Allergic transfusion reactions (ATRs) and febrile

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1 REVIEW Transfusion premedications: a growing practice not based on evidence Aaron A.R. Tobian, Karen E. King, and Paul M. Ness Allergic transfusion reactions (ATRs) and febrile nonhemolytic transfusion reactions (FNHTRs) have plagued the administration of blood since the early 20th century. One of the first reports of an ATR was in Ramirez 1 documented a patient with no underlying allergies, asthma, or bronchitis who developed bronchial asthma to horse dandruff within 2 weeks of receiving a 600-mL blood transfusion. The skin testing reactivity to horse dandruff was identical between the donor and the recipient. 1 Ramirez suggested that the reaction was due to anaphylactic bodies in the donor s blood, and donors should be screened for the possible transmission of anaphylactic or reaction bodies. Subsequently, Polayes and Lederer 2 evaluated 2500 transfusion reactions in the literature; they found reactions due to ABO mismatch, transmission of diseases, and allergic phenomena in the recipients. They did not note specific FNHTRs, but they stated that ATRs were not uncommon. Wiener and coworkers 3 in 1940 described febrile transfusion reactions that were not due to ABO mismatch or lack of aseptic techniques; it was hypothesized that the reactions were due to extraneous factors. Wiener and coworkers also noted that 1 percent of all transfusions presented with allergic symptoms. 3 In the 1950s, FNHTRs were finally categorized as they are known today and documented as the most common complication of blood transfusion, followed by ATRs. 4,5 Fifty years later, FNHTRs and ATRs are still the two most common complications of blood transfusion. FNHTRs have been reported to occur in up to 30 percent of transfusions. 6 Although the incidence decreases to less From the Department of Pathology, Transfusion Medicine Division, The Johns Hopkins Hospital, Baltimore, Maryland. Address reprint requests to: Aaron A.R. Tobian, Department of Pathology, Transfusion Medicine Division, The Johns Hopkins Hospital, 600 N. Wolfe Street, Carnegie 667, Baltimore, MD 21287; atobian1@jhmi.edu or pness@jhmi.edu. Received for publication November 25, 2006; revision received December 20, 2006, and accepted December 20, doi: /j x TRANSFUSION 2007;47: than 1 percent with current methods that use singledonor apheresis units and leukoreduced products, 7-10 FNHTRs are still a problem. Reactions occur more often in the transfusion of platelets (PLTs) compared to red blood cells (RBCs). 6,11-13 The incidence of ATRs ranges from 0.4 to 3 percent of all transfusions. 8,14,15 Although FNHTRs and ATRs are usually not lifethreatening, they remain a challenge for both patients and physicians. The clinical events surrounding transfusion reactions are often more severe than physicians are aware. Patients who receive blood transfusions are often among the sickest in the hospital; many have already experienced numerous complex procedures and medications including transplantation and chemotherapy. Thus, even minor reactions can be significant for these patients and their families. These reactions can also lead to hospitalization for outpatients or prolonged hospital stays for inpatients. Fever is also an initial presentation of more severe complications of blood transfusion such as acute intravascular hemolysis due to ABO blood group mismatch, transfusion-associated sepsis, and transfusion-related acute lung injury. Delay in evaluating and treating these more severe complications due to attributing the symptoms to FNHTRs may lead to increased morbidity and mortality. Besides the morbidity, transfusion reactions are expensive to evaluate. Owing to the cost of the blood components, clinical and laboratory workup, and physician s time, it has been estimated that a routine FNHTR costs $8602 to evaluate. 9 For all of these reasons, it is best to effectively prevent FNHTRs and ATRs. FNHTRs FNHTRs are common and are diagnosed in patients with a transfusion associated temperature increase of at least 1 C once other explanations are excluded. 15 Other symptoms that often occur with FNHTRs are rigors, nausea, vomiting, and hypotension. These symptoms may begin early in the transfusion or occur hours after completion of the transfusion. 15 Often, FNHTRs are treated with acetaminophen with apparent resolution within a few hours. Even though FNHTRs have been defined for more than 50 years and are among the most common complications of transfusions, the pathophysiology of FNHTRs Volume 47, June 2007 TRANSFUSION 1089

2 TOBIAN ET AL. is still poorly understood. The mechanism of FNHTRs was initially postulated to be due to white blood cell (WBC) antibodies in the recipient s plasma interacting with WBCs in the transfusion product. 16 The formation of antigen-antibody complexes then may result in complement binding and release of endogenous pyrogens. 17 This mechanism was initially described in RBC transfusions and supported by recent studies showing a significant decrease in FNHTRs with leukoreduced blood products. 7,8,10 Although recipient anti-hla or other WBC-specific antibodies may explain many RBC-associated FNHTRs, this classic explanation does not appear to be the only mechanism of FNHTRs. Although PLTs have many fewer WBCs, there are many more FNHTRs to PLTs compared to RBCs. 18 In addition, many males with no previous history of transfusions or alloimmunization have FNHTRs. 18 Heddle and associates 19,20 elegantly showed that bioreactive substances in the plasma supernatant cause most of the PLT-induced FNHTRs. They first illustrated this phenomenon by separating PLT concentrates into plasma and cellular components and then infusing these components separately. 20 Although the proinflammatory cytokines interleukin (IL)-1b, IL-6, and tumor necrosis factor-a were initially postulated to be the major bioactive substances involved in FNHTRs, further studies have suggested that IL-8, PLT factor 4, b-thromboglobulin, RANTES, and transforming growth factor-b may also be involved. 18 Other proposed biologic response modifiers include fragments of complement C3a and C4a (activated after plasma is exposed to a plastic surface) and lipid compounds that can prime neutrophils. 18 Concentrations of many of these biologic response modifiers are related to the number and severity of reactions. 20 The number of reactions increased with duration of product storage and the levels of contaminating WBCs that produce cytokines. 6,20 The biologic response modifier hypothesis is supported by other studies that show prestorage leukoreduction decreases cytokines in PLT products 6,21 and consequently there are fewer FNHTRs. 22 Although biologic response modifiers have a role in PLT-associated FNHTRs, Heddle and colleagues 20 found that several patients who only received the cellular component of PLT products had FNHTRs. Only one of the patients, however, had detectable lymphocytotoxic anti- HLA antibodies. Thus, other mechanisms that remain unknown may be involved in FNHTRs. ATRs Mild ATRs often present with urticaria or hives erythematous circumscribed lesions with or without pruritis. 15 The hives most often develop on the neck and trunk, but may appear anywhere. On the other end of the spectrum from mild ATRs, anaphylactic reactions produce systemic symptoms of dyspnea, wheezing, hypotension, tachycardia, loss of consciousness, shock, and in rare cases death. 15 Fever is characteristically absent in these reactions. Fortunately, most ATRs are mild and easily treated. Although ATRs are classically thought of as Type I hypersensitivity reactions due to immunoglobulin E (IgE) antibodies interacting with allergens to activate mast cells and basophils, the etiology of ATRs has not yet been fully established. Histamine historically is associated with ATRs. Unfortunately, the signaling proteins for these reactions are not absolutely defined. The primary mediators of anaphylaxis are biogenic amines (e.g., histamine, adenosine), eosinophil and neutrophil chemotaxic factors, enzymes (e.g., proteases), and proteoglycans (e.g., heparin). 23 Leukotrienes, prostaglandin, PLT-activating factor, and numerous cytokines have also been implicated in ATRs. 23 Although the mediators of ATRs are still not fully determined, numerous mechanisms that may induce these mediators have been implicated in transfusion reactions. Patients with IgA deficiency are especially prone to anaphylaxis after blood transfusion if they have existing class-specific anti-iga Recipients who lack specific allotypes of other normal serum proteins (e.g., haptoglobin, C3, C4) also form existing IgG or IgE antibodies and are at increased risk of ATRs. 23,27-29 One case report associates anaphylactic reactions with HLA-mismatched PLTs. 30 Similar to Ramirez s hypothesis that ATRs may occur by the transmission of anaphylactic or reaction bodies, it has been demonstrated that the transfusion of allergens (e.g., penicillin, aspirin, ethylene oxide and other chemicals used to sterilize tubing, and even some food allergens) have also been associated with ATRs. 1,31-33 Other proposed mechanisms of allergic or anaphylactic reactions include the passive transfer of IgE antibodies, mast cell activation by complement anaphylatoxins, and the transfusion of blood components that contain high levels of histamine. 14,23 Although the general mechanism of Type I hypersensitivity reactions is probably involved in most ATRs, the mediators of the reactions and the underlying pathophysiology are still poorly understood. HISTORICAL DATA DEMONSTRATING PREMEDICATION PREVENTS FNHTRs AND ATRs In the 1950s, nonhemolytic transfusion reactions were reported to occur in up to one-fourth of all transfusions; consequently studies were performed to find methods to decrease these reactions. Physicians and scientists believed that the majority of ATRs were due to an increase in histamine. Thus, it was proposed that prophylactic antihistamine could block histamine liberation in allergic individuals to prevent transfusion reactions. 34 Ferris and 1090 TRANSFUSION Volume 47, June 2007

3 TRANSFUSION PREMEDICATION colleagues 34 injected prophylactic tripelennamine (pyribenzamine hydrochloride), an antihistamine, into blood bottles and found a significant decrease in both febrile and ATRs. Several years later, injection of diphenhydramine into units of blood was shown to eliminate ATRs, while not affecting pyrogenic or hemolytic transfusion reactions. 35 Winter and Taplin 36 extended these early studies to demonstrate that when patients received both oral acetylsalicylic acid and chlorprophenpyridamine injected into units of blood, both FNHTRs and ATRs were significantly reduced. Although these studies provide a basis for the use of premedication, they are not wellcontrolled clinical trials that are the standard today. The injection of medications into the blood products is not a permitted practice today due to issues of contamination and potential drug-cell interactions. In addition, most of the studies lacked a placebo control, were not blinded, and consequently had increased reaction rates during the study. In addition to the lack of well-controlled clinical trials forming the basis of the premedication standards today, there have been many changes to transfusion medicine over the past 50 years. There has been a significant increase in product manipulation with the trend toward component therapy. Products may be leukoreduced by filtration and/or plasma depleted via automated cell washing techniques. The transfusion of apheresis PLTs is also considered standard therapy in many institutions. In addition, blood storage standards have changed with improvements in storage containers and coagulant preservative solutions and aseptic techniques. The practice of premedication to prevent transfusion reactions is not entirely without consequences. Although acetaminophen is generally safe, there have been reported cases of increased serum transaminases following therapeutic doses. 37 Acetaminophen-induced hepatotoxicity is often related to drug overdose. Patients who regularly consume alcohol or are fasting, or ill children receiving doses exceeding weight-based recommendations have increased susceptibility to hepatotoxicity. 38,39 In addition to the risk of hepatotoxicity, acetaminophen may mask the initial fever of acute hemolytic transfusion reactions or septic transfusion reactions, delaying critical treatment. Finally, acetaminophen may mask fever from other non transfusion-related etiologies in sick patients receiving transfusion (e.g., neutropenic fever in cancer patients). Even at low doses, diphenhydramine generally has even more possible side effects than acetaminophen. Diphenhydramine is a potent anticholinergic that leads to drowsiness, dry mouth, and urinary retention. Owing to the ability of the drug to cross the blood-brain barrier and cause sedation, even one dose of diphenhydramine leads to significantly impaired driving performance, which may be problematic for outpatients. 40 In addition, diphenhydramine has been shown to interfere acutely with memory function, attention, and psychomotor performance. 41 Diphenhydramine can induce delirium in hospitalized patients who are elderly and already metabolically unstable. Besides the medical consequences of premedicating patients to prevent transfusion reactions, the administration of these drugs is also expensive. It has been estimated that premedication with both acetaminophen and diphenhydramine may cost more than $40,000 annually at St Jude s Children s Hospital. 42 Thus, premedication of patients to prevent transfusion reactions should be critically evaluated. PREMEDICATION CONSIDERED STANDARD THERAPY TO PREVENT TRANSFUSION REACTIONS Despite the significant changes to transfusion medicine, the studies performed in the 1950s have formed the basis of standard premedication to prevent transfusion reactions. The AABB Technical Manual recommends acetaminophen for both the therapeutic or prophylactic approach to FNHTRs. 15 The manual also states, Recipients who have frequent transfusion-associated urticarial reactions may respond well to administration of antihistamine (e.g., mg of diphenhydramine) one-half hour before transfusion. 15 In addition, many review articles affirm that prophylactic medication decreases both FNHTRs and ATRs. 17,23 PREMEDICATION TOXICITY PREMEDICATION DOES NOT PREVENT FNHTRs OR ATRs Since the 1950s, there have only been a few studies that have evaluated the benefit of premedication to prevent transfusion reactions. In our literature search using the National Library of Medicine PubMed search engine, we found only four articles addressing this topic (Table 1). The searches that were performed included allergic transfusion reaction and premedication, febrile nonhemolytic transfusion reaction and premedication, transfusion reaction and premedication, benadryl and transfusion reaction, acetaminophen and transfusion reaction, allergic transfusion reaction prevention, and febrile transfusion reaction prevention. The related articles links on PubMed of all four published articles that are cited and evaluated below were also examined. In addition, all of the references of these four articles were examined for other publications on this subject. We were also aware of two abstracts presented at the annual meeting of the American Society for Hematology in 1999 and the AABB in 2006; thus, we also included these bodies of work in our review. The studies were evaluated accord- Volume 47, June 2007 TRANSFUSION 1091

4 TOBIAN ET AL. TABLE 1. Studies evaluating whether prophylactic medication prevents FNHTRs or ATRs Diphenhydramine dose (mg) Products ing to a scoring system developed by Jadad and colleagues 43 to assess clinical trials. Wang and associates 44 published a prospective randomized double-blind controlled trial evaluating the combination of 650 mg of acetaminophen and 25 mg of diphenhydramine versus placebo on the effect of nonhemolytic transfusion reactions. This study involved patients who had a malignancy and consented to the study. Patients who had a fever within the previous 24 hours of transfusion, previous hemolytic transfusion reaction, or currently taking corticosteroids, acetaminophen, or diphenhydramine were excluded. Patients with previous FNHTRs and ATRs were included. Patients were randomly assigned to receive premedication or placebo and then evaluated for possible FNHTR or ATR. The method of randomization was not reported. Of the 51 patients that received 98 prestorage leukoreduced apheresis PLTs, 13 patients had 15 nonhemolytic transfusion reactions. The treatment group had a transfusion reaction incidence of 15.4 percent (8 of 52 total transfusions), whereas the control group had an incidence of 15.2 percent (7 of 46 total transfusions). 44 FNHTRs occurred more often in the control group compared to the patients receiving premedication. Three patients in the control group experienced hives, whereas no patients who received premedication had ATRs following transfusion. The authors concluded that premedication does not significantly lower FNHTRs or ATRs, and patients with a previous transfusion reaction had an increased risk of a second transfusion reaction. Unfortunately, there were only 15 transfusion reactions in this entire study. Although the study lacked power and many patients who declined to participate in the trial reported having previous transfusion reactions, overall, this study was well designed. The subjects were randomized, both patients and physicians were blinded, the hypothesis and objectives were clear, inclusion and exclusion criteria was clearly stated, and there was adequate follow-up and appropriate analysis. Kennedy and associates conducted a randomized, double-blind, placebo-controlled trial to evaluate whether 500 mg of acetaminophen and 25 mg of diphenhydramine prevented FNHTRs or ATRs. 45 The trial included 323 individuals with malignancies; patients were excluded if they had any known allergies to acetaminophen or diphenhydramine or a history of previous transfusion reactions. 45 Of the 60 patients (18.6%) that had a reaction to either PLTs or RBCs, 32 (19.3%) belonged to the placebo group and 28 (17.8%) belonged to the study group; the two groups did not differ significantly in the number of patients experiencing a transfusion reaction. 45 The study appears to be well designed with randomization, blinding, and a clear hypothesis, objectives and outcomes; however, it is difficult to fully assess because the study is published only in abstract form so the information on sample size calculation and power are not pro- Acetaminophen dose (mg) Number of evaluable transfusion reactions* Total number of evaluable transfusions Number of patients included in the study Name Year Study type Controls Wang Randomized Placebo PLTs Kennedy Randomized Placebo PLTs and RBCs Patterson Prospective No treatment 716 3,472 NR NR NR PLTs Sanders Retrospective No treatment 385 7, NR NR PLTs and RBCs Szelei-Stevens Retrospective No treatment 31, , NR NR PLTs, RBCs, and FFP Ezidiegwu Retrospective No control NR 119, NA PLTs, RBCs, and FFP * All studies except for Ezidiegwu (only evaluated FNHTRs) evaluated both FNHTRs and ATRs. NR = not reported. NA = not applicable TRANSFUSION Volume 47, June 2007

5 TRANSFUSION PREMEDICATION vided. The authors are currently preparing it to submit for publication (L.D. Kennedy, personal communication). Patterson and associates 22 evaluated FNHTRs and ATRs in all hematology-oncology patients who received PLTs prospectively over 3 years. During the study period, two major changes in the hospitals transfusion practices were implemented which allowed the authors to evaluate the effectiveness of premedication. During the first year, there was no attempt to standardize transfusion practices and most PLT recipients (73%) were premedicated with acetaminophen, corticosteroids, meperidine, and/or antihistamines (Benadryl and Chlortripolon). Of these patients, 30 percent had nonhemolytic transfusion reactions. After instituting guidelines for premedicating patients before nonleukoreduced PLT transfusions (i.e., only patients who had previous transfusion reactions were allowed to receive premedications), patients receiving premedications before transfusion decreased substantially. Although there was a decrease of acetaminophen use from 47.8 to 28.6 percent of PLT recipients, febrile reactions actually increased from 14.1 to 15.1 percent of patients. 22 In addition, antihistamine premedication decreased from 60.9 to 30.9 percent, but patients presenting with hives after transfusion remained the same at 2.4 and 2.3 percent, respectively. 22 In contrast to the premedication results, Patterson and associates also demonstrated that prestorage leukoreduction significantly decreased FNHTRs to PLTs. Although this prospective study contributes nicely to the literature with clear study outcomes and many subjects involved, it was an observation study; hence, conclusions regarding efficacy of premedication to prevent acute reactions cannot be made. The patient population was not standardized in terms of premedications and the absolute number of transfusion reactions was not reported. Sanders and coworkers 42 conducted a retrospective review with multivariate analysis of 385 children who received 7900 prestorage leukoreduced, irradiated PLTs and RBCs. The patient population consisted almost entirely of children with a malignancy. The ordering clinician of the transfusions decided whether to premedicate the patient, including type and dose. The incidence was 0.75 percent (59 patients) for ATRs and 0.28 percent (22 patients) for FNHTRs. 42 FNHTRs occurred in 0.53 percent of transfusions in patients who had no premedication and increased to 0.95 percent of transfusions in patients who received acetaminophen premedication. 42 Similarly, ATRs occurred in 0.56 percent of transfusions in patients who did not receive premedication and increased to 0.90 percent of transfusions in patients with diphenhydramine premedication. 42 The multivariate analysis that adjusted for age, patient category, transfusion location, product, transfusion history, and reaction found that premedication with either diphenhydramine or acetaminophen was associated with a nonsignificant increase of both FNHTRs and ATRs. This study also analyzed patients who had previous transfusion reactions and still did not find that diphenhydramine or acetaminophen decreases the risk of FNHTRs or ATRs. Overall, this study is well designed with clear outcomes, a clear hypothesis, clear objectives, a large sample size, and superb multivariate analysis. Unfortunately, it is a retrospective analysis with a patient population that is not standardized in terms of premedications; thus, the results are not definitive. Szelei-Stevens and colleagues 46 retrospectively reviewed the transfusion of 301,210 units of RBCs, PLTs, and plasma to 31,665 patients (all patients who received a transfusion over a 2-year period). 46 There were 244 patients that had a nonhemolytic transfusion reaction (incidence, 0.8%), and the authors evaluated all of these patients. Of the 244 reactions, only 154 patients received diphenhydramine before the transfusion. 46 In the group with prophylactic diphenhydramine, 49.3 percent (76 patients) had an ATR. Ninety patients did not receive diphenhydramine before the transfusion, but only 39 percent (35 patients) had an ATR. Of the 105 patients that received acetaminophen before the transfusion, 41 percent (43 patients) had a FNHTR. A total of 139 patients did not receive acetaminophen before the transfusion, and only 34 percent (47 patients) had a FNHTR. 46 The authors concluded that neither acetaminophen nor diphenhydramine significantly affects the rate of FNHTRs or ATRs. The authors did not specify whether the blood products were leukoreduced or how many patients had previous transfusion reactions. This study appears to be well designed and conducted with a tremendously large patient population. It is a difficult study to assess, however, because it is a retrospective review that has only been published as an abstract. Ezidiegwu and coworkers 9 retrospectively evaluated FNHTRs from the administration of almost 120,000 units of PLTs, RBCs, and FFP over a 5-year period. The authors found an incidence of 0.09 percent. Ezidiegwu and coworkers concluded that because 80 percent of patients received an antipyretic before the transfusion and their incidence was lower than any other published rate, premedication with antipyretics decreased FNHTRs. 9 The authors also estimated the cost of a transfusion reaction evaluation to be more than $8000 and considered acetaminophen to be a safe, inexpensive, and effective medication that lowered overall costs. 9 Only the last two years of the study used leukoreduced products, and the study population was limited to patients with hematologic malignancy or those undergoing stem cell transplantation. 9 This study did not evaluate the difference in patients with previous transfusion reactions compared to those with no history of a transfusion reaction. This study has several limitations. The authors reevaluated and checked for consistency of diagnosis conformity with the established definition of FNHTR and consequently may have Volume 47, June 2007 TRANSFUSION 1093

6 TOBIAN ET AL. introduced bias into the study. In addition, the authors did not include any control patients. Thus, this study is an uncontrolled retrospective analysis, and consequently it is difficult to make any conclusions about the role of premedication to prevent FNHTRs. CONCLUSIONS AND RECOMMENDATIONS In summary, five of the six studies in the past 10 years concluded that prophylactic medication with acetaminophen and diphenhydramine does not reduce the incidence of FNHTRs or ATRs. The article by Ezidiegwu and colleagues 9 is the only study that contradicts this conclusion, but it is also the only study that had no control group. In addition, the lower rate of FNHTRs in patients receiving antipyretics in this study may be due to differences in patient population, clinicians underreporting, or clinicians not recognizing some of these reactions. Heddle and coworkers 6 found that routine antipyretic use prevented fevers, but not other symptoms of the FNHTR such as chills, cold, and discomfort. 6 Thus, patients may still be experiencing many of the negative consequences of FNHTRs, but clinicians may not be recognizing the reaction because the antipyretic is masking the fever. Unfortunately, there are no large randomized double-blind placebo controlled trials that enable one to definitively determine whether premedication decreases FNHTRs or ATRs. Although vast changes have occurred in transfusion therapy since the 1950s, studies to reevaluate whether premedication decreases or prevents FNHTRs or ATRs are limited. Of the six studies presented in this review, only Ezidiegwu and associates 9 evaluated transfusion reactions in nononcology patients. This study, however, was an uncontrolled retrospective review. The data evaluating premedication to prevent transfusion reactions are also limited for patients with a history of multiple transfusion reactions. Only two of the studies even considered patients with previous transfusion reactions. Wang and coworkers 44 only had seven reactions and Sanders and coworkers 42 only had 23 reactions in patients with a previous history of reactions. Although Sanders and coworkers 42 conducted a retrospective study for pediatric oncology patients, minimal data are available evaluating the potential role of premedication to prevent nonhemolytic transfusion reactions in children. In addition, there are no studies that evaluate the effect of premedication on the treatment of FNHTRs or ATRs. A large doubleblind randomized placebo-controlled trial is needed to fully determine whether premedication is beneficial. In the absence of definitive evidence-based studies, premedications should not be encouraged. We have noted many physicians ordering systems routinely couple transfusion orders with premedication selection. In the absence of supporting data, these practices should be discouraged. Making it easy for physicians to request premedications suggests that their use represents the standard of care, a status not supported by evidence. An increased understanding of the pathophysiology of FNHTRs and ATRs may significantly advance our ability to prevent these reactions. Although there are currently two proposed mechanisms behind FNHTRs, these mechanisms cannot fully explain all reactions. Our understanding of ATRs is also limited. The underlying pathology for initiating the reaction has multiple mechanisms proposed. The proposed mediators of ATRs are also diverse and not well defined. The pathophysiology behind both FNHTRs and ATRs is most likely multivariate so multiple methods may be necessary to prevent these transfusion reactions. Consequently, multiple drug combinations may be much more effective at preventing these reactions. For example, an inhibitor of eosinophil or neutrophil chemotaxic factors may be much more effective than antihistamines. Only continued research to better understand the pathophysiology of transfusion reactions will answer these issues. REFERENCES 1. Ramirez MA. Horse asthma following blood transfusion. JAMA 1919;73: Polayes SH, Lederer M. Reactions to blood transfusions: observation from 2500 transfusions with a review of the literature. J Lab Clin Med 1932;17: Wiener AS, Oremland BH, Hyman MA, Samwick AA. Transfusion reactions: experiences with more than three thousand blood transfusions. Am J Clin Pathol 1941;11: Payne R. The association of febrile transfusion reactions with leuko-agglutinins. Vox Sang 1957;2: Seldon TH. Management of blood transfusion reactions. Med Clin North Am 1956;40: Heddle NM, Klama LN, Griffith L, et al. A prospective study to identify the risk factors associated with acute reactions to platelet and red cell transfusions. Transfusion 1993;33: King KE, Shirey RS, Thoman SK, et al. Universal leukoreduction decreases the incidence of febrile nonhemolytic transfusion reactions to RBCs. Transfusion 2004;44: Enright H, Davis K, Gernsheimer T, et al. Factors influencing moderate to severe reactions to PLT transfusions: experience of the TRAP multicenter clinical trial. Transfusion 2003;43: Ezidiegwu CN, Lauenstein KJ, Rosales LG, et al. Febrile nonhemolytic transfusion reactions: management by premedication and cost implications in adult patients. Arch Pathol Lab Med 2004;128: Paglino JC, Pomper GJ, Fisch GS, et al. Reduction of febrile but not allergic reactions to RBCs and platelets after conversion to universal prestorage leukoreduction. Transfusion 2004;44: TRANSFUSION Volume 47, June 2007

7 TRANSFUSION PREMEDICATION 11. Heddle NM. Febrile nonhemolytic transfusion reactions to platelets. Curr Opin Hematol 1995;2: Mangano MM, Chambers LA, Kruskall MS. Limited efficacy of leukopoor platelets for prevention of febrile transfusion reactions. Am J Clin Pathol 1991;95: Chambers LA, Kruskall MS, Pacini DG, Donovan LM. Febrile reactions after platelet transfusion: the effect of single versus multiple donors. Transfusion 1990;30: Domen RE, Hoeltge GA. Allergic transfusion reactions: an evaluation of 273 consecutive reactions. Arch Pathol Lab Med 2003;127: Brecher ME, editor. Technical manual. 15th ed. Bethesda: American Association of Blood Banks; Heddle NM. Pathophysiology of febrile nonhemolytic transfusion reactions. Curr Opin Hematol 1999;6: Perrotta PL, Snyder EL. Non-infectious complications of transfusion therapy. Blood Rev 2001;15: Heddle NM, Kelton JG. Febrile nonhemolytic transfusion reactions. In: Popovsky MA, editor. Transfusion reactions. 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Abnormal serum transaminases following therapeutic doses of acetaminophen in the absence of known risk factors. Dig Dis Sci 1995;40: McClain CJ, Price S, Barve S, et al. Acetaminophen hepatotoxicity: an update. Curr Gastroenterol Rep 1999;1: Heubi JE, Barbacci MB, Zimmerman HJ. Therapeutic misadventures with acetaminophen: hepatoxicity after multiple doses in children. J Pediatr 1998;132: Verster JC, Volkerts ER. Antihistamines and driving ability: evidence from on-the-road driving studies during normal traffic. Ann Allergy Asthma Immunol 2004;92: ; quiz-5, Verster JC, Volkerts ER, van Oosterwijck AW, et al. Acute and subchronic effects of levocetirizine and diphenhydramine on memory functioning, psychomotor performance, and mood. J Allergy Clin Immunol 2003;111: Sanders RP, Maddirala SD, Geiger TL, et al. Premedication with acetaminophen or diphenhydramine for transfusion with leucoreduced blood products in children. Br J Haematol 2005;130: Jadad AR, Moore RA, Carroll D, et al. 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8 TOBIAN ET AL. transfusions: a prospective randomized double-blind placebo-controlled trial. Am J Hematol 2002;70: Kennedy LD, Cruz JM, Restino MS, et al. Comparison of acetaminophen and diphenhydramine versus placebo for the prevention of febrile or allergic transfusion-associated reactions. Blood 1999;94(Suppl 10):375a. 46. Szelei-Stevens KA, Narvios A, Al-Sammak M. Transfusion reactions: to premedicate or not to premedicate? Transfusion 2006;46(Suppl 9S):95A TRANSFUSION Volume 47, June 2007