HowHow We DoWe It Do It Implementing inpatient, evidence-based, -transfusion premedication guidelines at a single academic US hospital Ida Wong-Sefdan, MD,a Amine Ale-Ali, PharmD,b Patricia A DeMoor, PA-C, MS,a Samuel Martinez, PharmD,b Peter Curtin, MD,c Tomas Lane, MD,d and Eric Roeland, MDa aDepartment of Hematology/Oncology, bDepartment of Pharmacy, cDepartment of Bone Marrow Transplantation, cDepartment of Pathology, Moores Cancer Center, University of California, San Diego Allergic transfusion reactions (ATRs) are a common complication of blood transfusions. Advances in transfusion medicine have signifcantly decreased the incidence of ATRs; however, ATRs continue to be burdensome for patients and problematic for providers who regularly order packed red blood cells and platelet transfusions. To further decrease the frequency of ATRs, routine premedica- tion with is common practice and is part of “transfusion culture” in a majority of institutions. In this article, we re- view the history, practice, and literature of transfusion premedication, specifcally given the adverse-effect profle. We discuss the rationale and original academic studies, which have supported the use of premedication for transfusions for decades. However, despite the common use of premedication to prevent ATRs, recent literature has not conclusively validated its use. In addi- tion, the existing premedication that is routinely prescribed often causes a number of adverse effects. These fndings have motivated the Moores Cancer Center (University of California, San Diego) to change its current transfusion premedication practices, particu- larly with regard to ATRs and frst-generation antihistamines. We outline the preliminary development of an evidence-based and patient-specifc approach to transfusion premedication, including the challenges and steps taken to revise inpatient premedication protocols. We plan to expand this protocol to the outpatient setting at a later date. Future efforts require a prospective validation of our presented transfusion premedication guidelines.

cute transfusion reactions such as allergic Some donors are more frequently related to ATRs, transfusion reactions (ATRs) have compli- indicating a possible relationship of the donor to Acated the delivery of blood products since the developfment of an ATR.4 Elevated levels of the establishment of transfusions. Although the complement component, brain-derived neurotroph- true incidence of ATRs is not established, as there ic factor, and chemokine (C-C motif ) ligand 5 in are wide variations in institutional reporting rates, platelet units have also been associated with ATRs.5 the incidence of ATRs ranges from less than 1% up Prophylactic diphenhydramine, a frst-generation to 17%.1 ATRs are responsible for the majority of antihistamine, has conventionally been empirically transfusion interruptions and represent a major im- used for ATR prophylaxis. pediment to the delivery of needed transfusion sup- In an efort to reduce ATRs, transfusion medi- port. As a result, ATRs result in additional blood- cine physicians and researchers have developed new donor exposure and signifcant added health care techniques, including clearer defnitions of transfu- expenditures. sion thresholds, plasma volume reduction, the wash- ATRs range from mild (itching, hives) to ana- ing of blood products, and storage in additive solu- phylaxis (bronchospasm, hypotension, and shock).2 tion. Tese techniques have signifcantly decreased Te pathophysiology of ATRs is unclear. Patient the incidence of ATRs. Although transfusion immunoglobin E (IgE) antibodies have been clas- thresholds are regularly determined at the discretion sically elevated and associated with ATRs and pos- of the ordering provider, studies show that lower- tulated to be a main contributor in such reactions.3 than-conventional thresholds can be safe.6 Setting

Accepted for publication July 18, 2013. Correspondence: Ida Wong-Sefdan, MD; [email protected]. Disclosures: The authors have no disclosures to report. JCSO 2014;2:56-64. ©2014 Frontline Medical Communications. DOI 10.12788/jcso.0016.

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clearly defned, clinically relevant transfusion thresholds is deeply ingrained in medical culture. It is still common and avoiding unnecessary transfusions are two often over- to prescribe premedication, specifcally acetaminophen looked, but extremely important, means of decreasing all and diphenhydramine, prior to the transfusion of all blood transfusion reactions and overall cost. Additionally, the products without considering risk or prior transfusion reac- concentration of blood products by plasma volume reduc- tions.11 Although there has been discussion to change cur- tion, the washing of blood products, and the storage in ad- rent routine premedication practices, there are challenges ditive solution all reduce rates of ATRs. Removal of most to changing this deeply established medical practice.11,12 donor plasma in platelets has reduced the risk of ATRs Te leading reason for premedication may be the “cul- from 5.5% to 1.7% in patients with prior history of mul- ture of premedication.” Premedication has been ingrained tiple ATRs. Removing the donor plasma by washing plate- in medical practice as “what we do.” Literature on ATRs lets and packed red blood cells (PRBCs) has reduced the often recommends premedication, perpetuating and autho- risk of ATRs to 0.5%.7 Te transfusion of platelets stored rizing its use.13,14 Premedication is frequently written into in platelet-additive solution vs plasma, a storage technique institutional transfusion protocols. Moreover, past gener- recently approved by the US Food and Drug Administra- ations of physicians, nurses, nurse practitioners, physician tion (FDA), has also been shown to signifcantly decrease assistants, and even patients have communicated its utility ATRs.8 to future generations. Because of these continued practices, Despite these major advances in transfusion medicine, premedication has become the standard of care. ATRs continue to be a common complication of blood transfusions. Given the approximately 30 million blood Paucity of data components transfused in the United States each year,9 Te most debatable topic, however, is the wide use of anti- ATRs remain a challenge. In this article, we describe the histamine premedication, despite very limited data to sup- data regarding routine premedication prior to blood trans- port its use (Table 1). Although 1950s data for premedica- fusions and the risks associated with this practice, and pres- tion may have shown a decrease in ATRs, data over the past ent our evidenced-based and patient-specifc approach to decade have challenged the utility of routine premedication transfusion premedication, with particular emphasis on an- for all blood products.15-20 A small number of studies has tihistamines. examined the role of premedication for transfusions, but of the few that were published, the two prospective, random- The scope of the challenge ized trials did not yield any signifcant diference in ATRs Te history and rationale of transfusion premedication with premedication.16,17 In an attempt to prevent ATRs, physicians for decades have Furthermore, the available studies are limited by insuf- been prescribing transfusion premedication. In the 1950s, fcient details outlining the adopted transfusion-reaction antihistamines – specifcally chlorprophenpyridamine – were protocols. No standardized drug, dose, timing, or route of injected into the blood products to decrease ATRs.10 Since administration for antihistamines is provided. Although then, transfusion premedication has evolved to include an- most facilities and studies use diphenhydramine as the tihistamines such as diphenhydramine. choice antihistamine, a number of alternative antihista- Physicians and nurses prefer premedication prior to mines have fewer associated adverse efects. However, a transfusions for many reasons. Patients who receive blood PubMed literature search revealed no published studies products are often the most critically ill patients with mul- comparing the efcacy of other antihistamines as a trans- tiple comorbidities. Complications including fever or rash fusion premedication. In addition, no guidelines for pre- that are attributed to a transfusion reaction may prevent exist for specialized products such as human or delay the completion of necessary transfusions. Further- leukocyte antigen-matched platelets, antigen-negative more, given that the blood products and infusion-center platelets,and antigen-negative PRBCs. space are expensive and limited resources, medical provid- ers prefer to err on the side of premedication rather than Te dark side of routine transfusion antihistamine risk the possibility of a transfusion reaction. Te signifcant premedication cost, time, and resources required to work up a transfusion Te use of conventional premedication does have known reaction are also incentives to premedicate. adverse efects. Diphenhydramine, the most commonly used antihistamine, has a large adverse-efect profle. Di- Te culture of transfusion premedication phenhydramine falls in a class of antihistamines that in- Medical reasoning and cost aside, physicians who order hibit target receptors (such as muscarinic and α-adrenergic blood products continue to give premedication regularly receptors) and cross the blood-brain barrier. Consequently, for transfusions in the belief that premedication will fur- its adverse efects include dry mouth, tachycardia, urinary ther decrease the incidence of ATRs. Te practice of uni- retention, cognitive impairment, sedation, and delirium. versal premedication to avoid blood transfusion reactions Compared with patients who take nonsedating antihis-

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TABLE 1 Summary of studies evaluating premedication for allergic transfusion reactionsa

Author, year No. of Products evaluated Reactions Study type transfusions Aims evaluated (patients) administered evaluated

Kennedy, 200816 4,199 (315) Compare the Leukoreduced PRBCs Acetaminophen FNHTR, ATR Prospective, risk of transfusion and leukoreduced 500 mg plus randomized reactions in platelets (single- diphenhydramine hematology/ donor aphereis); 25 mg vs placebo oncology patients products administered 30 who receive irradiated for minutes before acetaminophen BMT patients frst transfusion with diphenhydramine or placebo before transfusion.

Wang, 200217 98 (51) Evaluate the Leukoreduced Acetaminophen NHTR, ATR Prospective, effcacy of platelets 650 mg plus randomized acetaminophen (single-donor diphenhydramine and aphereis) 25 mg IV vs diphenhydramine placebo as premedication for transfusions in hematology/ oncology patients.

Sanders, 200518 7,900 (385) Evaluate the Leukoreduced, Acetaminophen FNHTR, ATR Prospective effectiveness of irradiated PRBCs and/or premedication and platelets diphenhydramine with (single-donor (doses unspecifed) acetaminophen apheresis) and/or diphenhydramine in FNHTR and ATR.

Patterson, 200019 3,472 (716) Compare the Nonleukocyte Acetaminophen FNHTR, ATR Retrospective rates of reduced, pooled, and/or transfusion random-donor antihistamine reactions platelets (doses before and after unspecifed) pretransfusion guidelines.

Szelei-Stevens, 301,210 Investigate PRBCs, platelets Acetaminophen FNHTR, ATR 2006 (abstract)20 (31,665) whether (single-donor ordiphenhydramine Retrospective premedication apheresis), (doses with and FFP/ unspecifed) acetaminophen cryoprecipitate and (unknown if diphenhydramine leukoreduced) decrease FNHTR and ATR.

ATR, allergic transfusion reaction; BMT, bone marrow transplant; CI, confdence interval; FFP, fresh frozen plasma; FNHTR, febrile nonhemolytic transfusion reaction; NHTR, nonhemolytic transfusion reaction; PRBCs, packed red blood cells

aAdapted from Fry et al.15

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tamines, those who receive diphenhydramine have an in- creased risk of serious injury and increased risk of cognitive 21,22 Limitations Result changes in attention, working memory, and motivation. Given the usual population receiving blood transfusions (older, more seriously ill patients), these adverse efects may n Low event rates No difference in FNHTRs n Plasma transfusions (P = .08) or ATRs (P = .90) be heightened and potentially more dangerous. Terefore, were not evaluated based on one-sided P the routine use of diphenhydramine may place patients at n Lack of methodology value. No difference an even higher risk of unintentional injury, especially when of transfusion protocol in number of transfusions until frst reaction it is used in the outpatient setting from which patients have (P = .39). to drive home. Finally, the true cost beneft of premedication has not been fully analyzed. Although premedications alone are

relatively inexpensive, there are a number of indirect costs in administering them, including costs for nursing, phar- n Platelet transfusions No difference macy, infusion-center, and inpatient resources. For exam- only in NHTRs (P = .94); ple, hypotension or delirium associated with diphenhydr- n Lack of NHTRs occurred more amine may require clinical evaluation and work-up, and methodology often in patients with may therefore occupy necessary and expensive infusion- transfusion history of NHTR than protocol in those with center and inpatient space. Altogether, these less-obvious no history costs may be more expensive than those from rationally (P = .06). dosed premedication.

Approach to developing recommendations n Retrospective study No difference After reviewing the current literature on transfusion pre- n Pediatric population in FNHTRs (P = .22) or n Lack of methodology ATRs (P = .054). medication, we decided to revise the transfusion premedi- of transfusion protocol cation practices at our institution to better refect evidence- n Doses unspecifed based practices. Our blood bank distributes approximately

27,000 units of blood components yearly. For the scope of this article, we narrowed the focus to the inpatient bone marrow transplant (BMT) unit, which utilizes approxi- n Observational study No difference in FNHTRs mately 20% to 25% of all transfusions at our institution. n Platelet transfusions or ATRs. With 73% of Furthermore, we focused on ATRs and antihistamine use only patients premedicated, given the anticholinergic efects, as well as the impact on n No standardized 30% (95% CI, premedication dosing, 28% ± 33%) patient quality of life and medical cost. All transfused drugs of transfusions were blood products that are ordered through our blood bank n Lack of methodology complicated by FNHTRs for hematology/oncology/BMT patients are leukoreduced of transfusion protocol and ATRs. With 50% of and irradiated, and platelets are single-donor apheresis p atients premedicated the following year, 26% platelets. (95% CI, 24% ± 29%) To initiate the revision of transfusion premedication, of transfusions were the director of transfusion medicine, the clinical director of complicated by FNHTRs the BMT program, a supportive oncology physician, and a and ATRs. physician assistant from the cancer center’s infusion cen- ter formed a “Transfusion Premedication Utilization Com- n Retrospective study No difference in FNHTRs n Lack of methodology (P = .31). mittee.” Te committee met several times to identify the of transfusion protocol No difference in ATRs; current challenges with transfusion-premedication practice n Doses unspecifed of the 154 patients at our institution, to review the pharmacology and current premedicated with diphenhydramine, costs of premedication, and to develop an evidenced-based 49.3% had ATRs; of the protocol for inpatient transfusion premedication with the 90 patients not plan to initiate these measures in the hospital frst and then premedicated, to expand to the outpatient setting. 39% had ATRs Identifying the current problems Te frst challenge with the current transfusion-premed- ication protocol was the established electronic order set.

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Our institution utilizes computerized, provider-order entry (when appropriate) would be benefcial. Tere are 4 known

to order all inpatient transfusions. Tis order set includes histamine receptor subtypes; the H1 subtype is associ- a drop-down menu for premedication and blood products ated with allergic infammation resulting in pruritus and with modifers. When we focused on antihistamines, we smooth-muscle contraction.23 Both frst- and second-gen- found that the previous BMT inpatient order set was lim- eration antihistamines elicit their pharmacologic efects by

ited to oral diphenhydramine 25 mg. Unless the provider competitive antagonism of histamine for the H1 receptors selected to discontinue the diphenhydramine, the diphen- present in smooth muscles, nerve endings, and glandular 24 hydramine would be ordered automatically. If the provid- cells. H1 antihistamines downregulate allergic infamma-

er wanted an alternative premedication, she or he needed tion through the H1 receptor. However, H1-receptor an- order it outside the order set, which required extra steps. tagonism may potentially cause central nervous system Tus, most prescribers selected the preordered premedica- adverse efects, which manifest as dizziness, hypotension,

tion without changing or discontinuing these default op- and sedation. Antihistamines can also afect H1 receptors tions. Terefore, our committee desired to modify the com- through the muscarinic, α-adrenergic, and serotonin recep- puterized premedication order set in order to encourage tors as well as the cardiac ion channels, , which cause dry selective ordering of premedication for transfusion. mouth, urinary retention, sinus tachycardia, and cardiac ar- Another challenge facing the existing protocol was the rhythmias.25 adverse-efect profle of premedication, specifcally diphen- Benefts of second-generation antihistamines include a hydramine. Our team was contacted repeatedly by the in- lower incidence of central nervous system adverse efects, patient nurses to assess patients with hypotension and/or given that they are not considered to cross the blood-brain tachycardia who had been premedicated with diphenhydr- barrier. Second-generation antihistamines are specifc and

amine. Many patients also experienced sedation after re- selective to H1 receptors vs other receptors, such as musca- ceiving diphenhydramine, which placed them at risk for rinic and α-adrenergic receptors. Both the literature and falls. In the outpatient arena, the adverse efects of seda- institutional experience dictated a more desirable safety

tion required patients to be observed for a longer period profle for H1-specifc antihistamine premedication. After of time in the infusion center, and prohibited the patient review of the typical antihistamines, cetirizine appeared to from driving home from treatment. A handful of patients be the favored choice, based on a number of factors (Table reported a paradoxical restlessness and agitation associated 2). Cetirizine is a second-generation antihistamine with with diphenhydramine, which then required low-dose lo- decreased risk for sedation, tachycardia, hypotension, and razepam; the , however, further potentiated the urinary retention. Its cost is minimally diferent from that efects of diphenhydramine. Compared with oral of diphenhydramine, as cetirizine is available as a generic administration, intravenous diphenhydramine was also as- and is the least expensive second-generation antihistamine. sociated with a higher propensity for headaches, drowsi- Cetirizine also has a more potent and faster onset of action ness, ataxia, and restlessness. Patients often asked to dis- than do both fexofenadine and loratadine.26 Tus, a propos- continue diphenhydramine because of its adverse efects al to change the premedication antihistamine to cetirizine and because they planned to drive home. It was important was outlined and presented to the committee. to identify those who might be at higher risk of ATRs and to administer the appropriate premedication, but many of Changes in protocols these patients had no history of ATR, which put into ques- At a follow-up meeting, the committee reviewed informa- tion the benefts of premedication in the frst place. Te tion from the institutional evaluation as well as data from adverse-efect profle of diphenhydramine became such the published studies. A stepwise approach was taken to an issue that empirical switches from diphenhydramine to revise the transfusion premedication protocol. Because in- second-generation antihistamines were common practice, patients are under direct supervision for longer periods of especially if the patient had any prior history of hypoten- time than are outpatients, we focused our initial eforts on sion, tachycardia, drowsiness, or restlessness with diphen- the inpatient transfusion guidelines, with the goal of ex- hydramine. Occasionally, antihistamines were discontinued panding these guidelines to the outpatient setting. altogether. Tese experiences in the inpatient setting and To refect evidence-based standards, the inpatient BMT infusion center further emphasized the need to consider transfusion order set was changed so that the previously au- alternative antihistamine transfusion premedication. tomatic default of predetermined oral diphenhydramine 25 mg would be omitted. Now, if the medical provider wishes Pharmacology and costs to administer any premedication, he or she needs to actively Tese anecdotal cases moved the committee to reconsid- select, through a drop-down menu, either an antihistamine er the choice of diphenhydramine and evaluate other an- (oral certirizine 10 mg as the frst choice antihistamine) tihistamines commonly used as premedication for transfu- and/or an oral acetaminophen (Figure 1). Recognizing that sions, and to decide whether an alternative antihistamine each patient’s risk for a reaction may not be equivalent, the

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TABLE 2 Summary of antihistamines

Crosses blood-brain Onset of Notable Generation (class) Antihistamines barrier action, min Half-life, h Elimination adverse effects Cost, US $

First (ethanolamines) Diphenhydramine (oral) Yes 120 9.2 Renal Antimuscarinic 0.04 effects and –adrenergic receptor blockade, tachycardia

First (ethanolamines) Diphenhydramine (IV) Yes 2-3 8.5 Renal Antimuscarinic 0.78 effects and –adrenergic receptor blockade, tachycardia

First (piperazines) (oral) Yes 30 20 Renal Sedation 0.22

Second (piperidines) Cetirizine (oral) No 30-60 6.5-11 Renal NA 0.16

Second (piperidines) Fexofenadine (oral) No 120 14.4 Bile NA 1.51

Second (piperidines) Loratadine (oral) No 120 7.8 Renal NA 0.30

IV, intravenous; NA, not applicable committee recommended that patients who were at higher tate, fresh frozen plasma, and granulocytes) ordered, with risk of reaction (including multiple mild allergic reactions; 2,866 orders in the year prior to the change, and 3,266 or- unexplained hypotensive reaction with prior transfusion; ders in the year after the change. Te use of diphenhydr- moderate to severe allergic reaction; known preexisting amine dropped from 85.9% to 34.2%, whereas the use of anti-IgA antibodies; and haptoglobin defciency) be consid- cetirizine increased from 3.3% to 55.9% (Table 3). ered for more-aggressive premedication, such as cetirizine, an H2 blocker such as ranitidine, as well as corticosteroids Challenges and limitations prior to transfusion. Te efcacy of either corticosteroids or With this premedication policy change, several challenges

H2 blockers has not been evaluated prospectively in blood emerged. Staf and patient education regarding the change transfusions. Tey have, however, been used in the treat- was one of the biggest challenges. As expected, most staf ment and prevention of other severe allergic reactions, in- were unfamiliar with the evidence-based data surrounding cluding contrast allergies.27,28 Furthermore, in a high-risk premedication for transfusions, and therefore were skepti- allergy setting, the physician members of the committee cal of changing the routine practice. We were and are con- strongly advocated administering steroids and H2 block- stantly educating and reeducating the staf regarding the ers. In addition to the existing default blood-component new protocol and rationale behind the change. Further- specifcations (ie, leukocyte-reduced, irradiated blood), the more, because there is a constant change in nursing staf, committee determined that these high-risk patients should education about the change in premedication policy is not ideally be considered for plasma volume reduction, washed always successful, and some nurses continue to page phy- blood products, and/or additive solution platelets, if avail- sicians and midlevel practitioners to question the lack of able.7,29 Te committee developed a detailed algorithm for premedication orders. Additionally, patients are wary of the revised recommendations for BMT inpatient-transfu- discontinuing premedication that they believe is prevent- sion premedication, with a particular focus on antihista- ing allergic reactions. Patients occasionally still ask for pre- mine use (Figure 2). medication, regardless of our new policy. To complicate matters, a number of non–hematol- Preliminary results ogy/oncology physicians moonlight on the BMT service. In the year prior to and following the institutional change, If blood transfusions are ordered through the adult, non- the total BMT inpatient premedication orders decreased BMT transfusion-order set, the order set still includes a from 4,017 to 2,993. Tis was in the setting of an overall drop-down menu with preordered diphenhydramine. increase in blood products (PRBCs, platelets, cryoprecipi- Anecdotally, however, the new policy seems to be

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FIGURE 1 Screen shot of EPIC inpatient bone marrow transplant transfusion premedication order set, which was changed to omit automatic default, pre-ordered transfusion premedication. The provider must actively select an antihistamine (oral certirizine 10mg as the frst choice) through a drop-down menu.

having a positive efect. For example, the early adapting did not collect any data regarding acetaminophen premed- nursing staf has observed a reduced time to transfusion, ication use in febrile, nonhemolytic transfusion reactions. as well as decreased sedation and delirium in patients. In Furthermore, we did not compare the number of ATRs addition, because of the notable decrease in sedation, many during this period to the number of reactions in patients of the physicians have omitted premedication in their out- who did and did not receive premedication; unfortunately, patients, which has allowed patients to be observed for a we were unable to obtain these data because of multiple shorter period at the infusion center and permitted patients electronic-charting systems at our institution. For exam- to drive themselves home. A few patients who previously ple, medications are dated, charted, and fled in an order requested either to hold or to switch antihistamines were through our computerized system, but blood bank reac- supportive of the change in protocol. tions (including febrile reactions and ATRs) are charted Our retrospective review is limited in several ways. We in a progress note. Terefore, transfusion reactions are not restricted our scope to antihistamine premedication, and easily accessible or retrievable. For the same reason, there was no clear method to identify patients who received plas- ma-reduced or washed platelets. By identifying these ret- TABLE 3 Antihistamine dose counts before and after implementation of inpatient transfusion premedication protocol rospective limitations, our institution would like to imple- ment changes to the electronic system in order to provide Dose count, no. (%) improved data for prospective validation. Furthermore, ATRs will now be charted as an allergy, which is easily re- Drug Jul 2010-Jun 2011 Jul 2011-Jun 2012 trievable. Our plan is to prospectively track each transfu-

Cetirizine 131 (3.3) 1,672 (55.9) sion reaction, and to document premedication and type of blood product. Diphenhydramine 3,453 (85.9) 1,025 (34.2) Discussion and future directions Loratadine 433 (10.8) 296 (9.9) ATRs continue to be a challenge in blood transfusions. New blood-bank techniques and approaches, such as plas- Total 4,017 (100) 2,993 (100) ma reduction, have decreased ATRs. As plasma reduction, the washing of blood products, and platelet additives be

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quent increased use of cetirizine. We now plan to expand

PRBC/platelet these guidelines to the outpatient setting, focusing on our transfusion infusion center. Although the aim of our changes to pre- medication is to practice more evidence-based medicine, the larger motive is to improve quality of life for our pa- Has the patient had a No pre- tients. Te outpatient population would be a target popula- previous allergic NO medications transfusion reactions(s)? tion to measure quality-of-life changes before and after the change of premedication practices. ATRs continue to be a major difculty with transfu- YES sions. However, the role of premedication in the era of con- b Low riska High risk centration of blood products is unclear. As the literature on transfusion premedication is limited, prospective stud- ies evaluating the impact of rationally administered trans- Cetirizine Cetirizine fusion premedication are essential to appropriately avoid +/– ranitidine 30 min before +/– hydrocortisone transfusion-related toxicity and to mitigate cost. We hope transfusion 30 min before fransfusion that the description of our experience will encourage other institutions to reevaluate and challenge the culture of rou- tine transfusion premedication. Transfuse PRBC/ c platelets References 1. Martí-Carvajal AJ, Solà I, González LE, Leon de Gonzalez G, Rodriguez-Malagon N. Pharmacological interventions for the pre- FIGURE 2 Algorithm for premedication for inpatient bone mar- vention of allergic and febrile non-haemolytic transfusion reactions. row transplant-related allergic transfusion reactions. Cochrane Database Syst Rev. 2010;(6):CD007539. PRBC, packed red blood cells 2. National Healthcare Safety Network Biovigilance Component He- movigilance Module Surveillance Protocol. http://www.cdc.gov/ aLow-risk allergic reactions = one or no mild allergic reactions. nhsn/PDFs/Biovigilance/BV-HV-protocol-current.pdf. Accessed Mild allergic reactions are reactions with only mucocutaneous December 14, 2013. signs and symptoms that respond quickly to treatment. bHigh- 3. Savage WJ, Tobian AA, Savage JH, Hamilton RG, Ness PM. Atopic risk allergic reactions = multiple mild allergic reactions, un- predisposition of recipients in allergic transfusion reactions to apher- explained hypotensive reaction with transfusion, moderate to esis platelets. Transfusion. 2011;51:2337-2342. severe allergic reaction, IgA defciency, pre-existing anti-IgA 4. Savage WJ, Tobian AA, Fuller AK, Wood RA, King KE, Ness PM. Allergic transfusion reactions to platelets are associated more with antibodies, haptoglobin defciency. cLeukoreduced, irradiated recipient and donor factors than with product attributes. Transfu- PRBCs: if there is a history of multiple allergic reactions, consid- sion. 2011;51:1716-1722. er volume-reduced PRBCs, or washed PRBCs and/or ‘additive 5. Savage WJ, Savage JH, Tobian AA, et al. Allergic agonists in apher- solution’ PRBCs if available. Leukoreduced, irradiated apher- esis platelet products are associated with allergic transfusion reac- esis platelets: if there is a history of multiple allergic reactions, tions. Transfusion. 2012;52:575-581. consider volume-reduced platelets, and/or washed platelets or 6. Estcourt L, Stanworth S, Doree C, et al. Prophylactic platelet trans- ‘additive solution’ platelets if available. fusion for prevention of bleeding in patients with haematological disorders after and stem cell transplantation. Co- chrane Database Syst Rev. 2012;5:CD004269. 7. Tobian AA, Savage WJ, Tisch DJ, Toman S, King KE, Ness PM. come more readily available, these approaches may decrease Prevention of allergic transfusion reactions to platelets and red blood ATRs even further. Avoiding unnecessary blood transfu- cells through plasma reduction. Transfusion. 2011;51:1676-1683. sions and developing clear, clinically relevant transfusion 8. Kerkhofs JL, Eikenboom JC, Schipperus MS, et al. A multicenter randomized study of the efcacy of transfusions with platelets stored parameters are the most fundamental of these approaches in platelet additive solution II versus plasma. Blood. 2006;108:3210- to limiting ATRs. 3215. We propose that universal premedication to decrease 9. Blood Facts and Statistics. American Red Cross Web site. http:// www.redcrossblood.org/learn-about-blood/blood-facts-and-statis- ATRs should not be a default institutional practice. We tics. Accessed June 28, 2013. believe that the use of antihistamines should be selected 10. Ferris HE, Alpert S, Coakley CS. Prevention of allergic transfusion based on risk, including the patient’s prior history of ATR. reactions; the prophylactic use of antihistamine in blood to prevent allergic transfusion reactions. Am Pract Dig Treat 1952;3:177-183. We aimed to create an evidence-based, selective inpatient- 11. Geiger TL, Howard SC. Acetaminophen and diphenhydramine transfusion premedication protocol in order to update our premedication for allergic and febrile nonhemolytic transfusion institutional transfusion practices, based on the available reactions: good prophylaxis or bad practice? Transfus Med Rev. 2007;21:1-12. published data and patient-specifc needs. Our frst chang- 12. Tobian AA, King KE, Ness PM. Prevention of febrile nonhemolytic es included avoidance of preordered premedication, spe- and allergic transfusion reactions with pretransfusion medication: is cifcally diphenhydramine, in the BMT inpatient transfu- this evidence-based medicine? Transfusion. 2008;48:2274-2276. 13. Brecher ME, Hay SN. Bacterial contamination of blood compo- sion order set. Tis change resulted in a dramatic decrease nents. Clin Microbiol Rev. 2005;18:195-204. in the inpatient use of diphenhydramine and the subse-

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14. Perrotta PL, Snyder EL. Non-infectious complications of transfu- 22. Kay GG, Berman B, Mockoviak SH, et al. Initial and steady-state sion . Blood Rev. 2001;15:69-83. efects of diphenhydramine and loratadine on sedation, cogni- 15. Fry JL, Arnold DM, Clase CM, et al. Transfusion premedication tion, mood, and psychomotor performance. Arch Intern Med. to prevent acute transfusion reactions: a retrospective observational 1997;157:2350-2356. study to assess current practices. Transfusion. 2010;50:1722-1730. 23. del Cuvillo A, Mullol J, Bartra J, et al. Comparative pharmacol-

16. Kennedy LD, Case LD, Hurd DD, Cruz JM, Pomper GJ. A pro- ogy of the H1 antihistamines. J Investig Allergol Clin Immunol. spective, randomized, double-blind controlled trial of acetamino- 2006;16(Suppl 1):3-12. phen and diphenhydramine pretransfusion medication versus 24. Waldman SA. Does potency predict clinical efcacy? Illustration placebo for the prevention of transfusion reactions. Transfusion. through an antihistamine model. Ann Allergy Asthma Immunol. 2008;48:2285-2291. 2002;89:7-11.

17. Wang SE, Lara PN Jr., Lee-Ow A, et al. Acetaminophen and di- 25. Simons FE. Advances in H1-antihistamines. N Engl J Med. phenhydramine as premedication for platelet transfusions: a pro- 2004;351:2203-2217. spective randomized double-blind placebo-controlled trial. Am J 26. Grant JA, Danielson L, Rihoux JP, DeVos C. A double-blind, sin- Hematol. 2002;70:191-194. gle-dose, crossover comparison of cetirizine, ebastine, epinastine, 18. Sanders RP, Maddirala SD, Geiger TL, et al. Premedication with ac- fexofenadine, terfenadine, and loratadine versus placebo: suppression etaminophen or diphenhydramine for transfusion with leucoreduced of histamine-induced wheal and fare response for 24 h in healthy blood products in children. Br J Haematol. 2005;130:781-787. male subjects. Allergy. 1999;54:700-707. 19. Patterson BJ, Freedman J, Blanchette V, et al. Efect of premedica- 27. Lin RY, Curry A, Pesola GR, et al. Improved outcomes in patients

tion guidelines and leukoreduction on the rate of febrile nonhaemo- with acute allergic syndromes who are treated with combined H1 lytic platelet transfusion reactions. Transfus Med. 2000;10:199-206. and H2 antagonists. Ann Emerg Med. 2000;36:462-468. 20. Szelei-Stevens KA NA, Al-Sammak M. Transfusion reactions: to 28. Tramèr MR, von Elm E, Loubeyre P, Hauser C. Pharmacological premedicate or not to premedicate? In: Transfusion. Abstracts of prevention of serious anaphylactic reactions due to iodinated con- Papers to be presented at the 59th AABB Annual Meeting and trast media: systematic review. BMJ. 2006;333:675. TXPO. October 21-24, 2006. Miami Beach, Florida; 2006:95A. 29. Azuma H, Hirayama J, Akino M, et al. Reduction in adverse re- 21. Finkle WD, Adams JL, Greenland S, Melmon KL. Increased risk of actions to platelets by the removal of plasma supernatant and serious injury following an initial prescription for diphenhydramine. resuspension in a new additive solution (M-sol). Transfusion. Ann Allergy Asthma Immunol. 2002;89:244-250. 2009;49:214-218.

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