Infectious Diseases

Assessment of rabies immune globulin dose rounding at a university health system

a b s t r a c t

Purpose: Describe a dose rounding strategy for rabies immune globulin (RIG) administration.

Methods: Multicenter, retrospective, observational review of patients that received RIG following an exposure from an animal with potential to transmit rabies infection in one health-system from March 2011 through December 2021. The primary outcome was to describe the RIG dose rounding strategy and population of patients that received RIG rounded to the nearest vial size compared to those that did not. Secondary outcomes evaluated additional costs and RIG international units (IU) wasted that could have occurred (rounded group) or did occur (not rounded group), re-presentation to the ED or primary care provider (PCP) within 7 days due to RIG related complaint, and occurrence of rabies infection. Data collection included patient demographics, exposure informa- tion, and RIG dose administered. Descriptive data and univariate analyses are reported. Cost and RIG IU wasted were calculated for the dosing strategies.

Results: 426 patients were included; 373 (88%) had RIG rounded to the nearest vial size and 53 (12%) did not (mean age 36.1 years +-20.5, 51.6% male, most common exposures were bats [50%], type was bite [58%], and category III exposures [92%]). Those that had RIG rounded were younger and had lower total RIG doses, but similar IU/kg doses to those not rounded. A cost savings of $144,815 and prevention of 40,572 RIG IU wasted was calculated from those patients that had RIG rounded. There was no difference in the rate of re-presentation within 7 days and no cases of human rabies infection in the region during the study period.

Conclusions: RIG dose rounding to the nearest vial size is associated with cost savings and prevention of wasting RIG IU. There was no association with re-presentation to the ED or PCP with RIG related issues within 7 days from administration.

(C) 2022

  1. Introduction

Rabies virus is a Lyssavirus that causes a severe encephalitis in humans; it is responsible for an estimated annual 59,000 human deaths globally, primarily from transmission from dogs [1]. Once symptoms manifest, the disease is nearly universally fatal. However, prompt ad- ministration of rabies post-exposure prophylaxis (PEP) is nearly 100%

* Corresponding author at: Departments of Pharmacy and Emergency Medicine, University of Rochester Medical Center, 601 Elmwood Ave., Box 638, Rochester, NY 14642, United States of America

E-mail addresses: [email protected] (N.M. Acquisto), [email protected] (E. Uttaro), [email protected] (D. Debona), [email protected] (F.S. Minhaj).

effective at preventing disease. PEP following rabies exposure generally involves wound care, and administration of rabies vaccine and rabies immune globulin (RIG). RIG is administered into the bite wound and in- tramuscularly (IM) at the same time as the first dose of vaccine, or if un- available, within 7 days of the first rabies vaccine [2,3]. Specifically, RIG provides passive immunity until rabies virus neutralizing antibody (RVNA) production occurs following completion of the rabies vaccina- tion series. RIG derived from human blood (HRIG) is the only product used in the United States (US) and the usual dose is 20 international units (IU)/kg [4]. It is dosed based on actual body weight (ABW) and is infiltrated into and around the wound as much as anatomically feasi- ble. The remainder of the dose (or the entire dose if there is no wound) is recommended to be administered IM (single or multiple injections depending on the volume to be administered) at a distant site in the

https://doi.org/10.1016/j.ajem.2022.05.059

0735-6757/(C) 2022

deltoid or anterolateral thigh in the opposite limb from vaccine admin- istration.

There are several HRIG products available in the US in 150 IU/mL and 300 IU/mL concentrations with different diluent requirements. Available vial sizes are 1 mL, 2 mL, 5 mL, and 10 mL depending on the product. At our organization we have 150 IU/mL and 300 IU/ mL concentrations with vial sizes containing 300 IU and 1500 IU. Since RIG is a human derived product, there are inherent national shortages that occur. Also, RIG cost is about $1200 to $6500 per course to the patient or insurance companies [5]. Although there are dose sparing strategies for rabies vaccine and RIG for resource preservation recommend by the World Health Organization (WHO) (e.g., reduced vaccine schedules, intradermal instead of IM administration for vaccines for reduced volume adminstration, wound infiltration only for RIG administration), these are not rec- ommended by the Advisory Committee on Immunization Practices (ACIP) within the US Centers for Disease Control and Prevention (CDC) [3,6-8]. Also, RIG is unavailable in many countries with en- demic human rabies [9]. Given these considerations it would be both resource and cost conscious to round RIG to the nearest vial size to prevent waste.

In April 2017, the Departments of Emergency Medicine, Infectious Diseases, and Pharmacy at our organization developed and imple- mented an automatic rounding of 20 IU/kg to the nearest vial size for RIG in our electronic medical record (EMR) throughout the health- system as a collaborative cost reduction strategy (Table 1). Rounding of RIG was often being performed manually by the pharmacist reviewing the medication order prior to the automatic change. This standardized and automatic change was made with thoughtful consid- eration of the very low national rabies rate (1-3 human cases per year) following rabies elimination of the dog-mediated rabies virus variant from the US in 2007 [10,11]. Furthermore, timely wound care to decrease inoculum at the site and prompt vaccination are highly effective [1].

The purpose of this study was to describe a dose rounding strategy for RIG to the nearest vial size that may reduce the number of medica- tion vials used per patient and prevents any wasting of RIG IU. There have been no other reports of RIG dose rounding to the nearest vial size available in the literature to our knowledge.

  1. Methods
    1. Study design and setting

This is a multi-center, retrospective, observational study evaluating patients that received RIG at doses rounded and not rounded to the nearest vial size following exposure from an animal with the potential to transmit rabies infection. Patients from three emergency depart- ments (EDs) in separate hospitals and one free standing ED, all within the same health-system, were included for evaluation. The flagship hos- pital is an urban 886-bed university teaching hospital with greater than 115,000 annual ED patient visits and was the first to go live with an EMR on March 5, 2011. The other two hospitals are a community teaching hospital with 261 beds (EMR go-live June 11, 2011) and a rural commu- nity hospital with 113 beds (EMR go-live February 3, 2019). The free- standing ED opened August 2014 (EMR go-live August 1, 2014) and cares for approximately 18,000 ED patients annually. This study met federal and University criteria for exemption by the organization’s Re- search Subjects Review Board.

    1. Patient selection

Any patient that received a dose of RIG in the ED within the health- system documented in the EMR on the medication administration re- cord between March 5, 2011 through December 31, 2021 were in- cluded. Patients were excluded during screening if they did not have a documented weight or if the risk of rabies was deemed not a concern by investigators based on the exposure type. For example, patients that reported a bat in the room while conscious and had no contact, but received RIG, were excluded. However, cases were included as a possible contact if there was report of a bat in the room but uncertainty of contact due to situations such as a deeply sleeping person awakens to find a bat in a room or a bat in a room with a previously unattended child, mentally disabled person, or intoxicated person [3].

    1. Study outcomes

The primary outcome was to describe the RIG dose rounding strat- egy and population of patients that received RIG rounded to the nearest

Table 1

Rabies Immune Globulin Dose Rounding to the Nearest Vial Size(s) in the Electronic Medical Record

patient weight

Calculated Dose Lower Threshold

Calculated Dose Upper Threshold

Rounded Dose to Nearest 300 IU

Vials/Combination of Vials

(kg)

(IU)

(IU)

(IU)

Administered

< 14.9

< 300

20 IU/kg

Exact calculated IU

15 to 20

300

400

300

1 x 300 IU

20.5 to 35

401

700

600

2 x 300 IU

35.1 to 50.9

701

1019

900

3 x 300 IU

51 to 65

1020

1300

1200

4 x 300 IU

65.1 to 82

1301

1640

1500

1 x 1500 IU

82.1 to 97

1641

1940

1800

1 x 300 IU

97.1 to 113

1941

2260

2100

1 x 1500 IU

2 x 300 IU

113.1 to 127

2261

2540

2400

1 x 1500 IU

3 x 300 IU

127.1 to 143

2541

2860

2700

1 x 1500 IU

4 x 300 IU

1 x 1500 IU

143.1 to 157

2861

3140

3000

2 x 1500 IU

157.1 to 172

3141

3440

3300

1 x 300 IU

172.1 to 187

3441

3740

3600

2 x 1500 IU

2 x 300 IU

187.1 to 202

3741

4040

3900

2 x 1500 IU

3 x 300 IU

202.1 to 222

4041

4440

4200

2 x 1500 IU

4 x 300 IU

> 222

>4440

Manually rounded

2 x 1500 IU

Abbreviation: IU = international units.

vial size compared to those that did not have dose rounding performed. Rounding was determined if there was any change to the nearest vial size compared to the calculated dose based on the patient’s ABW multi- plied by the RIG dose of 20 IU/kg.

Secondary outcomes evaluated the cost and IU wasted of RIG in pa- tients with no dose rounding occurring (any percentage different from the exact 20 IU/kg dose). In those where rounding did occur, cost that would have been incurred and IU that would have been wasted had rounding not been performed were calculated. Although this study was underpowered to detect the incidence of rabies infection and asso- ciation with RIG dose (rounded or not rounded), the US annual rabies summary was reviewed to identify any human cases in our state and re- gion during the study period [12].

    1. Data collection

Data were extracted electronically from the EMR. Variables included age, sex, weight, RIG dose administered (total IU and IU/kg ABW), and if the rabies vaccine was administered. Manual inspection of the RIG doses administered were performed to determine which doses were rounded and which were not. Rounding to the nearest vial size resulting in a dose less than 90% and greater than 110% from the calculated dose are reported.

A manual review of the EMR to collect the time from exposure to ED presentation, type of animal related to the exposure, type of exposure (bite, scratch, lick, or confirmed contact or possible contact if it did not fit into one of the bite/scratch/lick categories), category of exposure (I, II, or III), and re-presentation to the ED or primary care provider (PCP) within 7 days for an RIG related issue (not vaccine) was completed. Con- firmed contact, for example, was in the case of a bat flying into a person whereas possible contact was a bat in the room but uncertainty of con- tact as discussed above in the exclusion criteria. The exposure categories were: Category 1 – touching or feeding, licks on intact skin, Category II – nibbling uncovered skin, minor scratches or abrasions without bleeding, Category III – single or multiple transdermal bites or scratches, licks on broken skin, contamination of mucous membrane with saliva from licks, contact with bats [13]. These details were found in the clinician, nursing, or social work progress notes in the EMR. Evaluation of re- presentation to the ED or PCP was evaluated in our organization’s EMR, but also in the regional health information exchange system.

Manual data collection was performed by two investigators using a data dictionary and entered into a standardized data collection form in Excel (Microsoft Corporation, Redmond, WA). Training led by a third in- vestigator was completed prior to the start of data collection and this in- vestigator reviewed the EMR when questions or clarifications were necessary to reduce variability in data collection. Electronically captured data were validated during manual data collection and any data points missing from the electronic data capture were manually collected.

    1. Data analysis

Data are reported descriptively as effect estimates with dispersion. Comparisons between patients that had RIG rounded to the nearest vial size to those that did not were analyzed with univariate methods. Specifically, the Wilcoxon Rank Sum test was used for continuous vari- ables and Chi-Squared analysis or Fisher’s Exact Test for dichotomous variables, as appropriate.

Direct cost and IU saved or wasted were calculated for the rounded and not rounded dose groups. The average wholesale prices (AWP) were obtained from our organization in April 2022; 300 IU/2 mL (150 IU/mL) $1034.44, 1500 IU/10 mL (150 IU/mL) $4083.89, 300 IU/1 mL (300 IU/mL) $804.53, 1500 IU/5 mL (300 IU/mL) $4022.63 or $804.53

per 300 IU. We converted our RIG stock to the more concentrated 300 IU/1 mL and 1500 IU/5 mL vials at the end of 2018 and beginning of 2019. To be more conservative with our cost estimates in this evalua- tion, we used the 300 IU/mL concentration pricing compared to the

150 IU/mL concentration pricing for the entire cohort since it is lower. All cost calculations were based on rounding to the nearest 300 IU/mL ($804.53 per 300 IU).

In the rounded patients, the cost and IU saved by this strategy are cal- culated as such:

      • Human-derived RIG 20 IU/kg x ABW = Total calculated RIG IU
      • Total calculated RIG IU – rounded RIG dose administered = + or – IU
      • Example rounded down: if the patient weighs 80 kg and received 1500 IU.
  • 20 IU/kg dose x 80 kg = 1600 IU, rounded down to 1500 IU (1 x 1500 IU vial).
  • 1600 IU – 1500 IU = + 100 IU.
  • If 1600 IU were administered (dose rounding did not occur), an ad- ditional 300 IU vial would have been used for the extra 100 IU (1 x 300 IU vial and 1 x 1500 IU vial), therefore an additional $804.53 for the 300 IU vial and 200 IU would have been wasted (not admin- istered to the patient).
      • Example rounded up: if the patient weighs 100 kg and received 2100 IU.
  • 20 IU/kg dose x 100 kg = 2000 IU, rounded up to 2100 IU (2 x 300 IU vials and 1 x 1500 IU vial).
  • 2000 IU – 2100 IU = – 100 IU
  • If 2000 IU were administered, no difference in cost since the same vial sizes would be used (2 x 300 IU vials and 1 x 1500 IU vial), but 100 IU would have been wasted (not administered to the patient).

In the not rounded patients, the additional cost and IU wasted from partial vials used are reported. Calculations were performed in the same fashion as above using what would have been administered had rounding occurred (Table 1) to calculate additional vials used and IU wasted.

  1. Results
    1. Study subjects

A total of 441 patients were screened; 426 patients were included during the study period and 15 excluded (Fig. 1). Mean age was 36.1 years +-20.5, 51.6% were male, and the most common exposures were related to bats (50%) and dogs (22%). The type of exposure was most often a bite (58%) or possible contact (31%) and the most common cat- egory of exposure was category III (92%). All patients received rabies vaccination. Patient demographics are detailed in Table 2.

    1. Outcomes

Three hundred and seventy-three (87.6%) patients had the RIG dose rounded to the nearest vial size and 53 (12.4%) did not. Patients in the not rounded group were younger and weighed less than in the rounded group (Table 2) which is expected since calculated doses of 300 IU and less are not rounded by our automatic rounding strategy (Table 1). Since ABW was lower in the not rounded group, the total RIG dose was lower as well, however the IU/kg RIG dose was not statistical different be- tween those patients in the rounded and not rounded groups (Table 2). There were 180 cases in the 373 patients that had their doses rounded down to the nearest vial size and 193 cases where the dose was rounded up. Doses were rounded down a median of 77 IU (IQR 42-115 IU) (n = 180/373) and rounded up a median of 76 IU (IQR 40-113 IU) (n = 193/373). Overall, 15/373 (4%) of patient had a dose administered that was less than 90% (< 18 IU/kg) and 50/373 (13%) of patients had a dose administered that was greater than 110% (> 22

IU/kg) of the calculated dose.

Fig. 1. Patient screening

The doses rounded down corresponds to 180 vials of RIG 300 IU not used, resulting in a direct cost savings of $144,815. If the dose had not been rounded down in these patients, 40,572 RIG IU would have been

wasted from partial vial use. There were 21 cases in the 53 patients that did not have their doses rounded where the dose would have been rounded down, saving 21 x 300 IU vials and $16,895. From partial

Table 2

Patient demographics.

Variable

Total Population (n = 426)

Rounded (n = 373)

Not Rounded (n = 53)

p-value

Age, mean years +- SD

36.1+-20.5

37.4+-19.8

26.8+-23.1

<0.01

Sex, n (%)

Male

220 (51.6)

194 (52.0)

26 (49.1)

0.69

Female

206 (48.4)

179 (48.0)

27 (50.9)

Weight, mean kg+-SD

73.2+-26.1

76.0+-24.1

53.8+-31.6

<0.01

Days from animal exposure to presentation, median days (IQR)

0 (0-1)

0 (0-1)

0 (0-2)

0.80

Animal, n (%)

Bat

215 (50.1)

183 (49.1)

32 (60.4)

0.20

Dog

94 (22.1)

85 (22.8)

9 (17.0)

Cat

58 (13.6)

54 (14.5)

4 (7.5)

Racoon

43 (10.1)

38 (10.2)

5 (9.4)

Fox

6 (1.4)

6 (1.6)

0 (0)

Skunk

2 (0.5)

1 (0.3)

1 (1.9)

Other

Type of Exposure, n (%) Bite

8 (1.9)

247 (57.9)

6 (1.6)

225 (60.3)

2 (3.8)

22 (41.5)

0.01

Possible contact

131 (30.7)

110 (29.5)

21 (39.6)

Confirmed contact

25 (5.9)

21 (5.6)

4 (7.5)

Scratch

15 (3.5)

13 (3.5)

2 (3.8)

Lick

Category of Exposure, n (%) I

8 (1.9)

31 (7.3)

4 (1.1)

23 (6.2)

4 (7.5)

8 (15.1)

0.20

II

2 (0.5)

2 (0.5)

0 (0)

III

RIG Dose

391 (91.8)

346 (92.8)

45 (84.9)

Median IU (IQR)

1500 (1200-1800)

1500 (1200-1800)

1260 (300-1500)

<0.01

Mean IU/kg+-SD

20.3+-1.7

20.3+-1.7

20.0+-1.1

0.47

Abbreviations: SD = standard deviation, IQR = interquartile range, RIG = Rabies immune globulin, IU = international units.

vials used in this group (from not being rounded down or up), a total of 11,557 RIG IU were wasted (not administered to patients).

Three patients in the rounded group (2 rounded up and 1 rounded down) and zero patients in the not rounded group re-presented to the ED (no patients presented to the PCP) with possible issues related to RIG administration within 7 days (p = 1.00). One patient presented 3 days later with lumbar back pain and decreased sensation in left hand (location of injury), one patient presented the following day with dizzi- ness/weakness/pins and needles throughout body, and one patient pre- sented one day later with abdominal pain and leg cramps and three days later with leg tingling and numbness (location of injury). There was one human rabies infection case in the state in 2011, however no cases in our region during the study period.

  1. Discussion

This study sought to describe a RIG dose rounding strategy to the nearest vial size to reduce Healthcare costs of expensive PEP and prevent waste with a sometimes resource limited medication. The majority of patients during our study period had their RIG dose rounded to the nearest vial size resulting in cost savings and prevented wasting RIG IU. There was no association with the RIG dose rounding strategy and re-presentation to the ED or PCP due to an RIG related event within 7 days and no patients had rabies infection, although the study is under- powered to detect an association.

Currently, the ACIP within the US CDC does not support any RIG con- servation strategies and recommends RIG administered at the exact cal- culated dose based on ABW [3]. While it has been shown in a case series of 17 patients exposed to rabies by wolf bite that RIG administration was lifesaving compared to vaccine alone (2/5 treated with vaccine alone survived vs. 11/12 treated with vaccine and antirabies serum sur- vived) [14], this current study is suggesting a strategy that rounds RIG to the nearest vial size or 300 IU and is not suggesting that RIG be excluded from PEP.

Alternatively, the WHO endorses using only a sufficient quantity of RIG for wound infiltration as a resource savings measure; a strategy that may have a more dramatic decrease in vials administered and re- sultant cost savings in some cases [15]. Studies have shown that IM RIG administration does not produce acceptable systemic protection and focusing on infiltration of RIG into the wound is most important [16-18]. A classic study evaluating rabies antiserum administration in deep puncture wounds in guinea pigs found that IM injection provides little or no protection compared to infiltration, deep flushing, or a com- bination of deep flushing and swabbing [16]. An experiment of equine RIG administration in normal, overweight, and obese subjects found that IM administration of RIG in the deltoid or gluteal area did not result in acceptable antibody titers at 24 and 48 h in all body weight groups in either administration area [17]. A case series of five children with mul- tiple and extensive bites on their face and head report failures of rabies PEP and attributed theses failures to inadequate RIG infiltration at the wound sites [18]. A clinical application of this recommendation is de- scribed in a study of 269 patients with category III exposures treated with equine RIG proportionate to the size and number of wounds and not dependent of their body weight (none required greater than their calculated weight-based dose) along with rabies vaccination [19]. This resulted in 42 vials of 5 mL of RIG administered instead of 363 vials and all patients were healthy following a 9-month observation period. These reports highlight that a strategy more focused on infiltration of RIG to the wound(s) compared to ensuring administration of the exact weight-based dose (by infiltration, infiltration and IM injection, or IM injection if no wound) may be more clinically appropriate. The po- tential variability of the actual RIG weight-based dose administered with an infiltration only strategy and data showing poor absorption with IM administration provides some confidence that rounding to the nearest vial size, as was done in our study, is likely not detrimental to patient outcome.

There are different dose rounding strategies suggested in the litera- ture for high-cost medications [20]. These strategies include rounding to the nearest vial size if the dose is within 10% of the calculated dose, rounding down to the nearest vial size if the rounded dose is within 5-10% of the calculated dose, or rounding to the nearest vial size incre- ment (as our study suggests). Dose rounding biologic agents within 10% of the ordered dose is an accepted practice and supported by the Hema- tology/Oncology Pharmacy Association for anti-cancer agents [20]. Pub- lications related to biologic and Cytotoxic agents rounded to the nearest vial size have shown significant annual cost savings for these expensive medications [20].

Rounding RIG to the nearest vial size is recommended in one other publication [21], however to our knowledge there are no other reports of RIG dose rounding similar to ours. Although intended to evaluate RIG guideline adherence and not a dose rounding strategy, one study used administered doses within 10% of the recommended 20 IU/kg cal- culated dose as the threshold for guideline adherence [22]. In this study, 219/223 (98%) patients received an RIG dose within 10% of the calcu- lated dose. This is similar to our findings with 411/426 (96%) patients receiving a dose within 10% of the calculated dose. Furthermore, they report 28 doses rounded to the nearest vial size (24 rounded down and 4 rounded up), whereas our study reports 373 doses rounded to the nearest vial size.

Since we report both rounding up in addition to rounding down to the nearest vial size, some patients received more RIG than the calcu- lated dose. It is suggested by the CDC that RIG might suppress active production of rabies virus antibody following vaccination and no more than the recommended RIG dose should be administered [4]. However, seroconversion still occurs with vaccination following RIG administration in obese patients (body mass index >30 kg/m2 with higher overall doses than control patients [body mass index <25 kg/m2]) and with double the HRIG dose (up to 40 IU/kg) making rounding RIG up to the nearest vial size, and most often within 10% of the calculated dose, less concerning with regards to suppressing RVNA production [23,24]. An observational study assessing humoral immune response following rabies vaccine and equine RIG adminis- tration of obese compared to control patients (as defined above) reported similar serum RVNA responses at days 7, 14, and 28 between groups [23]. Seroconversion to an adequate concentration deemed by the WHO of RVNA titer >=0.5 IU/mL was 100% at days 14 and 28 for both groups. Furthermore, at 14 and 28 days the RVNA Geometric mean titers were 9- and 15-fold higher, 4.6 IU/mL (95% CI 3.2, 6.6]) and 7.45 IU/mL (5.9, 9.5), respectively, than the accepted threshold (0.5 IU/mL) in the obese group. It is important to note that these stud- ies used the more conservative WHO cutoff of 0.5 IU/mL and not the ACIP cutoff of complete neutralization at 1:5 (equating to ~0.1-0.3 IU/mL) [3]. In the HRIG dose finding study evaluating RIG doses of 10, 20, and 40 IU/kg, HRIG doses administered up to 40 IU/kg (200% of the now accepted dose) with vaccination still elicit a RVNA response to vaccine [24]. These data support that a rounding up strategy does not limit adequate response to PEP vaccination. Also, rounding up to the nearest vial size in our study rarely resulted in a dose exceeding 110% of the calculated dose.

The cost of treating rabies exposure is estimated to be $245 to $510 million dollars annually and an estimated that 55,000 Americans re- ceive rabies PEP every year [5]. Obviously, there are limitations with ex- trapolating data, however, if all of those patients receive RIG and half have the dose rounded down (similar to our study 180/373 [49%] rounded down, which is a conservative estimate compared to Hwang SG, et al. [24 rounded down (86%) and 4 rounded up (14%)]) [22], this could result in approximately 27,500 of the 300 IU vials saved equating to $22 million in potential direct healthcare cost savings annually. Sep- arately, both round down or up would prevent RIG IU wasted. A conser- vative estimate, preventing 100 IU wasted for each patient dose, from rounding up or down could result in preventing at least 5.5 million RIG IU wasted annually.

Our analysis has limitations, the first being the generalizability of results due to a single health-system evaluation. Although we would not expect rabies PEP to be too different within the US, practices may be different in countries where rabies infection is endemic. Due to the rarity of human rabies infection in the US, it would be impossible to include an adequate sample size of patients to determine an asso- ciation or lack thereof of RIG dose rounding strategies and rabies in- fection. A study like this would need to be performed on a global level. However, given the scant number of human rabies cases in the US and significant cost to the healthcare system, this seems a rea- sonable option for conservation of cost and resources. Cost calcula- tions were performed using present day AWP of RIG vials and does not represent the cost at the time of administration. This also does not account for contract pricing or cost of goods sold discounts and may be an overestimate of the actual cost to the organization or pa- tient. Cost considerations only included direct costs of a reduced dose. It did not incorporate increased costs secondary to preparation, carrying, time, or administering the dose. Also, due to the retrospec- tive nature of the study we relied on the medication administration record for the RIG dose administered. It is possible, that a clinician may not have used the entire RIG dose ordered due to patient refusal of multiple injections or inability to administer the entire ordered volume and unused vials were returned to the refrigerator or phar- macy but not altered in the documentation on the medication ad- ministration record. This would have reduced the cost for that dose, but could not be accounted for in our study.

Although we included an over 11-year period, not all of the EDs were live on the EMR for the entire study period and therefore there are pa- tients that received RIG that were not included in this study and may alter the findings. Not including these patients likely reduced our effect size related to cost and IU wasted calculations, but it is possible this would have impacted the outcome related to ED re-presentation to the ED or PCP for an RIG related issue within 7 days. Re-presentation to the ED or PCP was used as a surrogate for potential RIG related issues that may be associated with administering a slightly higher RIG volume (0.1-1 mL in most cases) per dose in those patients that had the dose rounded up. There is potential that patients re-presented to an ED or PCP outside of the region were not captured in the health information exchange system or discussed RIG issues with the Department of Health during vaccine follow up and these results in our study are underreported. Due to the retrospective nature of the study, informa- tion regarding vaccine titers are not available to assess if there are titer response differences in the setting of rounding the RIG dose up to the nearest vial size. Regardless, most patients in this study (87%) did not receive a rounded dose that was greater than 110% of the calculated dose and as such would not expect RVNA production to be suppressed. As healthcare systems are looking for collaborative strategies for cost reduction, our study describes an RIG dose rounding strategy that is an easily implemented change that could be coordinated between emer- gency medicine, infectious diseases, and pharmacy that would have an immediate impact to reduce cost to patients and the healthcare system and preserve expensive medications. This contrasts with other labor- intensive strategies such as optimizing logistics of multiple repeat visits for vaccinations, improving the accuracy of rabies exposure assessment for the purpose of reducing unnecessary treatment, or implementing a 10% reduction dose strategy along with rounding to the nearest vial size that could create a greater cost savings for patients with higher

ABW.

  1. Conclusions

RIG dose rounding to the nearest vial size is associated with cost savings and prevention of wasting RIG IU. There was no association with re-presentation to the ED or PCP with RIG related issues within 7 days from administration.

Source of support

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Prior presentations

None.

CRediT authorship contribution statement Nicole M. Acquisto: Writing – original draft, Supervision, Project ad-

ministration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Elizabeth Uttaro: Writing – review & editing, Methodology, Formal analysis, Data curation, Conceptualiza- tion. Darlene Debona: Writing – review & editing, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Faisal

S. Minhaj: Writing – review & editing, Methodology, Investigation, Formal analysis, Data curation, Conceptualization.

Declaration of Competing Interest

NMA, EU, DD and FSM have no conflicts of interest to report.

Acknowledgements

Eric Kanouse, Pharm.D.; Bryan Neary, MPA

References

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