Evaluation of Intravenous Diphenhydramine Use in Patients with Sickle Cell Vaso-Occlusive Crisis
Authors: Osunkwo Ifeyinwa , Merchant Shelby , Crawford Rachel , Rector Katherine , Arnall Justin , Symanowski James T , Veeramreddy Padmaja 
Published: October 2019

Abstract
Inpatient management of sickle cell disease (SCD) vaso-occlusive crisis (VOC) often involves use of high-dose opioids, which may result in opioid-induced pruritus (OIP). This OIP is typically treated with antihistamines like diphenhydramine either orally or intravenously. The oversedation adverse effects of diphenhydramine may be magnified when given in combination with high-dose opioid therapy. Current recommendations made by the National Heart, Lung, and Blood Institute endorse using oral rather than intravenous (IV) antihistamines to avoid the cumulative effect on sedation. Despite this guideline, IV diphenhydramine use is still prevalent in many hospitals that treat persons with SCD. We performed a retrospective, single-center, cohort study comparing rates of oversedation among patients who received IV and oral diphenhydramine for management of opioid-induced pruritus in a large SCD inpatient population. Patients with SCD VOC admitted to an urban hospital between June 1, 2016 to July 30, 2017 were included if they were ≥ 18 years old and received either IV or oral diphenhydramine for OIP. Exclusion criteria: Pregnancy, received <24 hours of diphenhydramine, or <50% of their "as needed" doses of diphenhydramine. Primary endpoint: comparative incidence of oversedation in SCD VOC receiving IV versus oral diphenhydramine. Oversedation was defined as meeting two or more of the following criteria: documentation of oversedation in clinician notes, medication doses held by a nurse due to sedation, a PASERO opioid-sedation score ≤3, or documented hypoxemia with O2 percent saturation ≥ 2 points below baseline. Secondary endpoints included: evaluation of hospital length of stay, amount of diphenhydramine administered per day, indication for IV therapy, and number of days receiving diphenhydramine. Individual admissions were portioned by route of diphenhydramine administration cohorts (IV versus oral). Within each cohort, study endpoints were derived at the patient level. Oversedation was determined at the patient level i.e. experiencing at least one occurrence over the course of their admissions. The number of admissions, length of stay, and days of diphenhydramine treatment were totaled across admissions for each patient. The daily dose of diphenhydramine administration (mg/day) was averaged across the admissions per patient. The proportion of subjects experiencing oversedation was summarized by cohort and compared using Fisher's exact test. Length of stay, number of days on treatment, and average daily dose of diphenhydramine were analyzed with analysis of variance (ANOVA) techniques. Length of stay and number of days on treatment were log-transformed prior to statistical analyses. The number of admissions was analyzed with Poisson regression. Fifty unique patients were included in the analysis representing 121 admissions. Seven patients received both formulations on separate admissions and were included in both groups, 15 received oral diphenhydramine, and 42 received the IV formulation. The percent of patients experiencing oversedation was higher in the IV group, however the difference was not statistically significant (p = 0.312). The average number of admissions was significantly higher in the IV versus oral group (2.45 vs. 1.20; p = 0.005) with average and median length of stay also significantly higher in the IV versus oral group (30.57, 16.0 vs. 10.67, 10.0; p = 0.003). Similarly, the average and median number of days on diphenhydramine treatment in the IV group was significantly higher than in the oral group (28.79, 14.5 vs. 9.73, 7.0; p = 0.001). The average daily dose of diphenhydramine was similar in the two cohorts with no compelling indications documented for use of IV over oral formulation. In summary, while we did not find a statistically significant difference in the rates of oversedation with use of IV versus oral diphenhydramine formulations, patients with SCD VOC who received IV diphenhydramine were more likely to have more frequent admissions, and a longer length of stay. These findings have clear impact on clinical outcomes and cost of care and clinicians may consider oral diphenhydramine preferentially in appropriate patients over IV administration. Larger, prospective studies are needed to evaluate the absolute risk to benefit ratio between the two formulations particularly among person receiving concomitant parenteral opioid therapy.

Disclosures
Osunkwo: Terumo BCT: Speakers Bureau; Prolog Pharmaceuticals LLC: Consultancy; Novartis Pharmaceuticals LLC: Consultancy, Speakers Bureau. Symanowski:Immatics: Other: Data Safety Monitoring Board; Eli Lily & Co: Other: Data Safety Monitoring Board; Boston Biomedical: Other: Data Safety Monitoring Board ; Five Prime Therapeutics: Other: Data Safety Monitoring Board .