Some Remarks on Therapy for Anemia (PDF)

SOME REMARKS ON THERAPY FOR ANEMIA* William B. Castle, M.D.\s=d\

BOSTON AM sincerely appreciative of the honor be- cytic anemia, usually due to intestinal disturbances, I stowed on me by the invitation to deliver this all types of anemia fail entirely to respond to such oration. As you are aware, my distinguished pred- preparations. Valuable contributions to the prac- ecessors have annually instructed and entertained tical development of the present effective thera- you with words both wise and charming. I wish, peutic products have been made by both university especially at this preprandial hour, that I were and commercial research groups. Since the amount able to do so. Lacking such gifts, however, I have of active material remaining in the finished prod- believed that in accepting this honor it would be uct depends on the efficiency of the method of a more suitable expression of appreciation were I manufacture, it seems unwise and uneconomical to matters of speak of detail with which I have for physicians to prescribe products whose potency some experience than to discourse, perhaps naively, is defined only in terms of the amounts of tissue on a more general theme. with which the manufacturer started his process. # # * The obvious and satisfactory alternative definition of potency in terms of the amount of effective ma- The remarkable advances in the treatment of terial in the final product is described in of the decade and a when con- currently anemia past half, U.S.P. units for all antianemia remedies trasted with the yet unscalable obstacles, accepted perhaps by the United States or the Coun- an at a realistic of the Pharmacopoeia justify attempt appraisal cil on Pharmacy and Chemistry of the American possibilities and limitations of existing therapy. Medical Association. five methods of treatment of Today, general vary- Active commercial of the liver for effectiveness and are dis- preparations ing permanence clearly oral or parenteral use, and of the stomach or of cernible. there are substitution for Thus, therapy the stomach and the liver incuba- nutritional or for of the potentiated by deficiency dysfunction tion for oral use, are available. Because in the endocrine system, and chemotherapy, splenectomy average patient the effectiveness of a liver irradiation. on its own merits and also given Finally, preparation is from to one hundred times as as a means of for some other form of sixty preparation great when given as when taken therapy, there is transfusion. parenterally by mouth, the former route provides a distinctly more Substitution Therapy economical manner of administration. The small volume of material to be with the clinical observations of injected (several com- Starting pioneer mercial contain Minot and in the effectiveness of preparations at least 15 U.S.P. Murphy 1926, units cubic liver and later of stomach preparations in the per centimeter) and the infrequency of injections for maintenance or 30 treatment of patients with nutritional types of required (15 US.P. units at intervals of two weeks or a macrocytic anemia has become estab- month) thoroughly render the use of oral a lished. In this the conditions amenable any preparation doubt- locality, ful from the of view of both ef- to such therapy are usually Addisonian pernicious policy, point fectiveness of treatment and convenience or anemia and that of pregnancy. With the further ex- pense to the Few exception of certain rare cases of nutritional macro- patient. patients conscientiously persist in taking considerable amounts of medicine *The Annual Oration, delivered at the annual meeting of the Massachu- mouth two or three a setts Medical Society, Boston, May 26, 1942. by times day for long \s=d\Professor of medicine. Harvard Medical School; associate director, Thorn- periods after consider themselves dike Memorial Laboratory: director of Second and Fourth (Harvard) Medi- they perfectly cal Services, Boston City Hospital. well. Because a definite but unpredictable num-

The New England Journal of Medicine Downloaded from nejm.org by JOSH ROSENFELD on May 25, 2016. For personal use only. No other uses without permission. From the NEJM Archive. Copyright © 2009 Massachusetts Medical Society. All rights reserved. ber of patients in severe relapse fail more or less The effective use of iron in the treatment of to to administered completely respond products anemias now known to be hypochromic is older in usual it is unwise to orally amounts, certainly than the record of history. Its latest and presum- initiate treatment other method than that by any ably permanent reappearance on the platform of of parenteral therapy, usually in terms of mul- sound therapy dates from the independent observa- tiple US.P. units daily for the first few days. A tions of Barkan and in 1923, in similar indication with Meulengracht, is provided by patients pro- Europe. abandoned the small amounts of nounced neural manifestations. With They exceedingly iron advised by theory and used dosages compara- rare the and exceptions, present purified concen- ble to those effectively employed today. It is now trated seem to be as effective as the preparations known that almost any sort of iron, if orally admin- treatment older and cruder products in the of per- istered in a divided form or as a nonirritat- and neural finely nicious anemia its complications. A ing iron salt, is effective in the treatment of practical point in the early detection of the onset hypochromic anemias in which loss of hemoglobin of remission is to determine the reticulocyte per- and of iron has been about the fifth and seventh after consequently brought centage on days therapy by bleeding, pregnancy or growth. Observation with liver or stomach has been insti- preparations shows that ferrous are in general more tuted. In the compounds response of anemic patients, the in- effective than ferric. The dosage of ferrous com- crease of the is so much more reticulocytes striking pounds is about 5 gr. three times a day, best given than the change in red-blood-cell or hemoglobin just after meals to avoid gastric irritation. Many values in the first week that, relying only on the injections of iron have been made without much latter, the physician may fail to realize that the effect because of the minute amount of iron in these response has already begun. often and it liver the less expensive elegant ampules. Today, Although extracts, especially highly is recognized that it is very rarely necessary to purified products, are to some extent sources of members of the these promote hemoglobin regeneration by injections various vitamin B complex, of iron. If, however, because of failure of oral are unessential to the remission induced apparently in such a is the of liver. therapy adequate dosage, procedure by active hematopoietic principles suitable sterile solutions The treatment of pernicious anemia by vitamins required, preparations — of ferric ammonium citrate or ferrous gluconate is thus a waste of material. Whereas it is true — are available. that large amounts of whole or autolysed yeast The indication for the use of iron is a low may, under experimental conditions, cause detect- able improvement in pernicious anemia, it is prob- hemoglobin concentration in the red blood cells or a color index. able that these agents act only indirectly through low Unfortunately, the hypochromic anemia of chronic infections and that of their power to induce the formation of liver ex- the so-called "Mediterranean tract in the body. In actual practice, they are anemia," although these do not to without value compared to the effi- possessing characteristics, respond significant animals with ciency of active liver or stomach preparations, and iron. Experimental hypochromic anemia that have failed to to iron are their use is an additional burden on the patient respond often relieved vitamin but this is not true and his pocketbook. Whether or not vitamin C by Be, of at least In is an effective agent in the rare macrocytic anemia patients, in my experience. growing of access of scurvy remains to be Since fruit juice experimental animals, carefully deprived proved. been that containing vitamin C has been shown to be capable to copper, it has convincingly shown of causing blood regeneration in such patients, it this element as well as iron is essential for relief of anemia that Some authors have can be readily employed in any case whether its the develops. a similar use for in anemic infants activity depends on ascorbic acid or other factors. reported copper Today, the sole essential for maintaining continued given small doses of iron. There is, however, no and complete remission in pernicious anemia is the convincing evidence that patients failing to respond exhibition of sufficient amounts of active material to usual doses of iron will respond to the addition of Liver and stomach are by a single route at regular intervals. The ad- copper. preparations vances of the last fifteen years have almost deprived useless. Moreover, undiscriminating polypharmacy and to need- the adjective "pernicious" of any real meaning. obscures the effective agent may lead less and of maintenance Indeed, it is a puzzling question whether the expensive types therapy. to be the of diagnosis "pernicious anemia" should appear on the Iron, therefore, appears only agent . the treatment of death certificate of a patient who by adequate practical importance in hypo- treatment has been maintained through many chromic anemia. some years with a normal blood count and who has Patients with myxedema commonly have of and macro- died of causes entirely unrelated to his original degree hypochromic occasionally anemia. cytic anemia, especially if gastric anacidity is près-

The New England Journal of Medicine Downloaded from nejm.org by JOSH ROSENFELD on May 25, 2016. For personal use only. No other uses without permission. From the NEJM Archive. Copyright © 2009 Massachusetts Medical Society. All rights reserved. ent. Hypopituitary syndromes are also sometimes considerable number of hématologie complications, associated with anemia. Treatment in both con- immediate or remote. ditions depends on suitable endocrine therapy, and Splenectomy be accelerated the use of liver extract or may by In 1911, Micheli observed the benefit of iron, according to the character of the anemia. splenectomy in a case of acquired hemolytic jaundice, and Chemotherapy in the next two years, Eppinger and Banti inde- Chemotherapy, although primarily employed pendently reached the conclusion that it was a for the infection itself, is more than incidentally a logical and successful procedure in congenital means of combating hemolytic anemias, such as hemolytic jaundice. In this community, Dameshek those due to the streptococcus or to the malaria has recently done a service by calling attention to parasite. The unrecorded experiments of Indians various types of acquired hemolytic jaundice and with Peruvian bark long antedate modern chemo- by re-emphasizing the therapeutic value of sple- therapy. The latest advance is. that initiated by nectomy in some of them. The success of splenec- Domagk in 1933 by the discovery of the bacterio- tomy in such anemias depends on the predomi- static action of a sulfonamide in experimental nance of pathologic blood destruction in the spleen. streptococcal infections. To discuss in detail the In congenital hemolytic jaundice, the red blood use of sulfonamides or quinine is obviously beyond cells almost invariably exhibit some increase in fre- the scope of these remarks. Chemotherapy may gility in hypotonie saline solution, and the spleen also be of value as an accessory in the treatment is usually large and the pulp engorged with blood. of blood dyscrasias of which an infection is an A successful splenectomy is almost always dra- important complication. Thus, the advent of an matically effective in returning the patient's blood infection of the respiratory or urinary tract may values to normal. If necessary, as a preliminary to even be fatal in a patient with severe anemia operation, rapidly repeated transfusions should be otherwise easily amenable to therapy. The signs given to bring the hemoglobin level to at least 50 of infection, however, may be falsely simulated per cent of normal. Although this may be difficult in a patient with a hemoglobin level of less than in the face of a crisis of rapid blood destruction, 25 per cent by a fever of 1 or 2°F. that may be splenectomy not only promptly abolishes this phe- entirely due to the anemia; even higher tempera- nomenon but also, by extrusion of blood from the tures may result when an active hemolytic process spleen during operative manipulation, provides an is present entirely without infection. For the autotransfusion, often immediately raising the local-tissue necrosis and secondary infection en- hemoglobin level by 15 per cent or more. Con- countered, usually in the oral cavity, in agranulo- sequently, splenectomy should not be unduly de- cytosis, aplastic anemia or leukemia, especially the layed. monocytic variety, the relatively small experience In patients with acquired hemolytic jaundice, a available already indicates a value for the sulfon- term that includes several distinguishable acute check amides. Their utility consists in holding in and chronic forms of disease, a generalization con- the invasion of the infection until other remedies cerning the effect of splenectomy is impossible. may have an opportunity to act on the underlying Perhaps, however, it can be stated that after cer- blood dyscrasia. tain causes of hemolytic anemia that are amenable It seems clear that in general, as in the presence to other forms of treatment have been excluded, of primary infections associated with leukopenia, splenectomy is likely to be beneficial if the fragility the possibility of further depression of the granu- of the red blood cells in hypotonie saline solution locytes is not so great a risk as the danger from is significantly increased and if the spleen is dis- the infection when uncontrolled by chemotherapy. tinctly enlarged. Splenomegaly alone, however, Sulfonamides, like certain other cyclic compounds, provides no guarantee of success for splenectomy. have caused acute hemolytic anemia, leukopenia, Before the procedure is undertaken, the duration thrombopenic purpura and aplastic anemia. For- and nature of the hemolytic process should be tunately, such undesirable results occur in only a carefully studied. Thus, in acute cases, the his- very small percentage of cases, and their manifes- tory may reveal exposure to hemolytic compounds, tations can usually be prevented by early detection. such as phenylhydrazine, sulfanilamide and arsine, Because the chance of such an occurrence is small, or in other cases, dark urine (hemoglobinuria) one should never hesitate to administer these val- after exposure to cold or after sleep. A blood cul- uable drugs when a serious infection presents a ture or film may demonstrate septicemia due to clear for their use. the other or indication On hand, bacteria malaria parasites. Exposure to pure the widespread and indiscriminate employment of carbon dioxide causes anoxic microscopic sickling the sulfonamides for trivial infections may well in sickle-cell anemia, and in paroxysmal nocturnal produce from only a small percentage incidence a hemoglobinuria alone, the carbonic acid causes

The New England Journal of Medicine Downloaded from nejm.org by JOSH ROSENFELD on May 25, 2016. For personal use only. No other uses without permission. From the NEJM Archive. Copyright © 2009 Massachusetts Medical Society. All rights reserved. hemolysis. A positive sérologie test for syphilis the hemoglobin to a level of at least half the and hemolysis on chilling (Donath-Landsteiner normal value are indicated. confirm the of phenomenon) diagnosis paroxysmal The justification for discussing the use of irradia- e Such are not hemoglobinuria frigore. patients tion, a highly technical procedure requiring special suitable for splenectomy. In other patients, auto- apparatus and experience, is that the best results agglutination of the red blood cells has been re- from such therapy in leukemias can be obtained marked; Dameshek has found hemolysins in the only when collaboration between clinician and of a serum independent isohemolysins in certain roentgenologist is close and intelligent. It is as- group of cases. Bone-marrow biopsy or splenic sumed, for purposes of discussion, that the anemia puncture may disclose other causes of acquired in the leukemias is due to a considerable extent to hemolytic anemia, such as aleukemic leukemia, the mechanical inhibition of normal red-cell pro- disease and meta- Hodgkin's agnogenic myeloid duction in the marrow cavity by overcrowding Suffice to that if enu- plasia. it say the conditions with immature leukocytes. In other cases of myelo- merated which are amenable to other above, types phthisic disease, the bone marrow is invaded by of can be excluded and if severe therapy, hemolytic the cells of metastatic carcinoma or is replaced anemia with acholuric and manifest jaundice signs by lipoid-bearing cells or by fibrous or osseous tis- of active blood regeneration persist for some days sue, as in osteosclerotic anemia. Because the cells despite frequent transfusions, splenectomy may of most metastatic carcinomas, like those of fibrous be indicated, at least as a means of somewhat re- or osseous tissue, are insensitive to ir- blood destruction presumably ducing excessive and, possibly, radiation, no improvement of the red-cell level is of abolishing it. to be expected from irradiation in such cases. Ac- It is to be emphasized that the expectation of cordingly, when there is doubt regarding the char- success from splenectomy in so-called "acquired acter of the disturbance in the marrow, sternal is different from that hemolytic jaundice" quite in biopsy is indicated before one decides whether the and as congenital condition, in thrombopenic x-ray therapy is to be given. is the purpura, although splenectomy only therapy Although the use of x-rays in the treatment of to be its success is far from certain. likely effective, leukemia was introduced Senn as as in Banti's in by early 1903, Likewise, splenectomy syndrome, it is even now difficult to choose the most suitable which the anemia is to a hypochromic probably and amount among the variety of considerable extent due to chronic and often oc- procedure methods and dosages that have been and still are .cult bleeding from varices, is not always of benefit. that in The is often difficult because employed. Experience agrees, however, operation technically acute leukemias the process is of such a of the adherence of the to struc- inherently spleen nearby kind or its rate of is so that irradia- and when the vascular le- progress rapid tures, only obstructing tion is not useless but detrimental. By con- sion is confined to the vein is there con- only splenic trast, in the of chronic es- siderable of relief. Unfortu- management leukemias, certainty complete the the skillful use of irra- some of cirrhosis is most fre- pecially myelogenous, nately, type hepatic diation is a means of a com- for "chronic frequently providing quently responsible congestive spleno- fortable and useful existence months or the term during megaly," highly appropriate descriptive even years. for Banti's that was coined several years syndrome In the treatment of chronic leukemias, a trend ago by a Boston physician, the late Dr. Ralph C. Larrabee. can be observed toward the use of small amounts of irradiation applied to the body generally, in Irradiation contrast to heavy local exposure of obviously en- Irradiation by roentgen rays or radioactive phos- larged organs, such as the liver and spleen. Be- cause in leukemia phorus is today considered the chief weapon in the abnormal cells chronic dif- treating leukemias and related conditions. Yet, fusely invade the active bone marrow, this tend- although in discussions of such treatment great ency seems logical. Since, however, it is never attention is paid to the number and character of possible to gauge with accuracy the effect of a the leukocytes, a disabling and frequently fatality- physical agent on a complex biologic system, over- determining feature of leukemia is the anemia that dosage of the entire bone marrow is most surely sooner or later appears. Indeed, the problem in avoided by exposure of only a portion of it to the the irradiation of leukemias is not so much how action of x-rays at one time. It is desirable, when- to effect a reduction in the number of white blood ever possible, to avoid heavy local irradiation, cells as how to increase the number of red blood which, despite a selective effect on immature cells, cells Since it is considered injures all cells even those of normal tissues. I (or platelets). usually — unsafe to apply x-ray therapy in the presence of have observed enlargement of the spleen to severe anemia, preliminary transfusions to bring remain substantially undiminished after relatively

The New England Journal of Medicine Downloaded from nejm.org by JOSH ROSENFELD on May 25, 2016. For personal use only. No other uses without permission. From the NEJM Archive. Copyright © 2009 Massachusetts Medical Society. All rights reserved. large doses of x-ray therapy applied locally, only to preparation of glassware, tubing and citrate solu- have the organ later diminish in size, apparently tions has eliminated many of the febrile reactions as a result of repeatedly administered small to such transfusions. Since, with anemia, the he- amounts of general irradiation. If an interval moglobin content of the recipient's blood is always at first of a few days and later a week or two reduced, whole blood rather than fresh, preserved is allowed to elapse between exposures of a or reconstituted plasma is the medium of choice. quadrant of the body to no more than 75 to 100 r, Thus, in the treatment of anemias, the plasma a leukocyte count preceding each contemplated ir- serves largely as a vehicle for the conveyance of red radiation becomes a good measure of the effects of blood cells. Were it possible at present — when previous therapy and thus tends to prevent over- war places a premium on the collection of plasma dosage. Finally, observation suggests that signifi- to discover a means of preserving the discarded — cant increase of red blood cells may not begin for red blood cells intact over relatively long periods, some weeks after sufficient irradiation to cause this by-product of emergency activity would no marked lowering of the leukocyte count. Because longer largely be wasted. it is seemingly within the somewhat narrow range In the treatment of anemia, blood transfusion of dosage between suppression of leukocyte pro- plays a significant, although entirely passive, role. duction in the marrow and suppression of erythro- Since the hemoglobin concentration in the circu- cyte production that the effects of irradia- lating blood is increased, the blood is better able tion are most beneficial, it is desirable to proceed to carry oxygen from the lungs to the body tissues. with sufficient deliberation to allow for observa- With one unimportant exception, there is no evi- tions on the production of both types of cells. dence that transfusion has a stimulating action on The use of radioactive phosphorus, logically in- the bone marrow, so far as the production of red troduced in the treatment of leukemias by Dr. or white cells or platelets is concerned. The excep- John H. Lawrence, of San Francisco, is still under- tion is that, as a result of the eventual destruction going evaluation. Nevertheless, it seems probable of the transfused red blood cells, iron and pos- from the results already reported from several lo- sibly other materials necessary for new red-cell calities that radioactive phosphorus is not the production may slowly be made available. This final answer to the problem. The impression delayed and feeble action of transfusion, demon- gained by one who, it should be said, has had no strable only in hypochromic anemia, can scarcely personal experience with the method is that it compare with the effectiveness of the oral admin- represents, like x-ray therapy, a form of irradiation istration of a few grams of iron. On the other theoretically more selective in its effects on leukemic hand, there is no evidence that transfusion has cells and simple to administer. To my mind, how- any depressing effect on the bone marrow unless ever, it has the theoretical objection that all the it raises the hemoglobin above normal values. hematopoietic organs are exposed simultaneously Transfusion never passively raises the recipient's to irradiation. Nevertheless, eminently satisfac- leukocyte count for more than a few minutes, but tory results have been obtained with radioactive may, probably by introducing platelets, cause a phosphorus in the treatment of chronic leukemias, cessation of bleeding in thrombopenic purpura for especially those classified as myelogenous. It is several hours or a few days. The effect of transfu- still too early to be certain that such effects are sion on bleeding in hemophilia is by virtue of the superior to those obtained with modern x-ray introduction of a clot-accelerating agent, probably treatment. In the management of acute leukemias, enzymic, associated with the plasma globulins. aleukemic leukemias and leukemias in which Transfusion provides a valuable and sometimes severe anemia persists with or without previous lifesaving procedure in the treatment of anemia, x-ray treatment, radioactive phosphorus appears to for it may give time for other methods of treat- fail to cause benefit as consistently as any other ment to become effective or for spontaneous im- form of irradiation does. provement to occur. Thus, patients with sufficient- low values die before the Transfusion ly hemoglobin may effect of liver extract or iron therapy takes place. The final therapeutic aid in the treatment of The use of transfusions as a means of carrying pa- anemia is blood transfusion. Today, the use of tients through hemolytic crises or of preparing citrated blood, possessing as it does the important them for splenectomy or for x-ray therapy has advantages of comparative leisure in collection and already been mentioned. In patients with a tem- administration and convenience in transportation porary suppression of red-cell production, as in or storage, is the method of election. In spite of benzol poisoning, adequate hemoglobin levels may theoretical objections, fresh citrated blood appar- be artificially maintained until Nature initiates ently possesses no practical disadvantages compared new blood formation in the bone marrow. Finally, with unaltered whole blood. Increased care in the in patients with aplastic anemia, or with aleukemic

The New England Journal of Medicine Downloaded from nejm.org by JOSH ROSENFELD on May 25, 2016. For personal use only. No other uses without permission. From the NEJM Archive. Copyright © 2009 Massachusetts Medical Society. All rights reserved. leukemia, a reasonably comfortable existence may if, for any reason, hemoglobinuria results from sometimes be prolonged for many months by the the transfusion. As a "biologic test," it is desira- skillful use of transfusions alone. ble to inject not more than 50 cc. of blood in the For the effective employment of transfusions, first half-hour and to watch for symptoms and of a reaction. In the of two conditions must be met : blood must be readily signs management patients with the fact available and of the proper type; and the technic anemia, that subsequent transfusions be should borne mind. of the transfusions must be satisfactory and their may required always be in blood down on the vein use judicious. The availability of suitable Although cutting recipient's and its after transfusion are neces- in urban communities is largely an economic ques- ligation rarely this still a tion. In fact, the cost of repeated transfusions sary, unfortunate practice exists. As whose veins have been often becomes prohibitive for many persons able result, patients destroyed diffi- several transfusions a seri- to employ physicians. The relative by previous may present private ous technical such it culty of drawing blood in the past and the com- problem. Fortunately, in cases, to use the femoral ac- rarity and dramatic setting of the proce- is sometimes possible vein or, parative to the recent work of to infuse dure have much to do with the present high cost cording Tocantins, blood into the marrow of the ster- of a pint of blood in many localities. Rarely, to- directly cavity does the professional donor from whom blood num. Aside from its physiologic benefit to the pa- day, the facile of transfusion has a was drawn an incisional approach to tient, performance formerly by desirable effect in the dra- his veins have this unnecessary cause to raise the psychologic dispelling his contribution. The like matic or ominous connotations of the method in value of solution, the mind of the that of other situations depending on the layman. price If the use of transfusions to be economics of supply and demand, will probably is fully effective, extension of the and the objective to be obtained should be kept clearly come through organization in mind. For if the level invention that have produced the blood bank, the example, hemoglobin of a with anemia considered volunteer-donor registry and the emergency blood- patient pernicious is low for the a service. It is to the dangerously interval of few days procurement logical replace before liver-extract becomes iron lost by the donor by means of a two weeks' parenteral therapy effective, a transfusion often suffices. On course of orally administered ferrous iron. single the other hand, in a patient with a type of anemia Time does not a discussion of the prob- permit in which improvement may be long delayed or lems of blood typing except to say that mistakes may never occur, transfusions repeated at appro- can most be avoided the use of typing certainly by priate intervals should be given to raise the hemo- serums of titers. The relatively high agglutinating globin and to maintain it at a level compatible rare of the of anti-Rh ag- possibility development with moderate activity in convalescence or at the during pregnancy or as light glutinins by recipient work. It is a waste of precious and potentially a result of transfusions has been previous recently useful weeks or months of such a life if, the brilliant work of Landsteiner, patient's disclosed by owing to parsimony in the number of transfusions,, Levine and their associates. A final direct Wiener, he is needlessly confined to bed or home. test incubation of the donor's cells in involving # # # the recipient's serum for half an hour, with subsequent microscopic inspection, will almost certain- It is a truism that proper treatment depends ly detect incompatibilities, although to determine on accurate diagnosis of the type of anemia. Per- their precise nature may require special methods. haps it is not so well known that this is often im- However, despite the use of compatible blood and possible from the examination of the blood alone of scrupulous care, some unknown quality of cer- but requires, as in any other field of medicine, tain patients with anemia due to other causes than careful history taking and physical examination blood loss renders mild or even severe febrile and special laboratory examinations. The final reactions likely to occur. proof of the correct diagnosis of nutritional- From the recipient's point of view, the technic deficiency anemias is an orderly hematopoietic re- of transfusion includes skillful venipuncture with sponse to substitution therapy at the expected time. a short-bevel needle of small caliber that tends to Because certain types of anemia may masquerade minimize injury to the vein. The blood should as cardiac, renal, nervous or even orthopedic condi- a correct determination of the be run in slowly, especially in severely anemic pa- tions, patient's tients, to avoid a sudden increase in blood volume, hemoglobin level should be as routine a procedure the of a examination. which may overburden an already hard-pressed as performance urinary circulation. The alkalinization of the recipient's Even when one is dealing with an incurable ail- urine with 12 gm. of sodium bicarbonate, given ment, therapy effectively directed at an associated anemia reward to both an hour or two before transfusion, prevents the may sometimes bring pa- precipitation of hemoglobin in the renal tubules tient and physician.