The so-called “blood substitutes”

THE SOCALLED I. S. RAVDIN,

“BLOOD SUBSTITUTES”*

M.D. AND WILLIAM

T.

FITTS,JR.,

M.D.

Philadelphia, Pennsylvania

T

0 those interested in the broader aspects of trauma few probIems are of greater importance than the repIacement of the eIements of the bIood Iost foIlowing injury. The prevention and treatment of shock, whether caused by hemorrhage, burn or other severe tissue damage, depend chiefly on the earIy return to the circuIation of those eIements of the bIood that have been lost or destroyed. The proper healing of damaged tissues during the weeks foIIowing injury aIso demands replacement of those eIements of the bIood Iost graduaIIy through the wound. The dynamic equiIibrium’ between the body proteins and pIasma proteins requires that a norma pIasma protein volume be maintained before the body proteins wiI1 be adequate for tissue repair. If the building materials sufficient to maintain norma hemogIobin and plasma protein voIumes cannot be taken by mouth and assimiIated, they must be given parenteraIIy. Thus in the surgery of trauma the replacement of blood Ioss in a broad sense is of paramount concern. WHOLE

BLOOD,

FLUID

WITHOUT

A

SUBSTITUTE

The term blood substitute is a misnomer. The so-caIIed substitutes may maintain the circulating volume, but they cannot assume the oxygen-carrying function of the blood. When the bIood volume has been seriousIy depIeted by trauma, the initia1 probIem may of necessity be to restore the blood voIume with substitutes which tend to remain in circulation; eventuaIIy, however, the oxygen-carrying abiIity of the bIood must be revived and this requires replacement of lost red bIood cells. That whoIe bIood is the only entireIy effective repIacement folIowing severe trauma was repeatedly noted during World War II. At the beginning of the war it was naiveIy hoped that pIasma might indeed prove to be a compIete substitute. However, this hope was quickIy dispeIIed by combat experience. Churchill,* after extensive experience with the wounded in the Mediterranean Theatre, stated: “Plasma aIone is not adequate to prepare a seriousIy wounded

casuaIty to withstand the surgica1 procedures that are essentia1, or to carry him through the critica postoperative period. PIasma is a substitute for whoIe bIood onIy in the sense that it can be packaged and stored in adequate quantities in areas where blood cannot be obtained. PIasma is not a substitute for whoIe bIood in the physiologica sense.” Even though the circuIating voIume is maintained after trauma, faiIure to suppIy certain viscera with sufficient oxygen Ieads to an irreversible state of shock, after which the further administration of substitutes or even blood itseIf will not save the patient. The recent experiments of Fine and his collaborators3 on irreversibIe shock may partiaIIy expIain the need to maintain the oxygen-carrying power of the bIood. They observed that irreversible shock from hemorrhage could be prevented in dogs by perfusing the liver with we11 oxygenated bIood even though the arterial bIood pressure and the bIood volume were kept at a level identica1 with the contro1 animaIs which died. W-e11 oxygenated bIood perfused through the jugular vein did not prevent death. It seems Iikely that the liver is the “trigger organ” in the production of irreversible shock folIowing injury and that prevention of proIonged Iiver anoxia is vital. After severe injuries this usuaIIy requires whoIe blood. The recent reports of Evans” and Abbott5 emphasized that large volumes of whole bIood must be given to patients with burns. This is true not onIy during the later stages of burn anemia but aIso during the period immediately folIowing the burn, when shock is most apt to occur. According to hloyer6 whoIe bIood is Iost in burns from hemolysis and capiIIary stasis. In experimental burns in dogs Rloyer found that defibrinated whole bIood was much more effective in preventing death than plasma or other substitutes.7 By giving whoIe bIood soon after the burn occurs shock is more effectiveIy prevented and chronic anemia of the Iate stages is obviated. If, then, whole bIood is the best fluid re-

* From the Harrison Department of SurgicaI Research, Schools of Medicine, University of PennsyIvania Surgical Clinic of the Hospital of the University of PennsyIvania, PhiIadeIphia, Pa. 744

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placement foIIowing trauma, why is it pertinent to consider substitutes? Chieffy, for two reasons, namely, (I) because whoIe bIood can at present be preserved onIy for reIativeIy short periods, it is impossibIe to build stockpiIes suficient for a nationa emergency. The present blood procurement program is scarceIy abIe to meet the needs of civiIian hospitaIs in peacetime. In a nationa emergency, unIess better methods of preserving blood have been deveIoped, substitutes must be used as aIternative therapy. (2) In some injuries the Ioss of red ceIIs may be Iess than the Ioss of certain other fractions of the bIood. In these instances it is not onIy more economica but aIso safer to repIace only the substances Iost. To increase the number of red ceIIs above norma might overIoad the circuIation. In the stages of tissue repair following injury the pIasma proteins may be more depIeted than the red bIood ceils. In such instances it may be best to give pIasma alone. In stiI1 other instances when the red bIood ceIIs have been more depIeted than the pIasma, it may be advantageous to infuse suspensions of red bIood ceIIs separated from the pIasma. Suspensions of red ceIIs suppIy the elements most concerned with oxygen transport, whiIe not adding greatIy to the osmotic pressure of the blood. They are thus especiaIIy usefu1 in patients with anemia in whom there is unusua1 danger of overIoading the circuIation as, for exampIe, patients with heart disease. Methods of preserving the red ceIIs for Iong periods are being activeIy studied by several groups of investigators.8 HamiIton,g in our department, has been abIe to preserve the red bIood ceIIs of dogs for as Iong as eighty-one days by segregation at low temperatures and resuspension of ceIIs in suitabIe media. The fluids that have been used when whoIe bIood is not avaiIabIe or when it is desirabIe to suppIy especiaIIy depIeted fractions of bIood may be divided into the foIIowing two groups: bIood derivatives and pIasma substitutes. BLOOD

DERIVATIVES

The two bIood derivatives that have found genera1 use as substitutes for whoIe bIood are pIasma and aIbumin. Plasma. This bIood derivative was used extensiveIy in WorId War II. Before the war methods had been perfected for the preserva-

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tion of pIasma by drying it from a frozen state. Thus prepared and packaged the IabiIe components were preserved. PIasma can perform a11 the functions of whoIe bIood except those of the red bIood ceIIs. The functions of pIasma are maintenance and stabiIization of the pIasma voIume, transport of hormones between tissues, transport and mobiIization of antibodles, protection against bIood Ioss by components of the clotting mechanism, transport of Iipids and other substances cIoseIy associated with the pIasma proteins and nutritive functions of the pIasma proteins. Tremendous quantities of plasma were used during the war for the immediate treatment of shock from injury, for burns and to suppIy proteins when an adequate amount couId not be taken by mouth. PIasma saved many lives during the war. It must be reiterated, however, that pIasma is onIy an expedient and is not a complete substitute for whoIe blood in the treatment of shock due to hemorrhage or severe trauma. It must not be used to the excIusion of whoIe bIood in the immediate treatment of burns. The protein needs, at least of the experimental anima1, can be suppIied effectiveIy by giving pIasma intravenousIy. WhippIe et al.’ found that weight equilibrium and normal health couId be maintained in dogs for at Ieast three months with intravenous pIasma as the soIe source of protein, as Iong as the necessary carbohydrates, fats, saIts and vitamins were given by mouth. The cost of the method is excessive and this wiI1 probabIy prevent its use in man. The most serious complication from the use of pIasma has been homoIogous serum jaundice. Because the dried pIasma has been prepared from pooIs, consisting usuaIIy of eight donors, the virus of homoIogous serum jaundice has been spread much more wideIy by pIasma than by whole bIood. FoIIow-up studies of patients who have received pooled pIasma have shown that the incidence of homologous serum jaundice is about 5 per cent.l’,” Figure I shows the Iiver of a patient who received pooIed plasma on our service in 1946, because of a bIood pressure faI1 foIIowing choIecystectomy. He was readmitted sixty days Iater, severeIy jaundiced, and died of Iiver faiIure within five days. At postmortem examination aImost no viable Iiver ceIIs couId be discovered. Since that time we have not used

Ravdin, Fitts-BIood

FIG. I. Photomicrograph from homoIogous serum arc noted.

of liver of patient jaundice; no viable

who died Iiver cells

pooIed plasma unIess it has been treated to destroy the virus. Except in dire emergencies plasma from pools of more than two donors must not be given unIess the virus has been destroyed. Methods are urgently being sought which wiI1 destroy the hepatitis-producing virus in bIood and bIood derivatives without seriousIy affecting their usefu1 properties. The folIowing four methods have been proposed: heat, uItravioIet radiation, x-rays and cathode rays and the addition of chemica1 reagents. Of great promise are the reports of Hartman and his co-workers12 at the Henry Ford HospitaI. They observed that one of the nitrogen mustards, methyl-bisamine hydrochIoride (HNz), has effective viracida1 and bactericida1 effects in the presence of either pIasma, serum or whoIe bIood and that the end effects of the added nitrogen mustards are non-toxic if the pH of the system is not too Iow. Red bIood ceIIs, complement, immune bodies, phosphatase, and fibrinogen were reported to be affected onIy sIightIy by effective doses of HN2. The prothrombin time, however, was greatIy prolonged. WhiIe the use of nitrogen mustards is stiI1 in the experimenta stage, uItravioIet irradiation has been reported to be an effective and practica1 method of freeing pIasma from the hepatitisproducing virus. Levinson and co-workers13

Substitutes

have reported the administration of over 5,000 doses of irradiated human pIasma to patients with no iI effects and no evidence to indicate that the procedure does not destroy the virus. AbeIson,14 working with human volunteers, found that in seven of fifteen controIs hepatitis deveIoped when they were given serum containing the virus, while in none of eleven volunteers receiving irradiated serum did hepatitis develop. At the Hospital of the University of PennsyIvania we have just begun to use irradiated pIasma for routine use. Methods by which whoIe blood can be effectiveIy irradiated have not yet been reported. In fact this may not be possible. Of the two remaining methods proposed for steriIization heat has been used for serum aIbumin and wiI1 be discussed Iater; x-rays and cathode rays are stiI1 in the experimental stage. If these methods for sterilization prove practical and effective on a Iarge scale, Iarge stores of purified pIasma shouId be buiIt up for emergency use. War II human serum aIbumin was produced in purified form from the fractionation of pIasma and used chiefly as a substitute for whole blood in the treatment of shock.8,15 The aIbumin moIecuIe is Iarge enough to be heId in the bIood and yet smaI1 enough to have a high osmotic potency. One hundred m1. of 25 per cent norma human serum aIbumin is osmotically equivalent to 500 m1. of titrated pIasma. Thus it combines the advantages of a smaI1 voIume with high osmotic efficiency. It is stabIe and can be dispensed in an aqueous soIution. It has, therefore, severa advantages over dried pIasma: it can be administered immediateIy without having to be dissoIved and it does not require a soIute for shipping. Any of the soIutions for parentera use may be empIoyed in any desired concentration. A 5 per cent soIution of aIbumin in saIine is equivaIent to 500 m1. of pIasma and can be substituted for pIasma in the treatment of burns. Originally, aIbumin was suppIied dissoIved in twice isotonic sodium chIoride soIution containing a mercuria1 bacteriostatic agent. Its use for the treatment of cirrhosis of the Iiver with ascites and for the nephrotic syndrome led to the development of salt poor solutions without a mercuria1. The new standard aIbumin soIution is 24 per cent albumin at a pH of 6.8 with a Iow sodium content, with no mercuria1 agent, and with ten hours of heating at

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60’~. to destroy the virus of homoIogous serum jaundice. The intoIerance of the body to salt during the first twenty-four to forty-eight hours after surgery has been emphasized by CoIIer,@ and it is IikeIy that types of trauma other than surgery aIso produce salt intoIerance. A soIution of aIbumin with a Iow saIt content shouId be more acceptabIe for use in trauma than the oId soIution. An exception might be burns, however, in which large amounts of extraceIIuIar sodium are lost and must be repIaced. Because of the high osmotic efficiency of aIbumin, care must be taken not to overload the circulation and produce puImonary edema. Overloading is much more apt to occur when aIbumin is given for Iiver cirrhosis and for the nephrotic syndrome, but is possibIe even after trauma. PLASMA

SUBSTITUTES

Because of the great diff&Ities noted before in buiIding up stockpiles of whoIe bIood and bIood derivatives for a nationa emergency, the deveIopment of a safe and efficient pIasma substitute is needed. The two most promising substances that have been proposed as pIasma substitutes are geIatin and dextran. Gelatin. During the years 1942 to 1944 an intensive experimenta and cIinicaI study of gelatin was made in our department by Koop and his associates.‘7-21 Ossein geIatin prepared as a 4 or 6 per cent soIution was found to be both safe and effective when given intravenously for the treatment of the earIy stages of traumatic shock. This gelatin, prepared from the Iong bones of cattIe, is composed of reIatively Iong moIecuIar chains which are not excreted by the kidney as rapidIy as shorter molecular geIatin. It remains in the bIood stream from three to five days. No significant damage to vita1 organs has been noted either in animals or in humans. HeuperZ2 reported that in dogs large quantities of geIatin impaired the production of plasma proteins and hemoglobin, and produced degenerative and proIiferative arteria1 lesions of the scIerosing type. When given in amounts comparabIe to those which n-ouId be given to humans for the treatment of trauma, gelatin was found to be innocuous in experimental animaIs.23 Careful pathoIogic studies in human beings have failed to show significant tissue damage from geIatin infusions. Six per cent geIatin soIution has twice the os-

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motic pressure of pIasma and accordingly must be given with great care to patients with cardiac damage. The maximum blood voIume increase occurs about three hours after the infusion. DiflicuIty with bIood typing and crossing is encountered after infusions of many of the macromoIecuIar soIutions that have been used as pIasma substitutes. The cause is pseudoagglutination, and it is noted after infusions of geIatin. For this reason it is advisabIe to take a blood sampIe for typing and crossing before the pIasma substitutes are given. If no sampIes have been obtained, however, the addition of I per cent gIycine soIution to the serum mixture has been found to prevent pseudo-aggIutination.24 PracticaI advantages of geIatin are its avaiIability, Iow cost and freedom from reactions. The disadvantages of geIatin are (I) it is probabIy not metaboIized by the body and (2) it is in the physica state of a ge1 at low temperatures and runs sIowIy through intravenous equipment. The first disadvantage is a minor one, because the chief purpose of a pIasma substitute is the emergency treatment of shock or impending shock. Whether the infused solution suppIies caIories is of no rea1 importance. The second disadvantage is real and one that we found to Iimit its use greatly under battIe conditions in Burma during 1943 and 1944, especiaIIy during the winter months. The geIatin can be kept Iiquid by storing it at more than 30’~. or by heating the bottIe before use. In the emergencies in which a pIasma substitute is most needed, however, heating may be impossibIe. GeIatin soIutions that remain in a Iiquid state at low temperatures have been produced, but they consist of smaIIer moIecuIar particles that are rapidIy Iost from the circuIation and thus do not exert the same efficiency in the treatment of shock. Dextran. Dextran was first discovered in Germany as a mucoid materia1 formed during the extraction of sugar from beets.25z26 Found onIy in those sugar soIutions infected with the bacterium, Ieukonostic mesenteroides, it is a poIysaccharide buiIt from gIucose moIecuIes by this organism. For use as a pIasma substitute dextran is hydroIyzed so that its particIes attain a range of moIecuIar sizes cIose to that of the pIasma proteins, about IOO,OOO. The smaIIer dextran moIecuIes (from fo,ooo to 60,000) are excreted rapidIy through the kidneys, but the

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larger ones are retained Ionger in the bIood stream, disappearing onIy after four days. FoIIowing infusions of dextran the sedimentation rate is increased but it returns to norma within a few days. Dextran has been used extensively in Sweden during the Iast few years with the resuIts reported as exceIIent. Thorsen*’ reports the use of 20,000 units given to 3,000 patients and states that it is an effective pIasma substitute, that is non-injurious to tissues, IocaIIy and systemicalIy. He states that it is used routineIy at his hospita1 to prevent shock in major operations, and that the hospita1 transfusion services in Sweden reIy to a Iarge extent on dextran for emergency cases. Animal studies in this country have shown that when given in amounts comparabIe to those which wouId be used in humans, dextran is not harmfu1 to tissues.28 AI1 reports of the use of dextran have not been favorabIe. In 1946 a group of thirty patients at the Presbyterian Hospital in New York City were given dextran intravenousIy with severe anaphyIactic or anaphyIactoid reactions in one-third of them.2g Because of the freedom from reaction reported by others, it appears probabIe that the soIutions used by the Presbyterian HospitaI contained impurities. Dextran is now being studied at the HospitaI of the University of PennsyIvania.30 To date thirty patients have been given dextran with onIy one reaction (a miId chiI1 and fever), and with cIinica1 responses that indicate it is an effective pIasma substitute. Dextran has been especiaIIy vaIuabIe on the Iabor floor and in the receiving ward for the emergency treatment of hemorrhage whiIe whoIe bIood is being obtained. Whether dextran wiI1 prove to be of such vaIue that Iarge stockpiIes shouId be manufactured depends on the results of further study, but reports to date are encouraging. SUMMARY I. There are no substitutes for whole blood. The so-caIIed blood substitutes may maintain bIood voIume but do not replace the oxygencarrying capacity of bIood. Oxygenation of the tissues is vita1 foIIowing trauma and anoxia leads to irreversibIe shock-possibIy initiated through damage to the Iiver. 2. The bIood derivatives, pIasma and albumin, are usefu1 in the management oftrauma, especiaIIy in emergencies whiIe whoIe bIood is

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being procured and when the pIasma voIume has been more depIeted than the red ceI1 VOIume. Because of the danger of homoIogous serum jaundice, pooIed pIasma must never be given unIess it has been freed of virus. At present, uItravioIet irradiation is the most practica and efficient means of steriIization. 3. Effective pIasma substitutes are needed because it now appears impossibIe to build stockpiIes of bIood and bIood derivatives suff~cient to meet a nationa emergency. Of the pIasma substitutes now advocated, geIatin and dextran are the most promising. REFERENCES I.

2.

3.

4.

5.

6.

7.

TERRY, R., SANDROCK,W. E., NYE, R. E., JR. and WHIPPLE G. H. Parentera pIasma protein maintains nitrogen equilibrium over tong periods. J. Exper. Med., 87: 547-559, 1948. CHURCHILL, E. D. The surgical management of the wounded in the mediterranean theater at the time of the falI of Rome. Ann. Surg., 120: 268% 283, 1944. FRANK, H. A., SELIG~IAN, A. M., and FIXE, J. Traumatic shock; prevention of irreversibiIity in hemorrhagic shock by vivi-perfusion of Iiver. J. Clin. Investigation, 25: 22-29, 1946. EVANS, E. I. and BIGGER, I. A. The rationale of whoIe blood therapy in severe burns. Ann. Surg., 122: 693-705, 1945. ABBOTT, W. E., PILLING, M. A., GRIFFIN, G. E., HIRSHFELD, J. W. and MEYER, F. L. Metabolic. aIterations foIIowing thermaI burns. Ann. Surg., 122: 678-692, 1945. MOYER. C. A. Recent advances in the chemical supportive therapy of thermal injury. Texas State J. Med., 45:‘635-639, 1949. MOYER, C. A., &ILL&, F~~A.,-I~on, V., VAUGHAN, H. H. and MARTY. D. A studv of the interrelationship of saIt sol&ions, se,& and detibrinated blood in the treatment of severely scalded, anesthetized dogs. Ann. Surg., 120: 367-376,

1944. 8. JANEWAY, C. A. CIinicaI use of bIood derivatives. J. A. M. A., 138: 859-865, 1948. 9. HAMILTON, ANGIE. Personal communication. IO. SPURLIXG, N., SHONE, J. and VAUGHAN, J. The incidence, incubation period, and symptomatology of homologous serum jaundice. hit. M. J., 2: 409-412, 1946. 1I. BRIGHTMAN, I. J. and KORXS, R. F. Homologous serum jaundice in recipients of pooled plasma. J. A. M. A., 135: 268-272, 1947. 12. HARTMAN, F. W., MANGUN, G. I-i., FEELEY, N. and JACKSON, E. On the chemical sterilization of blood and blood oIasma. hoc. Sot. Emer. Biol. U Med., 70: 2481254, 1949. 13. LEVINSON, S. 0. and OPPENHEIMER, F. Condensed notes on uItravioIet sterilization of plasma and blood. The preservation of the formed elements and of the proteins of the bIood. Conference caIIed at the reauest of the Committe on Medica1 Sciences of the Research and Development

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14.

15.

16.

17.

18.

19.

20.

21.

Harvard MedicaI School, Boston. Janu8, 1949. ABELSON, N. Inactivation of hepatitis virus, J. H. clinical study. The preservation of the formed eIements and of the proteins of the blood. Conference calIed at the request of the Committee on Medical Sciences of the Research and DeveIopment Board, Harvard MedicaI School, Boston. January 6, 7, 8, Ig4g. SCATCHARD, G., STRONG, L. E., HUGHES, W. L., JR., ASHWORTH, J. N. and SPARROW, A. H. Chemical, cIinica1, and immunoIogica1 studies on the products of human pIasma fractionation. XXVI. The properties of solutions of human serum aIbumin of Iow salt content. J. Clin. Invesfigaiion, 24: 671679, 1945. COLLER, F. A,, IOB, V., VAUGHAN, H. H., KALDER, N. B. and MOYER, C. A. TransIocation of fluid produced by the intravenous administration of isotonic salt solutions in man postoperativeIy. Ann. Surg., IZZ: 663-677, 1945. KOOP, C. E., RIEGEL, C., VARS, H. M., RATCLIFFE, H. L., PARKINS, W. M. and LOCKWOOD, J. S. Observations on toxicity and eIimination of geIatin. Am. J. M. SC., 205: 876, 1943. PARKINS, W. M., KOOP, E. E., RIEGEL, C., VARS, IH. M. and LOCKWOOD,J. S. GeIatin as a pIasma substitute; with particuIar reference to the experimenta hemorrhage and burn shock. Ann. Surg., 118: 1g3-214, 1943. KOOP, C. E., FLETCHER, A. G., JR. and RIEGEL, C. Some cIinica1 experience with geIatin as a pIasma substitute. Am. J. M. SC., 207: 415, 1944. KOOP, C. E., FLETCHER, A. G., JR., RI~GEL, C. and LOCKWOOD, J. S. GeIatin as a pIasma substitute: a preliminary report of cIinica1 experiences. Surgery, 15 : 839-858, 1944. FLETCHER, A. G., JR., HARDY, J. D., RIEGEL, C. and KOOP, C. E. GeIatin as a pIasma substitute: the effects of intravenous infusion of gelatin on cardiac output and other aspects of the circuIation of normal persons, of chronicaIIy iI patients, and of norma voIunteers subjected to Iarge hemorrhage. J. Clin. Investigation, 24: 405-415, 7.

1945. 22. HEUPER, W. C. Experimental studies in cardiovascular pathology: effects of intravenous injections of solutions in gum arabic, egg aIbumin and geIatin upon bIood and organs of dogs and rabbits. Am. J. Patb., I 8: 895, 1942. 23. VAN DER BROOK, M. J., LYSTER, S. C., GRAHAM, B. E., POMEROY, N. E. and CARTLAND, G. F. Intravenously administered gelatin a toxicity study. J. Lab. Clin. Med., 32: 1115-r 120, 1947. 24. KOOP, C. E. and BGLLITT, L. GeIatin as a pIasma substitute: the effect of geIatin infusion on the subsequent typing and cross-matching of the bIood, with a method of eliminating the phenomenon of pseudo-agglutination. Am. J. M. SC., 209: 28-33, 1945. 25. EditoraI. Dextran as a pIasma substitute. J. A. M. A., 139: 850, 1949. 26. GRONWALL, A. and INGELMAN, B. Untersuchungen uber Dextran und sein VerhaIten bei parenteraler Zufuhr. Acta pbysiol. Scandinav., 7: 97, 1944 and 9: 1, 1945.

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27. THORSEN, GUNNAR. Dextran as a pIasma substitute. Lancet, I: 132, 1949. 28. GOLDENBERG, M., CRANE, R. D. and POPPER, H. Effect of intravenous administration of dextran, a macromoIecuIar carbohydrate, in animals. Am. J. Clin. Path., 17: 939-948, 1947. 29. TURNER, F. P., BUTLER, B. C., SMITH, M. E. and SCUDDER, J. Dextran. An experimenta pIasma substitute. Surg., Gynec. Ed Obst., 88: 661-675, 1949. 30. GIMBEL, N. S. Persona1 communication. DISCUSSION CURRY,

OF

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PAPERS

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LINDEM,

AND

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DODDS AND

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R. ARNOLD GRISWOLD, (LouisvilIe, KY.): The papers presented by Drs. Dodds and NeIson are on an extremeIy important subject. Whether the dye that is being used at present wilI be the finat answer, I am not sure. Many physioIogists object to this particular method because they believe that it is not accurate enough. This Iack of accuracy may be a hindrance in strictIy scientific Iaboratory work. However, the two papers this morning have shown that it is sufEcientIy accurate for cIinica1 work. I shouId Iike to emphasize that even with these laboratory methods we shouId not forget our clinical examination of or our cIinica1 impression of the patient. You have a11 had interns and residents, I am sure, tell you that a patient was not in shock because he had a systoIic pressure of 120; and yet, when you Iooked at him he was coId and clammy and you knew that he was in shock. This appIies to one of the patients shown in the first paper, one of the two women in the same automobiIe accident. The one who had multipIe fractures obviously had severe enough injury to produce shock, although her puIse and bIood pressure were within norma Iimits on admission. Very shortly, as shown by the chemica1 studies, and verified by her cIinica1 appearance, she was in shock. For this reason we shouId not forget to appraise these patients thoroughIy while awaiting the Iaboratory reports. The paper by Dr. Fitts re-emphasizes the fact that there are no adequate substitutes for whole bIood. In this connection I shouId Iike to remind you that in hemorrhage into the serous cavities, autotransfusion is stiI1 a safe, feasibIe and practical method of putting bIood into these patients whiIe you are waiting for bIood to come from a bIood bank or waiting for typing and cross-matching in an emergency. Autotransfusion is safe if it is done within the first twenty-four hours following injury. After that period of time hemoIysis is IikeIy to make it dangerous; but when it is done a short time after the hemorrhage, it is a safe, feasibIc and practical method of restoring bIood voIume. CHARLES G. JOHNSTON (Detroit, Mich.): I want to reiterate what Dr. Griswold has said about bIood

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volume studies and their accuracy. I, too, have great doubts about the accuracy, especially the accuracy in relation to injuries, because there are a great many changes which take place that will cause differences in what you are measuring. If it were just as simpIe as putting a batch of measured dye into a bucket of water, shaking it up and then taking a bit of the water and analyzing it to determine how much water was in that bucket, that wouId be a11 right; but we a11 know there are a great number of changes that take pIace in the blood stream in shock, not onIy IocaIIy but also generaIIy. Dr. Noer in our Iaboratories has been carrying on some studies with distention. Even slight amounts of distention cause great changes in the smaIIer vessels. The blood is heId IargeIy in Iarge and smaI1 vessels. Great amounts of it are heId in the smaIIer vessels which dilate and contract, and which Ieak blood out through the capiIIaries. Therefore, any measure of blood voIume which takes in onIy a measure of the circuIating vohrme wiII be quite variable and cause an inaccuracy if one is determining or trying to determine how much bIood to repIace. In this regard I think there is a tendency, with bIood banks available, to give too much bIood. FrequentIy, this is Ieft to the anesthetist, and the anesthetist often wiI1 pour blood into patients who reaIIy need no bIood repIacement at the time, with the incident dangers which are associated with blood transfusion. Blood transfusion is not an absoIuteIy safe procedure because there are probIems reIating to some of the side groups which cause serious troubIe, especially with massive transfusions, even if it is cross-matched weII. I have seen patients who have been compIeteIy saturated with blood when they needed onIy a IittIe bit, with continuous bIood transfusion running in, because the operative procedure seemed to be one which was going to be quite heavy. The anesthetist thought he wouId get ahead of the surgeon and pour in plenty of bIood. I think one must, therefore, be carefu1 about that aspect as well. Now, with regard to the blood substitutes, this has been a perennia1 probIem. Dr. Fitts and his group have been studying it for a long time and they have shaken it down to one of simplicity; that is, a matter of getting something which we can put into a vesse1 which wiI1 keep the circuIating voIume up even though there is a Iimited amount of hemoglobin to keep the respiratory mechanism going. Nevertheless, it does keep the bIood circuIating around the vita1 structures, and it is important that we have this immediately, especiaIIy in cases in which there is not bIood avaiIabIe and we11 crossmatched. It is important that we use a substitute that does not cause difficulties or harm; and whiIe we have had no experience with dextran, we do know that the gelatin substance, from experience

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of others, does do very IittIe harm and does give us a fairly good immediate restoration of volume. However, it must be replaced by bIood at some time or other. Whether one can put volume for volume back is: to me, stiI1 a moot problem. I do not believe it is possible to measure blood Ioss accurately enough to repIace voIume for volume, but Dr. Nelson’s and Dr. Dodds’ studies indicate that one can get a fair approximation from such studies, even though the possibiIities of error are great. MARTIN C. LINDEM (SaIt Lake City, Utah) : I am not going to make any apologies for blood voIume determinations. If the proper indications for making them are carried out, the accuracy of the method cannot be contested. We could review Dr. Nelson’s paper again and apply some of the proofs that we have, but I wiII direct my discussion to what Dr. NeIson has presented from our work and emphasize some of his points. I should like to stress our belief that the T-1824 blue dye method of quantitative determination of blood constituents and caIcuIating their deflection from standard is a dependable procedure. Let me emphasize that we caIcuIate the deficiency from a similarly determined standard. We are not trying to caIcuIate the actua1 amount of bIood that shouId be in the circuIatory system. This laboratory procedure, carried out for an objective determination, has a very negIigibIe coeffrcient of error. The dosage of blood needed for replacement is exactly measured; hence, guesswork about the amount of bIood to be transfused is eliminated. Of hemoglobin 75 gm. are contained in 500 units of transfused brood; and on that basis, we caIcuIate the hemogIobin deficiency and replace it voIumetricaIIy by that amount of blood bank blood. The clinical observation has been made that when voIumetric replacement of blood was done, no operative shock occurred in any one of our patients, although many of them were in very poor condition before they had been given a transfusion and brought back to the standard. A question asked is, should blood voIume studies be done preoperativeIy on a11 major surgical cases? The answer is definiteIy no. There is no more valid reason for doing routine bIood voIume tests on genera1 surgica1 patients than there wouId be for doing routine Iiver function tests on a11 cases coming to the internist. There is a specific indication based on clinica history of bIood loss or nutritional dehciency. There is also an inherent morbidity in a11 laboratory tests. Venipunctures are painful; hematomas occur, as we11 as extravasation, when you puncture the vein; and a protonged discoIoration about the skin puncture may occur from a spilIage of the dye. Other studies previously pubIished have shown that blood constituent depletion is a consequence of a variety of clinical and pathologic conditions. But

American

Journal

of Surgery

Ravdin,

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when trauma occurs on the ski slopes, (in this candidate for injury we wouId certainIy expect no depleted individuals; however, they are there) on the highway or in the home, this selective indication pertains. That a thorough cIinica1 evaIuation must first precede the indication for bIood voIumetric determination is evident. PHILLIP B. PRICE (Salt Lake City, Utah): It is significant that bIood voIume, which has long been IargeIy of academic interest, has now come to have sufficient cIinica1 interest for three papers in this conference to be devoted to it. After having worked with the probIem of bIood volume measurements for many years and having preached the cIinica1 importance of bIood voIume, I now find myself in the somewhat unfamiIiar role of voicing a word of caution against any rule-ofthumb approach to the probIem or any policy of blood repIacement by formuIa. We have the problem first of accurate measurement of bIood volume. Even assuming that our methods are suffrcientIy accurate for clinical use, we cannot use the hematocrit without great caution in any indirect measurement of either pIasma VOIume or ceI1 voIume. There is aIso the difficuIt problem of trying to measure bIood deficits, since we do not know in any given case what norma blood VOIume is. We have the diffrcuIt probIem aIso of proper bIood repIacement. The body is abIe to compensate to a certain extent; transfusions often have onIy transient effects; one must depend eventuaIIy on bIood regeneration. Each of those factors needs to be assessed, but we have at present no good way of assessing them. We need better Iaboratory methods to estimate bIood deficits, and we need more reIiabIe cIinica1 criteria of adequate re-estabIishment of bIood voIume and adequate circuIatory function. CHARLES H. MAGUIRE (LouisviIIe, KY.): I certainIy enjoyed a11 three of these beautifuIIy done papers, but I think the point that Dr. Johnston brought up shouId be emphasized and stressed. That is the practice, because of our bIood banks, of the wholesale use of bIood by the anesthetist in as he mentioned, to “get ahead of the order, surgeon.” In our experience it does not take much bIood, given during an operative procedure, to put the patient in a fairIy critica condition. Too much blood over a short period of time brings on an acute puImonary edema which, if it is not corrected, can be fatal. Two practica1 things that shouId be used at the very first sign of puImonary edema are the foIIowing: IOO per cent oxygen under positive pressure venesection. If you have given the patient too much bIood, if he shows a IittIe sign of puImonary edema, take some of that bIood away. We have had severa cases in which we realized shortIy after surgery was compIete that we had

November

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given the patient too much blood. They were given IOO per cent oxygen under pressure and as much as I ,000 cc. of bIood removed. Those are two practical things that can be done if the anesthetist tries to stay too far ahead of the surgeon. STEPHEN S. HUDACK (New York, N.Y.): I do not beIieve we should rest content with estimations of bIood voIume, because the voIume of the bIood, unIess it is circuIating, is physioIogicaIIy unimportant. For that reason we have been working on a practica1 use for the baIIistocardiograph so that we may know, from instant to instant, the cardiac output of a patient going through a severe surgica1 procedure. BIood voIumes, however, have been necessary in my experience in operating upon criticaIIy ill peopIe who have been III for a Iong time. In this way we have some idea of what their vascuIar tree is doing. I have found some individuaIs who, iI from a serious tumor Iesion for months before being seen, may have a contraction of the vascuIar tree of 40 per cent. When serious surgica1 procedures are contemplated on an individua1 Iike that unIess you know what the vascuIar tree has done and on what margin of safety you can operate, tread cautiousIy or you may be in trouble. ALEXANDER VON LUTZKI (BerIin, Germany): I do not think there is much that can be added to what has been said, but I wouId like to emphasize the fact that thirty years ago traumatic surgery deaIt chiefly with the mere sequeIae of the injury itself. The traumatic surgeon considered chiefly the fractures, wounds and a11 those things that were dcstroyed in the norma anatomy. Today, traumatic surgery is far more physioIogicaIIy minded, and in Germany we beIieve that this wonderful deveIopment is very much due to the efforts of American surgery. I think it is correct to state that it is most important to maintain, keep up and restore not only the norma anatomy but aIso the norma physioIogy. That can be achieved in this country by many wonderfu1 Iaboratory examinations which are possible because of the very compIete technica equipment here, which we do not have in Germany or in most European countries. I beIieve it is fine when you are abIe to determine exactIy what has to be repIaced, and you can give the proper repIacement on the basis of exact chemica1 and Iaboratory examinations. We must reIy far more on cIinica1 judgment and the clinica condition that the patient presents. I think in aImost a11 the cases that we see-and I think I am in agreement with the gentIeman who emphasized this fact in the emergency cases-it is more important to see quickIy what is the matter with the injured patient and to act quickIy rather than to wait for a lot of checks. There is one thing in particuIar which I shouId Iike to emphasize. We had one type of injury in

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which I beheve there was a strict contraindication to any bIood or plasma transfusion. Let us take a man who fell down from a roof and had a bhmt injury, for instance, of the abdomen, with no fractures and IittIe or no bIood 10s~. You see him first when he is brought into the hospita1 and notice he has a coId sweat on his forehead, his puIse is very strong and his bIood pressure is eIevated. We think these are cases in which there is an irritation of the sympathetic nervous system, which pIays an important roIe in this type of trauma, so that the vascuIar tree is contracted generaIIy. Here it wouId be wrong to pump bIood into the circulatory system, the capacity of which for the moment at least is narrowed. In such cases we wait and give the patient a rest. We give morphine or other sedative therapy, and wait until the irritation of the sympathetic nervous system is over and the vascuIar tree again widens. However, the patient may not recover from the reaction and passes into a state which we call coIIapse. The first condition I described is what we calI shock. When a coIlapse comes, we believe it is necessary to restore the circuIating bIood voIume by giving a blood transfusion. WOODRO~ NELSON (closing): I believe the inherent errors in the bIue dye method are minimized by the use of basal conditions during the determination. For this reason, because basa1 conditions are not obtained in the immediate posthemorrhagic period, we have not used this method immediateIy folIowing trauma. With regard to the discussions of Drs. Maguire and Johnston, I think the best protection against overtransfusion in the depIeted patient is bIood volume measurement and voIumetric repIacement. We have had no diffrcuIty with hydremia or with pulmonary edema in patients with quantitative correction preoperativeIy of measured hemogIobin deficits. I shouId have defined the state of chronic shock, which was originalIy defined as a syndrome characterized by weight Ioss, decreased bIood voIume, increased interstitia1 fluid voIume and increased SusceptibiIity to shock, rectifiable by bIood transfusion replacement. Why this state of affairs occurs, we are not sure. It has been hypothesized that it is on the basis of protein depIetion and decreased elasticity of the interstitia1 tissue. Certainly, a fertiIe heId awaits further investigation of better methods for determining bIood voIume and aIso further investigation of fluid interchange in the body. MAX E. DODDS (cIosing): I think that in a few words Dr. GriswoId and Dr. Johnston have given a very fair representation of the method. We have not by and Iarge attempted to repIace bIood exactIy volume for voIume. AIso, we have not replaced our tota caIcuIated deficits a11 at one

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time. We have repIaced what we thought was necessary, repeated our determinations and attempted to correIate them in that fashion. It has been surprising to us how quickly some patients, foIlowing acute trauma, have repIaced or even formed excessive pIasma vobrme. We beIieve that a compIete replacement of caIcuIated hemogIobin or tota voIume deficit, given over a short period of time, can very easiIy put the patient in puImonary edema. The one other point I want to mention is that regarding the caIcuIated normaI. We have used body weight simpIy because we have found no better coroIIary. That is probabIy one of the greatest sources of error in the method, not knowing the exact norma for various individuals. However, we have foIlowed the suggestion offered by Gregersen. In the very debiIitated and underweight, or in the very obese patients, rather than using their existing weight, take what wouId be considered a more norma1 weight for that individua1. ConsequentIy, the very obese person shouId not have the Iarge caIcuIated voIume repIaced, whiIe in the very debiIitated you may find that for the normaI weight their volume deficit is much greater than that calcuIated for their existing weight. WILLIAM T. FITTS, JR. (cIosing): SeveraI of the discussers brought up the probIem of giving too much blood and stated that the anesthesioIogist often overIoaded the circuIation with whoIe blood at the operating tabIe. For us this has not been a probIem in routine major operations, but for operations of the magnitude of WhippIe resections of the pancreas, portacava1 shunts or extensive chest operations, in which up to 4,000 or 3,000 cc. of blood may be Iost, it is a rea1 problem. In this regard some of the surgeons in our department have found it practica1 to use the dry sponge technic described by Dr. Gross of Boston: a11 sponges are weighed before operation and the blood Ioss estimated by calcuIating the increase in weight of the sponges discarded during operation. Blood can then be repIaced as it is Iost. Certainly, this method is not absoIuteIy accurate, but our chest surgeons, who have used it extensiveIy, believe that it is extremeIy heIpfu1. Often, patients who have been given as much as 3,000 cc. of blood on the operating tabIe are noted postoperativeIy to have bIood voIume determinations close to normaI, blood repIacement having been guided at operation by the dry sponge technic. The probIem of pseudo-agglutination was not discussed because of lack of time. Those of you who use geIatin or dextran shouId remember that they may produce pseudo-agglutination of red ceIIs, which interferes with bIood typing and crossing. A specimen for typing and crossing should be obobtained before such macromoIecuIar soIutions are injected.

American

Journal of Surgery