Premedication with acetaminophen or diphenhydramine for transfusion with leucoreduced blood products in children

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1 research paper Premedication with acetaminophen or diphenhydramine for transfusion with leucoreduced blood products in children Robert P. Sanders, 1 Sunil D. Maddirala, 2 Terrence L. Geiger, 3 Stanley Pounds, 4 John T. Sandlund, 1,5,6 Raul C. Ribeiro, 1,5,6 Ching-Hon Pui 1,3,5,6 and Scott C. Howard 1,5,6 1 Department of Hematology-Oncology, St Jude Children s Research Hospital, Memphis, TN, 2 Department of Pediatrics, Mercy Children s Hospital, Toledo, OH, 3 Department of Pathology, St Jude Children s Research Hospital, 4 Department of Biostatistics, St Jude Children s Research Hospital, 5 International Outreach Program, St Jude Children s Research Hospital, and 6 Department of Pediatrics, University of Tennessee College of Medicine, Memphis, TN, USA Received 20 May 2005; accepted for publication 14 June 2005 Correspondence: Robert P. Sanders, MD, Carolinas Medical Center, 1000 Blythe Boulevard, 7th Floor Children s Specialty Center, Charlotte, NC 28203, USA. robert.sanders@carolinashealthcare.org Summary Febrile non-haemolytic or allergic reactions occur in 0Æ1 30% of ; physicians often premedicate patients with acetaminophen or diphenhydramine to prevent these reactions. The effectiveness of this practice has not been demonstrated. In this retrospective review of all at our institution during 2002, 385 patients received 7900 evaluable leucoreduced, irradiated blood products (4280 single-donor apheresis platelets and 3620 packed red blood cells). Febrile reactions occurred in 0Æ95% of 4108 with, and 0Æ53% of 3792 without, acetaminophen premedication. Allergic reactions occurred in 0Æ90% of 4315 with, and 0Æ56% of 3585 without, diphenhydramine premedication. In a multivariate analysis that adjusted for age, patient category, transfusion location, product, transfusion history, and reaction history, premedication with acetaminophen was associated with a statistically non-significant increase in the odds of a febrile reaction (odds ratio 1Æ74; 95% confidence interval 0Æ71 4Æ23; P ¼ 0Æ22), and diphenhydramine with a non-significant increase in allergic reactions (odds ratio 1Æ74; 95% confidence interval 0Æ99 3Æ06; P ¼ 0Æ054). Reactions occurred in only 1Æ3% of the 518 to patients with a history of two or more prior reactions. Febrile and allergic transfusion reactions were rare in paediatric patients transfused with leucoreduced, irradiated blood products, whether premedication was used or not. Keywords: transfusion, paediatric haematology, paediatric oncology, allergy, clinical transfusion medicine. Thrombocytopenia and anaemia occur commonly in paediatric patients treated for a blood disorder or cancer, many of whom require transfusion. Transfusion may result in adverse events, including rare, but potentially life-threatening reactions such as ABO blood group incompatibility-induced haemolysis, transfusion-associated sepsis, circulatory overload, and transfusion-related acute lung injury (Perrotta & Snyder, 2001; Brecher, 2002). More common are febrile non-haemolytic reactions and allergic transfusion reactions, which usually do not cause serious clinical sequelae (Perrotta & Snyder, 2001) or decrease the effectiveness of the transfusion (Sarkodee-Adoo et al, 1998). In the past, febrile non-haemolytic reactions occurred in up to 30% of (Heddle et al, 1993; Heddle, 1999). However, the reported incidence is only 0Æ03 2Æ18% when leucoreduced blood products, including only single-donor apheresis platelet units stored for a limited time, are used (Heddle et al, 1993; Hebert et al, 2003; Ezidiegwu et al, 2004; King et al, 2004; Paglino et al, 2004; Pruss et al, 2004; Yazer et al, 2004). Allergic reactions occur in less than 1% of (Paglino et al, 2004; Pruss et al, 2004). Perhaps in response to the high frequency of febrile reactions in patients who receive pooled platelet units and non-leucoreduced blood products, clinicians commonly premedicate patients with acetaminophen, diphenhydramine, or both (Wang et al, 2002). Although no clinical trial has demonstrated the efficacy of premedications for transfusion, estimated premedication rates range from 61Æ5% to 80% (Heddle et al, 1993; Ezidiegwu et al, 2004). In light of the success of prestorage leucoreduction, exclusive use of singledonor apheresis platelets, and limited platelet storage time in reducing the incidence of febrile reactions, the utility of routine premedication becomes questionable. In fact, in the ª 2005 Blackwell Publishing Ltd, British Journal of Haematology, 130, doi: /j x

2 R.P. Sanders et al only randomised, double-blinded, placebo controlled clinical of premedication use, Wang et al (2002) reported that the combination of acetaminophen and diphenhydramine did not prevent non-haemolytic transfusion reactions. The trial included 98 in 51 patients, and the rate of reactions was 15Æ2% in patients premedicated with placebo and 15Æ4% in patients premedicated with acetaminophen and diphenhydramine (P ¼ 0Æ94) (Wang et al, 2002). The routine practice of premedication is not entirely benign. Acetaminophen is well known to cause hepatotoxicity with acute overdose (Hinson et al, 2004), and has also been reported to cause hepatic injury after repeated doses in the mildly supratherapeutic range (Heubi et al, 1998). Diphenhydramine has significant effects on memory, psychomotor performance, and mood (O Hanlon & Ramaekers, 1995; Verster et al, 2003). While both medications are relatively inexpensive, routine premedication may result in substantial cumulative costs, both in drug purchases and in expenditure of pharmacy and nursing time. Conservative estimates suggest that premedication with acetaminophen and diphenhydramine cost our institution more than 800 h of pharmacist time and 700 h of nursing time, and more than $ (approximately ) in drug costs during the 1-year period of this study. In this retrospective study, we measured the risk of febrile non-haemolytic and allergic reactions in consecutive paediatric patients transfused exclusively with prestorage leucoreduced blood products, including only single-donor apheresis platelets. We then evaluated the impact of premedication with acetaminophen or diphenhydramine on the risk of these reactions in both univariate and multivariate analyses. Methods Clinical practice During the study period, standard institutional practice was to administer prestorage leucoreduced blood products, including single-donor apheresis platelet units that had been stored no longer than 5 d, to all patients. In addition, because our patient population consists almost entirely of oncology and haematopoietic stem cell transplant patients, all cellular blood products are irradiated per Blood Bank policy to eliminate the risk of transfusion-associated graft-versus-host disease. The ordering clinician for each transfusion decided whether to premedicate the patient, as well as the type and dose of premedication. In each case of suspected transfusion reaction, the clinician completed a Report of Suspected Transfusion Reaction form that included patient information, the type and unique identifier of the blood product, times of transfusion and reaction, vital signs, symptoms of the suspected reaction, any intervention required, and outcome. These forms were submitted to the blood bank, whose medical director reviewed the form, the results of laboratory studies, and, if necessary, other information from the medical record to arrive at an interpretation of the event based on terminology in the American Association of Blood Banks (AABB) Technical Manual (Brecher, 2002) and other published studies of acute transfusion reactions (Buck et al, 1987; Heddle et al, 1993; Riccardi et al, 1997; Heddle, 1999; Perrotta & Snyder, 2001; Wang et al, 2002; Domen & Hoeltge, 2003). Specifically, febrile reactions were defined as a new temperature 38 C or an increase in temperature of 1 C above baseline that developed during or within 3 hours of completion of a transfusion in which another cause of fever, such as sepsis or haemolysis, was excluded. The occurrence of urticaria or other rash, pruritus, wheezing, or angioedema during or within 3 h of transfusion was considered an allergic reaction. When more than one transfusion was administered within a 24-h period and a reaction occurred, the reaction was presumed to be caused by the transfusion administered at the time of, or most immediately prior to, the onset of symptoms. Data collection After obtaining approval from the Institutional Review Board, we reviewed blood bank records to identify all patients transfused at St Jude Children s Research Hospital during the year Patient medical records were reviewed for demographics, primary diagnosis, and history of transfusion reactions preceding each analysed transfusion event. Patients were considered to have a history of reaction if a prior nonhaemolytic transfusion reaction was noted during their initial evaluation, if a non-haemolytic reaction was documented in blood bank records for 2000 or 2001, or if a reaction occurred during 2002 and the patient received subsequent. For each transfusion, we noted the type of blood product transfused, whether the patient received premedications, and whether any adverse reactions occurred. Three reactions in which an allergic aetiology could not be ruled out and another cause could not be established were included in this analysis as allergic reactions: a non-productive cough during a transfusion in a previously asymptomatic patient; back pain and diaphoresis in a second patient; and nausea, vomiting, and abdominal pain in a third patient. In all three patients, symptoms developed during the transfusion and resolved with cessation of transfusion, and no other potential cause for the symptoms was documented. Data analysis For purposes of this analysis, patients were classified into five categories based on their primary diagnosis or treatment: leukaemia/lymphoma, brain tumour, solid tumour, benign haematologic illness, and haematopoietic stem cell transplantation. Patient category was defined at the time of each transfusion. Prior to and during the study, 101 patients underwent transplantation. Patients who received transplants during the study period were considered to be in the transplant category from the start of their transplant conditioning regimen through the end of the study. All prior 782 ª 2005 Blackwell Publishing Ltd, British Journal of Haematology, 130,

3 Transfusion Premedications to transplant conditioning were considered to have occurred in the category of the primary diagnosis (e.g. leukaemia/lymphoma, brain). For the risk factor analysis, age was also defined at the time of each transfusion. Transfusions were administered in the outpatient clinic, the inpatient Bone Marrow Transplant unit, the general inpatient unit, or other locations (intensive care unit, operating suite, procedure area, and pheresis centre). Transfusions were selected as the units of analysis. Because transfusion reactions are rare (about 1% in previous reports), use of only the first reaction for each patient would have allowed assessment of only a few hundred and less than five reactions of each type, which would be too few to assess the impact of premedication use. Limiting the study sample in this way would also have precluded analysis of several potentially important variables: the number and timing of prior and a history of prior transfusion reactions. We modelled the risk of allergic and febrile non-haemolytic transfusion reactions by using logistic regression and fit the model by using generalised estimating equations according to the method of Liang and Zeger (1986). The model treated as repeated measurements for each patient. Results are reported as odds ratios (ORs) (Agretsi, 2002) comparing the odds of febrile reaction based on acetaminophen premedication and other clinical variables and the odds of allergic reaction based on diphenhydramine use and clinical variables. In general, the group with the lowest frequency of reactions was defined as the reference group for calculation of the OR. Each factor was first examined in a univariate analysis; factors yielding at least one OR estimate significant at the 0Æ15 level were included as predictors in a subsequent multivariate analysis. The same groups were defined as reference groups in both the univariate and multivariate analyses. Fisher s exact test (Agretsi, 2002) was used to examine the association of reaction with premedication in the first transfusion. No adjustments for multiple testing were performed. All analyses were conducted using sas software (SAS Institute, Cary, NC, USA), Windows version 9Æ1. P-values <0Æ05 were considered significant. Results During the study period, 8277 were administered to 385 patients, including 218 male (57%) and 167 female patients (43%). A total of 275 patients were Caucasian (71%), 82 African-American or African (21%) and 28 of other races (7%). Transfusions premedicated with corticosteroids (n ¼ 207) or antihistamines other than diphenhydramine (n ¼ 62) were excluded from analysis, as were in which haemolytic reactions (n ¼ 2) or transfusion-related acute lung injury (n ¼ 1) occurred. Transfusions were also excluded if data regarding any premedication or transfusion variable was unavailable or contradictory (e.g. an order for premedications was present but there was no documentation that the medications were administered) (n ¼ 105). In all, 7900 evaluable were included in the analysis. This total comprised 4280 platelet and 3620 packed red blood cell. The median number of per patient was 8 (range, 1 264). Transfusions by primary diagnosis are detailed in Table I. The median age of patients at the time of transfusion was 12Æ5 years (range, 7 d to 29 years). Transfusion reactions were rare. During the study period, there were 81 non-haemolytic transfusion reactions (1Æ0% of all ), including 59 allergic (0Æ75%) and 22 febrile (0Æ28%) reactions (Table II). In 10 of the 59 allergic reactions, patients experienced respiratory symptoms including cough, wheezing or dyspnoea, and three patients required bronchodilator therapy. One of the three was classified as severe by the blood bank director, and resolved after treatment with hydrocortisone and albuterol. One patient required admission to the hospital for febrile neutropenia after a febrile transfusion reaction, but no outpatients were admitted specifically to treat a reaction, and no inpatients required transfer to intensive care as a result of a transfusion reaction. No premedication was administered prior to 2521 (32%) ; acetaminophen alone was used as premedication in 1064 (13%), diphenhydramine alone in 1271 (16%), and both drugs in 3044 (38%). The number of and frequency of reactions according to clinical parameters and use of acetaminophen and diphenhydramine are detailed in Tables II and III. Because each patient s age and category could change throughout the study period, these variables (Table II) were defined at the time of each transfusion for the purpose of the statistical analysis. In the univariate analysis, an increased rate of allergic reactions was associated with a diagnosis of leukaemia or lymphoma [OR 2Æ74; 95% confidence interval (CI) 1Æ14 6Æ62, P ¼ 0Æ025], transfusion in the outpatient clinic (OR 8Æ60; 95% CI 2Æ24 33Æ03, P ¼ 0Æ002) or general inpatient unit (OR 6Æ76; 95% CI 1Æ83 25Æ01, P ¼ 0Æ004) compared with the stem cell transplant unit, and fewer prior (OR for Æ45; 95% CI 1Æ24 4Æ84, P ¼ 0Æ010). There was a trend toward an increased rate of allergic reactions with platelet (OR 1Æ51; 95% CI 0Æ92 2Æ46, P ¼ 0Æ1), and the type of blood product was therefore included in the multivariate analysis. Sex, race, age, and a history of allergic or febrile reaction were not associated with the rate of allergic reactions in the univariate analysis. In the multivariate analysis (Table II), in the outpatient clinic and general inpatient unit, a history of fewer than 20 prior, and platelet were each associated with a significantly higher rate of allergic reactions. Diphenhydramine premedication did not, however, significantly affect the rate of allergic reactions in either the univariate or multivariate analyses; indeed, the odds of allergic reaction were higher when premedication with diphenhydramine was used, although this increase was not statistically significant (multivariate OR, 1Æ74; 95% CI 0Æ99 3Æ06, P ¼ 0Æ054). The effect of premedication and other clinical variables on the risk of febrile reactions was evaluated in a separate set of ª 2005 Blackwell Publishing Ltd, British Journal of Haematology, 130,

4 R.P. Sanders et al Table I. Transfusions and reactions by primary diagnosis. Primary diagnosis patients (% of total) (% of total) Number (%) of Transfusions administered after stem cell transplantation* reactions Allergic (%) Febrile (%) Leukaemia/lymphoma 190 (49) 4975 (63) 1796 (36) 39 (0Æ78) 14 (0Æ28) Acute lymphoblastic leukaemia 104 (27) 1572 (20) 659 (42) 8 (0Æ51) 4 (0Æ25) Acute myeloid leukaemia 42 (11) 2084 (26) 693 (33) 23 (1Æ1) 8 (0Æ38) Other leukaemias and lymphomas 44 (11) 1319 (17) 444 (34) 7 (0Æ61) 2 (0Æ15) Brain tumours 51 (13) 748 (9Æ5) 162 (22) 3 (0Æ40) 2 (0Æ27) Medulloblastoma/primitive 25 (6Æ5) 507 (6Æ4) 132 (26) 1 (0Æ20) 0 neuroectodermal tumour Glioma and other brain tumours 26 (6Æ8) 241 (3Æ1) 30 (12) 2 (0Æ83) 2 (0Æ83) Solid tumours 110 (28Æ6) 1348 (17) 274 (20) 10 (0Æ74) 5 (0Æ37) Neuroblastoma 26 (6Æ8) 296 (3Æ8) 172 (58) 2 (0Æ68) 1 (0Æ34) Primary bone tumours 37 (9Æ6) 613 (7Æ8) 92 (15) 4 (0Æ65) 3 (0Æ49) Sarcomas and other solid tumours 47 (12) 439 (5Æ6) 10 (2) 4 (0Æ91) 1 (0Æ23) Benign haematological disordersà 24 (6Æ2) 415 (5Æ2) 114 (27) 4 (0Æ96) 0 Non-malignant haematopoietic 10 (2Æ6) 414 (5Æ2) 414 (100) 3 (0Æ72) 1 (0Æ24) stem cell transplantation Total (35) 59 (0Æ75) 22 (0Æ28) *Transfusions administered after stem cell transplant are included in the Transplant category for statistical analysis (Table II). Percentage of with reaction. àbenign haematological disorders comprised haemoglobinopathies (n ¼ 8), bone marrow failure (n ¼ 10), histiocytoses (n ¼ 5), and coagulopathies (n ¼ 1). Non-malignant transplant diagnoses included Wiskott Aldrich syndrome (n ¼ 2), osteopetrosis (n ¼ 3), severe combined immunodeficiency (n ¼ 3), and Hurler syndrome (n ¼ 2). analyses. As with allergic reactions, to patients in the leukaemia or lymphoma category (OR 6Æ14; 95% CI 1Æ37 27Æ43, P ¼ 0Æ018), patients on the general inpatient unit (OR 12Æ09; 95% CI 1Æ29 112Æ94, P ¼ 0Æ029), and those with a history of fewer prior (OR for Æ96; 95% CI 1Æ30 12Æ07, P ¼ 0Æ016) were each associated with a higher rate of febrile reactions in the univariate analysis. Unlike the analysis of allergic reactions, outpatients did not have an increased risk of febrile reactions. A history of a prior febrile reaction was also associated with a modestly increased risk of febrile reactions in the univariate analysis (OR 2Æ74; 95% CI 1Æ18 6Æ35, P ¼ 0Æ019). Age 10-year old (OR 2Æ25; 95% CI 0Æ99 5Æ08, P ¼ 0Æ052) and history of allergic reaction (OR 4Æ38; 95% CI 0Æ71 27Æ14 P ¼ 0Æ112) were associated with a trend toward increased risk of febrile reactions, and were included in the multivariate analysis. In the multivariate analysis (Table II), none of the potential risk factors was associated with an increased or decreased risk of febrile reactions, including the use of acetaminophen premedication (OR, 1Æ74; 95% CI 0Æ71 4Æ23, P ¼ 0Æ22). During the study period, 222 patients received a first transfusion and experienced four allergic (1Æ8%) and two febrile (0Æ85%) reactions. Febrile reactions occurred in two of the 74 patients (2Æ7%) who were premedicated with acetaminophen, and none of the 148 patients who did not receive acetaminophen (P ¼ 0Æ11). Allergic reactions occurred in one of the 44 patients (2Æ3%) who were premedicated with diphenhydramine and three of the 178 (1Æ7%) patients who were not (P ¼ 1Æ00). Regardless of whether the patients had a history of reaction or the number of previous reactions, acetaminophen or diphenhydramine premedication failed to decrease febrile or allergic reactions (Table III). Discussion We found that transfusion reactions were rare in paediatric patients with a blood disorder or cancer who were transfused with prestorage leucoreduced, irradiated blood products, including only single-donor apheresis platelets. Among the transfusion reactions detected, few were serious, and none was fatal. The 1Æ0% incidence of reactions in our study was consistent with the 0Æ03 2Æ2% incidence in other studies in which patients received leucoreduced blood products (Heddle et al, 1993; Hebert et al, 2003; Ezidiegwu et al, 2004; King et al, 2004; Paglino et al, 2004; Pruss et al, 2004; Yazer et al, 2004). We attribute the low incidence of non-haemolytic transfusion reactions in our study to the uniform practice of prestorage leucoreduction in our blood bank and the policy of limiting platelet storage to 5 d. The exclusive use of singledonor apheresis platelet units may also reduce the risk of reactions, although the advantage of single-donor apheresis platelets over random-donor units in the setting of universal leucoreduction is debatable (Heal & Blumberg, 2004). The low frequency of non-haemolytic transfusion reactions in this 784 ª 2005 Blackwell Publishing Ltd, British Journal of Haematology, 130,

5 Transfusion Premedications Table II. Risk of febrile and allergic transfusion reactions according to clinical parameters results of multivariate analysis. Allergic reactions Febrile reactions Group Transfusions reactions Percentage of with reaction Odds ratio (95% CI) P-value reactions Percentage of with reaction Odds ratio (95% CI) P-value Total Æ Æ28 Age* 10 years Æ Æ42 1Æ67 (0Æ82 3Æ39) 0Æ155 >10 years Æ69 9 0Æ29 Reference group Product Platelets Æ86 1Æ86 (1Æ06 3Æ27) 0Æ Æ21 Packed red Æ61 Reference group 13 0Æ36 blood cells Category*à Brain/solid tumour Æ71 1Æ01 (0Æ33 3Æ03) 0Æ Æ31 1Æ81 (0Æ38 8Æ54) 0Æ452 and haematology Leukaemia or Æ01 2Æ28 (0Æ86 6Æ08) 0Æ Æ44 2Æ59 (0Æ64 10Æ51) 0Æ184 lymphoma Transplant Æ47 Reference group 2 0Æ07 Reference group Location Outpatient Æ15 7Æ38 (1Æ63 33Æ37) 0Æ Æ09 1Æ16 (0Æ06 23Æ00) 0Æ923 Transplant Æ45 2Æ83 (0Æ4 19Æ83) 0Æ Æ06 1Æ71 (0Æ05 56Æ07) 0Æ765 Inpatient Æ89 4Æ71 (1Æ13 19Æ68) 0Æ Æ70 7Æ6 (0Æ60 96Æ4) 0Æ118 Other Æ14 Reference group 1 0Æ07 Reference group History of febrile reaction Yes Æ02 3 0Æ38 1Æ81 (0Æ65 5Æ02) 0Æ254 No Æ Æ27 Reference group History of allergic reaction No Æ Æ33 2Æ79 (0Æ6 13Æ03) 0Æ193 Yes Æ05 1 0Æ07 Reference group prior Æ05 2Æ77 (1Æ16 6Æ62) 0Æ Æ42 1Æ99 (0Æ68 5Æ85) 0Æ Æ99 2Æ40 (0Æ94 6Æ09) 0Æ Æ34 2Æ25 (0Æ63 8Æ07) 0Æ214 > Æ38 Reference group 4 0Æ12 Reference group Acetaminophen premedication Yes Æ95 1Æ04 (0Æ59 1Æ84) 0Æ Æ37 1Æ74 (0Æ71 4Æ23) 0Æ225 No Æ53 Reference group 7 0Æ18 Reference group Diphenhydramine premedication Yes Æ9 1Æ74 (0Æ99 3Æ06) 0Æ Æ30 No Æ56 Reference group 9 0Æ25 *Age and category defined at time of each transfusion. Category is determined by both primary diagnosis and treatment; patients were considered Transplant patients from the start of transplant conditioning, regardless of primary diagnosis. Not significant in univariate analysis, therefore not included in multivariate analysis. àmedian (lower quartile, upper quartile) /patient/category ¼ brain/solid/tumour/hematology 5 (2,15); leukaemia/lymphoma 7 (4,19); transplant 13 (6,34); 52 patients received in two categories during the study period (e.g. leukaemia/lymphoma and transplant). Other location includes intensive care unit, operating suite, procedure area, and pheresis centre. clinical setting argues against the need for routine premedication, regardless of its efficacy. Our data also suggest that acetaminophen and diphenhydramine are not effective in preventing febrile or allergic reactions in this clinical setting. In fact, use of diphenhydramine and acetaminophen were associated with nonsignificant increases in the odds of allergic and febrile reactions, respectively. Since this is a retrospective, nonrandomised study, the results should not be considered definitive. The low incidence of reactions during the study period also limits the power to detect a treatment effect, despite the large number of evaluated. Nonetheless, the findings of our study support the negative result of the only published randomised clinical trial of transfusion premedications. In this small, placebo-controlled trial of 51 patients, Wang et al (2002) found that the combination of acetaminophen and diphenhydramine did not prevent nonhaemolytic transfusion reactions (Wang et al, 2002). A larger, ª 2005 Blackwell Publishing Ltd, British Journal of Haematology, 130,

6 R.P. Sanders et al Table III. Transfusion reactions by history of previous reaction and premedication used. Allergic Febrile Previous reactions and premedications used reactions Percentage of with reaction* reactions* Percentage of with reaction* No previous reactions Æ Æ31 None Æ47 3 0Æ14 Diphenhydramine Æ33 4 0Æ43 Acetaminophen Æ06 5 0Æ59 Both Æ94 6 0Æ31 One previous reaction Æ77 4 0Æ26 None Æ Diphenhydramine Æ Acetaminophen Æ75 Both Æ81 3 0Æ35 Greater than or equal to two previous reactions Æ None Diphenhydramine Æ3 0 0 Acetaminophen Both Æ Total Æ Æ28 *Note that regardless of the number of previous reactions, premedication was not associated with a decreased incidence of reactions. prospective, randomised trial would be necessary to demonstrate conclusively that these medications are not effective in preventing transfusion reactions. However, given the low incidence of reactions, such a trial would require a very large number of patients, would be costly to perform, and is probably unnecessary. In fact, even if premedication reduced reactions by 50%, it would only decrease the absolute risk of reaction from 1% to 0Æ5%, so premedication would have to be used 200 times to prevent one reaction. Finally, when reactions do occur, they are generally mild and easily treated. We found an increased rate of reactions in certain subgroups of patients. Outpatients and patients who received platelets had higher rates of allergic reactions. Patients with leukaemia and lymphoma, those with fewer prior, and those transfused in the general inpatient unit had higher rates of both allergic and febrile reactions. Patients with a history of febrile reactions had a higher rate of subsequent febrile reactions. We have no clear explanation for most of these findings based on our understanding of the pathophysiology of allergic and febrile non-haemolytic transfusion reactions. None of the associations with febrile reaction was significant in the multivariate analysis. The associations between platelet transfusion, number of prior, and outpatient or general inpatient location and the rate of allergic reactions remained statistically significant in the multivariate analysis. As the incidence of allergic reactions ranged from 0Æ14% to 1Æ15% in the various subgroups studied, however, these differences are of questionable clinical importance. Given the very low incidence of febrile and allergic reactions, the absence of any evidence that premedication is effective, and the cost and risk of premedication, we feel that universal premedication should not be the standard of care in this population. It may be argued, however, that premedication is warranted for high-risk patients, including those with a history of multiple or severe reactions. The number of patients with multiple reactions in our study was small: only six patients had three or more reactions, and they were premedicated for 116 of the 122 (95%) that they received during the study period. We cannot, therefore comment on the efficacy of premedication in this subgroup. For the infrequent patient with recurrent reactions, or those with a history of severe or anaphylactoid allergic reactions, the use of washed or plasmareduced blood products may be helpful (Buck et al, 1987; Perrotta & Snyder, 2001). Corticosteroid premedication would also be reasonable in these situations, although no clinical trials have demonstrated their efficacy for this purpose. Acknowledgements This work was supported by the American Lebanese Syrian Associated Charities (ALSAC), by the American Cancer Society F.M. Kirby Clinical Research Professorship, and by a National Institutes of Health Cancer Centre support grant CA The authors thank Alicia Rodriguez for assistance with data entry, William Humphrey and Alice Morrell for help in estimating costs of premedication, and Lori Sweat for help obtaining access to blood bank records. References Agretsi, A. (2002) Categorical Data Analysis, 2nd edn. John Wiley & Sons, Hoboken, NJ. 786 ª 2005 Blackwell Publishing Ltd, British Journal of Haematology, 130,

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