Vol. 19, No.

2 February 1997

Continuing Education Article

FOCAL POINT 5Many transfusion reactions can
be prevented.

KEY FACTS
s The most important decision is whether transfusion is truly needed. s Blood component therapy can be less risky than transfusion of whole blood. s Unless the blood type of the recipient is known, universal blood should always be used. s A crossmatch should be performed for all dogs receiving red cells, even if universal blood is used. s The severity of most transfusion reactions is dose dependent, and early recognition of a reaction can avert disaster.

Canine Transfusion Reactions. Part II. Prevention and Treatment
North Carolina State University University of Minnesota

Karyn Harrell, DVM
Novo Nordisk Gentofte, Denmark

Janice Parrow, CVT, LATg

Annemarie Kristensen, DVM, PhD

R

ecent advances in transfusion medicine and the increased availability of canine blood components have made transfusion an important part of veterinary medicine. Transfusion is potentially life-saving, but it carries some risk. Part I discussed the immunologic and nonimmunologic causes of transfusion reactions. This part discusses the prevention and treatment of transfusion reactions.

PLANNING TRANSFUSION THERAPY The most important decision a clinician must make is whether transfusion therapy is truly needed. An accurate assessment of the animal’s overall condition and prior history must be made; the decision to use blood components should not be based on numbers alone.1–3 As with all forms of medical therapy, avoiding unnecessary drug administration is the first step in preventing undesirable complications. After deciding to initiate transfusion therapy, the veterinarian must carefully choose the component to be given. The use of whole blood has been dramatically reduced recently in human and veterinary medicine.2,4–6 More precise and efficient replacement for distinct deficiencies can be accomplished through the use of specific component therapy. Use of component therapy will also decrease the risk of transfusion reactions.4–7 If only coagulation factors are needed, plasma or cryoprecipitate is the most appropriate therapy; hemolytic reactions can thus be avoided. A dog that is anemic and has significant heart disease will be less likely to develop circulatory overload if packed red cells are given instead of whole blood. Reviews

Small Animal

The Compendium February 1997

of the indications for administering specific blood components have been published.5,8

SELECTING DONORS Blood Type Many transfusion reactions can be prevented simply by following appropriate transfusion medicine guidelines (see Preventing Transfusion Reactions in Dogs) when choosing donors, collecting and preparing blood products, and administering these products to patients. Several of these points warrant further discussion.

curate card test for dog erythrocyte antigen (DEA) 1.1 is now available. This test allows for the immediate identification of the DEA 1.1 status of donor and recipient. Donor dogs can then be typed for other important antigens by established laboratories. 13,14 Although most donors should have the universal blood type, donors of other blood types may be used when the recipient’s blood type is known to be compatible (DEA 1.1–positive blood may be given to a DEA 1.1–positive patient).

Crossmatching Not all DEA groups have been well characterized, so Nonuniversal Blood a crossmatch should be performed for all dogs receiving Use of nonuniversal blood increases the risk of acute red blood cells—even when universal blood is used.15 A hemolytic transfusion reactions in a sensitized patient full crossmatch includes a major part (which tests for and might induce antibody formation in the recipiantibodies in the recipient’s blood to the donor’s red ent.4,5,7,9,10 These antibodies will decrease survival of cells) and a minor part (which detects antibodies in the donor red cells and sensitize the patient to additional donor’s blood to the recipient’s red blood cells).3,7,15,16 Controls testing reaction of the recipient’s cells with its transfusions. Transfusion of nonuniversal blood to a own serum and the donor’s cells with its own serum are bitch might lead to neonatal isoerythrolysis in puppies also run. Unless large quantities of plasma are transthat are subsequently born.8,11,12 Unless the blood type of the recipient is known, unifused, a minor crossmatch is unnecessary.7,15 5,9,13 A quick and acA major crossmatch is a superb screening test for inversal blood should always be used. compatibilities that could cause serious hemolytic transfusion rePreventing Transfusion Reactions in Dogs actions.3,7,16 This test is especially useful for patients that have been Donor* s Administer diphenhydramine previously transfused (antibodies s Type all donors—at least for (0.5 mg/kg subcutaneously or can form in as few as 4 days), in DEA 1.1. intramuscularly). patients with natural antibodies, and in multiparous females.3,15,16 s Screen for metabolic and The major crossmatch (see the infectious diseases. Administration Major Crossmatch protocol) is s Use sterile technique when s Never use outdated or hemolyzed simple and can be performed in collecting blood. products. any clinic with a centrifuge, a s Use appropriate separation s Use only isotonic saline to dilute heat block, and a microscope. methods, and store blood packed red cells. Antigen–antibody reactions can be temperature dependent. products at suggested s Warm blood products to Consequently, the crossmatch is temperatures. appropriate temperatures. run at 37˚C, 25˚C, and 4˚C. 3 s Avoid mechanical damage to Red blood cells that show a reaccellular components by using Recipient tion at 37˚C or 25˚C should not s Perform a major crossmatch. appropriate pumps, filters, needle be given. It may also be necessary s Use universal blood (unless the sizes, and administration rates. to compare the results with the self-controls (especially in cases of patient’s blood type is known). s Use warmed or open units within immune-mediated hemolytic s Consider the patient’s underlying 24 hours. anemia) and determine a “best diseases when choosing s Complete each transfusion within fit” transfusion. components and administration 4 hours. The incidence of hemolytic rate. s Monitor transfusions carefully. transfusion reactions will be reduced by performing crossmatch*Screened and typed canine blood products can also be obtained from an established es when red cells are given. Even blood bank. when blood showing a compatiDEA 1.1 s NATURAL ANTIBODY s MULTIPAROUS FEMALES

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ble crossmatch is given, however, certain reactions may still occur.7,15,16 As a crossmatch tests only for preexisting antibodies, posttransfusion sensitization may occur—even when appropriately matched blood is given (which emphasizes the need to use universal red cells).7,16 A mild hemolytic reaction may also occur when antibodies are present at levels too low for the crossmatch to detect. In addition, a crossmatch does not test for antibodies to white blood cells or platelets; these antibodies may be responsible for mild to severe nonhemolytic reactions.17–20

Major Crossmatch
s Collect 2 ml of EDTA anticoagulated blood from donor and recipient. (Pigtails on stored blood can be used.) s Centrifuge the blood samples for 1 minute (1000 rpm); remove the plasma to prelabeled tubes. s Wash the donor cells: Make a 2% suspension of red blood cells by taking 0.1 ml of the red blood cells and adding 5 ml of 0.9% saline; mix the suspension. s Centrifuge the suspension for 1 minute. Discard the supernatant. Resuspend the red blood cells in another 5 ml of 0.5% saline. Repeat this procedure twice more. s Place two drops of the recipient’s plasma or serum and two drops of the donor cell suspension in a 3-ml test tube. Mix well and incubate tubes for 30 minutes at room temperature. Centrifuge for 1 minute at 1000 rpm. s For controls, follow the same procedure as in the previous step but place the recipient’s cells with the recipient’s plasma or serum and the donor’s cells with the donor’s plasma or serum. s To read the tubes: s Check for agglutination. s Check for hemolysis. s Place a drop from the tube on a slide and examine under the microscope for agglutination.

Prophylactic Treatment The benefit of prophylactic treatment for the prevention of type I hypersensitivity reactions has been debated.5,21 In one experiment, an antihistamine given before plasma transfusion prevented acute hypersensitivity reactions. 21 No controlled clinical or prospective studies have been published to date. Although we are currently unable to document a definitive decrease in type I reactions when an antihistamine is given in clinical cases, diphenhydramine (0.5 mg/kg intramuscularly or subcutaneously) may reduce the risk of these reactions. Glucocorticoids do not acutely suppress the production of IgG or IgM antibodies. For this reason, administration of glucocorticoids before red cell transfusions will not prevent a hemolytic transfusion reaction from occurring when incompatible blood is given to a sensitized patient.7,22 In addition, steroids do not prevent the binding of IgE to mast cells or the subsequent release of vasoactive cellular products. Thus, there is no reason to administer steroids in an attempt to prevent a type I hypersensitivity reaction. Steroids should be given only if necessary to treat the primary disease or to treat shock if a severe transfusion reaction does occur.

Monitoring The severity of most transfusion reactions is dose dependent; early recognition of a problem can avert disaster. Careful patient observation is critical, especially during the first 30 minutes of the transfusion.5,18,21,23,24 Accurate monitoring is facilitated by the use of a standardized form to record significant data. When any blood component is to be given, baseline measurements of temperature, pulse, and respiratory rate should be recorded. Mucous membrane color, packed cell volume, total protein, a coagulation factor test, and platelet count should also be noted. The temperature, pulse, and respiratory rate should also be

checked at 15, 30, and 60 minutes into the transfusion and at 1, 12, and 24 hours after transfusion.5 When red cells are given, packed cell volume is recorded and serum examined for hemolysis at 15 minutes and at 1, 12, and 24 hours after transfusion. More specific information (e.g., blood pressure, coagulation testing, renal function) may be collected as needed. It is also useful to record the primary disease, a summary of prior transfusions or reactions, the component and specific donor used, crossmatch information, and premedications or other therapy. If a reaction does occur, particular details should be summarized. Conscientious monitoring and documentation will enhance early recognition of reactions and aid in the identification of the overall incidence of problems in the transfusion practices in your clinic.

TREATMENT If a reaction is suspected, the transfusion must be stopped immediately.2,7,11,16,25,26 While the transfusion is

DIPHENHYDRAMINE s FEVER s HEMOLYSIS

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The Compendium February 1997

40
60

35
Percent of Transfusions

Other WB

PRBC FFP

Whole Blood

30 25 20 15 10 5 0 1988 1989 1990 1991 1992 1993 1994 1995

50 40 30 20 10 0 1988 1989 1990 1991 1992 1993 1994 1995

Year
Figure 1A Figure 1B

1988

Figure 1—(A) Whole blood has accounted for a declining percentage of all transfusions at the University of Minnesota Veterinary Teaching Hospital. (B) Fresh-frozen plasma (FFP) and packed red blood cells (PRBC) are increasingly being used instead of whole blood (WB).

discontinued (for a minimum of 10 to 15 minutes), the severity of signs is evaluated (see Treatment of Transfusion Reactions). The veterinarian should verify whether the appropriate administration rate and technique are being used. The signs of mild febrile or type I hypersensitivity reactions often dissipate, and the transfusion may be restarted at a slower rate.7,16 External cooling and antipyretics may be necessary if the fever is persistent or more severe.16,26 Mild to moderate hypersensitiv-

ity reactions (pruritus, erythema, and urticaria) often respond well to diphenhydramine (1 to 2 mg/kg intramuscularly).3,23,27,28 Some clinicians recommend an antiinflammatory dose of a glucocorticoid.7,29,30 Hypocalcemia secondary to citrate toxicity is generally transient and reversible by discontinuing the transfusion until the signs subside.7,23 Often, the transfusion can be restarted at a slower rate without further problem.3,23,26 Specific therapy with 10% calcium gluconate

Treatment of Transfusion Reactions
General s Stop the transfusion. s Evaluate specific signs—if mild, restart transfusion at slower rate and monitor closely. Fever s Consider external cooling and/or antipyretics. s Monitor temperature for 24 to 48 hours. Vomiting s If mild, restart transfusion at slower rate and monitor for additional vomiting. s Withhold food and water for 12 to 24 hours (or as necessary). s Consider antiemetics and/or intravenous fluids. Pruritus or urticaria s If mild, restart transfusion at a slower rate and monitor. s Administer diphenhydramine and/or glucocorticoids. Hemolysis s Monitor temperature. s Monitor for shock, disseminated intravascular coagulation, acute renal failure, and sepsis. s Consider the following: s Intravenous fluid diuresis s Glucocorticoids s Furosemide s Dopamine s Heparin Respiratory distress s Administer furosemide. s Consider oxygen therapy with or without assisted ventilation.

EXTERNAL COOLING s ANTIPYRETICS s DIPHENHYDRAMINE s GLUCOCORTICOID

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TABLE I Incidence of Reactions to Transfusion of Blood Components Reaction/Total Transfusions (n/n) 2/48 5/134 3/186 10/322 9/271 7/328 13/376 14/413 63/2078 Total Incidence (%) 4.2 3.7 1.6 3.1 3.3 2.1 3.4 3.4 3.0 Packed Red Blood Cells and Fresh-Frozen Plasma 0 1 1 2 4 1 2 1

Year 1988 1989 1990 1991 1992 1993 1994 1995 Total

Packed Red Blood Cells 0 1 1 2 4 4 8 3

Fresh-Frozen Plasma 1 1 0 3 1 1 3 9

Fresh Whole Blood 1 2 1 1 0 0 0 1

Other

0 0 0 2 (platelet-rich plasma) 0 1 (autotransfusion) 0 0

is seldom necessary; if An earlier study of 131 red TABLE II needed, it can be adminisblood cell transfusions evaluattered at 50 to 150 mg/kg Frequency of Clinical Signs of Transfusion Reactions ed acute and delayed reacslowly to effect.3,4,7,16,27 As tions.35 Seventeen dogs (13%) Frequency calcium infusion may proexhibited adverse side effects, Reaction Mild Signs Severe Signs duce ventricular arrhythwith 10 dogs having an acute mia, the electrocardiogram Fever reaction (emesis, hemolysis, 41 — must be monitored.26 Se- Vomiting hematuria, or icterus); 7 dogs 13 — vere transfusion reactions Facial edema exhibited delayed hemolysis. 6 — resulting in shock, dissem- Hemolysis None of these reactions were 3 — inated intravascular coagu- Tachypnea/dyspnea fatal. A crossmatch was not 2 1 lation, renal failure, respi- Hemolysis (acute) performed on all of these dogs. 1 1 ratory distress, and sepsis Tremors We have recently tabulated 1 — must be treated aggressive- Shock the results from an 8-year ret— 1 ly. Further information on rospective study conducted at the appropriate treatment the University of Minnesota of severe reactions has been published.2,4,16,25,30–33 Veterinary Teaching Hospital and documenting the inMost of the delayed transfusion reactions that are cidence and clinical significance of transfusion reacrecognized are self-limiting.7,2 If transfusion-related distions. Transfusion request forms were reviewed for posease transmission is suspected, specific treatment of that sible adverse reactions from the period of September 1, disease is indicated. 1988 through December 31, 1995. The complete clinical record of any dog listed as having a transfusion reacINCIDENCE AND CLINICAL SIGNIFICANCE tion was reviewed to confirm that a reaction occurred The incidence of canine transfusion reactions has only and to determine the type and outcome of that reacrecently begun to be studied. Documentation of an acute tion. Most of the blood products used were from inhemolytic transfusion reaction due to DEA 1.1 incompathouse universal donors. Crossmatches were conducted ibility has recently been published.24 A 1992 study of 307 for 85% of the dogs receiving red blood cells, and most red blood cell transfusions given over a 1-year period at of the dogs were pretreated with diphenhydramine. the University of Pennsylvania Veterinary School docuFrom 1988 to 1995, the use of whole blood demented 10 acute reactions (3.3%).34 All were mild and creased dramatically and there was a concurrent rise in self-limiting and consisted of pyrexia (4 dogs), vomiting (4 the use of specific components (Figure 1). This trend dogs), and facial edema (2 dogs). Most of these dogs had agrees with other reports.6,34,35 The specific components (excluding autotransfusion) used in the last 3 years of been crossmatched, and no hemolytic reactions were seen.
DELAYED REACTIONS s FOLLOW-UP s DOCUMENTATION

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the study included packed red cells (40.8%), plasma products (56.0%), and whole blood (3.2%). A total of 2078 transfusions were given over the 8year period. Sixty-three suspected acute or delayed reactions occurred (3.0%). Table I gives a breakdown of the yearly results. The vast majority of these reactions (92%) were acute hypersensitivities or febrile reactions. Two (3.2%) acute and three (4.8%) delayed hemolytic reactions also occurred. Additional delayed reactions may have been missed because of inadequate follow-up. No nonimmunologic reactions were documented. Table II summarizes the variety and incidence of clinical signs observed during these transfusion reactions. Although the use of specific component therapy increased dramatically over the 8-year study period, the incidence of reactions did not decrease significantly, possibly because monitoring and documentation of reactions improved. Fever and vomiting were the two most common side effects documented. Most of these reactions were considered mild and either resolved spontaneously or responded well to slowing or discontinuing the transfusion, administration of diphenhydramine, and/or mild cooling techniques. One death was attributed to acute shock. The remaining two dogs with severe reactions (consisting of pulmonary edema, pyrexia, and acute hemolysis) recovered completely with supportive therapy, which included discontinuation of the transfusion and administration of diphenhydramine, furosemide, dexamethasone, aminophylline, and oxygen therapy. As previously stated, approximately 15% (140 of 943) of the red cell products were not crossmatched. One hemolytic and 10 nonhemolytic reactions occurred after these uncrossmatched transfusions. Eleven percent of the animals did not receive prophylactic treatment. Only 0.1% (1 of 104) of these animals exhibited a transfusion reaction. A well-controlled prospective study is needed before conclusions can be drawn about the effect of crossmatching and prophylactic treatment in canine transfusion medicine. Adequate monitoring and continued reporting of the significance and incidence of transfusion reactions are also needed in order to enhance the ability of veterinarians to safely administer transfusions to dogs.

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CONCLUSION When appropriately prepared and administered, transfused blood products can be an extremely useful and low-risk form of therapy in veterinary medicine. Recent advances in transfusion medicine, along with the increased availability of reliable blood components, have made transfusion therapy accessible to most practitioners. Responsible use of these blood products must inCROSS-MATCHING s PROPHYLAXIS

VLS

VE T E R I N A RY

L E A R N I NG

BOOKS
SYS T E M S

The Compendium February 1997

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clude an awareness of possible adverse effects. Veterinarians who understand the underlying mechanism of transfusion reactions can prevent many of these reactions.

About the Authors
Dr. Harrell is affiliated with the Department of Companion Animals and Special Species Medicine, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina. Dr. Kristensen is affiliated with Novo Nordisk in Gentofte, Denmark, and is a Diplomate of the American College of Veterinary Internal Medicine. Ms. Parrow is affiliated with the Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota.

REFERENCES
1. Killingsworth CR: Use of blood and blood components for feline and canine patients. JAVMA 185:1452, 1984. 2. Brecher ME, Taswell HF: Hemolytic transfusion reactions, in Rossi CE, Simon TL, Moss GS (eds): Principles of Transfusion Medicine. Baltimore, Williams & Wilkins, 1991, p 619. 3. Authement JM, Wolfsheimer KJ, Catchings S: Canine blood component therapy: Product preparation, storage, and administration. JAAHA 23:483, 1986. 4. Hohenhaus AE: Canine blood transfusions. Probl Vet Med 4:612, 1992. 5. Kristensen AT: General principles of small animal blood component administration, in Kristensen AT, Feldman BF (eds): The Veterinary Clinics of North America: Canine and Feline Transfusion Medicine. Philadelphia, WB Saunders Co, 1995, pp 1277–1290. 6. Stone E, Badner D, Cotter SM: Trends in transfusion medicine in dogs at a veterinary school clinic: 315 cases (1986–1989). JAVMA 200:1000, 1992. 7. Cotter SM: Clinical transfusion medicine, in Cotter SM (ed): Comparative Transfusion Medicine. Advances in Veterinary Science and Comparative Medicine. Vol. 36. San Diego, CA, Academic Press, 1991, p 188. 8. Pichler ME, Turnwald GH: Blood transfusion in the dog and cat. Part I. Physiology, collection, storage, and indications for whole blood therapy. Compend Contin Educ Pract Vet 7(1)1:64–71, 1985. 9. Smith CA: Transfusion medicine: The challenge of practical use. JAVMA 198:747, 1991. 10. Bucheler J, Cotter SM: Outpatient blood donor program. Probl Vet Med 4:572, 1992. 11. Greenberger PA: Plasma anaphylaxis and immediate type reactions, in Rossi CE, Simon TL, Moss GS (eds): Principles of Transfusion Medicine. Baltimore, Williams & Wilkins, 1991, p 635. 12. Paradis MR: Neonatal transfusion medicine, in Cotter SM (ed): Comparative Transfusion Medicine. Advances in Veterinary Science and Comparative Medicine. Vol 36. San Diego, CA, Academic Press, 1991, p 225. 13. Hale AS: Canine blood groups and their importance in veterinary transfusion medicine, in Kristensen AT, Feldman BF (eds): The Veterinary Clinics of North America: Canine and Feline Transfusion Medicine. Philadelphia, WB Saunders Co, 1995, pp 1323–1332.

14. Andrews AA, Chavey PS, Smith JE: Production, characterization, and applications of a murine monoclonal antibody to dog erythrocyte antigen 1.1. JAVMA 201:1549, 1992. 15. Kristensen AT: Modern veterinary blood banking practices and their applications in companion animal practice, in Kristensen AT, Feldman BF (eds): The Veterinary Clinics of North America: Canine and Feline Transfusion Medicine. Philadelphia, WB Saunders Co, 1995, pp 1231–1244. 16. Turnwald GH, Pichler ME: Blood transfusion in dogs and cats. Part II. Administration, adverse effects, and component therapy. Compend Contin Educ Pract Vet 7(2):115–126, 1985. 17. Bull RW: Antigens, graft rejections, and transfusions. JAVMA 181:1115, 1982. 18. Brubaker DB: Clinical significance of white cell antibodies in febrile nonhemolytic transfusion reactions. Transfusion 30:733, 1990. 19. Thulstrup H: The influence of leukocyte and thrombocyte incompatibility on non-haemolytic transfusion reactions. Vox Sang 21:233, 1971. 20. Kevy SV, Schmidt PJ, McGinniss MH, et al: Febrile, nonhemolytic transfusion reactions and the limited role of leukoagglutinins in their etiology. Transfusion 2:7, 1962. 21. Bliss JQ, Johns DG, Burgen SV: Transfusion reactions due to plasma incompatibility in dogs. Circ Res 7:79, 1959. 22. Hardaway RM, McKay DG, Wahle GH, et al: Pathologic study of intravascular coagulation following incompatible blood transfusion in dogs. Am J Surg 91:24, 1956. 23. Cotter SM: Blood banking—Indications and side effects. Proc 6th Annu Members Meetg ACVIM Forum:48, 1988. 24. Giger U, Galens CJ, Callan MB, et al: An acute hemolytic transfusion reaction caused by dog erythrocyte antigen 1.1 incompatibility in a previously sensitized dog. JAVMA 206:9, 1995. 25. Ramsey G: The pathophysiology and organ-specific consequences of severe transfusion reactions. New Horizons 2:575, 1994. 26. Snyder EL, Stack G: Febrile and nonimmune transfusion reactions, in Rossi CE, Simon TL, Moss GS (eds): Principles of Transfusion Medicine. Baltimore, Williams & Wilkins, 1991, p 641. 27. Hohenhaus AE: Transfusions, infusions and other solutions. Proc 12th Annu Members Meetg ACVIM Forum:158, 1994. 28. Tizard I: Erythrocyte antigens and type II hypersensitivity, in Tizard I (ed): Veterinary Immunology: An Introduction, ed 4. Philadelphia, WB Saunders Co, 1992, p 351. 29. Tizard I: Type I hypersensitivity, in Tizard I (ed): Veterinary Immunology: An Introduction, ed 4. Philadelphia, WB Saunders Co, 1992, p 335. 30. Isbister JP: Adverse reactions to plasma and plasma components. Anaesth Intensive Care 21:31, 1993. 31. Capon SM, Sacher RA: Hemolytic transfusion reactions: A review of mechanisms, sequelae, and management. J Intensive Care Med 4:100, 1989. 32. Hardie EM, Krase-Elliot K: Endotoxic shock part II: A review of treatment. J Vet Intern Med 4:306, 1990. 33. Hardie EM, Rawlings CA: Septic shock. Part II. Prevention, recognition, and treatment. Compend Contin Educ Pract Vet 5(6):483–493, 1983. 34. Callan MB, Oakley DA, Schofer SS, Giger U: Canine red blood cell transfusion practice. JAAHA 32:303, 1996. 35. Kerl ME, Hohenhaus AE: Packed red cell transfusions in dogs: 131 cases (1989). JAVMA 202:1495, 1993.

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