War I, during which the use of blood was an occasional rather than a general procedure. The Committee on Surgical Shock and Allied Conditions, established by the Medical Research Committee of Great Britain, made comprehensive studies on suitable crystalloid and colloid solutions to correct the physiologic alterations that occur in shock, and similar studies were made in the United States (1). By the end of the war, two important, if negative, facts had been established:

1. Experimental studies on crystalloid solutions showed that they were too readily diffusible to be useful in elevating a decreased blood volume and maintaining it at an adequate level. Clinical experience confirmed the experimental data.

2. There was an obvious need for a macromolecular substance that could be used in solution to provide an intravascular osmotic effect sufficient to maintain an adequate plasma volume. Gum acacia, which was studied extensively for this purpose (p. 384), proved to have two serious defects, that it caused toxic reactions and that it was stored in the tissues.

Policies of National Research Council

Gum acacia continued to be used in replacement therapy by a number of observers, particularly Dr. John S. Lundy at the Mayo Clinic, after World War I, but its use had been generally abandoned long before World War II broke out. It was logical, therefore, that at the first meeting of the Committee on Transfusions, on 31 May 1940 (2), one of the committee functions should be listed as the development of possible substitutes for human plasma or the possible synthesis of plasma.

1Although the term, "blood substitutes," was dignified during World War II by being used in the designation of one of the most active and most useful groups of the National Research Council (the Subcommittee on Blood Substitutes, Committee on Transfusions), it was little more than an example of wishful thinking. No blood substitutes existed when the nomenclature was first employed, and no thinking person really expected that any would be devised. A more correct term, "plasma expanders," came into use after World War II, and, in official documents, the still more accurate- though very cumbersome-term, "plasma substitutes not derived from human blood," was employed. As a convenience, however, the term "blood substitutes" has persisted, and, for this reason, it is frequently used in this volume.


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The search continued throughout the war, for the fundamental reason that, in spite of the success of the plasma program, the requirements for replacement fluids were likely to prove considerably in excess of the amount of blood contributed. The search for effective, nontoxic blood substitutes, nonhuman in origin, therefore had to be expedited. At the meeting of the Subcommittee on Blood Substitutes on 13 May 1943 (3), at which these views were expressed, it was reported that Dr. Alfred N. Richards, Chairman, Committee on Medical Research, NRC (National Research Council), had indicated the agreement of his committee with this point of view. Projects related to the search for blood substitutes would be considered urgent; it was fully understood that they would be long term and more or less speculative. It was agreed that, as far as was practical, these studies should be integrated with the studies of the groups working on experimental and clinical shock.

A really urgent need for blood substitutes never arose in World War II because of the generous donations of whole blood; rapid advances in the processing of blood into plasma; and similar advances in the fractionation of plasma and the development of some of its derivatives, particularly serum albumin. Extensive research was continued, however, and considerable experience was gathered, particularly in the use of gelatin, which proved the safest and most effective of the agents investigated.

The results of the various studies are summarized briefly in the following pages. Readers who wish further details are referred to the minutes of the Subcommittee on Blood Substitutes, its ad hoc committees, and the various conferences on special subjects.

Criteria

In one respect, the investigation into gelatin as a blood substitute was duplicated in investigations into most other substances: At the 20 October 1942 meeting of the Subcommittee on Blood Substitutes (4), Dr. Robert F. Loeb reported that most applications for research studies revealed incomplete knowledge of the problems involved and were notably lacking in tests for toxicity as well as in reports of clinical testing. Such tests as had been carried out were fragmentary.

At the First Conference on Gelatin on 10 November 1942 (5), Dr. Loeb pointed out to the participants that the experience of the Subcommittee on Blood Substitutes to date had been such that "certain criteria had come to be recognized as the sine qua non for any substance to be seriously considered for the treatment of shock in human beings." These criteria were:

1. The colloidal osmotic pressure of the substance in question must be equivalent to that of normal blood plasma.

2. The substance must be capable of production with a constant and reproducible composition.

3. The mode of preparation must be such as to exclude or eliminate pyrogens.


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4. The viscosity of the substance must be such as to permit easy intravenous administration.

5. Its stability must be such that it could withstand the wide ranges of temperature encountered in a global war. Also, it must remain stable for long periods of time.

6. It must be easily sterilized.

7. It must not be toxic. It must not cause leukocytosis, hemolysis, or an increase in the sedimentation rate. It must be either utilized in the body or readily eliminated from it. It must not be stored in the liver, adrenal glands, spleen, brain, or any other organ.

8. Its repeated injection into human beings must not provoke sensitivity.

In addition to these criteria, Dr. Loeb mentioned two other considerations which would affect the decision to develop and use a blood substitute:

1. During the war, ease of production and accessibility of source materials were obviously of great importance.

2. The ability to manufacture or process any substance under aseptic conditions might conceivably have considerable bearing on the decision to develop it, since the introduction of bacteria might lead to the production of toxins or antigens.

GELATIN

Initial Suggestions

Gelatin was first mentioned as a possible blood substitute at the meeting of the Subcommittee on Blood Substitutes on 10 March 1942 (6). The principal reason for the suggestion was that a 6-percent solution had been found to have the viscosity of whole blood at room temperature and an oncotic (osmotic) pressure of 65 mm. H2O. Also, allergists had used gelatin for years as an injection vehicle and there was ample proof that it was not antigenic.

At the 20 October 1942 meeting of the subcommittee (4), Dr. Loeb proposed a meeting of all groups interested in research on gelatin, so that research workers could present their studies to members of the subcommittee and could be made aware of the problems that must be solved before gelatin could be recommended as a blood substitute. He also stated that he had interviewed a manufacturer of gelatin, who viewed with alarm the proposal to inject this substance into human beings, chiefly because it was impossible to manufacture a product of entirely uniform quality.

November 1942

At the First Conference on Gelatin on 10 November 1942 (5), the following data were brought out in reports by various investigators:

1. In general, no toxic effects were observed from injections of gelatin. The temperature elevations occasionally noted in both clinical and experimental studies were believed to be caused by pyrogens or by the specific dynamic action of a readily available protein.


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2. Studies at the University of Louisville School of Medicine showed that gelatin satisfactorily restored the blood pressure of animals in shock, and that they withstood second hemorrhages as well as dogs resuscitated with whole blood. Studies at the Bowman-Gray School of Medicine, however, showed that the blood pressure was frequently not restored completely, and that most of the animals died when shock was produced by the Blalock clamp. Some observers found gelatin lifesaving in slow hemorrhage.

3. There was no evidence of storage of gelatin in the tissues in animals studied at autopsy, sometimes as long as 103 days after injection.

4. Excretion of gelatin via the urine was not attended with oliguria.

5. Reinjection experiments confirmed the prevailing opinion that gelatin was not antigenic.

6. Hemodilution was usually evident after injection.

7. A controlled study of burn shock in dogs showed gelatin solutions effective in compensating for the loss of plasma and maintaining survival beyond the period death might be expected from that cause.

8. In vitro, gelatin produced marked conglutination and acceleration of sedimentation of erythrocytes, though neither phenomenon was observed in experimental animals.

At this conference, it was reported that various gelatin preparations had retained their stability for several months at 37° F. (3° C.). Dr. Samuel E. Sheppard, of the Eastman Kodak Co., reported perfection of a process of fractionation of gelatin that eliminated the products of lower molecular weight and resulted in gelatins of higher and more uniform molecular sizes. The studies were made by a precision viscometric control device.

Also at this conference, Mr. Joseph H. Cohen, president of the Edible Gelatin Manufacturers' Research Society of America, discussed the production of gelatin for medical purposes. As it was often produced commercially in 1-ton lots, it was a heterogeneous substance, and no factory controls existed to insure a uniform product for intravenous injection. If a special gelatin, of a specified uniform quality, were required for military purposes, it would be advisable to set up a pilot plant in which the entire manufacturing process could be subjected to biologic and other laboratory controls.

At the meeting of the Subcommittee on Blood Substitutes immediately after this conference (7), there was a full discussion of the need for a gelatin of uniform quality with which all experiments could be conducted. Dr. Loeb appointed Dr. Edwin J. Cohn and Dr. Sheppard to draw up specifications for such a preparation.

These specifications were presented at the meeting of the subcommittee on 15 December 1942 (8). They concerned the source of the material, methods of processing it, molecular homogeneity (size and shape), hydrolytic control, viscosity, colloid osmotic pressure, and pH.

February 1943

At the Second Conference on Gelatin on 23 February 1943 (9), much of the discussion still concerned the production of a uniform product, pyrogen-free,


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stable, and without the property of causing clumping of erythrocytes. It was noted that the presence of pyrogens might be due not to the product but to the use of water that was not pyrogen-free, a point laboratory workers were remarkably prone to overlook (p. 651).

At the conclusion of this conference, Dr. Loeb asked for a show of hands to determine who, at this time, would be willing to recommend to the Subcommittee on Blood Substitutes that it recommend to the Armed Forces that gelatin be used as a blood substitute. No hands were raised.

September 1943

At the Third Conference on Gelatin (10), it was again necessary to point out that the reports made were not directly comparable because the preparations of gelatin used were in various stages of degradation and because the variables introduced modified the results. Some progress, however, had been made. It was now evident that gelatin could be prepared in solutions that were not pyrogenic for man, that were not toxic, and that were physiologically active. The most urgent requirement at this time was considered to be a clinical comparison of the gelatins made by the Knox Gelatin Co. and the Upjohn Laboratories. Dr. Cohn believed that the largest molecule consistent with stability should be used.

The following resolutions were passed:

1. That the Subcommittee on Blood Substitutes recommend to the Committee on Medical Research that comparative studies of gelatin solutions with different physicochemical characteristics be made in various types of injury by physiologic and clinical groups.

2. That solutions degraded as little as possible be compared with those degraded to the point at which their loss from the bloodstream was relatively rapid, with special attention to deposition and excretion of the gelatin and sedimentation of red blood cells as well as to the therapeutic effects achieved. It was admitted that the accomplishment of fluidity and stability compatible with military conditions would probably be difficult.

3. That the subcommittee recommend to the Chairman, Division of Medical Sciences, NRC, that the Pure Food and Drug Administration be informed of the conferences held on gelatin (and pectin) as replacement agents.

November 1943

At the subcommittee meeting on 17 November 1943 (11), it was reported that tests with the Upjohn Co. product had been carried out on Welfare Island volunteers. No toxic reactions had followed the injection of 5-percent solution in amounts up to 1,000 cc. Fifty percent of the amount injected was eliminated in the urine within 24 hours. Dr. Owen H. Wangensteen had injected 10 patients with the same preparation, with one reaction. All products used had caused conglutination, but when the gelatin was made up in solutions without electrolytes, pseudoagglutination had not occurred.


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December 1943

At the 1 December 1943 meeting of the Subcommittee on Shock (12), Dr. John S. Lockwood, University of Pennsylvania School of Medicine, made a comprehensive report on the use of gelatin in shock:

1. The effectiveness of physiologic salt solution in shock is definitely enhanced by the addition of 4- to 6-percent of nonantigenic, nonpyrogenic gelatin. The resulting solution seems entirely adequate to restore circulating blood volume and maintain colloid osmotic pressure, even when hemorrhage has been massive and repeated. When gelatin is used, the volume of blood which can be withdrawn is limited in repeated hemorrhages only by the need for red blood cells.

2. Experimental studies with a carefully determined tolerated blood loss (blood pressure below 20 mm. Hg) and immediate replacement with plasma, gelatin, or saline solution were repeated an hour later, with survival of all the animals. After the third hemorrhage, another hour later, the amount of red blood cell depletion was so great that death occurred within an hour unless red blood cells were administered with the fluid replacement. All the animals survived when their red cells were replaced after the third hemorrhage. After gelatin infusion, the volume of blood that could be withdrawn on the second and third hemorrhages was twice as great as with saline solution and half as great again as with plasma.

3. Since the 4-percent gelatin solution developed a colloid osmotic pressure 50 percent greater than that of plasma, it produced hemodilution more rapidly. Because of the rapid hemodilution, the tolerated bleeding volume of the gelatin-treated animal was greater on the second and third hemorrhages than that of the plasma-treated animal. Blood pressure was as well maintained after gelatin infusion as after plasma replacement.

When a critical level of hypotension was prolonged, as in graduated blood withdrawal, factors other than simple maintenance of colloid osmotic pressure entered the picture, and gelatin was apparently less effective than plasma in achieving permanent survival.

Clinical tests at the Hospital of the University of Pennsylvania covered 103 infusions of 100 liters of gelatin solution to 62 patients. There were no toxic reactions. Three patients in the group who were in shock received only gelatin infusions; they recovered without incident.

April 1944

Continued favorable reports on the use of gelatin in shock at succeeding meetings (13-15) led to the adoption of the following resolution at the 21 April 1944 meeting of the Subcommittee on Blood Substitutes (16):

That the Subcommittee on Blood Substitutes has agreed on the publication of a statement on its evaluation of studies on gelatin preparations for intravenous use. It does this to make available its conclusions regarding the proper use and the limitations of gelatin and at the same time to make it clear that the preparation and use of gelatin in no way decreases the need for the procurement of blood by the American Red Cross and the preparation from it of blood substitutes for the Armed Forces. The above statements are limited to gelatin solutions specifically prepared for intravenous use. Such solutions should be prepared only in specially constructed plants under the most rigid physicochemical and biological control.

The statement in question covered:

1. The chemical composition of gelatin and its degradation.


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2. Its physiologic and clinical properties. At this time, the solution considered of optimal value in the treatment of hemorrhage and shock was a 6-percent solution, in physiologic salt solution, with the general physicochemical characteristics of what was known as the Knox P-20 type.

3. The limitations of gelatin as a replacement agent and the unanswered questions concerning it, which included the following:

a. Solutions of gelatin gel at about 68° F. (20° C.) and therefore cannot be used in the field in cool or temperate climates.

b. The optimal solution of gelatin presently available shows slow but definite and continued degradation at temperatures encountered in certain theaters of operation.

c. The viscosity of the optimal solution of gelatin is greater than that of whole blood.

d. The proper typing of blood after the administration of gelatin solutions requires further study. It may be well to issue the warning that a sample for typing must be withdrawn before gelatin is administered.

e. It is not known whether the optimal solution will impair the return of normal function to kidneys in sustained ischemia, severe burns, or the crush syndrome.

f. Gelatin solutions probably do not contribute significantly to nutrition. Their only place in medical therapy would be to restore circulating blood volume depleted in various types of acute injury.

g. The influence of gelatin upon the equilibrium in the distribution of plasma proteins between the circulating blood and the tissues requires further investigation.

End of Investigation

The only other significant investigation of gelatin during World War II concerned the abolition of rouleaux formation by the addition of glycine (0.28 molar) to the cell suspension. This observation, originally reported by Dr. Johannes Vogelaar (17), New York City Cancer Institute, Welfare Island, N.Y., was confirmed by studies at the University of Pennsylvania School of Medicine and at the Harvard laboratory (13).

The ample supplies of blood, plasma, and albumin available during the last year of World War II made it unnecessary to carry out further studies with gelatin. The investigation was revived when the Korean War broke out (p. 786).

PECTIN

At the Conference on Pectin on 24 February 1943 (18), it was noted in one of the reports that the intravenous use of pectin sols was first discussed by Feissly in 1925 and that, to date, 22 articles on the subject, covering some 500 clinical cases, had appeared in the literature. Much of this work had been done by Hartman and his associates at the Henry Ford Hospital. No thrombosis or other ill effects had been reported.

Experimental Studies

It was also pointed out at this conference that pectin was defined in the seventh edition of the National Formulary as "a purified carbohydrate product obtained from dilute acid extract of the inner portion of the rind of citrus fruits


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or from apple pomance. It consists chiefly of partially methoxylated polygalacturonic acids."

The proposal that pectin be studied as a possible blood substitute was made to Dr. Loeb on 6 October 1941, in a letter from Dr. Richard M. Johnson, Medical Director, Frederick Stearns & Co. At the meeting of the Subcommittee on Blood Substitutes on 3 November 1941 (19), Dr. Loeb stated, as the result of his survey to date, that he considered all studies on pectin up to this time to be unsatisfactory in respect to the toxicity factor. Dr. Cohn found no evidence in the material submitted to him for examination to indicate that pectin was not antigenic. It was emphasized that all reports must state the method of preparation and the approximate composition of the pectin used.

At this conference, representatives of the Research Department, California Fruit Growers Exchange, stated that for the previous 4 years the possible medical use of pectin had been studied under their auspices in a total of 776 experimental animals, as follows:

1. From 30 to 50 percent of the pectin injected was recovered from the urine within the first 24 hours after injection and from 45 to 60 percent within 6 days.

2. From 80 to 85 percent of the injected pectin was found in the blood 20 minutes after the injection, about 19 percent in 24 hours, and about 10 percent in 48 hours.

3. No significant changes were noted in the coagulation time after the injection.

4. After massive injections, no deposits of pectin were found in the liver, kidneys, and spleen on chemical examination, and the weights of these organs were comparatively normal.

5. Animals given injections every other day for 6 weeks maintained their normal weight and appetite.

These investigators pointed out that pectin occurs along with cellulose in the white inner portion of the rind of citrus fruit (albedo). The blood from a million donors would produce plasma equivalent in volume to 2.0 percent pectin sols made from only about 11,000 pounds of purified pectin, an amount that could be made in a few weeks. In view of this prospect, and because of the emergency, further studies with pectin were considered justified.

A number of reports on pectin were made at the February 1943 conference, but they were extremely disorganized. The criteria for blood substitutes developed by the subcommittee (p. 372) were presented to the investigators, and they were told that some investigations, notably that on gelatin, had made great progress because these criteria had been observed. It was emphasized that the first problem in the investigation of pectin was to secure samples for physicochemical analysis; measurement of osmotic pressure in an osmometer did not give a satisfactory idea of the size of molecules or molecular aggregates. When the Subcommittee on Blood Substitutes met on 17 November 1943 (11), Dr. Loeb reported that, although testing facilities for physicochemical studies of pectin had first been offered in February 1942, no samples had yet been submitted by any workers. Cutter Laboratories, however, had discontinued the distribution of its pectin until the lots produced had been evaluated at the Massachusetts Institute of Technology.


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Solutions of pectin made up by the Hartman technique and by the technique used at the Cutter Laboratories were studied under the direction of Dr. Loeb. In the course of the investigation, he expressed himself as skeptical of the value of this agent except, possibly, as a capillary cement; on the basis of present evidence, he doubted that it had any place in medicine. When the final report was made in April 1942, it was Dr. Loeb's conclusion that the osmotic pressure of pectin solutions was inadequate and that they were no more effectual than salt solution (14).

Clinical Studies

Investigators at the University of Illinois College of Medicine and at the Henry Ford Hospital were convinced, from clinical experience, of the value of pectin, though not many of the patients they had tested were in shock (18). A similar study at Cook County Hospital was not impressive. A later report from the same hospital, by Dr. Hans Popper, made it clear that it would not be safe to recommend pectin as a blood substitute to the Armed Forces (20).

OTHER BLOOD SUBSTITUTES

Little or no progress was made on other blood substitutes during World War II.

Isinglass.-Isinglass (fish gelatin) was studied both clinically and experimentally under the auspices of the Canadian National Research Council. It was discussed at numerous meetings of the Subcommittee on Blood Substitutes, but no formal studies with it were made beyond an investigation of its physicochemical properties in the Harvard laboratory (3, 5, 6, 10, 11, 16, 21, 22).

Glutamyl polypeptide -Glutamyl polypeptide (d (-)-glutamic acid polypeptide) was prepared by Dr. Maxwell Bovarnick, at the Albany Hospital, who found that it could be isolated in large quantities from cultures of Bacillus subtilis and obtained in pure form by copper precipitation (23). When it was discussed for the first time by the Subcommittee on Blood Substitutes on 20 October 1942 (4), Dr. Cohn stated that it was the most promising blood substitute suggested in some time. Further investigation, unfortunately, did not bear out its early promise (24, 25).

Aldobionic acid -Aldobionic acid was discussed as a blood substitute at the meeting of the Subcommittee on Blood Substitutes on 10 November 1942 (7). It was prepared by treating cotton with nitrogen peroxide. It had a highly effective osmotic pressure. Injection into rabbits produced hemodilution; afterward, a certain amount of the substance appeared in the urine as sugar.

In the discussion, Dr. Alphonse R. Dochez pointed out that bacterial polysaccharides such as aldobionic acid were not in themselves antigenic, but,


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when they became congested in the body, they might serve as antigens. Dr. Cohn did not think this new agent should be rejected without further investigation, since a whole series of chainlike polymers could probably be broken down to molecules of a size that would produce effective osmotic pressures.

No further study was made of this agent.

Oxidized cotton -Experiments at the College of Physicians and Surgeons, Columbia University, indicated that when cotton was oxidized with nitrogen tetroxide, it became soluble in bicarbonate solutions and exerted a high osmotic pressure (8). Some hemodilution apparently occurred after injections of solutions of relatively high osmotic pressure. Studies on six rabbits had shown it to be nonanaphylactogenic but moderately pyrogenic. Large amounts were tolerated when they were given in repeated small injections. The single animal that died had had 50 cc. of 4-percent solution; no pathologic changes were found to explain the death. When the other five animals were sacrificed, the only significant findings were swelling and vacuolization of the convoluted tubules of the kidneys.

Oxidized cotton appeared unchanged in the urine within 3 hours after injection. Within 24 hours, 80 percent or more had left the bloodstream. In vitro studies showed no changes in the hemoglobin, the red blood cell and platelet counts, the sedimentation rate, and blood agglutination. There was a moderate drop in the hematocrit and a slight increase in the venous clotting time.

It was thought that it might be possible to prepare oxidized cotton with a lower carboxyl content and, presumably, a higher molecular weight, that would pass through the kidneys less rapidly and be effective in the bloodstream for a longer time. No further action, however, was taken.

Alginic acid.-The Subcommittee on Blood Substitutes did not follow up a suggestion that alginic acid prepared from kelp might be a satisfactory blood substitute (7).

Amino acids -The suggestion that nitrogen lost in shock be replaced by intravenous injections of solutions of pure amino acids was based on the observation that urinary nitrogen is increased in shock (7). In the discussion, however, it was brought out that the loss is no greater than occurs in an upper respiratory infection with fever, when no such therapy would be contemplated (25). It was the consensus of the Subcommittee on Blood Substitutes both times the proposal was brought up that the method might be applicable in prolonged protein starvation but had no place in the management of shock.

Sodium glycerol polysuccinate.-Studies on dogs and mice at the College of Physicians and Surgeons, Columbia University, with sodium glycerol polysuccinate showed no toxic reactions in the animals tested and no pathologic changes at autopsy but also held no promise for its use in shock (26).

Periston.-Periston (polyvinylpyrrolidone), the proprietary preparation used by the Germans in World War II, was first mentioned at the 13 May


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1943 meeting of the Subcommittee on Blood Substitutes (3), in a letter from England calling attention to its description in a German medical journal. The previous experience in the United States with vinyl derivatives suggested that this one would not be particularly helpful.

At the 28 July 1943 Conference of the Albumin and By-Products Group (27), a bottle of Periston (Blutflüssigkeitersatz) that had been captured in Tunisia, with other German medical material, was exhibited, and arrangements were made for various studies to be conducted on it. These studies were reported at the 24 September 1943 meeting of the Subcommittee on Blood Substitutes, as follows (28):

Dr. Orville T. Bailey's anaphylaxis studies were entirely negative, both in vivo and at autopsy. His toxicity experiments revealed gross pathologic changes in the spleen (splenomegaly) and, on microscopic examination, very active hematopoiesis throughout the splenic sinusoids. These changes were described as the type to be expected in severe bone marrow damage, though sections from several bones showed no changes in the marrow. Autopsy also revealed changes in the liver that were apparently progressive, even after treatment had been discontinued. The pathogenesis and significance of the hepatic and splenic changes were difficult to evaluate.

At this same meeting of the subcommittee, Dr. George Scatchard and his associates at the Massachusetts Institute of Technology described the physical properties of Periston as follows:

1. The material is a colorless solution with a pH of 7.2, containing about 2.45 gm. per 100 cc. of solids other than sodium chloride. It remains completely liquid even when stored at 32° F. (0° C.).

2. The average molecular weight calculated from studies of osmotic pressure measurements is about 37,000.

3. The viscosity is somewhat greater than that of normal plasma or serum but considerably less than that of blood.

4. Studies with the ultracentrifuge show behavior of the type exhibited by most linear polymers.

No other samples of Periston became available for study during the war. Further investigations were conducted by U.S. observers before the Korean War (p. 788).

Dextran.-The only mention of dextran at the meetings and conferences of the National Research Council during the war was at the 16 March 1945 meeting of the Subcommittee on Blood Substitutes (29), at which Dr. Scatchard called attention to reports in the lay press of studies on it at the University of Upsala. The material to be made available for study to The Surgeon General was late in arriving because of manufacturing difficulties, and all investigations on it were conducted after the war (p. 790).


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Part II. Other Intravenous Fluids

Provision of Intravenous Fluids

The unsuccessful attempt of the Subcommittee on Blood Substitutes to provide for a special service in the Medical Department to handle all intravenous fluid therapy, together with the arguments for the proposal, is described elsewhere (p. 76). It was fortunate that the additional recommendation that salt and glucose solutions and other intravenous fluids be procured commercially was accepted.

From the beginning of the war, there were numerous discussions at various levels as to how distilled water and physiologic salt solution and glucose solution should be provided for field use. The matter was fully discussed at the meeting of the Subcommittee on Blood Substitutes on 9 April 1943 (30). Maj. A. L. Chute, RCAMC, remarked that the British were distributing their fluids from Cairo, where they were prepared by officers and laboratory assistants especially trained for the work (p. 16). Col. (later Brig. Gen.) George B. Callender, MC, said that similar arrangements were being planned in the U.S. Army. It was agreed that the many difficulties in the preparation of intravenous fluids and the operation of autoclaves and stills that must be overcome, even when repair parts and skilled technical assistance were readily available, would be multiplied overseas in a combat zone.

The tonnage of shipping required for a given amount of commercially prepared solutions would be about 20 percent more (2,200 tons, 120,000 cu. ft.) than for equipment and materials to prepare them in the zone of combat (1,693 tons, 100,000 cu. ft.). In spite of the added space they would require, it was the sense of the meeting that it was sound policy to have intravenous fluids prepared in the Zone of Interior and shipped overseas rather than prepared overseas.

One reason for the recommendation was that the most efficient still would yield acceptable distilled water only if the raw water had a low content of solids and was not heavily contaminated with pyrogens. A still could not take originally dirty water, as much water overseas would be, and convert it into distilled water which could safely be injected intravenously. It would also be necessary to autoclave bottles, sterilize equipment, and train personnel to prepare the solutions. All of these requirements would be difficult to provide overseas.

The impracticability of preparing intravenous fluids in the field is well illustrated in a report of the 77th Evacuation Hospital on 18 April 1943:

The hospital was provided with a water still (Market Forge Co., Everett, Mass.) designed to burn kerosene. But in North Africa, at that time, kerosene was practically impossible to obtain and so was unleaded gasoline. Leaded gasoline was therefore used. It burned with such an intense flame that it was necessary to use only one of the two burners, but the small orifice through which


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the gasoline was sprayed before combustion promptly became clogged, and the frequent cleaning necessary took time and was a great nuisance.

When the hospital had to depend upon a distant water supply, as it usually did, a Lister bag was utilized as a container for the water to be distilled. It was suspended on three 9-ft. tent poles, 4 ft. off the ground, this height being necessary to secure the head of pressure required to circulate the water through the condenser jacket. A rubber tube connected the bag with the condenser. The outflow water from the still was collected in an enamel pail and emptied back into the Lister bag every 10 minutes. The distilled water was collected in a separate container.

Under these conditions, it was possible to distill 1 gallon of water every 2 hours. One person had to be in constant attendance while the still was in use.

This was obviously not an efficient operation, and its duplication, in one form or another, in the multiple field and other Army hospitals resulted in an enormous waste of manpower and in the production of fluids limited in amount and not always safe. It was a relief to all concerned when intravenous fluids began to be supplied from the Zone of Interior in late 1943.

SALT SOLUTION

Historical note.-When the United States entered World War I, there was almost general agreement that the use of physiologic salt solution, as well as of Ringer's solution, in shock and hemorrhage had only temporary effects at best (1). Saline solution, because it is a crystalloid solution, promptly passes from the capillaries into the tissue spaces and, as it passes out of the circulation, probably carries some protein molecules with it. As a result, the blood pressure, when saline solution was used, was shortly as low as it was before, or even lower. It was generally agreed that the decrease of osmotic pressure in the vascular system was detrimental.

Subcutaneous injections of salt solution were equally ineffective; the solution simply spread into the fascia in the area of injection. The suggestion that hypertonic salt solution be used to withdraw fluids from the tissues, in an attempt to increase the blood volume by a sort of "internal transfusion," was as ineffective as it was irrational (31).

Rous and Wilson (32), who analyzed all the available blood substitutes in 1918, considered all of them preferable to salt solution.

World War II experience -Both salt and glucose solutions were occasionally used early in World War II, partly through ignorance, more often because nothing else was available. Within a short time, these solutions were used only as they would be used in civilian practice; that is, for the correction of dehydration and impairment of the electrolyte balance. Their use for these purposes was infrequent immediately after wounding and quite frequent, as in civilian practice, after operation.


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GUM ACACIA

Historical note -Experimental studies in World War I (1) indicated that gum acacia had a number of properties which might make it useful in replacement therapy. These studies showed that a solution of 6-7 percent in 0.9-percent sodium chloride had the same viscosity as whole blood and the same osmotic pressure as plasma. It was chemically inert. It did not cause thrombosis or promote clotting. It could be sterilized without chemical or physical alteration, and did not induce anaphylatic reactions when it was used repeatedly.

There was considerably less agreement about the clinical value of gum acacia. In October 1918, Maj. Oswald H. Robertson, MC, visited forward hospitals and systematically collected observations on its use from a large number of resuscitation teams (33). Some opinions were laudatory, some indifferent, and some decidedly condemnatory. The poorest results were reported in shock that had been untreated for 15-20 hours, in patients who were treated without first being warmed, in very severe hemorrhage, and in gas bacillus infection. Major Robertson's observations coincided with those of Maj. W. Richard Ohler, MC (34), who had had an extensive experience as a resuscitation officer.2

World War II experience -The use of gum acacia was never considered by the Subcommittee on Blood Substitutes in World War II. After World War I, however, it was used in a number of civilian institutions, including the Mayo Clinic. It is interesting to note that Baer's bibliography (p. 785) contains references to its experimental use as late as 1950 and to its clinical use as late as 1948.

SODIUM BICARBONATE

Historical note -In World War I, a number of observers, including Lt. Col. Walter B. Cannon, MC, Chairman of the Subcommittee on Shock, NRC, in World War II, suggested the use of soda bicarbonate solution in shock characterized by acidosis and air hunger, the objective being to increase the low alkali reserve (1). Later, it was realized, that this low reserve was the consequence of hypotension and was the effect, not the cause, of shock. When acidosis occurred, sensitive structures had already been gravely injured by oxygen deficiency.

World War II experience -The use of sodium bicarbonate solution was never seriously discussed in World War II, in the light of the newer knowledge of shock (35).

COMPLAINTS

Intravenous Solutions

Intravenous solutions were prepared under strict specifications, including a rigid pyrogen test, and the commercial products were excellent. The Office

2It should be noted again that resuscitation was a term developed in World War I, in spite of the general belief that it was originated in World War II.


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of The Surgeon General did not test the material before it was distributed, but the policy was that sample bottles from lots which had given rise to reactions would be sent to the Division of Surgical Physiology, Army Medical School, for investigation. There were only three really serious complaints.

Southwest Pacific -At the meeting of the Subcommittee on Blood Substitutes on 13 May 1943 (3), it was stated that private reports from New Caledonia were to the effect that the distilled water in some packages of plasma had a foul odor and that reactions had been noted of a degree proportionate to the intensity of the odor. In the circumstances, these criticisms could not be evaluated, but it was pointed out that report forms existed for making complaints through channels. No such reports were received. At this meeting, Dr. Max M. Strumia exhibited rubber stoppers which had suffered no apparent deterioration after being in use on bottles of distilled water for 30 months at temperatures of 98.6° to 104° F. (37° to 40° C.).

China-Burma-India theater -On 12 July 1943, Lt. Col. (later Brig. Gen.) Isidor S. Ravdin, MC, Chief, Surgical Service, 20th General Hospital, reported through channels (36) that difficulties had arisen with solutions "supposedly prepared for intravenous use" because of:

1. Erosion of the aluminum caps due to leakage and resultant chemical action.
2. Fungus growth in the bottles.
3. Pyrogenic substances in a large percentage of the flasks.

These solutions had been prepared more than a year ago. Since they were put up in a cheap type of soft glass, Colonel Ravdin thought that substances from the glass might have got into the solution, though, in flasks from one processing laboratory, the presence of fungus growths raised a serious question as to the original sterility of the solutions or their ability to maintain sterility after preparation and bottling. Solutions from another firm had given rise to 10 percent reactions in one lot, and to 7 percent reactions in another. The high incidence at the 20th General Hospital was in sharp contrast to the 1 to 1.5 percent of reactions in the Zone of Interior with solutions of greater age, but Colonel Ravdin was unwilling to entertain the suggestion of Col. Douglas B. Kendrick, MC, that some local error in the preparation of the intravenous sets might be responsible for the reactions.

In the considerable correspondence which followed the original complaints, the following information was received, chiefly in reply to direct questions:

1. The aluminum caps showed signs of erosion in 40 of 400 bottles. These stoppers were sometimes cracked, and they looked "tacky."

2. Nearly all the bottles with eroded caps had lost vacuum.

3. About 25 bottles showed signs of fungus contamination.

4. The bottles with eroded caps showed fungus formation but no evidence of precipitates or increased turbidity.

5. The rubber diaphragms of the stoppers were intact and all stoppers were tightly fitted to the bottles.

6. The bottles with eroded tops often arrived in damaged cardboard containers. Those in secure wooden crates were generally in good condition.

7. The fungus growth seemed to parallel the increase in environmental temperature


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FIGURE 75.-Closures for bleeding, plasma, and intravenous solution bottles (Baxter). A. Early type of closure: Airway (a), point (X) of insertion of needle at time of bleeding (b), outlet (c), thin rubber disk which occludes two openings when vacuum is pulled on bottle (d), and aluminum cap (e). This stopper depends on diaphragms to provide integrity. B. Lateral view of modified, integrally molded stopper (still in use in 1962) which provides completely closed system for collection of blood and storage of plasma and other fluids, as the early model did not: Diaphragms, approximately 2 mm. thick-one provides an airway when it is penetrated by the needle, the other provides an entrance into the bottle for the giving set (a); diaphragm (X) 6-8 mm. in thickness, through which bleeding needle is inserted; when needle is removed after donation, stopper seals itself and the closed system is thus maintained (b); top of modified stopper (c).

during the monsoon. It sometimes appeared while the bottles were in storage on shelves in the central dressingroom, which was always excessively hot during the day because the sterilizer was in it.

8. The bottles with eroded tops invariably had either a reduced vacuum or none, probably from absence of a diaphragm. Otherwise, there was no relation between (1) the presence of erosion and the status of the vacuum and (2) the number of reactions and the fungus growth.

This experience illustrated the absolute necessity of utilizing a completely closed, continuous piece of rubber in the bottling of solutions for intravenous use (fig. 75). The presence of fungus growth was to be expected in solutions


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stored for long periods of time in improperly closed containers. When closure was by a single piece of rubber, the vacuum within the container was maintained and contaminants could not enter. Solutions thus packaged had been observed for 3-year periods without deterioration of either the rubber stopper or the solution. The bottles in which fungus growth had developed were closed by a thin rubber diaphragm disk that covered the two holes in the stopper. Maintenance of the vacuum depended upon the disks' remaining in contact with the openings. If the containers were handled roughly, this contact could be lost and contamination could occur.

Because of this experience, Capt. Lloyd R. Newhouser, MC, USN, and Colonel Kendrick, with the aid of industry, devised specifications to provide for an integrally molded stopper which completely sealed the opening of the bottle and maintained a vacuum of 27-29 inches (Hg) without leakage. The closure was further strengthened by the use of an aluminum cap and seal. Thereafter, all bottles for intravenous fluids and for blood were provided with this type of closure.

Since the experience, unfortunate as it was, was limited to a single hospital and steps had already been taken to correct the difficulties, Colonel Kendrick did not concur with the proposal that this hospital prepare its own solutions and also prepare them for other hospitals in the vicinity.

European theater -Inquiries made in the European theater after the experience in the China-Burma-India theater produced the information that, in general, the intravenous fluids supplied were extremely satisfactory and that no known reactions had followed their use. It had been necessary to discard about 2 percent of the flasks supplied by each of two firms because of the presence of a visible precipitate in the solution. There was no loss of vacuum in these flasks. Cultures showed no growth, and efforts to identify the precipitate as a mold had been unsuccessful.

It was decided that these solutions, like the ones that had been unsatisfactory in the China-Burma-India theater, had been prepared when commercial production was just beginning, before the new specifications for closure of the flasks were written.

Distilled Water

In the summer of 1943, a number of complaints were received in the Supply Division, Office of The Surgeon General, (1) that the equipment provided did not produce distilled water of the quality required for the production of intravenous fluids, and (2) that the production of distilled water never equaled the capacity stated by the manufacturers. Inspection of installations in and near Washington and New York revealed that the stills currently supplied were entirely satisfactory for medical needs when they were properly cared for and operated. The principal factors required for their efficient operation were maintenance of thermal pressure, a steady flow of water, and cleansing of the apparatus at regular intervals. Neglect of any of these factors caused unsatis-


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factory qualitative and quantitative production. The intervals at which cleansing was necessary varied; the chemical composition of the water used might make it necessary every 24 hours. The efficiency of personnel was the determinate factor in every operation.

The installation at one hospital was an ideal demonstration of faulty operation and maintenance. A battery of three 10-gal. capacity precision-type stills, set up to produce 10 gal. of triple-distilled water each hour, was actually producing 1 gal. per hour because of leaks in the steam and waterlines and lack of cleansing. The operating personnel could not recall ever having cleaned the apparatus.

These visits of inspection furnished assurance that the equipment provided to Zone of Interior hospitals was adequate for the purposes for which it was intended. In his report, Colonel Kendrick described a new still, manufactured by the American Sterilizer Co., whose main advantage was its simple design. It could be operated with any standard heating element and cleaned with an ordinary scrubbing brush. He recommended that due consideration be given to this item in the preparation of future equipment specifications.

Colonel Kendrick also recommended that a circular letter be issued, announcing the policy of The Surgeon General that hereafter commercially produced intravenous solutions would be furnished and that distilling apparatus would not be required to produce distilled water of the quality essential for intravenous use. This letter was issued on 27 July 1943.

References

1. Cannon, Walter B.: Wound Shock. In The Medical Department of the United States Army in the World War. Washington: Government Printing Office, 1927, vol. XI, pt. 1, pp. 185-213.

2. Minutes, meeting of Committee on Transfusions, Division of Medical Sciences, NRC, 31 May 1940.

3. Minutes, meeting of Subcommittee on Blood Substitutes, Division of Medical Sciences, NRC, 13 May 1943.

4. Minutes, meeting of Subcommittee on Blood Substitutes, Division of Medical Sciences, NRC, 20 Oct. 1942.

5. Minutes, First Conference on Gelatin, Division of Medical Sciences, NRC, 10 Nov. 1942.

6. Minutes, meeting of Subcommittee on Blood Substitutes, Division of Medical Sciences, NRC, 10 Mar. 1942.

7. Minutes, meeting of Subcommittee on Blood Substitutes, Division of Medical Sciences, NRC, 10 Nov. 1942.

8. Minutes, meeting of Subcommittee on Blood Substitutes, Division of Medical Sciences, NRC, 15 Dec. 1942.

9. Minutes, Second Conference on Gelatin, Division of Medical Sciences, NRC, 23 Feb. 1943.

10. Minutes, Third Conference on Gelatin, Division of Medical Sciences, NRC, 4 Sept. 1943.

11. Minutes, meeting of Subcommittee on Blood Substitutes, Division of Medical Sciences, NRC, 17 Nov. 1943.


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12. Minutes, Conference on Shock, Subcommittee on Shock, Division of Medical Sciences, NRC, 1 Dec. 1943.

13. Minutes, Conference of the Albumin and By-Products Group, Division of Medical Sciences, NRC, 14 Dec. 1943.

14. Minutes, meeting of Subcommittee on Blood Substitutes, Division of Medical Sciences, NRC, 5 Jan. 1944.

15. Minutes, meeting of Subcommittee on Blood Substitutes, Division of Medical Sciences, NRC, 3 Mar. 1944.

16. Minutes, meeting of Subcommittee on Blood Substitutes, Division of Medical Sciences, NRC, 21 Apr. 1944.

17. Vogelaar, J.: The Suitability of Gelatin as a Component of a Blood Plasma Substitute. Factors Affecting the Conglutination of Human Erythrocytes by Gelatin. Blood Substitutes Report No. 23, Division of Medical Sciences, NRC, 7 Dec. 1943.

18. Minutes, Conference on Pectin, Division of Medical Sciences, NRC, 24 Feb. 1943.

19. Minutes, meeting of Subcommittee on Blood Substitutes, Division of Medical Sciences, NRC, 3 Nov. 1941.

20. Popper, H.: Deposition of Material in the Tissues After Injections of 1.5% Pectin Solution. Blood Substitutes Report No. 17, Division of Medical Sciences, NRC, 10 Apr. 1944.

21. Minutes, meeting of Subcommittee on Blood Substitutes, Division of Medical Sciences, NRC, 19 Sept. 1941.

22. Minutes, meeting of Subcommittee on Blood Substitutes, Division of Medical Sciences, NRC, 23 Mar. 1943.

23. Bovarnick, M.: The Formation of Extracellular d (-)-Glutamic Acid Polypeptide by Bacillus Subtilis. J. Biol. Chem. 145: 415-424, October 1942.

24. Minutes, meeting of Subcommittee on Blood Substitutes, Division of Medical Sciences, NRC, 24 Feb. 1943.

25. Minutes, meeting of Subcommittee on Blood Substitutes, Division of Medical Sciences, NRC, 10 Aug. 1943.

26. Seegal, D.: Studies on Glycerol Polysuccinate. Blood Substitutes Report No. 9, Division of Medical Sciences, NRC, December 1945.

27. Minutes, Conference of Albumin and By-Products Group, Division of Medical Sciences, NRC, 28 July 1943.

28. Minutes, meeting of Subcommittee on Blood Substitutes, Division of Medical Sciences, NRC, 24 Sept. 1943.

29. Minutes, meeting of Subcommittee on Blood Substitutes, Division of Medical Sciences, NRC, 16 Mar. 1945.

30. Minutes, meeting of Subcommittee on Blood Substitutes, Division of Medical Sciences, NRC, 9 Apr. 1943.

31. Kendrick, D. B., and Wakim, K. G.: Intra-Arterial Hypertonic Saline Solution in Experimental Shock. Proc. Soc. Exper. Biol. & Med. 40: 114-116, January 1939.

32. Rous, P., and Wilson, G. W.: Fluid Substitutes for Transfusion After Hemorrhage. First Communication. J.A.M.A. 70: 219-222, 26 Jan. 1918.

33. Robertson, O. H.: Transfusion With Preserved Red Blood Cells. Brit. M. J. 1: 691-695, 22 June 1918.

34. Ohler, W. R.: Treatment of Surgical Shock in the Zone of the Advance. Am. J. M. Sc. 159: 843-853, June 1920.

35. Minutes, meeting of Subcommittee on Shock, Division of Medical Sciences, NRC, 29 Jan. 1944.

36. Correspondence, Lt. Col. I. S. Ravdin, MC, and Office of The Surgeon General, 12 July-23 Oct. 1943, subject: Deficiencies in Intravenous Fluids, China Burma India Theater of Operations.

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