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Frequency of Severe Infusion Reactions Associated With Outpatient Infusion of Infliximab Without Premedications

Hutsell, Stephanie Q.*; Wu, May*; Park, K.T.

Journal of Pediatric Gastroenterology and Nutrition: October 2017 - Volume 65 - Issue 4 - p 430–431
doi: 10.1097/MPG.0000000000001535
Short Communications: Gastroenterology: Inflammatory Bowel Disease

ABSTRACT In this report, we describe incremental changes, during a 2-year period at a single center with the administration of maintenance infliximab infusions. Given practice-driven changes consisting of 1-hour infusions and omission of premedications, we aimed to investigate if these changes contributed to severe infusion reactions. We reviewed approximately 900 infliximab infusions in a pediatric ambulatory infusion center from January 1, 2014, to December 31, 2015, for severe adverse reactions requiring either rescue epinephrine or a code blue or “rapid response” activation. In 2015, these practice changes resulted in a 51% decrease in total infusion hours (1281 to 630 infusion hours), despite a 9% increase in total number of infusions. No increase in severe adverse events associated with either rapid 1-hour infusion or omission of premedications. Our findings highlight a quality-improvement opportunity to standardize infliximab infusions to streamline care in an ambulatory setting.

*Department of Pharmacy, Lucile Packard Children's Hospital, Stanford

Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA.

Address correspondence and reprint requests to K.T. Park, MD, MS, Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA 94304 (e-mail:

Received 28 October, 2016

Accepted 23 January, 2017

K.T.P. is supported by National Institutes of Health (DK094868) for this research.

K.T.P. also received research support from AbbVie, Janssen, and Takeda, but not directly pertaining to this research.

The authors report no conflicts of interest.

What Is Known

  • Rare, severe adverse reactions have happened with infliximab administration in children with inflammatory bowel disease.
  • There is poor strength of evidence for the use of premedications, especially antihistamines, in preventing infliximab-related reactions.
  • It is unknown whether rapid infliximab administration (≤1 hour) is associated with higher risk of severe reactions.
  • What Is New Findings
  • During a 2-year review period, practice-driven changes included 1-hour infliximab administration and omission of premedications in children with inflammatory bowel disease.
  • In a 1-year review, these 2 changes resulted in a 51% decrease in total infusion hours (1281 to 630 infusion hours), despite a 9% increase in total number of infusions.
  • There were no epinephrine administrations or code blue/rapid response calls associated with severe reactions to infliximab in 2014 or 2015.

Infliximab is a chimeric monoclonal antibody targeting tumor necrosis factor alpha (TNF-α). It is a mainstay of therapy for children with inflammatory conditions such as Crohn disease, ulcerative colitis, and rheumatoid arthritis (1–8). As with all biologic therapies, infliximab is associated with the potential, although rare, to cause severe infusion related hypersensitivity reactions including anaphylaxis (4). Medications, such as antipyretics, antihistamines, and corticosteroids, are often administered before infusion to prevent such reactions (1–3). It is known that premedications have some benefit in reducing infusion reactions once an instigating event has occurred; however, it is unclear whether premedicating in the absence of an infusion reaction serves any additional benefit (1–3). Recent studies in adults reveal an increased risk of infusion reaction in the setting of premedications, especially antihistamines like diphenhydramine (2). In addition, there is poor strength of evidence describing which patients are at risk for severe infusion reactions, and there is high variability in current standard-of-care regarding premedications (9). We observed practice variation regarding the use of premedications and the infusion rate of infliximab at our institution and investigated the consequences.

In this study, we aimed to determine the variability in the standard of care that may be associated with increased risk of an adverse reaction during an infliximab infusion, and the number of patients receiving rescue epinephrine and/or rapid response/code blue events as the result of a reaction to infliximab infusion.

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We performed a review of ambulatory maintenance infliximab infusions between January 1, 2014, and December 31, 2015. Hospital-wide longitudinal data were available from a total of 427 infusions in 2014 and 466 infusions in 2015, representing a total of 123 unique patients (Cerner, Kansas City, MO; Epic, Madison, WI). This study was approved by the Stanford University Human Subjects Research Committee. The patient demographics are summarized in Table 1 and represent 2 distinct pediatric divisions, rheumatology (Rheum) and gastroenterology, hepatology, and nutrition (GI). This information was cross-referenced with electronic pharmacy records of epinephrine removal and return from the automated dispensing cabinets (Pyxis, Franklin Lakes, NJ; Omnicell, Mountain View, CA). Of note, there were 3 epinephrine removals during the 2-year review; none of these removals are documented as administered to the patient, and the automated dispensing cabinet data confirm the return of the medication. Data collected by the hospital code committee regarding rapid response and code blue calls were analyzed for significant events involving patients receiving infliximab infusions. At our institution, any reaction to infliximab requiring evaluation by an attending physician at the ambulatory setting would require escalation to a rapid response or code blue call. The data regarding unplanned diphenhydramine and/or hydrocortisone administration are unavailable.



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During the 2-year review period, 2 significant practice changes occurred regarding ambulatory infliximab infusions. In 2015, in light of emerging evidence, the gastroenterology service converted to a 1-hour infliximab infusion from 3-hour infusions (10–13), whereas the rheumatology maintained their infusions at 3 hours. Also in 2015, 1 gastroenterology provider omitted premedications from all infliximab infusions. For a 1-year time span, these changes resulted in a 51% decrease in total infusion hours (1281 to 630 infusion hours), despite a 9% increase in total number of infusions. One hundred eleven infusions were administered without premedications, representing 22 patients. There were no epinephrine administrations associated with infliximab maintenance infusions in 2014 or 2015. In addition, there were no code blue/rapid response calls associated with infliximab maintenance infusions (Table 2).



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In our experience, the frequency of severe infliximab infusion reactions requiring epinephrine is very low, and corresponds with recently published literature (1–13). The reported severe reaction frequency is estimated between 0.04% and 1% (1,2,11), and we would have expected approximately between 1 and 9 severe reactions. Infusing infliximab more than 1 hour rather than 3 and omitting standard premedications does not appear to increase the risk for severe infusion reactions. The adult data available support 1 hour infusions for both GI and rheumatologic indications. A meta-analysis by Neef et al (11) reports infusion reactions occurred in 2.2% of standard infliximab infusions, and in 0.9% of 1-hour infusions, without stratifying the reaction type. Our results and the growing body of literature support the omission of premedications without an instigating event. Omission of premedications translates to improved patient experience, shorter length of monitoring, and avoidance of potential adverse drug events. In addition, shortening infusion times presents an excellent opportunity to reduce cost associated with infusions, as non-drug cost constitutes more than 75% of the total health care cost, the highest percentage of that attributing to personnel costs (14). These findings highlight a quality-improvement opportunity to standardize infliximab infusions to streamline care in a pediatric ambulatory setting.

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adverse reaction; infliximab; pediatric; premedications; rapid infusion

© 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,