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Immunohematology Acute Intraoperative Hemolysis Following Rapid Infusion of Hypotonic Solution Richard J. Davey, MD; Brenda J. Lee, BB(ASCP); and Sandra M. Coles, SBB(ASCP) A patient undergoing intraoperative .radiation was noted to have marked hemoglobinemia and hemoglobinuria after the transfusion of 2 units of packed red cells. Laboratory investigation revealed no evidence of immune hemolysis, and the patient recovered uneventfully following diuresis. The patient had received 280 mL of a radiopotentiating agent, misonidazole, immediately prior to the hemolysis. The drug had been suspended in sterile water, was markedly hypotonic (118 mosm/L), and completely lysed red cells in vitro. Other causes of nonimmune hemolysis related to transfusion were ruled out. Whenever unexplained hemolysis occurs in the absence of immunologic findings, the infusion of hypotonic solutions should be considered as a cause. A 34-year-old man underwent an esophagogastectomy for a malignant gastric neoplasm. As part of the surgical procedure, radiation was administered to the tumor bed through the operative site. When the radiation had been almost completely administered, the anesthesiologist noted that the patient's urine had changed from yellow to dark red. No free cells were found in the urine sample, and a blood specimen revealed bright red plasma. The patient's vital signs remained stable. Before the onset of hemoglobinuria and hemoglobinemia, the patient had received 2 units of packed red cells during surgery. Preoperative serologic data were as follows: The patient's blood type was A, Rh positive, and the direct antiglobulin test (DAT) was negative using polyspecific antisera. The serum was negative for unexpected antibodies, according to the 37 °C saline and indirect antiglobulin test, and 8 units of red cells were compatible, as determined by the albumin to indirect antiglobulin phase crossmatch. From the Department of Transfusion Medicine, National Institutes of Health, Bethesda, MD 20205. Diagnosis and Treatment Planning In the case reported herein, a presumptive diagnosis of an acute hemolytic transfusion reaction should be made. The blood bank should be notified, and postreaction samples should be obtained. Prompt diuresis should be initiated to prevent renal failure, which may accompany massive immune red cell destruction. In this case, the patient was given furosemide and mannitol, which resulted in brisk diuresis. The patient's vital signs were closely monitored and remained stable. The surgeon noted no excessive bleeding or oozing from the operative sites. Such bleeding would suggest diffuse i n t r a v a s c u l a r c o a g u l a t i o n (DIC). The p a t i e n t recovered uneventfully. An evaluation for evidence of a hemolytic transfusion reaction should be performed, 1 including a clerical check of all transfused products. A DAT must be performed on a postreaction specimen, and the serum/plasma must be examined for hemolysis; a prereaction sample should be used for comp a r i s o n . If t h e r e is e v i d e n c e of hemoglobinemia or a positive DAT 282 LABORATORY MEDICINE • VOL. 17, NO. 5, MAY 1986 caused by the transfusion, then additional studies to determine the cause should be undertaken. To evaluate for possible i m m u n e - m e d i a t e d hemolysis, an ABO and Rh typing should be repeated on samples both before and after the reaction. Screening tests for unexpected antibodies and donor-recipient compatibility tests should also be repeated. In the case reported, there was no indication that a clerical error had been made, and the post-transfusion DAT was negative. Free hemoglobin, however, was present in the serum obtained after the reaction; the results of further serologic tests indicated that this hemoglobinemia was not immune mediated. Nonimmune causes of acute intravascular hemolysis should be considered once a clerical error has been ruled out and there is no evidence of an i m m u n o h e m a t o l o g i c problem. Nonimmune hemolysis may be caused by infusion of hypotonic solution, mechanical trauma to red cells, glucose6-phosphate d e h y d r o g e n a s e deficiency, the heating or freezing of blood, drugs added to the blood line, and bacterial c o n t a m i n a t i o n of the infused unit. The patient received no blood under pressure and was not sustained using a cardiopulmonary bypass m a c h i n e , m a k i n g mechanical trauma unlikely. The residual blood in the transfused units was examined and showed no evidence of hemolysis or bacterial contamination. No medication had been added to the admini s t r a t i o n line. A r a d i o p o t e n t i a t i n g agent, misonidazole, had been infused immediately prior to the intraoperative radiation. • M iso nidazole /Water ion n / Albumin III to n n / ~~** IUUTO • - m m Misonidazole/Saline Albumin inn'v 0% -•100% Effect of decreasing concentrations of misonidazolel water solution and misonidazolel normal saline solution on red cell hemolysis. Equal volumes of diluent and red cells in each tube. In this case, serial blood samples were obtained from the patient in the period surrounding the hemolytic episode. The plasma remained clear after the red cell infusion but turned deep red immediately following the rapid infusion (10 minutes) of 280 mL of the misonidazole solution. Investigation revealed that the misonidazole had been suspended in 280 mL of sterile water prior to infusion. The clear, colorless misonidazole solution had an osmolarity of 118 mosm/L. Serial dilutions in albumin of misonidazole/ water and misonidazole/normal saline showed that the drug/water combination was clearly hemolytic (Figure). Discussion The sudden appearance of hemoglobinuria and hemoglobinemia in temporal proximity to blood transfusion during surgery should be regarded as a hemolytic transfusion reaction until proved otherwise. In this case, a completely negative serologic evaluation in a clinically stable p a t i e n t suggested a nonimmune hemolytic process. There are several causes of nonimmune red cell destruction. 2 Donor red cells may be damaged by improper blood administration. Drugs or other medications added to the blood line may cause oxidant or osmotic damage to the red cells as may im- proper red cell washing or deglycerolyzing techniques. Dilution of the red cells in solutions other than normal saline, such as 5% dextrose and water, also results in osmotic damage. Accordingly, drugs or medications, including those for intravenous (D7) use, must not be added to blood or blood components; 0.9% sodium chloride injection, however, may be added to increase t h e volume and facilitate mixing and administration. 3 Forcing red cells through a small-bore needle under high pressure will mechanically lyse the red cells. Bacterial contamination of the unit rarely occurs because of the strict adherence to proper aseptic venipunct u r e t e c h n i q u e , as w e l l as t h e bacteriocidal activity of donor neutrophils in the freshly drawn unit. A grossly contaminated unit, however, can c a u s e c a t a s t r o p h i c r e s u l t s if transfused. The hemolyzed red cells will cause immediate hemoglobinemia and hemoglobinuria. In addition, the infusion of bacterial organisms and endotoxin will produce an immediate clinical syndrome of "warm" septic shock, with flushing, fever, hypotension, and DIC, followed by rapid clinical deterioration. Enzyme deficiencies in donor red cells may produce nonimmune hemolysis if these cells are exposed to an oxidant drug present in the recipie n t ' s c i r c u l a t i o n . Glucose-6-phosp h a t e d e h y d r o g e n a s e deficiency, however, the most common of all red cell enzyme defects, h a s not been shown conclusively to cause clinically significant hemolysis of affected donor red cells upon transfusion. 4 The storage of red cells in unmonitored refrigerators or freezers or the inappropriate use of blood-warming devices can cause thermal injury and resultant hemolysis of donor cells. The infusion of free hemoglobin from these units will result in hemoglobinemia and hemoglobinuria but will rarely cause clinical problems. Recipient red cells can be mechanically t r a u m a t i z e d by cardiopulmonary bypass machines or by strong suction devices attached to red cell salvage machines. The appearance of hemoglobinemia in such patients can be especially confusing, since blood, IV solutions, and medications are often administered simultaneously. In the patient described, investigation revealed that the rapid infusion of a hypotonic solution resulted in i n t r a v a s c u l a r h e m o l y s i s . T h e Pharmacy Department had followed the manufacturer's instructions for d i l u t i n g t h e d r u g (misonidazole), which specified the use of either sterile water or normal saline. However, since misonidazole was being used in a research protocol that dictated rapid infusion of a large volume of the diluted drug, normal saline was the only acceptable diluent. A hypotonic solution can also accidentally be infused if the solution containers are mislabeled or if an inappropriate product is selected. Fatalities have been reported with the inadvertent infusion of large volumes of distilled water. 6 Whenever unexpected acute hemolysis occurs in a patient with no evidence of an immune hemolytic process, the infusion of hypotonic solutions should be considered as a cause. References 1. American Association of Blood Banks: Technical Manual, ed 9. Arlington, Va, 1985. 2. Davey RJ: Mechanism of premature red cell destruction, in Judd WJ, Barnes A (eds): Clinical and Serological Aspects of Transfusion Reactions. Arlington, Va, American Association of Blood Banks, 1982, pp 18-27, 3. American Association of Blood Banks: Standards for Blood Banks and Transfusion Services, ed 11. Arlington, Va, p 31. 4. McCurdy PR, Morse EE: Glucose-6-phosphate dehydrogenase deficiency and blood transfusion. Vox Sang 1975;28:230. 5. Mollison PL: Blood Transfusion in Clinical Medicine, ed 7. Oxford: Blackwell Scientific Publications, 1983,p 564. LABORATORY MEDICINE • VOL. 17, NO. 5, MAY 1986 283