The use of oral H1RAs and H2RAs have not been studied for paclitaxel premedication regimens, and intravenous premedications are the standard of care. Our study shows no clinical or statistically significant difference in the severity or incidence of HSRs with oral diphenhydramine and famotidine. Institutional standardization resulted in decreased incidence of first and second infusion HSRs, although not statistically significant.
There was an increased use of oral premedications after the numerous interventions and standardization efforts. Oral administration prevents the use of syringe pumps and other means of infusing intravenous medications, improving safety through the ability to precisely time the premedications. This also serves as a cost-saving initiative and results in ease of administration for nursing staff. The cost of premedications can be seen in Table 6 with oral premedication being cheaper than intravenous administration. The multidisciplinary group decided not to move to oral dexamethasone as the only premedication regimens studied for oral dexamethasone are 12 and 6 hours prior to paclitaxel infusions at the time of the study. However, a recent paper by Lansinger et al that looked at steroid premedication in first administration of any type taxane had found no correlation with route or dosing with incidence/severity of HSRs. This paper, in conjunction with our study, may catalyze other institutions to implement entirely oral premedication regimens to aid in reduction in infusion chair time and nursing demand. In addition to removing syringe pumps from infusion areas, the institution developed standard dilution guidelines for IV push medications, including dexamethasone. Due to concerns of perineal pruritis, nursing staff diluted dexamethasone and ran it slowly over a syringe pump. Standardizing the dilution and push time helped alleviate concerns of adverse effects.
Prior to this study, institutional practice required pre-medications for only first dose of weekly paclitaxel, and pre-medications for subsequent infusions were only required if a prior reaction was reported. Our change to requiring pre-medications for first and second doses demonstrated a downward trend in reaction rates. Although the trend is not statistically significant, we believe our sample size post-implementation is not large enough to demonstrate statistical significance. Stopping premedications after the first two infusions without demonstration of reaction in patients may reduce the exposure to systemic glucocorticoids, decreases appointment times/chair time, and aids in convenience of administration of paclitaxel.
The implementation strategy was key to the successful deployment of the interventions. Where possible, the changes were built into workflow processes, removing the need for providers, nursing, or pharmacists to refer to guidelines or policy. To prevent variation in prescribing practices, the oral route was defaulted in the computerized order entry for diphenhydramine and famotidine. Pre-medications for first and second doses were defaulted. Syringe pumps were removed from all infusion areas to prevent use. Nursing staff were educated about all the changes implemented including standard dilution practices. Dedicated nursing education days were used, and competency assessments were completed. A multidisciplinary approach provided a comprehensive outlook of workflow processes and stronger support to implement institutional changes.
Through this retrospective review, a comprehensive review of deviations from our standard practice were performed. There were some patients who received IV premedications in the post-standardization group. This may be explained by legacy order sets with non-standard premedication regimens. Additionally, there may be a subset of patients who are unable to take oral medications, necessitating the need for IV administration. There is a subset of patients in the post-standardization group who did not have documented premedication that may be explained by transferring from an outside institute or re-entry of an order set flagging as a “new” initiation.
A hypersensitivity trigger tool may serve others in identifying and characterizing hypersensitivity for other types of medications. Paclitaxel infusion reactions were flagged when rescue medications were provided to patients after the start of the paclitaxel infusion and confirmed by cross-referencing nursing notes. Nursing documentation is key to ensure the interdisciplinary team’s ability to formulate a plan for the patient, accounting for the severity and management of the HSR. A manual retrospective review was necessary to ensure that the trigger tool reflected a paclitaxel HSR, as paclitaxel is often administered with carboplatin. Carboplatin carries a risk for infusion reactions usually occurring after multiple exposures to the platinum agent.[19, 20] Additionally, this trigger tool is only able to capture infusion reactions grade 2 and above, because of the necessity for administration of an supportive care agent. Overall, using rescue medications as a trigger tool for adverse drug events can be implemented at infusion centers assesses the rates of HSRs to paclitaxel and other agents with unique rescue pharmacotherapeutic agents. This generalization to other medications can help improve workflow processes that may not be easily identified by staff.
There are some limitations to this retrospective trial. Clear documentation was necessary to grade HSRs. Additionally, some treatment plans may have continued past the post intervention date, as an adoption grace period was not implemented. Another limitation is the small sample size of the post-intervention group due to the limited time frame compared pre-implementation group.
In conclusion, this retrospective interventional study demonstrated that same day intravenous dexamethasone, oral H1RA, and oral H2RA is a convenient and safe option for the prevention of paclitaxel HSRs. The study also showed a statistically non-significant decline in 1st and 2nd dose HSRs with the implementation of required pre-medications, improved ability to time pre-medications with the change to oral administration, and cost savings for diphenhydramine, famotidine, and ondansetron. Dropping pre-medications after 2nd dose of weekly paclitaxel may prove useful in decreasing the systemic exposure to corticosteroid. Additionally, there may be a theoretical benefit with the reduction of line manipulations using an oral premedication regimen. Through multidisciplinary collaboration, standardization of order sets, and education prescribing habits were effectively changed. This study demonstrated the usefulness of a trigger tool to identify workflow improvements in paclitaxel, and the possibility of generalization for other medications that are commonly associated with infusion reactions. More studies are needed to further elucidate if these changes could translate to other clinical outcomes such as infection risk or patient satisfaction.