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 onso-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 theMedical Research Committee of Great Britain, made comprehensive studies onsuitable crystalloid and colloid solutions to correct the physiologicalterations that occur in shock, and similar studies were made in the UnitedStates (1). By the end of the war, two important, if negative, facts hadbeen established:
1. Experimental studies on crystalloid solutions showed thatthey were too readily diffusible to be useful in elevating a decreased bloodvolume and maintaining it at an adequate level. Clinical experience confirmedthe experimental data.
2. There was an obvious need for a macromolecular substancethat could be used in solution to provide an intravascular osmotic effectsufficient to maintain an adequate plasma volume. Gum acacia, which was studiedextensively for this purpose (p. 384), proved to have two serious defects, thatit 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 anumber of observers, particularly Dr. John S. Lundy at the Mayo Clinic, afterWorld War I, but its use had been generally abandoned long before World War IIbroke out. It was logical, therefore, that at the first meeting of the Committeeon Transfusions, on 31 May 1940 (2), one of the committeefunctions should be listed as the development of possible substitutes for humanplasma 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 fundamentalreason that, in spite of the success of the plasma program, the requirements forreplacement fluids were likely to prove considerably in excess of the amount ofblood contributed. The search for effective, nontoxic blood substitutes,nonhuman in origin, therefore had to be expedited. At the meeting of theSubcommittee on Blood Substitutes on 13 May 1943 (3), at which theseviews were expressed, it was reported that Dr. Alfred N. Richards, Chairman,Committee on Medical Research, NRC (National Research Council), had indicatedthe agreement of his committee with this point of view. Projects related to thesearch for blood substitutes would be considered urgent; it was fully understoodthat 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 ofthe groups working on experimental and clinical shock.
A really urgent need for blood substitutes never arose inWorld War II because of the generous donations of whole blood; rapid advances inthe processing of blood into plasma; and similar advances in the fractionationof plasma and the development of some of its derivatives, particularly serumalbumin. Extensive research was continued, however, and considerable experiencewas gathered, particularly in the use of gelatin, which proved the safest andmost effective of the agents investigated.
The results of the various studies are summarized briefly inthe following pages. Readers who wish further details are referred to theminutes of the Subcommittee on Blood Substitutes, its ad hoc committees, and thevarious conferences on special subjects.
Criteria
In one respect, the investigation into gelatin as a bloodsubstitute was duplicated in investigations into most other substances: At the20 October 1942 meeting of the Subcommittee on Blood Substitutes (4), Dr.Robert F. Loeb reported that most applications for research studies revealedincomplete knowledge of the problems involved and were notably lacking in testsfor toxicity as well as in reports of clinical testing. Such tests as had beencarried 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 theSubcommittee on Blood Substitutes to date had been such that "certaincriteria had come to be recognized as the sine qua non for any substance to beseriously considered for the treatment of shock in human beings." Thesecriteria were:
1. The colloidal osmotic pressure of the substance inquestion must be equivalent to that of normal blood plasma.
2. The substance must be capable of production with aconstant and reproducible composition.
3. The mode of preparation must be such as to exclude oreliminate pyrogens.
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4. The viscosity of the substance must be such as to permiteasy intravenous administration.
5. Its stability must be such that it could withstand the wide ranges oftemperature encountered in a global war. Also, it must remain stable for longperiods of time.
6. It must be easily sterilized.
7. It must not be toxic. It must not cause leukocytosis, hemolysis, or anincrease in the sedimentation rate. It must be either utilized in the body orreadily 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 considerationswhich would affect the decision to develop and use a blood substitute:
1. During the war, ease of production and accessibility of source materialswere obviously of great importance.
2. The ability to manufacture or process any substance under asepticconditions might conceivably have considerable bearing on the decision todevelop it, since the introduction of bacteria might lead to the production oftoxins or antigens.
GELATIN
Initial Suggestions
Gelatin was first mentioned as a possible blood substitute at the meeting ofthe Subcommittee on Blood Substitutes on 10 March 1942 (6). The principalreason for the suggestion was that a 6-percent solution had been found to havethe viscosity of whole blood at room temperature and an oncotic (osmotic)pressure of 65 mm. H2O. Also, allergists hadused gelatin for years as an injection vehicle and there was ample proof that itwas not antigenic.
At the 20 October 1942 meeting of the subcommittee (4), Dr. Loebproposed a meeting of all groups interested in research on gelatin, so thatresearch workers could present their studies to members of the subcommittee andcould be made aware of the problems that must be solved before gelatin could berecommended as a blood substitute. He also stated that he had interviewed amanufacturer of gelatin, who viewed with alarm the proposal to inject thissubstance into human beings, chiefly because it was impossible to manufacture aproduct of entirely uniform quality.
November 1942
At the First Conference on Gelatin on 10 November 1942 (5), thefollowing data were brought out in reports by various investigators:
1. In general, no toxic effects were observed from injectionsof gelatin. The temperature elevations occasionally noted in both clinical andexperimental studies were believed to be caused by pyrogens or by the specificdynamic action of a readily available protein.
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2. Studies at the University of Louisville School of Medicineshowed that gelatin satisfactorily restored the blood pressure of animals inshock, and that they withstood second hemorrhages as well as dogs resuscitatedwith whole blood. Studies at the Bowman-Gray School of Medicine, however, showedthat the blood pressure was frequently not restored completely, and that most ofthe animals died when shock was produced by the Blalock clamp. Some observersfound gelatin lifesaving in slow hemorrhage.
3. There was no evidence of storage of gelatinin the tissues in animals studied at autopsy, sometimes as long as 103 daysafter injection.
4. Excretion of gelatin via the urine was notattended with oliguria.
5. Reinjection experiments confirmed theprevailing opinion that gelatin was not antigenic.
6. Hemodilution was usually evident afterinjection.
7. A controlled study of burn shock in dogsshowed gelatin solutions effective in compensating for the loss of plasma andmaintaining survival beyond the period death might be expected from that cause.
8. In vitro, gelatin produced markedconglutination and acceleration of sedimentation of erythrocytes, though neitherphenomenon was observed in experimental animals.
At this conference, it was reported that various gelatinpreparations had retained their stability for several months at 37? F. (3?C.). Dr. Samuel E. Sheppard, of the Eastman Kodak Co., reported perfection of aprocess of fractionation of gelatin that eliminated the products of lowermolecular weight and resulted in gelatins of higher and more uniform molecularsizes. The studies were made by a precision viscometric control device.
Also at this conference, Mr. Joseph H. Cohen, president ofthe Edible Gelatin Manufacturers' Research Society of America, discussed theproduction of gelatin for medical purposes. As it was often producedcommercially in 1-ton lots, it was a heterogeneous substance, and no factorycontrols existed to insure a uniform product for intravenous injection. If aspecial gelatin, of a specified uniform quality, were required for militarypurposes, it would be advisable to set up a pilot plant in which the entiremanufacturing process could be subjected to biologic and other laboratorycontrols.
At the meeting of the Subcommittee on Blood Substitutesimmediately after this conference (7), there was a full discussion of theneed for a gelatin of uniform quality with which all experiments could beconducted. Dr. Loeb appointed Dr. Edwin J. Cohn and Dr. Sheppard to draw upspecifications for such a preparation.
These specifications were presented at the meeting of thesubcommittee on 15 December 1942 (8). They concerned the source of thematerial, 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 oferythrocytes. It was noted that the presence of pyrogens might be due not to theproduct but to the use of water that was not pyrogen-free, a point laboratoryworkers were remarkably prone to overlook (p. 651).
At the conclusion of this conference, Dr. Loeb asked for ashow of hands to determine who, at this time, would be willing to recommend tothe Subcommittee on Blood Substitutes that it recommend to the Armed Forces thatgelatin be used as a blood substitute. No hands were raised.
September 1943
At the Third Conference on Gelatin (10), it was againnecessary to point out that the reports made were not directly comparablebecause the preparations of gelatin used were in various stages of degradationand because the variables introduced modified the results. Some progress,however, had been made. It was now evident that gelatin could be prepared insolutions that were not pyrogenic for man, that were not toxic, and that werephysiologically active. The most urgent requirement at this time was consideredto be a clinical comparison of the gelatins made by the Knox Gelatin Co. and theUpjohn Laboratories. Dr. Cohn believed that the largest molecule consistent withstability should be used.
The following resolutions were passed:
1. That the Subcommittee on Blood Substitutesrecommend to the Committee on Medical Research that comparative studies ofgelatin solutions with different physicochemical characteristics be made invarious types of injury by physiologic and clinical groups.
2. That solutions degraded as little aspossible be compared with those degraded to the point at which their loss fromthe bloodstream was relatively rapid, with special attention to deposition andexcretion of the gelatin and sedimentation of red blood cells as well as to thetherapeutic effects achieved. It was admitted that the accomplishment offluidity and stability compatible with military conditions would probably bedifficult.
3. That the subcommittee recommend to theChairman, Division of Medical Sciences, NRC, that the Pure Food and DrugAdministration be informed of the conferences held on gelatin (and pectin) asreplacement agents.
November 1943
At the subcommittee meeting on 17 November 1943 (11), itwas reported that tests with the Upjohn Co. product had been carried out onWelfare Island volunteers. No toxic reactions had followed the injection of5-percent solution in amounts up to 1,000 cc. Fifty percent of the amountinjected was eliminated in the urine within 24 hours. Dr. Owen H. Wangensteenhad injected 10 patients with the same preparation, with one reaction. Allproducts used had caused conglutination, but when the gelatin was made up insolutions 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 acomprehensive report on the use of gelatin in shock:
1. The effectiveness of physiologic saltsolution in shock is definitely enhanced by the addition of 4- to 6-percent ofnonantigenic, nonpyrogenic gelatin. The resulting solution seems entirelyadequate to restore circulating blood volume and maintain colloid osmoticpressure, even when hemorrhage has been massive and repeated. When gelatin isused, the volume of blood which can be withdrawn is limited in repeatedhemorrhages only by the need for red blood cells.
2. Experimental studies with a carefullydetermined tolerated blood loss (blood pressure below 20 mm. Hg) and immediatereplacement with plasma, gelatin, or saline solution were repeated an hourlater, with survival of all the animals. After the third hemorrhage, anotherhour later, the amount of red blood cell depletion was so great that deathoccurred within an hour unless red blood cells were administered with the fluidreplacement. All the animals survived when their red cells were replaced afterthe third hemorrhage. After gelatin infusion, the volume of blood that could bewithdrawn on the second and third hemorrhages was twice as great as with salinesolution and half as great again as with plasma.
3. Since the 4-percent gelatin solutiondeveloped a colloid osmotic pressure 50 percent greater than that of plasma, itproduced hemodilution more rapidly. Because of the rapid hemodilution, thetolerated bleeding volume of the gelatin-treated animal was greater on thesecond and third hemorrhages than that of the plasma-treated animal. Bloodpressure was as well maintained after gelatin infusion as after plasmareplacement.
When a critical level of hypotension was prolonged, as ingraduated blood withdrawal, factors other than simple maintenance of colloidosmotic pressure entered the picture, and gelatin was apparently less effectivethan plasma in achieving permanent survival.
Clinical tests at the Hospital of the University ofPennsylvania covered 103 infusions of 100 liters of gelatin solution to 62patients. There were no toxic reactions. Three patients in the group who were inshock received only gelatin infusions; they recovered without incident.
April 1944
Continued favorable reports on the use of gelatin in shock atsucceeding meetings (13-15) led to the adoption of the followingresolution at the 21 April 1944 meeting of the Subcommittee on Blood Substitutes(16):
That the Subcommittee on Blood Substitutes hasagreed on the publication of a statement on its evaluation of studies on gelatinpreparations for intravenous use. It does this to make available its conclusionsregarding the proper use and the limitations of gelatin and at the same time tomake it clear that the preparation and use of gelatin in no way decreases theneed for the procurement of blood by the American Red Cross and the preparationfrom it of blood substitutes for the Armed Forces. The above statements arelimited to gelatin solutions specifically prepared for intravenous use. Suchsolutions should be prepared only in specially constructed plants under the mostrigid physicochemical and biological control.
The statement in question covered:
1. The chemical composition of gelatin and itsdegradation.
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2. Its physiologic and clinical properties. Atthis time, the solution considered of optimal value in the treatment ofhemorrhage and shock was a 6-percent solution, in physiologic salt solution,with the general physicochemical characteristics of what was known as the KnoxP-20 type.
3. The limitations of gelatin as a replacementagent 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 temperateclimates.
b. The optimal solution of gelatin presentlyavailable shows slow but definite and continued degradation at temperaturesencountered in certain theaters of operation.
c. The viscosity of the optimal solution ofgelatin is greater than that of whole blood.
d. The proper typing of blood after theadministration of gelatin solutions requires further study. It may be well toissue the warning that a sample for typing must be withdrawn before gelatin isadministered.
e. It is not known whether the optimalsolution will impair the return of normal function to kidneys in sustainedischemia, severe burns, or the crush syndrome.
f. Gelatin solutions probably do notcontribute significantly to nutrition. Their only place in medical therapy wouldbe to restore circulating blood volume depleted in various types of acuteinjury.
g. The influence of gelatin upon theequilibrium in the distribution of plasma proteins between the circulating bloodand the tissues requires further investigation.
End of Investigation
The only other significant investigation of gelatin during WorldWar II concerned the abolition of rouleaux formation by the addition of glycine(0.28 molar) to the cell suspension. This observation, originally reported byDr. Johannes Vogelaar (17), New York City Cancer Institute, WelfareIsland, N.Y., was confirmed by studies at the University of Pennsylvania Schoolof Medicine and at the Harvard laboratory (13).
The ample supplies of blood, plasma, and albumin availableduring the last year of World War II made it unnecessary to carry out furtherstudies with gelatin. The investigation was revived when the Korean War brokeout (p. 786).
PECTIN
At the Conference on Pectin on 24 February 1943 (18), itwas noted in one of the reports that the intravenous use of pectin sols wasfirst discussed by Feissly in 1925 and that, to date, 22 articles on thesubject, covering some 500 clinical cases, had appeared in the literature. Muchof this work had been done by Hartman and his associates at the Henry FordHospital. No thrombosis or other ill effects had been reported.
Experimental Studies
It was also pointed out at this conference that pectin wasdefined in the seventh edition of the National Formulary as "apurified carbohydrate product obtained from dilute acid extract of the innerportion of the rind of citrus fruits
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or from apple pomance. It consists chiefly of partiallymethoxylated polygalacturonic acids."
The proposal that pectin be studied as a possible bloodsubstitute was made to Dr. Loeb on 6 October 1941, in a letter from Dr. RichardM. Johnson, Medical Director, Frederick Stearns & Co. At the meeting of theSubcommittee on Blood Substitutes on 3 November 1941 (19), Dr. Loebstated, as the result of his survey to date, that he considered all studies onpectin 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 toindicate that pectin was not antigenic. It was emphasized that all reports muststate the method of preparation and the approximate composition of the pectinused.
At this conference, representatives of the ResearchDepartment, California Fruit Growers Exchange, stated that for the previous 4years the possible medical use of pectin had been studied under their auspicesin a total of 776 experimental animals, as follows:
1. From 30 to 50 percent of the pectininjected was recovered from the urine within the first 24 hours after injectionand from 45 to 60 percent within 6 days.
2. From 80 to 85 percent of the injectedpectin was found in the blood 20 minutes after the injection, about 19 percentin 24 hours, and about 10 percent in 48 hours.
3. No significant changes were noted in thecoagulation time after the injection.
4. After massive injections, no deposits ofpectin were found in the liver, kidneys, and spleen on chemical examination, andthe weights of these organs were comparatively normal.
5. Animals given injections every other dayfor 6 weeks maintained their normal weight and appetite.
These investigators pointed out that pectin occurs along withcellulose in the white inner portion of the rind of citrus fruit (albedo). Theblood from a million donors would produce plasma equivalent in volume to 2.0percent pectin sols made from only about 11,000 pounds of purified pectin, anamount that could be made in a few weeks. In view of this prospect, and becauseof the emergency, further studies with pectin were considered justified.
A number of reports on pectin were made at the February 1943conference, but they were extremely disorganized. The criteria for bloodsubstitutes developed by the subcommittee (p. 372) were presented to theinvestigators, and they were told that some investigations, notably that ongelatin, had made great progress because these criteria had been observed. Itwas emphasized that the first problem in the investigation of pectin was tosecure samples for physicochemical analysis; measurement of osmotic pressure inan osmometer did not give a satisfactory idea of the size of molecules ormolecular aggregates. When the Subcommittee on Blood Substitutes met on 17November 1943 (11), Dr. Loeb reported that, although testing facilitiesfor 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 beenevaluated at the Massachusetts Institute of Technology.
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Solutions of pectin made up by the Hartman technique and bythe technique used at the Cutter Laboratories were studied under the directionof Dr. Loeb. In the course of the investigation, he expressed himself asskeptical of the value of this agent except, possibly, as a capillary cement; onthe 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 conclusionthat the osmotic pressure of pectin solutions was inadequate and that they wereno more effectual than salt solution (14).
Clinical Studies
Investigators at the University of Illinois College ofMedicine and at the Henry Ford Hospital were convinced, from clinicalexperience, of the value of pectin, though not many of the patients they hadtested were in shock (18). A similar study at Cook County Hospital wasnot impressive. A later report from the same hospital, by Dr. Hans Popper, madeit clear that it would not be safe to recommend pectin as a blood substitute tothe Armed Forces (20).
OTHER BLOOD SUBSTITUTES
Little or no progress was made on other blood substitutes duringWorld War II.
Isinglass.-Isinglass (fish gelatin) was studied bothclinically and experimentally under the auspices of the Canadian NationalResearch Council. It was discussed at numerous meetings of the Subcommittee onBlood Substitutes, but no formal studies with it were made beyond aninvestigation of its physicochemical properties in the Harvard laboratory (3,5, 6, 10, 11, 16, 21, 22).
Glutamyl polypeptide -Glutamyl polypeptide (d (-)-glutamicacid polypeptide) was prepared by Dr. Maxwell Bovarnick, at the Albany Hospital,who found that it could be isolated in large quantities from cultures of Bacillussubtilis and obtained in pure form by copper precipitation (23). Whenit was discussed for the first time by the Subcommittee on Blood Substitutes on20 October 1942 (4), Dr. Cohn stated that it was the most promising bloodsubstitute suggested in some time. Further investigation, unfortunately, did notbear out its early promise (24, 25).
Aldobionic acid -Aldobionic acid was discussed as ablood substitute at the meeting of the Subcommittee on Blood Substitutes on 10November 1942 (7). It was prepared by treating cotton with nitrogenperoxide. It had a highly effective osmotic pressure. Injection into rabbitsproduced hemodilution; afterward, a certain amount of the substance appeared inthe urine as sugar.
In the discussion, Dr. Alphonse R. Dochez pointed out thatbacterial polysaccharides such as aldobionic acid were not in themselvesantigenic, but,
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when they became congested in the body, they might serve asantigens. Dr. Cohn did not think this new agent should be rejected withoutfurther investigation, since a whole series of chainlike polymers could probablybe broken down to molecules of a size that would produce effective osmoticpressures.
No further study was made of this agent.
Oxidized cotton -Experiments at the College ofPhysicians and Surgeons, Columbia University, indicated that when cotton wasoxidized with nitrogen tetroxide, it became soluble in bicarbonate solutions andexerted a high osmotic pressure (8). Some hemodilution apparentlyoccurred after injections of solutions of relatively high osmotic pressure.Studies on six rabbits had shown it to be nonanaphylactogenic but moderatelypyrogenic. Large amounts were tolerated when they were given in repeated smallinjections. The single animal that died had had 50 cc. of 4-percent solution; nopathologic changes were found to explain the death. When the other five animalswere sacrificed, the only significant findings were swelling and vacuolizationof the convoluted tubules of the kidneys.
Oxidized cotton appeared unchanged in the urine within 3hours after injection. Within 24 hours, 80 percent or more had left thebloodstream. In vitro studies showed no changes in the hemoglobin, the red bloodcell and platelet counts, the sedimentation rate, and blood agglutination. Therewas a moderate drop in the hematocrit and a slight increase in the venousclotting time.
It was thought that it might be possible to prepare oxidizedcotton with a lower carboxyl content and, presumably, a higher molecular weight,that would pass through the kidneys less rapidly and be effective in thebloodstream for a longer time. No further action, however, was taken.
Alginic acid.-The Subcommittee on Blood Substitutesdid not follow up a suggestion that alginic acid prepared from kelp might be asatisfactory blood substitute (7).
Amino acids -The suggestion that nitrogen lost in shockbe replaced by intravenous injections of solutions of pure amino acids was basedon the observation that urinary nitrogen is increased in shock (7). Inthe discussion, however, it was brought out that the loss is no greater thanoccurs in an upper respiratory infection with fever, when no such therapy wouldbe contemplated (25). It was the consensus of the Subcommittee on BloodSubstitutes both times the proposal was brought up that the method might beapplicable in prolonged protein starvation but had no place in the management ofshock.
Sodium glycerol polysuccinate.-Studies on dogs andmice at the College of Physicians and Surgeons, Columbia University, with sodiumglycerol polysuccinate showed no toxic reactions in the animals tested and nopathologic changes at autopsy but also held no promise for its use in shock (26).
Periston.-Periston (polyvinylpyrrolidone), theproprietary preparation used by the Germans in World War II, was first mentionedat 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 Germanmedical journal. The previous experience in the United States with vinylderivatives suggested that this one would not be particularly helpful.
At the 28 July 1943 Conference of the Albumin and By-ProductsGroup (27), a bottle of Periston (Blutfl?ssigkeitersatz) that had beencaptured in Tunisia, with other German medical material, was exhibited, andarrangements were made for various studies to be conducted on it. These studieswere reported at the 24 September 1943 meeting of the Subcommittee on BloodSubstitutes, as follows (28):
Dr. Orville T. Bailey's anaphylaxis studies were entirelynegative, both in vivo and at autopsy. His toxicity experiments revealed grosspathologic changes in the spleen (splenomegaly) and, on microscopic examination,very active hematopoiesis throughout the splenic sinusoids. These changes weredescribed as the type to be expected in severe bone marrow damage, thoughsections from several bones showed no changes in the marrow. Autopsy alsorevealed changes in the liver that were apparently progressive, even aftertreatment had been discontinued. The pathogenesis and significance of thehepatic and splenic changes were difficult to evaluate.
At this same meeting of the subcommittee, Dr. GeorgeScatchard and his associates at the Massachusetts Institute of Technologydescribed the physical properties of Periston as follows:
1. The material is a colorless solution with apH of 7.2, containing about 2.45 gm. per 100 cc. of solids other than sodiumchloride. It remains completely liquid even when stored at 32? F. (0? C.).
2. The average molecular weight calculatedfrom studies of osmotic pressure measurements is about 37,000.
3. The viscosity is somewhat greater than thatof normal plasma or serum but considerably less than that of blood.
4. Studies with the ultracentrifuge showbehavior of the type exhibited by most linear polymers.
No other samples of Periston became available for studyduring the war. Further investigations were conducted by U.S. observers beforethe Korean War (p. 788).
Dextran.-The only mention of dextran at the meetingsand conferences of the National Research Council during the war was at the 16March 1945 meeting of the Subcommittee on Blood Substitutes (29), atwhich Dr. Scatchard called attention to reports in the lay press of studies onit at the University of Upsala. The material to be made available for study toThe 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 BloodSubstitutes to provide for a special service in the Medical Department to handleall intravenous fluid therapy, together with the arguments for the proposal, isdescribed elsewhere (p. 76). It was fortunate that the additional recommendationthat salt and glucose solutions and other intravenous fluids be procuredcommercially was accepted.
From the beginning of the war, there were numerousdiscussions at various levels as to how distilled water and physiologic saltsolution and glucose solution should be provided for field use. The matter wasfully discussed at the meeting of the Subcommittee on Blood Substitutes on 9April 1943 (30). Maj. A. L. Chute, RCAMC, remarked that the British weredistributing their fluids from Cairo, where they were prepared by officers andlaboratory assistants especially trained for the work (p. 16). Col. (later Brig.Gen.) George B. Callender, MC, said that similar arrangements were being plannedin the U.S. Army. It was agreed that the many difficulties in the preparation ofintravenous fluids and the operation of autoclaves and stills that must beovercome, even when repair parts and skilled technical assistance were readilyavailable, would be multiplied overseas in a combat zone.
The tonnage of shipping required for a given amount ofcommercially 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 ofcombat (1,693 tons, 100,000 cu. ft.). In spite of the added space they wouldrequire, it was the sense of the meeting that it was sound policy to haveintravenous fluids prepared in the Zone of Interior and shipped overseas ratherthan prepared overseas.
One reason for the recommendation was that the most efficientstill would yield acceptable distilled water only if the raw water had a lowcontent of solids and was not heavily contaminated with pyrogens. A still couldnot take originally dirty water, as much water overseas would be, and convert itinto distilled water which could safely be injected intravenously. It would alsobe necessary to autoclave bottles, sterilize equipment, and train personnel toprepare the solutions. All of these requirements would be difficult to provideoverseas.
The impracticability of preparing intravenous fluids in thefield is well illustrated in a report of the 77th Evacuation Hospital on 18April 1943:
The hospital was provided with a water still (Market ForgeCo., Everett, Mass.) designed to burn kerosene. But in North Africa, at thattime, kerosene was practically impossible to obtain and so was unleadedgasoline. Leaded gasoline was therefore used. It burned with such an intenseflame that it was necessary to use only one of the two burners, but the smallorifice through which
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the gasoline was sprayed before combustion promptly becameclogged, 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 bedistilled. 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 circulatethe water through the condenser jacket. A rubber tube connected the bag with thecondenser. The outflow water from the still was collected in an enamel pail andemptied back into the Lister bag every 10 minutes. The distilled water wascollected in a separate container.
Under these conditions, it was possible to distill 1 gallonof water every 2 hours. One person had to be in constant attendance while thestill was in use.
This was obviously not an efficient operation, and itsduplication, in one form or another, in the multiple field and other Armyhospitals resulted in an enormous waste of manpower and in the production offluids limited in amount and not always safe. It was a relief to all concernedwhen intravenous fluids began to be supplied from the Zone of Interior in late1943.
SALT SOLUTION
Historical note.-When the United States entered WorldWar I, there was almost general agreement that the use of physiologic saltsolution, as well as of Ringer's solution, in shock and hemorrhage had onlytemporary effects at best (1). Saline solution, because it is acrystalloid solution, promptly passes from the capillaries into the tissuespaces and, as it passes out of the circulation, probably carries some proteinmolecules with it. As a result, the blood pressure, when saline solution wasused, was shortly as low as it was before, or even lower. It was generallyagreed that the decrease of osmotic pressure in the vascular system wasdetrimental.
Subcutaneous injections of salt solution were equallyineffective; the solution simply spread into the fascia in the area ofinjection. The suggestion that hypertonic salt solution be used to withdrawfluids 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 availableblood substitutes in 1918, considered all of them preferable to salt solution.
World War II experience -Both salt and glucosesolutions were occasionally used early in World War II, partly throughignorance, more often because nothing else was available. Within a short time,these solutions were used only as they would be used in civilian practice; thatis, for the correction of dehydration and impairment of the electrolyte balance.Their use for these purposes was infrequent immediately after wounding and quitefrequent, as in civilian practice, after operation.
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GUM ACACIA
Historical note -Experimental studies in WorldWar I (1) indicated that gum acacia had a number of properties whichmight make it useful in replacement therapy. These studies showed that asolution of 6-7 percent in 0.9-percent sodium chloride had the same viscosity aswhole blood and the same osmotic pressure as plasma. It was chemically inert. Itdid not cause thrombosis or promote clotting. It could be sterilized withoutchemical or physical alteration, and did not induce anaphylatic reactions whenit was used repeatedly.
There was considerably less agreement about the clinicalvalue of gum acacia. In October 1918, Maj. Oswald H. Robertson, MC, visitedforward hospitals and systematically collected observations on its use from alarge number of resuscitation teams (33). Some opinions were laudatory,some indifferent, and some decidedly condemnatory. The poorest results werereported in shock that had been untreated for 15-20 hours, in patients who weretreated without first being warmed, in very severe hemorrhage, and in gasbacillus infection. Major Robertson's observations coincided with those ofMaj. W. Richard Ohler, MC (34), who had had an extensive experience as aresuscitation officer.2
World War II experience -The use of gum acaciawas 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 itsclinical 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 shockcharacterized by acidosis and air hunger, the objective being to increase thelow alkali reserve (1). Later, it was realized, that this low reserve wasthe consequence of hypotension and was the effect, not the cause, of shock. Whenacidosis occurred, sensitive structures had already been gravely injured byoxygen deficiency.
World War II experience -The use of sodiumbicarbonate solution was never seriously discussed in World War II, in the lightof the newer knowledge of shock (35).
COMPLAINTS
Intravenous Solutions
Intravenous solutions were prepared under strictspecifications, including a rigid pyrogen test, and the commercialproducts 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 itwas distributed, but the policy was that sample bottles from lots which hadgiven rise to reactions would be sent to the Division of Surgical Physiology,Army Medical School, for investigation. There were only three really seriouscomplaints.
Southwest Pacific -At the meeting of the Subcommitteeon Blood Substitutes on 13 May 1943 (3), it was stated that privatereports from New Caledonia were to the effect that the distilled water in somepackages of plasma had a foul odor and that reactions had been noted of a degreeproportionate to the intensity of the odor. In the circumstances, thesecriticisms could not be evaluated, but it was pointed out that report formsexisted for making complaints through channels. No such reports were received.At this meeting, Dr. Max M. Strumia exhibited rubber stoppers which had sufferedno apparent deterioration after being in use on bottles of distilled water for30 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 GeneralHospital, reported through channels (36) that difficulties had arisenwith solutions "supposedly prepared for intravenous use" because of:
1. Erosion of the aluminum caps due to leakageand 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. Sincethey were put up in a cheap type of soft glass, Colonel Ravdin thought thatsubstances from the glass might have got into the solution, though, in flasksfrom one processing laboratory, the presence of fungus growths raised a seriousquestion as to the original sterility of the solutions or their ability tomaintain sterility after preparation and bottling. Solutions from another firmhad given rise to 10 percent reactions in one lot, and to 7 percent reactions inanother. The high incidence at the 20th General Hospital was in sharp contrastto the 1 to 1.5 percent of reactions in the Zone of Interior with solutions ofgreater age, but Colonel Ravdin was unwilling to entertain the suggestion ofCol. Douglas B. Kendrick, MC, that some local error in the preparation of theintravenous sets might be responsible for the reactions.
In the considerable correspondence which followed theoriginal complaints, the following information was received, chiefly in reply todirect questions:
1. The aluminum caps showed signs of erosionin 40 of 400 bottles. These stoppers were sometimes cracked, and they looked"tacky."
2. Nearly all the bottles with eroded caps hadlost vacuum.
3. About 25 bottles showed signs of funguscontamination.
4. The bottles with eroded caps showed fungusformation but no evidence of precipitates or increased turbidity.
5. The rubber diaphragms of the stoppers wereintact and all stoppers were tightly fitted to the bottles.
6. The bottles with eroded tops often arrivedin damaged cardboard containers. Those in secure wooden crates were generally ingood condition.
7. The fungus growth seemed to parallel theincrease in environmental temperature
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during the monsoon. It sometimes appeared while the bottleswere in storage on shelves in the central dressingroom, which was alwaysexcessively hot during the day because the sterilizer was in it.
8. The bottles with eroded tops invariably had either areduced vacuum or none, probably from absence of a diaphragm. Otherwise, therewas no relation between (1) the presence of erosion and the status of the vacuumand (2) the number of reactions and the fungus growth.
This experience illustrated the absolute necessity of utilizing a completelyclosed, continuous piece of rubber in the bottling of solutions for intravenoususe (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 closurewas by a single piece of rubber, the vacuum within the container was maintainedand contaminants could not enter. Solutions thus packaged had been observed for3-year periods without deterioration of either the rubber stopper or thesolution. The bottles in which fungus growth had developed were closed by a thinrubber diaphragm disk that covered the two holes in the stopper. Maintenance ofthe vacuum depended upon the disks' remaining in contact with the openings. Ifthe containers were handled roughly, this contact could be lost andcontamination could occur.
Because of this experience, Capt. Lloyd R. Newhouser, MC, USN,and Colonel Kendrick, with the aid of industry, devised specifications toprovide for an integrally molded stopper which completely sealed the opening ofthe bottle and maintained a vacuum of 27-29 inches (Hg) without leakage. Theclosure was further strengthened by the use of an aluminum cap and seal.Thereafter, all bottles for intravenous fluids and for blood were provided withthis type of closure.
Since the experience, unfortunate as it was, was limited to asingle hospital and steps had already been taken to correct the difficulties,Colonel Kendrick did not concur with the proposal that this hospital prepare itsown solutions and also prepare them for other hospitals in the vicinity.
European theater -Inquiries made in the Europeantheater after the experience in the China-Burma-India theater produced theinformation that, in general, the intravenous fluids supplied were extremelysatisfactory and that no known reactions had followed their use. It had beennecessary to discard about 2 percent of the flasks supplied by each of two firmsbecause of the presence of a visible precipitate in the solution. There was noloss of vacuum in these flasks. Cultures showed no growth, and efforts toidentify the precipitate as a mold had been unsuccessful.
It was decided that these solutions, like the ones that hadbeen unsatisfactory in the China-Burma-India theater, had been prepared whencommercial production was just beginning, before the new specifications forclosure of the flasks were written.
Distilled Water
In the summer of 1943, a number of complaints were receivedin the Supply Division, Office of The Surgeon General, (1) that the equipmentprovided did not produce distilled water of the quality required for theproduction of intravenous fluids, and (2) that the production of distilled waternever equaled the capacity stated by the manufacturers. Inspection ofinstallations in and near Washington and New York revealed that the stillscurrently supplied were entirely satisfactory for medical needs when they wereproperly cared for and operated. The principal factors required for theirefficient operation were maintenance of thermal pressure, a steady flow ofwater, and cleansing of the apparatus at regular intervals. Neglect of any ofthese factors caused unsatis-
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factory qualitative and quantitative production. Theintervals at which cleansing was necessary varied; the chemical composition ofthe water used might make it necessary every 24 hours. The efficiency ofpersonnel was the determinate factor in every operation.
The installation at one hospital was an ideal demonstrationof faulty operation and maintenance. A battery of three 10-gal. capacityprecision-type stills, set up to produce 10 gal. of triple-distilled water eachhour, was actually producing 1 gal. per hour because of leaks in the steam andwaterlines and lack of cleansing. The operating personnel could not recall everhaving cleaned the apparatus.
These visits of inspection furnished assurance that theequipment provided to Zone of Interior hospitals was adequate for the purposesfor which it was intended. In his report, Colonel Kendrick described a newstill, manufactured by the American Sterilizer Co., whose main advantage was itssimple design. It could be operated with any standard heating element andcleaned with an ordinary scrubbing brush. He recommended that due considerationbe given to this item in the preparation of future equipment specifications.
Colonel Kendrick also recommended that a circular letter beissued, announcing the policy of The Surgeon General that hereafter commerciallyproduced intravenous solutions would be furnished and that distilling apparatuswould not be required to produce distilled water of the quality essential forintravenous 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 onTransfusions, Division of Medical Sciences, NRC, 31 May 1940.
3. Minutes, meeting of Subcommittee on BloodSubstitutes, Division of Medical Sciences, NRC, 13 May 1943.
4. Minutes, meeting of Subcommittee on BloodSubstitutes, 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 BloodSubstitutes, Division of Medical Sciences, NRC, 10 Mar. 1942.
7. Minutes, meeting of Subcommittee on BloodSubstitutes, Division of Medical Sciences, NRC, 10 Nov. 1942.
8. Minutes, meeting of Subcommittee on BloodSubstitutes, 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 BloodSubstitutes, Division of Medical Sciences, NRC, 17 Nov. 1943.
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12. Minutes, Conference on Shock, Subcommitteeon 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 ofa Blood Plasma Substitute. Factors Affecting the Conglutination of HumanErythrocytes by Gelatin. Blood Substitutes Report No. 23, Division of MedicalSciences, NRC, 7 Dec. 1943.
18. Minutes, Conference on Pectin, Division of MedicalSciences, 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 AfterInjections of 1.5% Pectin Solution. Blood Substitutes Report No. 17, Division ofMedical 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 (-)-GlutamicAcid Polypeptide by Bacillus Subtilis. J. Biol. Chem. 145: 415-424, October1942.
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. BloodSubstitutes 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-ArterialHypertonic Saline Solution in Experimental Shock. Proc. Soc. Exper. Biol. &Med. 40: 114-116, January 1939.
32. Rous, P., and Wilson, G. W.: Fluid Substitutes forTransfusion After Hemorrhage. First Communication. J.A.M.A. 70: 219-222, 26 Jan.1918.
33. Robertson, O. H.: Transfusion With Preserved Red BloodCells. Brit. M. J. 1: 691-695, 22 June 1918.
34. Ohler, W. R.: Treatment of Surgical Shock in the Zone ofthe Advance. Am. J. M. Sc. 159: 843-853, June 1920.
35. Minutes, meeting of Subcommittee on Shock, Division ofMedical Sciences, NRC, 29 Jan. 1944.
36. Correspondence, Lt. Col. I. S. Ravdin, MC, and Office ofThe Surgeon General, 12 July-23 Oct. 1943, subject:Deficiencies in Intravenous Fluids, China Burma India Theater of Operations.
