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Studies of Hemoglobinemia and Hemoglobinuria Produced in Man by Intravenous Injection of Hemoglobin Solutions

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Studies of Hemoglobinemia and Hemoglobinuria Produced in Man by Intravenous Injection of Hemoglobin Solutions STUDIES OF HEMOGLOBINEMIA AND HEMOGLOBINURIA PRODUCED IN MAN BY INTRAVENOUS INJECTION OF HEMOGLOBIN SOLUTIONS D. Rourke Gilligan, … , Mark D. Altschule, Evelyn M. Katersky J Clin Invest. 1941;20(2):177-187. https://doi.org/10.1172/JCI101210. Research Article Find the latest version: https://jci.me/101210/pdf STUDIES OF HEMOGLOBINEMIA AND HEMOGLOBINURIA PRODUCED IN MAN BY INTRAVENOUS INJECTION OF HEMOGLOBIN SOLUTIONS By D. ROURKE GILLIGAN, MARK D. ALTSCHULE, AND EVELYN M. KATERSKY (From the Medical Service and the Medical Research Laboratories, Beth Israel Hospital, and the Department of Medicine, Harvard Medical School, Boston) (Received for publication October 18, 1940) Hemoglobinuria is a striking feature of several then it was inspected for cloudiness or particulate matter hemolytic disorders, such as blackwater fever, the and a culture in broth was made to ascertain its sterility. As noted previously (3), the solution, after centrifuging various paroxysmal hemoglobinurias, and certain and before filtering through the Seitz filter, would re- types of acute hemolytic anemia. Available in- peatedly show further clouding on addition of a few formation indicates that hemoglobinuria in these more drops of the hypertonic saline solution. However, conditions results from intravascular hemolysis after filtration through the Seitz filter, clouding with with liberation of hemoglobin into the plasma. additional saline no longer occurred. Passage through the Seitz filter was extremely slow; accordingly, when Quantitative studies of the plasma and urine the larger volumes were prepared, the solutions were first hemoglobin and of pigments derived from hemo- filtered without sterilizing the apparatus, and the filter globin have been made recently in this laboratory pad was changed as filtration became slowed. The entire on several patients with hemoglobinuria. It was amount was then passed again through a sterilized Seitz thought that comparison of the findings in normal filter. The concentration of hemoglobin in the solution was measured by the Evelyn method. individuals in whom hemoglobinemia and hemo- From 20 cc. to 280 cc. of the solution were injected globinuria were induced by intravenous injections into an antecubital vein at the rate of approximately 20 of hemoglobin solutions, together with the findings to 30 cc. per minute. Before injection of the larger vol- in clinical cases showing hemoglobinuria, might umes of hemoglobin solutions the subject's urine was clarify certain aspects of these clinical problems. made alkaline by oral administration of sodium bicar- bonate and was maintained alkaline throughout the period Sellards and Minot (1), Duesberg (2), and of hemoglobinuria. A glass of water was taken approxi- Ottenberg and Fox (3) have demonstrated that mately every hour in addition to the fluid of meals. small amounts of stroma-free solutions of human These precautions against possible kidney damage due to hemoglobin may be injected in man without seri- hemoglobin products are based on the observations of ous toxic reactions. The findings of these authors Baker and Dodds (4) and others. Chemical methods. Venous blood was drawn as sug- will be discussed below. gested by Ham (5) with a sterile syringe and needle which had been rinsed several times with sterile physi- METHODS ological saline solution. The blood was transferred to a tube containing a volume of 3 per cent sodium citrate Preparation and injection of hemoglobin solutions. solution equivalent to 10 per cent of the volume of blood, The hemoglobin solutions were prepared essentially as and gently mixed. The sample was centrifuged immedi- described by Sellards and Minot (1) and by Ottenberg ately and the plasma separated with care to avoid any and Fox (3). In some instances "bank" blood, dis- contamination with red cells. The hematocrit value was carded for intravenous use ten days after collection, was measured on a blood sample using oxalate mixture as used as the source of hemoglobin without regard to the the anticoagulant (6). The dilution of the plasma by blood grotup; when this was not available, fresh blood the citrate solution was calculated and the plasma hemo- was collected, using sodium citrate as the anticoagulant. globin and bilirubin values were corrected accordingly. The cells were washed three times with physiological The concentration of hemoglobin in the plasma and saline, then laked with four volumes of fresh distilled urine was measured by the benzidine method essentially water maintained at approximately 370 C. for one hour, as described by Bing and Baker (7, 8). The stock with frequent shaking. An amount of freshly prepared hemoglobin solution used by Bing and Baker is not 18 per cent saline solution equivalent to %o of the volume stable. A fresh hemoglobin standard was made daily of hemoglobin solution was added with resultant clouding, by diluting 0.5 cc. of blood of normal hemoglobin con- apparently due to aggregation of stromata. The solution centration to 2000 cc. with distilled water. The hemo- was centrifuged for an hour and the clear supernatant globin concentration of the blood was measured with fluid carefully removed and filtered through a Seitz filter the Evelyn colorimeter (9). Control plasmas were di- to remove micro-organisms and remaining stromata (3); luted one to 10 with water and 1.0 cc. was taken for 177 178 D. ROURKE GILLIGAN, MARK D. ALTSCHULE, AND EVELYN M. KATERSKY INTRAVENOUS .I'NJECTIQNS OF HEMOGLOBIN IN NORMAL SUBJECTS. Ploemo " imogllobin ~~~2. mOm. Pei 2001° c_c. Hqgbln- 17gm. 100 Kgb. lno2.3gm 100 |50 so 5o Plosm Sli 0 0 mgm.per IC 0.8 Urine - Hm 2 and ~A No Hemoloin No Hemoglobin 200 No Hemolobin Urine Albuiado Ng Al uiN% Alb mIn tLENotAlbumiA mgom oi utw0 0 - ~~~~~~00__ 0 24 6 02 4 66 02 46 8 0.2 46 8 L1 5. Hob. b ". 400 400 9. 10. 350 Hgb. 1n.-9. 9 350 Hinj-1649m. 300 300 250 250 Plim* Hemoglobin mom. per 100 c.c. 200 200 ISO ISO 100 100 50 50 0 O 1.4 _1_ 10'^. sho---- dbt22---dL2- PI@OSO BIIUDb" 1.0 - 1.0 -- 1 mgm. per 100 C.c. °'2 0 6 O 1210.6O4-2 6 10 Urine Hemoglobin eoeumndreogl n 2400 ead Albwakend ]o 80 |6 -t H_e0hl~~~~~4hbowrsater 0. Urine Albumin Ilnjetio 0 2 4 6 21 600 oglobin0 2 4 6 10 12 14'24 DUrine Albumin FIG. 1. THE HEmOGLOBIN AND BILIRUBIN CONCENTRATIONS OF THE PLASMA, AND THE HEMOGLOBIN AND ALBUMIN EXCRETION IN THE URINE FoLLowING INTRAVENOUS INJECTIONS OF SOLUTIONS OF HEMOGLOBIN IN NORMAL SUBJEcrs The experiment number is given at the top of each diagram; each experiment was made in a different subject. INTRAVENOUS HEMOGLOBIN INJECTIONS 179 analysis. Appropriately smaller amounts of a one to 10 TABLE I dilution were used for plasmas of moderate hemoglobin Effect of hemolysis on plasma bilirubin values obt4ined by concentration. A one to 50 dilution was made of plasmas the Malloy and Evelyn method (10) with 200 mgm. or more of hemoglobin per 100 cc. The hemoglobin standards were made from 0.1, 0.2, and 0.5 Final hemoglobin concentration of cc. of the standard hemoglobin solution so that the un- plasma after adding hemoglobin Experi- Control knowns could be read in the colorimeter against a stand- ment plasma ard which closely matched. Samples of 0.1 cc. of un- num- 12 mgm. 30 mgm. 60 mgm. 120 mgm. diluted urine, or 0.1 cc. of a diluted urine equivalent to ber per 100 cc. per 100 cc. per 100 cc. per 100 cc. approximately 5 mgm. per 100 cc., were used. This Bilirubin Bilirubin Bilirubin Bilirubin Bilirubin amount of an undiluted urine with high specific gravity mgm. per mgm. per mgm. per mgm. per mgm. per precipitates some of the benzidine reagent and probably 100 cc. 100 cc. 100 cc. 100 cc. 100 cc. 1 0.69 0.69 introduces a slight inaccuracy; if amounts of urine are 2 0.83 0.87 chosen to read against the low standard, no precipitation 3 0.18 0.17 0.21 occurs except in urines of very low hemoglobin concen- 4 0.20 0.18 0.19 tration, which cannot be diluted. Appropriate amounts 5 0.49 0.35 0.31 6 0.84 0.67 0.69 of water are added to the tubes containing 2 cc. of benzi- 7 0.92 0.63 0.58 dine reagent to make the total of the unknown or stand- ard hemoglobin samples plus water up to 1 cc. The bilirubin concentration of the plasma was meas- was multiplied by 20 to give the concentration of total ured by the method of Malloy and Evelyn (10), using the in 100 cc. of urine. with solutions Evelyn colorimeter. It was noted repeatedly that the protein Experiments bilirubin of known hemoglobin concentration and of known al- value obtained immediately after the hemoglobin bumin concentration gave satisfactory results with this injection was appreciably lower than that of the control simple method. Acetic acid and acid blood, suggesting the tungstic precipita- that presence of hemoglobin inter- tions were tried with very precipitation fered with the bilirubin measurement. Accordingly, he- unsatisfactory of protein in urines containing hemoglobin and very moglobin solutions were added to normal plasma samples little albumin. to give various final concentrations of hemoglobin and examinations of and urine the effect on the Spectroscopic plasma were bilirubin was measured. The bilirubin made with a Zeiss hand In one instance values were corrected for the 10 per cent dilution caused spectroscope. spectrophotometric examination of the urine was made by the addition of the hemoglobin solution. The values with a of obtained when the concentration of hemoglobin in the Konig-Martens type spectrophotometer. plasma was 30 mgm. per 100 cc., or over, were appreci- ably lower than those of the hemoglobin-free plasma RESULTS (Table I).
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