420 POST GRADUATE MEDICAL JOURNAL Se.temb'err [949LOUIS, P. C. A. (1829), 'Recherches anatomiques, pathologiques

et th6rapeutiques sur la malade connue sous les noms de gastro-enterite, etc.,' Paris, J. B. Bailldre.

McSWEENEY, C. J. (I937), Brit. Med.7., 2, 1118.McSWEENEY, C. J. (I946), Lancet, 2, II114.Med. Research Council (i943), War Memo. Io.Monthly Bull. Emerg. Publ. Hlth. Lab. Service (1943), 2, 59.MURGATROYD, F. (I949), Brit. Med. Y., x, 851.ONODERA, N., MURAKANA, G., and LIU, S. (I93i), Dtsch.

Arch. f. Klin. Med., 171, 503.PARSONS, C. G. (I948), Lancet, I, SIo.PARTINGTON, C. N., and COOPER, T. V. (1948), Brit. Med. .,

2, 298.PETIT, and SERRES (I813), 'Trait6 de la fibvre entero-

mesent6rique,' Paris.PETTENKOFER, MAX von (I929), cited by GARRISON,

F. H., 'An introduction to the History of Medicine,' W. B.Saunders Coy.

PIJPER, A., and CROCKER, C. G.'(x939), S. Afr. Med. 7., 13, 255.REIMANN, H. A., ELIAS, W. F., and RICE, A. H. (i945),

J. Am. Med. Ass., I28, 175.RITCHIE, C. (I846-7), Monthly J. Med. Sci. Lond. & Ed., 7, 247.ROBERTSON, R. C., and YU, H. (1936), Brit. Med. 7., 2, II38.RUMBALL, C. A., and MOORE, L. G. (I949a), Brit. Med. J., ,

615.RUMBALL, C. A., and MOORE, L. G. (I949b), bid., ., 943.RUSSELL, F. F. (I913), Harvey Lecture.RUSTEIN, D. D., STEBBINS, R. B., CATHCART, R. T., and

HARVEY, R. M. (I945), 7. Clin. Invest., 24, 898.SAPHIR, W., BAER, W. H., and PLOTKE, F. (1942), J. Am.

Med. Ass., II8, 964.SAPHIR, W., and HOWELL, K. M. (1940), Ibid., 114, 1988.

SAVINO, E., and MENENDEZ, P. E. (r934), Rev. Inst. Bact., 6,347.

SCH(ENLEIN, J. L. (x839), 'Allegemeine und specielle Pathologieund Therapie,' Freiburg.

SCHOTTMULLER, H. (x900), Dtsch. med. Wschr., 26, 5Ix;SCHOTTMULLER, H. (i90I), Z. Hyg. Infektkr., 36, 368.SCHWABACHER, H., TAYLOR, J., and WHITE, M. H. G.

(1943), Brit. Med. J., 2, 358.SMADEL, J. E., LEON, A. P., LEY, H. L., and VARELA, G.

(I948), Proc. Soc. Exper. Biol. N.Y., 68, 12.SMITH, J. and SCOTT, W. M. (I930), J. Hyg., Camb., 30, 32.STUART,V. E. (I948), Brit. Med. Y., 2, 77.TOPLEY, W. W. C., and WILSON, G. S. (1946), 'Principles of

Bacteriology and Immunity,' 3rd ed. Revised by G. S. Wilsonand A. A. Miles, London, Edward Arnold & Co.

TROUSSEAU, M. (I826), Arch. Gin. de Mid., to 67. Quoted byMAJOR, R. H. (I945), 'Classic Descriptions of Disease,' 3rded. Illinois, C. C. Thomas.

WARD, W. E. (z943), J. Infect. Dis., 72, I72.WIDAL, G. F. I., and SICARD, A. (I896), Bull. Mim. Soc. Mid.

H6p., Paris, 3 ser., 13, 68i.WILLIS, THOMAS (I684), ' Practice of Physick,' Basset, London.

Quoted by MAJOR, R. H. (I945), 'Classic Descriptions ofDisease,' 3rd ed. Illinois, C. C. Thomas.

WOODWARD, T. E., SMADEL, J. E., LEY, H. L., GREEN,R., and MANIKAR, D. S. (1948), Ann. Intern. Med., 29,131.

WRIGHT, A. E. (I902), Lancet, 2, 65I.WRIGHT, A. E., and LEISHMAN, W. B. (I9oo), Brit. Med. J.

I, I22.WRIGHT, A. E., and SEMPLE, D. (I897), Brit. Med. J., x, 256

A SURVEY OF RECENT DEVELOPMENTS INBLOOD TRANSFUSION

PART I

By R. DRUMMOND, M.R.C.S.(Eng.), L.R.C.P.(Lond.)Regional Transfusion Officer, Region VIII (Wales)

At the outbreak of the recent world war, thestudy of blood transfusion passed from theclinician to the laboratory worker. Since thattime bacteriologists, pathologists, serologists,geneticists, physicists, biochemists, statisticiansand engineers have all played a part in covering avast field of study. The developments resultingfrom their work have been such that it is no easymatter for even the full-time laboratory worker tokeep abreast of the times. These two articles cantherefore survey only some of the advances, asseen by the author, which are of common interestto the laboratory worker and to the clinician.

Developments will be considered under thefollowing headings:

I. Collection, storage, preservation andhandling of blood. The in vivo survival oftransfused red cells.

2. Plasma. The recognition of homologousserum jaundice.

3. Blood grouping and compatibility tests.Blood group antigens and their practical im-portance, especially the Rh factor.

4. The diagnosis and treatment of haemolytictransfusion reactions, including incompatibletransfusion.

5. The study ofdisease with the aid oftransfusion.1. Collection, Storage, Preservation

and Handling of Blood. Study of theSurvival of Transfused Red Cells.Selection of DonorsThe past ten years has seen greatly improved

standards with regard to blood donation. TheNational Transfusion Service permits only healthypersons who have not suffered from certaindiseases to be bled. This is essential since theassurance must be given that blood donation isharmless. Such an assurance, presumably, hasalways been given, but cannot always have beenjustifiable since, persons suffering from certaindiseases, for instance high blood pressure, wereoften used as donors, and such persons may sufferserious harm when bled, especially repeatedly,the standard amount (420 cc.). Rigid precautionsmust be taken to see that donors are in fact

Protected by copyright.

on January 7, 2021 by guest.http://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.25.287.420 on 1 Septem

ber 1949. Dow

nloaded from

-September 1949 DRUMMOND : A Survey of Recent DevJijpments in Blood Transfusion 421

healthy and, so far as can be foreseen, will sufferno harm from blood donation.Donors may be of either sex, the age limits

being i 8 to 65 years. Consent of parents isnecessary for minors. A haemoglobin test* mustbe done before each blood donation, howeveroften the donor is bled, and the result recorded onthe donor's record card. Before each proposeddonation, a donor should read through a question-naire asking whether he or she has suffered fromany of the following diseases :-tuberculosis,epilepsy (fits), cancer, diabetes, goitre, blooddisease (e.g. polycythaemia, etc.), rheumatic fever(within the last ten years), heart disease, kidneydisease, high blood pressure, stroke, jaundice(within the last i2 months-see below) or malaria.A person who has had any of these diseases is

not acceptable as a blood donor. The donor,having read the questionnaire and been accepted,should sign or initial his or her record card.

Exceptionally, certain persons affected with amoderately raised blood pressure may donate bloodprovided.they are able, without any inconvenience,to do a full day's normal work. Persons sufferingfrom high blood pressure must never be used asdonors because of the liability to such complica-tions as stroke, cardiac failure, or even death afterblood donation, as shown by experience duringthe recent war. A person who has had cerebralseizures, stroke, hemiplegia or a heart attackshould never be a donor. With older personspalpation of the pulse, auscultation of the heartand estimation of the blood pressure may benecessary. Palpation of the pulse may reveal un-suspected cardiac disease-e.g. auricular fibrilla-tion. A person suffering from, or recentlyaffected with tonsillitis, influenza, other infectiousillness or boils, should not be bled until recoveryis complete. Persons giving a history of mentalbreakdown, neurosis, etc., should not be used asdonors. A donor who has had hepatitis andjaundice must not donate blood until six monthshave elapsed from the time of recovery from thejaundice. This is to ensure that the agent (? virus) re-sponsible for homologous serum jaundice shall notbe transmitted to the recipient by blood transfusion.

It is the responsibility of the doctor who usesfresh blood to ensure that the donor has not hadsyphilis or other transmissible disease such asmalaria. Complete reliance cannot be placed on anegative serological test for syphilis done sometime previously, since the donor may subsequentlyhave acquired infection. Ideally, if fresh blood isused, a serological test for syphilis should be doneimmediately before each blood donation. Onlyblood which gives a negative serological test for

* The minimum acceptable haemoglobin level is 85%

syphilis is issued by the National TransfusionServices, i.e. a test for'syphilis is done each timea donor is bled. In recently-acquired syphilis, aserological test for syphilis may be negative butthe person's blood may, nevertheless, be highlyinfective at this stage. Hence, if fresh blood is tobe used, discreet enquiry should be made of theprospective donor as to possible infection. Instored blood in cold storage, the spirochaete sur-vives about four days and the malarial parasite notlonger than ten days.A person who has had malaria should never be

used as a donor for blood transfusion no matterhow many years have elapsed since the lastmalarial attack, lest the parasite be transmitted tothe recipient. Ex-malarial subjects are used asdonors for plasma manufacture, the red cells beingdiscarded. Complete medical examination ofprospective donors, generally, is not necessary.Suitability to donate blood should be assessed onthe general condition. Persons of frail and smallphysique are generally not suitable. Robust healthis essential. Females may be bled during themenstrual flow. Blood donation during pregnancyis not desirable, and a mother should preferablynot donate blood until two years have elapsedfrom the date of her last confinement.

Collection of Blood. RecordsCollection of blood must be by venepuncture

only and local anaesthesia must be used. Underno circumstances should a donor's vein be cutdown upon. The volume of blood taken must notexceed 44o cc. A donor should not be bled oftenerthan twice a year, and preferably only once. Sixmonths should elapse between donations. Adonor should rest recumbent for at least 20 minutesafter donation. Thereafter the donor should situp for 5 or io minutes before being allowed todepart. Light refreshment should be given duringthe rest period: Before departure the site ofvenepuncture should be inspected and a lightdressing applied and instructions as to ' self-care'given the donor. Complaints by donors shouldreceive careful attention. The donor's record cardmust show the date of donation, the result ofhaemoglobin tests, amount of blood taken, theinitials of the donor (see above) and the name ofthe doctor responsible for venepuncture. Un-toward sequelae, e.g. haematoma, syncope, etc.,which may complicate blood donation should berecorded on the donor's record card. Donors whofaint after each donation should be rejected.The Donor and the CommunityThese regulations are designed to protect the

donor, though they obviously protect the doctorresponsible for blood collection as well as the

Protected by copyright.

on January 7, 2021 by guest.http://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.25.287.420 on 1 Septem

ber 1949. Dow

nloaded from

422 POST GRADUATE MEDICAL JOURNAL September 1949

recipient. They apply also to donors selectedfrom friends or relatives of patients. A Trans-fusion Service cannot exist without donors andthe community owes them a considerable debt.Every consideration should, therefore, be given tothe donors' welfare. The regulations governingthe bleeding of donors, drawn up since the war bythe National Transfusion Service, are an im-portant step forward. The general availability ofdonors and blood banks today is in striking con-trast to the state of affairs which existed beforethe outbreak of the recent war. Donors of allABO groups are now regularly utilized andutilization of group O donors only is now largelyobsolete. The organizationi of donor panels on anational scale is a really great advance. In general,each area of population meets the blood andplasma needs of its own hospitals. Rh-negativeblood, a commodity unheard of ten years ago, isnow (with care) generally available and has provedan inestimable boon, especially in maternitypractice. Blood donation is a most importantsocial service and is of incalculable value to thenation.

Storage and Handling of BloodAn understanding of the principles involved in

blood storage is essential. Many disasters haveoccurred in consequence of faulty management ofblood banks simply because those in charge hadlittle or no knowledge of the principles involved.Hospital blood banks have been, and are still, aconstant source of anxiety to the Regional Trans-fusion Officer. Blood banks should always be theresponsibility of a medical officer, preferably apathologist. Knowledge of the principles under-lying storage of blood has advanced considerablyin the past few years and its application in practiceis important.

Blood, when taken from the donor, shouldwithin 30 minutes go into refrigeration and bestored at a temperature of 2° to 60 C. Food, orpathological samples such as excreta, pus, etc.,should never be put in a blood bank refrigerator.A responsible person, e.g. a laboratory technicianor hospital pharmacist, should check and record,each morning and evening, the temperature ofthe refrigerator. A maximum-minimum record-ing thermometer, or a thermograph, should beused. Freezing must not occur, and the tem-perature must not rise unduly. A TransfusionOfficer may justifiably decline to stock a bankunless these precautions are taken. The tempera-ture records should be kept for periodic inspectionand an engineer should examine the refrigeratorregularly, at least every three months, to ensurethat the machinery is in working order, sincefaulty refrigeration may cost lives. Transfusion

of blood which has been frozen, and thereforehaemolyzed, may prove fatal. Blood should notbe left longer than 30 minutes out of refrigeration.Blood left unduly long out of refrigeration maybecome unsafe to use because of bacterial growth,etc., and should be labelled 'Dangerous forTransfusion' or discarded. For a discussion onthe effect of temperature on blood storage and itsin vivo survival, see Gibson, et al. (I947). Bloodshould not be warmed before transfusion ; trans-fusion of overheated blood may prove fatal(Baker, I937). It is quite safe to transfuse bloodcold from refrigeration. Unauthorised personsshould not have access to blood banks. A bottleof blood should show on its label(s) the bloodgroup (ABO and Rh), date of collection, serialnumber of the donor, expiry date, tem-perature for storage (2° to 6° C.) and the preserva-tive solution. A special register should show thefate of all bottles of blood put in the blood bank.A knowledge of the preservative solution used, aswill be seen, is of very great practical importance.The labels on blood bottles exist for a purpose,namely, to state precisely what is in the bottle andto act as a guide to the doctor who transfuses theblood. Hence blood bottle labels are of medico-legal importance. Many transfusion disasters areattributable to failure to examine blood bottlelabels before transfusion, with the consequencethat time-expired or incompatible blood has beentransfused.

Differential AgglutinationBefore dealing with glucose-preservation of

blood, differential agglutination must be con-sidered, as it will be frequently alluded to and is ofimmense practical importance in elucidating thefate of transfused blood. The routine application,in recent years, of differential agglutination to thestudy of the fate of transfused blood constitutesa notable advance, ranking in importancewith the general introduction of stored bloodpreserved with glucose. With the aid ofdifferential agglutination, it is possible to state withconsiderable precision the fate of the transfusedblood in the recipient's circulation. Differentialagglutination, like glucose-preservation of blood, isnot new. As long ago as i919 it was described byAshby, who pointed out that after transfusion ofO blood to an A recipient, the blood of the re-cipient was a mixture of O and A cells. Accord-ingly, if a sample of the patient's blood taken aftertransfusion was mixed with anti-A serum, the Acells would be agglutinated and the free un-agglutinated group O cells of the donor could becounted in a red cell counting chamber. Wiener(1934) used the MN groups. If the recipient wasM and the donor N, the survival of the donor's red

Protected by copyright.

on January 7, 2021 by guest.http://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.25.287.420 on 1 Septem

ber 1949. Dow

nloaded from

September I949 DRUMMOND: A Survey of Recent Developments in Blood Transfusion 423

cells could be directly followed simply by using ananti-N serum, and vice versa. Differentialagglutination until i939 was sporadically used byvery few workers. Mollison and Young (1940)suggested the combined use of sera of the ABOand MN systems. Hitherto the method had givenonly approximate results. Dacie and Mollison(I943) pointed out that much more accurate re-sults with the Ashby technique could be obtainedby using potent agglutinating sera and intensifyingagglutination by centrifugation. The technique isnot difficult but requires practice. Some highlypotent ABO grouping sera may exhibit thephenomenon of' zoning.' It is important to find(by experiment) at what dilution such sera willcause maximum agglutination. Such 'zoning'sera, appropriately diluted; may cause intenseagglutination and are very suitable for differentialagglutination work. Diluted high titre 'zoning'ABO grouping sera were used by Mollison' (I944M.D. Thesis, cited by Loutit, 1945 ; Mollison,1947). Loutit (I945) used high titre zoning seradiluted as much as I:32. When a mixture 6fagglutinable cells and agglutinating serum is made,e.g. B cells and anti-B serum, some cells may notbe agglutinated despite centrifugation. These un-agglutinated cells constitute the inagglutinable orblank count, and with good sera may be less thanIo,ooo and should certainly not be more than5o,ooo per c.mm. In differential agglutinationstudies, the blank count must be determined byexperiment before transfusion and due allowancemade for it in subsequent counts. A wide range ofantigens and their anti-sera may be used indifferential agglutination. This is a great ad-vantage when blood homologous in the ABOsystem has been transfused, because differences inMN or Rh groups, etc., can be exploited. Thefollowing is a list of some of the antigen-antibodysystems which can be used in differential agglutina-tion :--() ABO system; anti-A, anti-B. (2)MN system ; anti-M, anti-N, anti-S. (3) FactorP; anti-P. (4) Rh Factor; anti-C, anti-Cw,anti-D, anti-Du, anti-E, anti-c, anti-d, anti-e.Other antigen antibody systems which could beused are Kell, Lewis, Lutheran, etc. Several ofthe sera are very rare. It may be of great im-portance, in a particular transfusion, to know thefate of the transfused red cells and their in vivosurvival can be followed by the use of differentialagglutination.With the aid of transfusion and differential

agglutination studies, Ashby (I9I9), Wiener(i934), Mollison and Young (1940) and otherssubsequently showed that fresh red cells normallysurvived in the circulation of the recipient for Iooto I20o days which, presumably, is the normal lifespan of the erythrocyte. It is something of a

paradox, therefore, that standard textbooks of re-cent printing give the life of the red cell as 30 days.Radio-Active Red Cells in in vivo Survial StudiesAn interesting recent advance in the study of the

the fate of transfused blood is the use of transfusedred cells tagged with isotopes of radio-active iron(see Gibson, Aub, et al., 1947, and Gibson, Evans,et al., 1947). The donor is dosed with an ironsalt such as ferrous sulphate which has incor-porated in it the radio-active isotope of iron. Newerythrocytes of the donor take up the radio-activeiron and such tagged cells can be detected aftertransfusion in the circulation of the recipient. Thetest is exceedingly sensitive and very accurate, butis of limited value since radio-active iron releasedfrom destroyed donor red cells becomes rapidlyincorporated in new erythrocytes made by therecipient. Accordingly, the test is not reliableafter 48 hours. The method is of use in that itwill detect only intact donor cells containing radio-active iron in the blood of the recipient. If mostof the donor blood is destroyed within a few hoursof transfusion, it follows that few, if any, taggedred cells of the donor will be detected in thepatient's blood, say, 24 hours after transfusion.The test can only be done by skilled workers with'special apparas us.

Blood PreservationConsiderable advances have been made in re-

cent years in our understanding of blood preserva-tion. An important advance is the proof, with theaid of differential agglutination, that glucose ise3sential to the preservation (in vitro) of stored redcells and to their survival (in vivo) in the circula-tion of the recipient. In any given transfusion, theoldest or effete red cells of the donor will be thefirst to be eliminated. An anticoagulant is not ablood preservative. For instance, sodium citrate,heparin or defibrination will prevent coagulationbut will not preserve blood. A preservative solu-tion must contain, of course, an anticoagulant butit must also contain glucose. Without glucose thered cells will undergo rapid deterioration. Bloodshould never be stored without glucose.

Glucose-preservation of blood is no new dis-covery. In I9I6, Rous and Turner publishedtheir experimental observations on using amixture of three parts of blood, two parts ofisotonic sodium citrate and five parts of isotonicdextrose solution for red cell preservation.Erythrocytes would keep for a month in thismixture, whereas with citrate alone haemolysiswas marked in less than two weeks. In the GreatWar of 19I4-I9I8, Captain 0. H. Robertson(I9I8) made use of this experimental work andused a mixture consisting of 500 cc. blood, 350

Protected by copyright.

on January 7, 2021 by guest.http://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.25.287.420 on 1 Septem

ber 1949. Dow

nloaded from

424 POST GRADUATE MEDICAL JOURNAL September I949

cc. isotonic sodium citrate and 850 cc. isotonicglucose solution. Red cells preserved well in thissolution and could be safely transfused, even after26 days, with good results. Moreover, the bloodmixture could be transported without harm to thered cells. Before transfusion, the supernatantfluid was syphoned off and the sedimented redcells then suspended in dilute gelatin solution, thefinal volume being I,ooo cc. It is remarkable thatthis important work was allowed to lie dormantuntil about the time of the outbreak of the recentworld war. Despite this work, early in the recentwar many blood banks were, in fact, operatedusing simply citrated blood (i.e. without glucose),and many transfusion disasters were directlyattributable to this. The general adoption ofglucose-preservation of blood during and sincethe war constitutes a very notable and importantadvance. Stored glucose-preserved blood is agreat advance, since it ensures that blood can beprocured from banks at any time and secondly, aswill be seen, the results of transfusion are about asgood as the transfusion of absolutely fresh blood.Since concentrated red cells must be prepared fromstored blood, its preservation with glucose is veryimportant. The tremendous advantage of havinggrouped and tested blood on hand for immediateuse, especially of homologous group in the ABOand Rh systems, needs no elaboration here. Bloodbanks are now generally available throughoutGreat Britain and have been of incalculablebenefit to the community. It is, apparently, notgenerally appreciated that the safe and successfuluse of preserved blood is dependent on the factthat the erythrocyte cannot survive withoutglucose. All concerned with the transfusion ofblood should be conversant with the importanceof glucose in the preservation of bloodOur krowledge of the principles underlying

blood preservation has improved considerably inthe past ten years Transfused fresh bloodnormally survives in vivo for Ioo to I20o days, sothat its rate of elimination is about I per cent. perdiem. Wiener and Schaefer (1940) showed thatthe longer citrated blood withoutglucose was stored,the less good was its in vivo survival. Patients re-ceiving blood stored seven days or less did notdevelop hyperbilirubinaemia. With blood olderthan ten days, jaundice and haemoglobinuriamight complicate transfusion. Blood aged 2Idays was eliminated from the recipient's circula-tion within 24 hours. Blood stored seven days orless survived in the recipient almost as well asfresh blood. Therefore seven days was set as thetime limit for storage of citrated blood. However,Mollison and Young (1940) pointed out that thein vivo survival of citrated blood stored withglucose was little inferior to that of fresh blood.

They confirmed the observations of Rous andTurner (I9i6). Mollison and Young (1942) con-firmed that citrated blood stored without glucoseup to six days survived in vivo almost as well asfresh blood, and that when storage was longer thedonor erythrocytes were rapidly destroyed in therecipient's circulation. Thus 14-day old bloodstored without glucose survived poorly in vivosince 75 per cent. of the red cells were eliminatedin 24 hours, and in three weeks all were eliminated.On the other hand the in vivo survival of glucose-preserved blood aged I6 to i8 days was littleinferior to that ot fresh blood. It should be notedhere that transfusion of blood stored withoutglucose for more than ten days may be dangerous,especially if large amounts be given, since destruc-tion of the donor erythrocytes in the recipient'scirculation may be sufficient to result in jaundice,haernoglobinuria and suppression of urine, as thewriter has observed. The importance to theclinician of having stored red cells preserved sothat they will survive normally in vivo is obvious.While glucose effectively prolongs in vivo survivalof stored red cells, other sugars such as dextrinand sucrose, do not have this effect.A very important advance was the establish-

ment, by the aid of differential agglutinationstudies on the in vivo survival of transfused blood,that the value or effectiveness of a preservativesolution could not be assessed on in vitro tests,which in fact might be of little value (Mollisonand Young, I94I). Such in vitro tests as spon-taneous haemolysis, osmotic fragility in saline andresistance of red cells to trauma such as shaking(mechanical fragility) may, in fact, be quite mis-leading. Thus, red cells stored in certain pre-servative solutions, e.g. Rous-Turner solution, maybecome very fragile as judged by osmotic fragilitytests but, nevertheless, the in vivo survival of suchpreserved red cells may be excellent, even whenstored up to 2i days (Mollison and Young, I942).A solution causing much haemolysis in vitrowould, obviously, be contraindicated. A solutiongiving slight haemolysis in vitro might not becontraindicated if the in vivo survival of the redcells was satisfactory. On the other hand, certainsubstances, e.g. dextrin and sucrose, will in thesame way as g'ucose delay the onset of haemolysisin vitro, but have little effect in prolonging invivo survivalWhen stored blood is transfused there is an

immediate rise in the recipient's serum bilirubin(Mollison and Young, i940), and this rise ismaximal four to five hours after transfusion. Thesix hours following transfusion are a period ofrapid destruction of effete erythrocytes. Initially,with stored glucose-preserved blood, there will besome destruction of the transfused erythrocytes

Protected by copyright.

on January 7, 2021 by guest.http://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.25.287.420 on 1 Septem

ber 1949. Dow

nloaded from

September I949 DR MMOND : A' Survey of Recent Developments in Blood Transfusion 425

(dependent on length of storage), though theultimate survival of the bulk of the red cells willbe good (about 8o per cent.) when storage is aslong as 2I days.The most important advance yet made with

preservative solutions* is the introduction of citricacid-sodium citrate-glucose (acid-citrate-dextroseor, briefly, A.C.D.) blood preservative mixtures.Hitherto the best preservative solution was theRous-Turner mixture which was objectionablebecause it was bulky and caused over-dilution ofthe plasma. Consequently the plasma was notsuitable for drying. Loutit and Mollison (I943),and Loutit, et al. (x943), showed that blood pre-served in citric acid-sodium citrate-glucose pre-servative solution was safe to transfuse, caused nountoward reactions, and the in vivo survival of thetransfused red cells was better than with any otherpreservative solution yet tested. Moreover thecitrate and glucose solutions could be autoclavedtogether without caramelization, a most importanttechnical advance which has eased the work oftransfusion laboratories considerably. With tri-sodium citrate-glucose solutions, the two com-ponents must be autoclaved separately to avoidcaramelization. The fact that acid citrate andglucose solutions can be autoclaved together meansthat sterility can be guaranteed, which was notabsolutely possible when glucose had to be addedto the trisodium-citrate solution after autoclaving,however careful the technique. Caramelizationproduces a brown or coffee colour of varyingdegree, but a clear solution is essential to permit ofeasy examination before use. Further, carameliza-tion means some reduction of glucose contentwhich must be avoided since this may adverselyaffect the in vivo survival of the transfused pre-served red cells. The final concentration of glu-cose in the mixture of blood and preservativesolution should be about o.6 per cent. Of thevarious A.C.D. preservative mixtures yet devised,the best appears to be disodium citrate-glucose(Loutit and Mollison, I943); this is now ingeneral use in this country. Standard Britishblood mixtures contain 120 cc. citrate-glucoseand 420 cc. blood, and this yields excellent plasmafor processing. The biochemical and biophysicalchanges occurring in the stored and transfused redcell are not likely to be of interest to the clinician,but for a discussion of this subject see Loutit(1945) and a Symposium by various workers(I947).

2. Plasma. The Recognition of homo-logous serum jaundice.The wi despread availability of plasma is one of

the great boons of modem Transfusion Servicesa nd is one of the important developments made in

transfusion therapy in recent years. Plasma maybe issued in dried or liquid state. Dried plasmawill, apparently, keep indefinitely, but the time-expiry date is provisionally set at five years fromthe date of preparation. Plasma has savedthousands of lives. It is first and last a bloodsubstitute and, lacking red cells, it can never be asefficient as whole blood in the treatment ofoligaemic shock. Nevertheless, it has been re-peatedly shown that it can effectively tide overgrave emergencies many patients who have bledseverely. Whenever possible, homologous bloodshould be used in the treatment of oligaemicshock. When homologous blood is not availablefor the emergency treatment of haemorrhage'inchildbirth, the hazards of the Rh factor mustparticularly be kept in mind and plasma is then ofespecial value ; homologous blood can be givenlater. Excessive plasma transfusion may cause aforced dilution of the patient's haemoglobin.However, on occasion, large volumes must begiven as in the treatment of bums. Dried plasma,when reconstituted, should be used within anhour or discarded lest it become contaminated bybacterial growth. It has been used in concentratedform in acute hypoproteinaemia. If transfusedconcentrated, e.g. double strength, the dangers ofcirculatory overloading in diseased subjects shouldbe borne in mind. Brown, et al. (I942), foundthat concentrated serum was of little value in thetreatment of the nephrotic syndrome and mighthave adverse effects. However Golden andFraser (I947) recommend its use for the oedemaof toxaemia of pregnancy. Convalescent plasma orserum has, apparently, been used with'success inboth the prophylaxis and treatment of infectiousdiseases such as whooping cough, measles, mumpsand scarlet fever.One of the great advances of recent years is the

successful fractionation' of the plasma proteins.It would be out of place here to discuss thesevarious fractions, fibrinogen, fibrin, the globulins,etc., since they are used for purposes other thantransfusion. Serum albumin has been isolatedalmost pure. It is mainly responsible for theosmotic pressure of the plasma and maintenanceof blood volume is in large part dependent on it.It is, therefore, effective in the treatment ofoligaemic shock. Its use in states of protein de-ficiency such as occur in renal or hepatic disease isstill in the experimental stage.

Plasma transfusion is not without complications.Embolism due to fibrin particles in liquid plasmahas been reported. Angio-neurotic oedema andurticaria are occasional complications, but seem

* Solutions must be made up in pyrogen-free dis-tilled water to avoid febrile reactions.

Protected by copyright.

on January 7, 2021 by guest.http://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.25.287.420 on 1 Septem

ber 1949. Dow

nloaded from

426 POST GRADUATE MEDICAL JOURNAL September 1949to cause no serious harm. Plasma is prepared bypooling plasma of different ABO groups so as tocross-absorb the anti-A and anti-B isoagglutininson the A or B agglutinogen present in plasma ofcorresponding group. This reduces the titre ofthe anti-A and anti-B isoagglutinins so that theycan cause no harm to a recipient's red cells whentransfused. Circulatory overloading and heartfailure may complicate transfusion of excessiveamounts of plasma.

Homologous Serum JaundiceThis is a late and serious complication of trans-

fusion of plasma and, rarely, of blood.. Theapproximate incidence (Lehane, 1949) of homolo-gous serumjaundice aftertransfusion is:-(I) Largepool plasma, Io per cent. (2) Small pool plasma, I.5per cent. (3) Blood, o.8 per cent. The recognitionduring the recent war of homologous serumjaundice, probably a virus infection of the liver, asa late complication of transfusion was a notableadvance. The virus can apparently survive in-definitely in liquid, frozen, or dried plasma. Thedisease was first recognized just before the recentwar following the use of convalescent measlesserum. It has complicated the use of humanserum in yellow fever vaccination and the in-jection of plasma from a person convalescent frommumps. Only a minute amount of infected plasmaor serum injected intravenously or subcutaneouslyis necessary to transmit the disease. Scrupuloussterilization of syringes and needles has eliminatedthis disease as a complication of intravenous in-jections in diabetic or venereal disease clinics andin hospital wards. The disease can be transmittedexperimentally to human volunteers, but not toanimals, by injection of blood or serum frompatients in the icteric or pre-icteric stage of thedisease. The diagnosis is made on clinical grounds.A history of transfusion is essential. The diseasebecomes manifest 40 to I20 days after transfusionor inoculation of human plasma, serum, or blood.Joint pains, erythematous rashes, urticaria, ano-

rexia, malaise and vomiting may occur, followed byjaundice (see Ministry of Health Memorandum,1943). It seems that some persons may carry thevirus but not develop the disease. The mortalityrate is not less than I per cent., and may be muchhigher. Death is due to liver necrosis. Thedisease is, apparently, not identical with infectivehepatitis (catarrhal jaundice) and it may be thatit is never transmissible naturally, but only byinoculation of blood, plasma or serum. Trans-mission of the disease by naso-pharyngeal washingshas not been successful (Bradley, et al., 1946).During the war, plasma was made in pools fromthe donations of many donors, and Spurling, et al.(I946), found an incidence of jaundice of 7.3 percent. in patients who received such pooled plasma.It is now made in small pools from the donationsof not more than ten donors. This has appreciablyreduced the incidence of the disease. A singleinfected donor will contaminate an entire pool.This disease will continue to occur since there isas yet no test which will detect the icterogenicagent other than inoculation of human volunteers.Moreover, not all volunteers inoculated will de-velop the disease. The virus resists heat and dis-infectants (Bradley, et al., I946) ; recent work,however, suggests that it may be destroyed byultra-violet light. It is regrettable that there isstill considerable laxity among clinicians in re-cording serial numbers of bottles of plasma orblood transfused .; such recording is essential andshould be compulsory. When the serial numberof a bottle of plasma (or blood) which has causedthe disease is, known, it at once becomes feasibleto withdraw all bottles of plasma of the samebatch, and to track down and eliminate infecteddonors from the donor panel. It is too early yetto state what the late results of this disease maybe. Cirrhosis is a possibility. Patients apparentlydying of the disease have been successfully treatedby intravenous injections of protein hydrolysate(Bradley, et al., 1946).

(To be continued)

Protected by copyright.

on January 7, 2021 by guest.http://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.25.287.420 on 1 Septem

ber 1949. Dow

nloaded from