Things We Do for No Reason™: Routinely Prescribing Transfusion Premedication To Prevent Acute Transfusion Reactions

In the past 20 years, three double-blind randomized controlled trials published show that premedication with a combination of acetaminophen and an antihistamine (either diphenhydramine or chlorpheniramine) does not reduce the risk of ATR and FNHTR. The first study, published in 2002, randomized 51 patients with hematological malignancies receiving prestorage-irradiated, leukocyte-reduced, single-donor apheresis platelets to premedication with either acetaminophen and diphenhydramine or placebo.⁶ Patients with a history of either ATR or FNHTR were included, but patients with a history of hemolytic transfusion reaction were excluded.⁶ The study found that premedication did not significantly lower the incidence of these transfusion reactions (15.4%) as compared with placebo (15.2%; P = .94).⁶

In a larger study published in 2008, Kennedy et al. randomized 315 patients with hematological malignancies receiving RBC or platelet transfusion to either pretransfusion acetaminophen and diphenhydramine or placebo.⁷ Patients with a documented history of an ATR or FNHTR were excluded, which may have contributed to the lower incidence compared with the aforementioned earlier clinical trial. There was no significant difference in the overall rate of transfusion reactions between the two groups (1.44 per 100 transfusions vs 1.51 per 100 transfusions, P = .433). When the rates of ATRs and FNHTRs were analyzed separately, there was no significant difference between the treatment and control groups for either reaction type (P = .899 and P = .084, respectively). There was a trend toward a reduction in FNHTRs, but the authors calculated that we would need to premedicate approximately 344 transfusions to prevent one febrile reaction.⁷

A more recent study published in 2018 evaluated 147 Thai children and adolescents with thalassemia receiving leukoreduced blood products.⁸ Researchers randomized them to either premedication with acetaminophen and chlorpheniramine or placebo.⁸ The incidences of FNHTR were not statistically significantly different: 6.9% in the intervention group, compared with 9.5% in the placebo group (P = .565).⁸ These three studies constitute the best currently available evidence and suggest that pretransfusion antihistamines and/or antipyretics are not effective.

Beyond a lack of proven benefit, the use of premedication is not without risk. Diphenhydramine, the most commonly used antihistamine for premedication, can cause cognitive impairment, sedation, and delirium.⁹ Such adverse effects are potentially heightened in the elderly and seriously ill populations where transfusion commonly occurs. Acetaminophen, although generally safe, can result in hepatotoxicity in patients who are fasting, regularly consume alcohol, or have underlying liver disease. Since there is both a lack of clinical benefit and potential for harm, avoid premedication.

Rather than pretreating the patient, consider modifying the blood product selected for transfusion. Administering platelet and/or RBC components with certain modifications (a product-­centered approach) is effective at reducing mild transfusion reactions.¹⁰ A well-known product-centered modification method includes prestorage leukoreduction of RBC and platelet components to remove donor leukocytes to a level <5 × 10⁶ per unit. This intervention reduces the incidence of FNHTRs by approximately 50%.¹¹ A recent large, national survey demonstrated 90% of institutions (2,712/3,032) use universal leukoreduction.¹² This widely employed and effective prevention strategy has likely helped reduce FNHTRs nationwide, so there are now fewer to prevent.¹²