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Figure 1.  Rabies Postexposure Prophylaxis (PEP) Electronic Health Record Enhancements
Rabies Postexposure Prophylaxis (PEP) Electronic Health Record Enhancements

ED indicates emergency department; HRIG, human rabies immune globulin; IM, intramuscular.

Figure 2.  Patient Inclusion Flowchart
Patient Inclusion Flowchart

HRIG indicates human rabies immune globulin; PEP, postexposure prophylaxis.

aPatients who received HRIG or rabies vaccine.

bPatients did not receive HRIG in our health system.

Figure 3.  Full Adherence to Human Rabies Immune Globulin (HRIG) Quality Indicators Following Implementation of Rabies Postexposure Prophylaxis (PEP) Bundle
Full Adherence to Human Rabies Immune Globulin (HRIG) Quality Indicators Following Implementation of Rabies Postexposure Prophylaxis (PEP) Bundle

Circles represent the proportion of patients with full adherence for each year, and whiskers represent 95% CIs. The horizontal dotted line at 37% represents the proportion with full adherence during the entire preimplementation period. Data in 2018 only includes January 2018 through June 2018. One postimplementation patient was treated in December 2019 following bundle implementation and is displayed under 2020. EHR indicates electronic health record.

Figure 4.  Adherence to Individual Human Rabies Immune Globulin (HRIG) Quality Indicators Following Implementation of Postexposure Prophylaxis (PEP) Bundle
Adherence to Individual Human Rabies Immune Globulin (HRIG) Quality Indicators Following Implementation of Postexposure Prophylaxis (PEP) Bundle

Absolute differences in adherence were significant for infiltration into wounds (17%; 95% CI, 5%-30%; P = .009), administration distant from wound site (12%; 95% CI, 2%-22%; P = .04), and administration avoids the buttock (17%; 95% CI, 6%-27%; P = .007).

Table.  Patient Demographics and Characteristics
Patient Demographics and Characteristics
1.
Manning  SE, Rupprecht  CE, Fishbein  D,  et al.  Human rabies prevention–United States, 2008: recommendations of the Advisory Committee on Immunization Practices.   MMWR Recomm Rep. 2008;57(RR-3):1-28. PubMedGoogle Scholar
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World Health Organization.  Rabies vaccines: WHO position paper, April 2018—recommendations.   Vaccine. 2018;36(37):5500-5503. doi:10.1016/j.vaccine.2018.06.061PubMedGoogle ScholarCrossref
3.
US Centers for Disease Control and Prevention. Human Rabies. Updated September 22, 2021. Accessed March 16, 2021. https://www.cdc.gov/rabies/location/usa/surveillance/human_rabies.html
4.
Howington  GT, Nguyen  HB, Bookstaver  PB, Akpunonu  P, Swan  JT.  Rabies postexposure prophylaxis in the United States: opportunities to improve access, coordination, and delivery.   PLoS Negl Trop Dis. 2021;15(7):e0009461. doi:10.1371/journal.pntd.0009461PubMedGoogle ScholarCrossref
5.
Wilde  H, Sirikawin  S, Sabcharoen  A,  et al.  Failure of postexposure treatment of rabies in children.   Clin Infect Dis. 1996;22(2):228-232. doi:10.1093/clinids/22.2.228PubMedGoogle ScholarCrossref
6.
Wilde  H, Lumlertdacha  B, Meslin  FX, Ghai  S, Hemachudha  T.  Worldwide rabies deaths prevention—a focus on the current inadequacies in postexposure prophylaxis of animal bite victims.   Vaccine. 2016;34(2):187-189. doi:10.1016/j.vaccine.2015.11.036PubMedGoogle ScholarCrossref
7.
Wilde  H.  Failures of post-exposure rabies prophylaxis.   Vaccine. 2007;25(44):7605-7609. doi:10.1016/j.vaccine.2007.08.054PubMedGoogle ScholarCrossref
8.
Bharti  OK, Madhusudana  SN, Gaunta  PL, Belludi  AY.  Local infiltration of rabies immunoglobulins without systemic intramuscular administration: an alternative cost effective approach for passive immunization against rabies.   Hum Vaccin Immunother. 2016;12(3):837-842. doi:10.1080/21645515.2015.1085142PubMedGoogle ScholarCrossref
9.
Bharti  OK, Madhusudana  SN, Wilde  H.  Injecting rabies immunoglobulin (RIG) into wounds only: a significant saving of lives and costly RIG.   Hum Vaccin Immunother. 2017;13(4):762-765. doi:10.1080/21645515.2016.1255834PubMedGoogle ScholarCrossref
10.
Madhusudana  SN, Aggarwal  P, Tripathi  KK.  Failure of rabies postexposure treatment with purified chick embryo cell (PCEC) vaccine.   Vaccine. 1989;7(5):478-479. doi:10.1016/0264-410X(89)90185-0PubMedGoogle ScholarCrossref
11.
Chomchay  P, Khawplod  P, Wilde  H.  Neutralizing antibodies to rabies following injection of rabies immune globulin into gluteal fat or deltoid muscle.   J Travel Med. 2000;7(4):187-188. doi:10.2310/7060.2000.00057PubMedGoogle ScholarCrossref
12.
Rupprecht  CE, Briggs  D, Brown  CM,  et al.  Use of a reduced (4-dose) vaccine schedule for postexposure prophylaxis to prevent human rabies: recommendations of the advisory committee on immunization practices.   MMWR Recomm Rep. 2010;59(Rr-2):1-9. PubMedGoogle Scholar
13.
Salva  EP, Dimaano  EM, Villarama  JB, Suquilla  JT.  An evaluation of the safety and potency of equine rabies immunoglobulin through measurements of suppression on vaccine induced antibody production among healthy volunteers.  Philipp J Intern Med. 2014;52(2):1-7.
14.
Jung Kim  H, Hyun Park  S.  Sciatic nerve injection injury.   J Int Med Res. 2014;42(4):887-897. doi:10.1177/0300060514531924PubMedGoogle ScholarCrossref
15.
Kroger  AT, Atkinson  WL, Marcuse  EK, Pickering  LK; Advisory Committee on Immunization Practices.  General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP).   MMWR Recomm Rep. 1994;43(RR-1):1-38. PubMedGoogle Scholar
16.
HyperRab. Package insert. Grifols Therapeutics Inc; 2018.
17.
HyperRab S/D. Package insert. Grifols Therapeutics Inc; 2012.
18.
Kline  DG, Kim  D, Midha  R, Harsh  C, Tiel  R.  Management and results of sciatic nerve injuries: a 24-year experience.   J Neurosurg. 1998;89(1):13-23. doi:10.3171/jns.1998.89.1.0013PubMedGoogle ScholarCrossref
19.
Gilles  FH, French  JH.  Postinjection sciatic nerve palsies in infants and children.   J Pediatr. 1961;58:195-204. doi:10.1016/S0022-3476(61)80158-3PubMedGoogle ScholarCrossref
20.
Bergeson  PS, Singer  SA, Kaplan  AM.  Intramuscular injections in children.   Pediatrics. 1982;70(6):944-948. doi:10.1542/peds.70.6.944PubMedGoogle ScholarCrossref
21.
Hwang  GS, Rizk  E, Bui  LN,  et al.  Adherence to guideline recommendations for human rabies immune globulin patient selection, dosing, timing, and anatomical site of administration in rabies postexposure prophylaxis.   Hum Vaccin Immunother. 2020;16(1):51-60. doi:10.1080/21645515.2019.1632680PubMedGoogle ScholarCrossref
22.
Texas Department of State Health Services Zoonosis Control. Rabies Prevention in Texas. Updated March 3, 2021. Accessed October 26, 2020. https://www.dshs.texas.gov/idcu/disease/rabies/information.aspx
23.
Venkat  A, Hunter  R, Hegde  GG, Chan-Tompkins  NH, Chuirazzi  DM, Szczesiul  JM.  Perceptions of participating emergency nurses regarding an ED seasonal influenza vaccination program.   J Emerg Nurs. 2012;38(1):22-29. doi:10.1016/j.jen.2010.08.015PubMedGoogle ScholarCrossref
24.
Jerrard  DA.  The use of rabies immune globulin by emergency physicians.   J Emerg Med. 2004;27(1):15-19. doi:10.1016/j.jemermed.2004.02.005PubMedGoogle ScholarCrossref
25.
Bookstaver  PB, Akpunonu  P, Nguyen  HB, Swan  JT, Howington  GT.  Administration of rabies immunoglobulin: Improving evidence-based guidance for wound infiltration.   Pharmacotherapy. 2021;41(8):644-648. doi:10.1002/phar.2604PubMedGoogle ScholarCrossref
26.
Meyerhoff  P, Manekeller  S, Saleh  N,  et al.  Rabies post-exposure prophylaxis in Germany—what are the challenges?   Epidemiol Infect. 2021;149:e119. doi:10.1017/S0950268821000601PubMedGoogle ScholarCrossref
27.
Bharti  OK, Thakur  B, Rao  R.  Wound-only injection of rabies immunoglobulin (RIG) saves lives and costs less than a dollar per patient by “pooling strategy”.   Vaccine. 2019;37(suppl 1):A128-A131. doi:10.1016/j.vaccine.2019.07.087PubMedGoogle ScholarCrossref
28.
Suwansrinon  K, Jaijaroensup  W, Wilde  H, Sitprija  V.  Is injecting a finger with rabies immunoglobulin dangerous?   Am J Trop Med Hyg. 2006;75(2):363-364. doi:10.4269/ajtmh.2006.75.363PubMedGoogle ScholarCrossref
29.
Haradanhalli  RS, Kumari  N, Sudarshan  MK, Narayana  DHA, Prashanth  RM, Surendran  J.  Defining the volume of rabies immunoglobulins/rabies monoclonal antibodies requirement for wound infiltration of category III animal exposures—an exploratory study.   Hum Vaccin Immunother. 2021;17(12):5355-5360. doi:10.1080/21645515.2021.2013079PubMedGoogle ScholarCrossref
30.
Agarwal  A, Kumar  P, Mathur  SB, Khan  AM.  Estimating the volume of equine rabies immunoglobulin (eRIG) required for local infiltration in soft tissue animal bites in children using a wound size-based approach.   J Trop Pediatr. 2021;67(4):fmab082. doi:10.1093/tropej/fmab082PubMedGoogle ScholarCrossref
31.
Centers for Disease Control and Prevention. Rabies in the U.S. Updated April 6, 2020. Accessed April 5, 2021. https://www.cdc.gov/rabies/location/usa/index.html
32.
Harrigan  RA, Kauffman  FH.  Postexposure rabies prophylaxis in an urban emergency department.   J Emerg Med. 1996;14(3):287-292. doi:10.1016/0736-4679(96)00023-6PubMedGoogle ScholarCrossref
33.
Moran  GJ, Talan  DA, Mower  W,  et al; Emergency ID Net Study Group.  Appropriateness of rabies postexposure prophylaxis treatment for animal exposures.   JAMA. 2000;284(8):1001-1007. doi:10.1001/jama.284.8.1001PubMedGoogle ScholarCrossref
34.
Texas Department of State Health Services Zoonosis Control. Rabies Prevention in Texas. Updated March 2020. Accessed November 19, 2020. https://www.dshs.texas.gov/IDCU/disease/rabies/information/prevention/Pamphlet/prevention.pdf
35.
Hassan  K, Prescher  H, Wang  F, Chang  DW, Reid  RR.  Evaluating the effects of COVID-19 on plastic surgery emergencies: protocols and analysis from a level I trauma center.   Ann Plast Surg. 2020;85(2S Suppl 2):S161-S165. doi:10.1097/SAP.0000000000002459Google ScholarCrossref
36.
Westgard  BC, Morgan  MW, Vazquez-Benitez  G, Erickson  LO, Zwank  MD.  An analysis of changes in emergency department visits after a state declaration during the time of COVID-19.   Ann Emerg Med. 2020;76(5):595-601. doi:10.1016/j.annemergmed.2020.06.019PubMedGoogle ScholarCrossref
37.
Cordova  LZ, Savage  N, Ram  R,  et al.  Effects of COVID-19 lockdown measures on emergency plastic and reconstructive surgery presentations.   ANZ J Surg. 2021;91(3):415-419. doi:10.1111/ans.16625PubMedGoogle ScholarCrossref
38.
Texas Department of State Health Services Zoonosis Control. Human Cases. Updated May 2, 2022. Accessed May 17, 2021. https://www.dshs.texas.gov/IDCU/health/zoonosis/disease/Human-Cases.aspx
Original Investigation
Emergency Medicine
June 21, 2022

Implementation of Clinical Decision Support on Emergency Department Delivery of Human Rabies Immune Globulin

Author Affiliations
  • 1Department of Pharmacy, Houston Methodist, Houston, Texas
  • 2Department of Surgery, Houston Methodist, Houston, Texas
  • 3Department of Emergency Medicine, Houston Methodist Hospital, Houston, Texas
  • 4Center for Outcomes Research, Houston Methodist, Houston, Texas
JAMA Netw Open. 2022;5(6):e2216631. doi:10.1001/jamanetworkopen.2022.16631
Key Points

Question  Is implementation of a rabies postexposure prophylaxis bundle, consisting of electronic health record enhancements, staff education, and patient education, associated with improved human rabies immune globulin (HRIG) patient selection and delivery in the emergency department?

Findings  In this quality improvement study that included 324 patients, the primary outcome of full adherence to 6 HRIG quality indicators increased from 37% preimplementation to 61% postimplementation.

Meaning  These results suggest that a rabies postexposure prophylaxis bundle was associated with a statistically significant improvement in HRIG patient selection and delivery in emergency departments across a health system.

Abstract

Importance  Fatal human rabies infections can be prevented through appropriate rabies postexposure prophylaxis (PEP). Errors in patient selection and administration of human rabies immune globulin in the emergency department (ED) setting were identified in a previous study of rabies PEP administration.

Objective  To test the a priori hypothesis that implementation of a rabies PEP bundle in the ED would improve full adherence to 6 human rabies immune globulin quality indicators compared with preimplementation controls.

Design, Setting, and Participants  This quality improvement study was conducted in 15 EDs in a US multihospital health system. Patients who received human rabies immune globulin or rabies vaccine in the ED from January 2015 to June 2018 were included in the preimplementation control group and from December 2019 to November 2020 were included in the postimplementation intervention group. Data were analyzed in January 2021.

Exposure  The PEP bundle was implemented in December 2019 and consisted of electronic health record enhancements, including clinical decision support, ED staff education, and patient education.

Main Outcomes and Measures  Full adherence to 6 human rabies immune globulin quality indicators: patient selection, dose, timing, infiltration into wounds, administration distant from rabies vaccine site, and administration that avoids the buttock.

Results  The study included 324 patients; 254 patients were in preimplementation group (mean [SD] age, 39 [21] years; 135 [53%] women) and 70 in the postimplementation group (mean [SD] age, 38 [19] years; 33 [47%] women). Most patients presented to EDs embedded in a community hospital (231 patients [71%]). Full adherence increased from 37% in the preimplementation group to 61% postimplementation (absolute increase, 24%; 95% CI, 11% to 37%; P < .001). Adherence improved for quality indicators for infiltration into wounds (137 of 254 patients [54%] to 50 of 70 patients [71%]; P = .009), administration distant from rabies vaccine site (180 of 254 [71%] to 58 of 70 [83%]; P = .04), and administration that avoids the buttock (168 of 254 [66%] to 58 of 70 [83%]; P = .007). No instances of sciatic nerve injury or compartment syndrome were observed.

Conclusions and Relevance  In this quality improvement study, implementation of a rabies PEP bundle was associated with improved patient selection and delivery of human rabies immune globulin in EDs across a multihospital health system. Although the bundle included ED staff education and patient discharge education, the observed improvement was likely driven by clinical decision support from the rabies PEP ED order set. Future research should evaluate implementation of this clinical decision support at other health systems.

Introduction

Human rabies infection is almost always fatal if clinical symptoms develop following exposure to a rabid animal. Fortunately, infection can be prevented through appropriate rabies postexposure prophylaxis (PEP) that consists of wound cleansing, administration of human rabies immune globulin (HRIG), and administration of rabies vaccine.1,2 An estimated 30 000 to 60 000 patients initiate rabies PEP each year in the US.3 A single administration of HRIG provides an immediate supply of virus-neutralizing antibodies while the body is developing active immunity from the rabies vaccine series. Since rabies is a rare disease and HRIG is a high-cost medication, HRIG is rarely stocked in non–emergency department (ED) facilities in the US. Therefore, patients are commonly referred to the ED for evaluation and initiation of rabies PEP, including HRIG; thus, ED staff should be proficient in appropriate HRIG patient selection and delivery.4

Human rabies infection can occur if rabies PEP is not given appropriately.1,5-7 Because intramuscular administration of HRIG results in low systemic antibody levels that may not confer protection, infiltration of HRIG into and around wounds, if anatomically feasible, is critical to provide effective passive immunity.2,5,7-11 Administration of HRIG and rabies vaccine into the same muscle group may attenuate the effect of the vaccine.12,13 Administration of HRIG into the buttock can cause sciatic nerve injury.14-20 Therefore, we previously identified 3 opportunities to improve delivery of HRIG in the ED: (1) increase the proportion of patients who receive HRIG infiltration of wounds, (2) avoid administration of HRIG and rabies vaccine into the same muscle group, and (3) avoid HRIG administration into the buttock area.21

A pharmacist-led research team developed and implemented a rabies PEP bundle consisting of electronic health record (EHR) enhancements, ED staff education, and patient education in 15 EDs across a health system. The objective of this quality improvement study was to test the hypothesis that implementation of a rabies PEP bundle in the ED would improve full adherence to 6 HRIG quality indicators compared with preimplementation controls.

Methods
Study Design and Setting

This pre-post quality improvement study was conducted in 15 EDs of a multihospital health system, which includes 1 academic medical center, 6 community hospitals, and 8 freestanding emergency care centers staffed by board-certified physicians, in Houston, Texas. During the study period, HRIG 150 IU/mL and 300 IU/mL (Grifols Therapeutics), rabies human diploid cell culture vaccine (Sanofi Pasteur), and rabies chick embryo cell–derived vaccine (GlaxoSmithKline) were used. The study was approved by the Houston Methodist health system’s institutional review board, and a waiver of informed consent was granted for this minimal risk study. The study was registered at ClinicalTrials.gov (identifier NCT04213950) prior to bundle implementation. This study adhered to revised Standards for Quality Improvement Reporting Excellence (SQUIRE 2.0) reporting guidelines.

Selection of Participants

Patients who received rabies PEP (defined as ≥1 dose of HRIG or rabies vaccine) at any ED in the health system were included. Patients treated from January 2015 to June 2018 were included in the preimplementation group and were identified using reports extracted from the EHR. The bundle was implemented in December 2019. Using a protocol that was specified a priori, the first 4 patients treated after bundle implementation were used for quality assurance of the bundle and were not included in the study analysis. Following this quality assurance period, patients treated from December 2019 to November 2020 were included in the postimplementation group and were identified using real-time alerts (VigiLanz) of rabies PEP medication orders. These alerts were validated by medical record review of the EHR and monthly extract reports from the EHR. This real-time identification of postimplementation patients facilitated monthly reports of bundle performance to the study team. The main outcomes were analyzed in January 2021.

Interventions

A quality improvement team of ED clinicians and clinical investigators developed the rabies PEP bundle using historical data on rabies PEP delivery from our health system, guidance from the state department of health, and national guidelines from the US Centers for Disease Control and Prevention (CDC).1,21,22 The rabies PEP bundle included EHR enhancements, ED staff education, and patient education (eFigure 1 in the Supplement). An additional component of the rabies PEP bundle was changing the health system’s preferred formulary product from HRIG 150 IU/mL to HRIG 300 IU/mL with a goal of increasing the proportion of the HRIG dose that is infiltrated into wounds because a smaller volume is required (eAppendix in the Supplement).

The EHR enhancements included a rabies PEP order set with clinical decision support for clinicians (ie, physicians and advanced practice clinicians) and administration instructions for nurses, structured fields for HRIG administration documentation, and a rabies PEP discharge order set to facilitate discharge planning (Figure 1). Hospital formulary committee approval was obtained to restrict rabies PEP medications to the new rabies PEP order set, which required clinicians to interact with the new clinical decision support during order entry. To assist with patient selection, the order set presented guidance on animals that carry rabies based on Texas State Department of Health guidance and the telephone number for Zoonosis Control Unit consultation for patient-specific decisions.22 The order set provided preconfigured orders for wound management, rabies vaccine, HRIG, and tetanus vaccine. Although the EHR medication administration record only provides 1 documentation site per medication order, HRIG is commonly administered at multiple sites. Therefore, the EHR enhancement provided nurses with additional structured fields to document multiple HRIG administration sites and administration volumes, as necessary. The quality improvement team identified retail pharmacies and outpatient clinics that stock and can administer rabies vaccine. A discharge order set was built to dynamically display nearby referral locations to facilitate discharge planning, provide preconfigured discharge prescriptions for rabies vaccine, and print patient educational materials. The educational campaign to ED staff consisted of live education sessions that reached 36% of ED staff, emails, and tip sheets (eMethods in the Supplement).

Measurements

Two investigators (F.Y. and T.I.) independently abstracted study data and outcomes from the EHR using standardized procedures and data collection forms built in Microsoft Access 2013. Discrepancies between investigators were arbitrated through study team discussion. Documentation of compartment syndrome within 7 days and sciatic nerve injury within 21 days of HRIG administration was collected for both preimplementation and postimplementation groups. After implementation, investigators adjudicated all adverse events documented within 21 days of HRIG administration.

Outcomes

The primary outcome was full adherence to all 6 quality indicators for HRIG patient selection and delivery that were based on CDC guideline recommendations and prescribing information.1,17 The 6 quality indicators were (1) patient selection based on history of rabies prophylaxis, (2) dosing within 10% of 20 IU/kg, (3) timing within 7 days of the first dose of rabies vaccine, (4) infiltration into wounds if anatomically feasible, (5) administration distant from rabies vaccine site, and (6) administration that avoids the buttock unless wounds are in the buttock. Each quality indicator was assigned a score of 1 for adherence or 0 for nonadherence. The primary outcome was a total score of 6. The primary outcome was assessed once per patient during the index ED visit, defined as the first ED visit where a patient met inclusion criteria.

Secondary outcomes were adherence to each quality indicator individually, incidence of compartment syndrome within 7 days of HRIG administration, and incidence of sciatic nerve injury within 21 days of HRIG administration. Other adverse events in the postimplementation group that were possibly or definitely related to HRIG were reported.

Exploratory Subgroup Analyses

We conducted 3 a priori and 3 post hoc subgroup analyses. For a priori subgroup analysis 1, the proportion of patients with clear documentation of HRIG administration sites was evaluated among those who received HRIG. For subgroup analysis 2, the proportion with HRIG infiltration was evaluated among patients with clear documentation of HRIG administration sites and wounds for which infiltration was anatomically feasible. For subgroup analysis 3, percentage of HRIG infiltrated into wounds and the proportion receiving the full dose of HRIG as wound infiltration were evaluated among patients with clear documentation of HRIG infiltration volume.

For post hoc analysis 1, full adherence was analyzed among patients with active wounds (readily visible and unhealed) and treated using the new EHR implemented in 2016. For post hoc analysis 2, full adherence was stratified by ED location (academic medical center vs 14 other locations) because all study team members practiced at the academic medical center. For post hoc analysis 3, full adherence in the postimplementation group was stratified by appropriate use of the rabies PEP order set. Appropriate use was defined as ordering rabies PEP (vaccine or HRIG) through the order set and choosing the clinical pathway that matched that patient’s wound status and history of rabies prophylaxis.

Statistical Analysis

A sample size of 254 preimplementation patients and 70 postimplementation patients was determined a priori to have 80% power to detect an absolute increase of 20% in the primary outcome from 37% to 57% using a 2-sided α = .05. Pearson χ2 test was used to evaluate the primary analysis, adherence to individual quality indicators, subgroup analyses 1 through 3, and post hoc analysis 1. Multivariable logistic regression was used for a sensitivity analysis and for subgroup analysis 2. Multivariable linear regression was used for subgroup analysis 3. Fisher exact test was used for post hoc analysis 3. Patient demographics and characteristics were analyzed using an unpaired t test for continuous variables and a Pearson χ2 test or Fisher exact test for categorical variables. All analyses were conducted using Stata version 16.0 (StataCorp).

Results
Characteristics of Study Subjects

The study included 324 patients; 254 patients were in preimplementation group (mean [SD] age, 39 [21] years; 135 [53%] women) and 70 in the postimplementation group (mean [SD] age, 38 [19] years; 33 [47%] women) (Figure 2 and Table). Most patients were bitten by animals (245 of 324 [76%]) and presented to community hospital EDs (231 of 324 [71%]). Five patients (1%) had a history of rabies prophylaxis, and 8 patients (2%) were immunocompromised. Patient characteristics were similar between study groups except for an increase in bat exposure (63 of 254 preimplementation patients [25%] to 37 of 70 postimplementation patients [53%]; P < .001) and decrease in presence of wounds (213 of 254 preimplementation patients [84%] to 44 of 70 postimplementation patients [63%]; P < .001). Exposure to high-risk animals increased from 32% preimplementation to 63% postimplementation (risk difference, 31%; 95% CI, 18%-44%; P < .001), which were predominately bats and also included coyotes, foxes, raccoons, and skunks. Of 224 preimplementation patients who received HRIG, 222 (99%) received HRIG 150 IU/mL and 2 (1%) received HRIG 300 IU/mL. Of 60 postimplementation patients who received HRIG, 59 (98%) received HRIG 300 IU/mL and 1 (2%) received both HRIG 300 IU/mL and 150 IU/mL.

Adherence to 6 Quality Indicators

Full adherence increased from 37% (95 of 254 patients) in the preimplementation group to 61% (43 of 70 patients) in the postimplementation group, for an absolute increase of 24% (95% CI, 11%-37%; P < .001) and an odds ratio (OR) of 2.67 (95% CI, 1.55-4.59; P < .001) (Figure 3). This association remained statistically significant (adjusted OR [aOR], 2.32; 95% CI, 1.32-4.07; P = .003) in a sensitivity analysis that adjusted for animal type (bat vs other) and animal exposure (bite vs other).

For secondary outcomes, the rabies PEP bundle was associated with an absolute increased adherence of 17% (95% CI, 5% to 30%) for infiltration into wounds, 12% (95% CI, 2%-22%) for administration distant from rabies vaccine site, and 17% (95% CI, 6%-27%) for administration that avoids the buttock, which were identified as focus areas during development of the rabies PEP bundle (Figure 4; eTable 1 in the Supplement). A high baseline adherence of 91% to patient selection, 89% to dosing, and 91% to timing was observed preimplementation, and implementation of the rabies PEP bundle was not associated with a change in adherence to these quality indicators.

A total of 29 patients (23 preimplementation and 6 postimplementation) were not adherent to the patient selection indicator and were therefore not adherent to the 5 other quality indicators (eTable 2 in the Supplement). The HRIG dose was inappropriate for 8 patients (4 preimplementation and 4 postimplementation). Insufficient HRIG inventory in the ED led to 2 of 4 (50%) dosing errors postimplementation. Among 21 patients (18 preimplementation and 3 postimplementation) who received both HRIG and rabies vaccines in the same muscle groups, the medications were injected in the deltoid muscle (10 preimplementation and 3 postimplementation), gluteus muscle (6 preimplementation), and thigh muscle (2 postimplementation).

No instances of sciatic nerve injury or compartment syndrome were observed. Fourteen adverse events from 3 postimplementation patients were possibly related to HRIG 300 IU/mL (eTable 3 in the Supplement).

A Priori Subgroup Analyses

In subgroup analysis 1, the proportion with clear administration site documentation did not change from 198 of 224 patients (88%) in the preimplementation group to 57 of 60 (95%) in the postimplementation group (absolute difference, 7%; 95% CI, 0% to 14%; P = .16). In subgroup analysis 2, HRIG infiltration of anatomically feasible wounds did not change from 97 of 172 patients (56%) preimplementation to 22 of 35 (63%) postimplementation (absolute difference, 6%; 95% CI, –11% to 24%; P = .48), even after adjusting for wound location (leg and foot vs other) and animal type (aOR, 1.26; 95% CI, 0.58 to 2.73; P = .56). In subgroup analysis 3, infiltration of the entire HRIG dose increased from 34 of 142 patients (24%) preimplementation to 13 of 30 (43%) postimplementation (absolute difference, 19%; 95% CI, 0% to 38%; P = .03). The mean (SD) infiltration volume did not change from 2.9 (4.1) mL preimplementation to 2.2 (2.5) mL postimplementation (absolute difference, –0.7; 95% CI, –2.2 to 0.8; P = .39). The mean (SD) percentage of HRIG infiltrated into wounds was unchanged from 31% (42%) preimplementation and 47% (48%) postimplementation (unadjusted coefficient, 15%; 95% CI, –2% to 32%; P = .08), even after adjusting for wound location and animal type (adjusted coefficient, 15%; 95% CI, –1% to 32%; P = .06).

Post Hoc Analyses

For post hoc analysis 1 (eFigure 2 in the Supplement), full adherence increased from 42 of 111 patients (38%) preimplementation to 22 of 39 (56%) postimplementation (absolute increase, 19%; 95% CI, 1% to 37%; P = .04). For post hoc analysis 2, the relative risk for full adherence was 2.0 (95% CI, 1.3 to 3.2) at the academic medical center and 1.5 (95% CI, 1.1 to 2.0) at other EDs with a nonsignificant Mantel-Haenszel test for homogeneity (P = .34). For post hoc analysis 3, full adherence was attained for 39 of 60 patients (65%) with appropriate use of order set and 4 of 10 (40%) otherwise (absolute increase, 25%; 95% CI, –8% to 58%; P = .17). The ED clinician specified a target infiltration volume for 21 of 29 HRIG orders (72%) generated using the wound present clinical pathway. Nurses correspondingly administered the prescribed volume (9 patients), a smaller volume (4 patients), a larger volume (4 patients), or an undocumented volume (4 patients).

Discussion

The rabies PEP bundle was associated with significant improvements in adherence to HRIG quality indicators that were based on CDC guidelines and prescribing information.1,17 The bundle was associated with improvements in all 3 quality indicators related to HRIG administration that we previously identified as opportunities for improvement: infiltration into wounds, administration distant from rabies vaccine site, and administration that avoids the buttock. The rabies PEP order set likely had the largest contribution for improving adherence to HRIG quality indicators since education only reached 36% of ED staff and the educational flyers were given to patients at ED discharge. The rabies PEP order set presented bundles of orders for 5 clinical pathways, prompted clinicians to specify a target HRIG infiltration volume for patients with wounds, and provided nurses with critical medication administration instructions. These clinical decision support features were designed to help address previously identified knowledge gaps related to suboptimal HRIG wound infiltration, administration of HRIG near rabies vaccine, and unnecessary administration of HRIG into the buttock.4,21,23-25 The low adherence to quality indicators observed preimplementation is not unique to our center, as a 2021 study from Germany26 reported deviations from guideline recommendations regarding HRIG selection and wound infiltration in 51% of patients.

Infiltration of wounds with HRIG is critical to prevent the spread of the rabies virus from wounds to the central nervous system.5-9,27 The proportion of patients who received infiltration of the full dose of HRIG significantly increased from 24% to 43% in subgroup analysis 3. This has meaningful implications, as recent international guidelines recommend HRIG infiltration only without supplemental intramuscular injection.2 Although the mean infiltration volume provided did not increase after implementation, the proportion of patients who received infiltration of the full dose of HRIG increased, and this increase is likely because of the use of concentrated HRIG 300 IU/mL postimplementation compared with HRIG 150 IU/mL preimplementation.

Since limited guidance exists on HRIG infiltration volume targets based on wound size and location, our rabies PEP bundle provided guidance on HRIG infiltration volume targets by wound location based on internal data and published literature.8,9,27,28 Researchers in India are developing recommendations for HRIG infiltration volume based on wound site, size, and severity.29,30 Further research is needed to provide a consensus on HRIG infiltration volume targets based on wound location, size, and depth and to optimize clinician-nurse collaboration regarding patient-specific HRIG infiltration volume targets.

In the US, more than 90% of animal rabies cases occur in wildlife.31 Although rabies PEP is commonly started following exposure to a dog or cat, rabies PEP is unnecessary following low-risk exposure to dogs or cats that are vaccinated or available for observation.24,32,33 The Texas Department of State Health Services designates bats, coyotes, foxes, raccoons, and skunks as having a high risk of carrying rabies.34 The rabies PEP ED order set emphasized risk assessment based on animal type, encouraged clinicians to consult the Texas Department of State Health Services for complex cases, and encouraged working with animal control agencies to capture and observe animals before starting rabies PEP. The order set generated a nursing order to contact animal control and provided phone numbers for local animal control agencies. Exposures to high-risk animals increased from preimplementation to postimplementation, which suggests improvements in risk assessment and patient selection for rabies PEP and may warrant further investigation.

Despite EHR enhancements with preconfigured HRIG dosing and vial size rounding logic, we observed errors of low doses (14.0 to 17.9 IU/kg) in 4 postimplementation patients. Clinicians and pharmacists modified the orders that were generated by the order set. Two dosing errors occurred when the currently available inventory of 4500 IU of HRIG in a single ED was insufficient to provide 2 concurrently treated patients with obesity with 20 IU/kg doses. Maintaining a minimum inventory of 5100 IU of HRIG would be sufficient to prevent these types of dosing errors. Dosing HRIG for patients with obesity is a known challenge that can lead to high injection volumes, dosing errors, and exhaustion of HRIG inventory on-hand.25 Although the CDC and manufacturer’s labeling recommend actual body weight, some institutions may use lean body weight for patients with obesity to limit HRIG doses for this patient group.25

Limitations

This study had several limitations. The bundle was simultaneously implemented at all EDs, and therefore a contemporary control group was not available. An 18-month transition period (June 2018 to December 2019) occurred between the preimplementation group and implementation to provide time to analyze preimplementation data, secure research funding, and develop EHR enhancements. The COVID-19 pandemic changed patterns of seeking ED care and ED workflow at many EDs,35-37 and this may have affected 8 of 12 months during the postimplementation period. Although the study did not conduct follow-up monitoring, no human rabies infection cases were reported in Texas during the historical control period or postimplementation period.38 Some study data were collected from unstructured EHR fields; to address this limitation, 2 independent reviewers abstracted data using standardized processes. However, the study did not analyze interrater reliability between reviewers. The EHR documentation that investigators used to determine if a wound could be feasibly infiltrated with HRIG was not standardized between the old EHR and the new EHR implemented in 2016. Small (eg, bat bites) or healing wounds were classified as anatomically feasible for HRIG infiltration; however, there is a lack of consensus among clinicians on infiltrating these small or healing wounds. Therefore, post hoc analysis 1 was conducted among patients with active wounds who were treated using the new EHR, and the bundle remained associated with improved adherence. Future research is needed to evaluate the impact of ED discharge order sets on postdischarge care and completion of the rabies vaccine series

Conclusions

In this quality improvement study, implementation of a rabies PEP bundle was associated with significantly improved HRIG patient selection and delivery in the ED. Although the bundle included ED staff education and patient discharge education, the observed improvement was likely driven by clinical decision support from the rabies PEP ED order set. Future research should evaluate implementation of this clinical decision support at other health systems.

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Article Information

Accepted for Publication: April 26, 2022.

Published: June 21, 2022. doi:10.1001/jamanetworkopen.2022.16631

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2022 Yuan F et al. JAMA Network Open.

Corresponding Author: Joshua T. Swan, PharmD, MPH, Department of Surgery, Houston Methodist, 6550 Fannin St, SM1661, Houston Methodist Hospital, Houston, TX 77030 (swan.joshua@gmail.com).

Author Contributions: Dr Swan had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Iso, Rizk, Saldana, Nguyen, Boyareddigari, Espino, Swan.

Acquisition, analysis, or interpretation of data: Yuan, Iso, Rizk, Tran, Nguyen, Boyareddigari, Swan.

Drafting of the manuscript: Yuan, Swan.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Yuan, Iso, Rizk, Swan.

Obtained funding: Rizk, Swan.

Administrative, technical, or material support: Yuan, Iso, Rizk, Saldana, Tran, Boyareddigari, Espino, Swan.

Supervision: Swan.

Conflict of Interest Disclosures: Dr Swan reported receiving an advisory board stipend that was paid to his employer by Kedrion Biopharma and investigator-initiated research funding that was paid to his employer by Grifols Shared Services North America, Inc, Kedrion Biopharma (both are manufacturers of rabies immune globulin), and VigiLanz Corporation. No other conflicts were reported.

Funding/Support: Under the direction of principal investigator Dr Swan, this research was supported by research grants from Grifols Shared Services North America Inc, which manufactures and sells human rabies immune globulin in the US, and VigiLanz Corporation. This article was supported by the John F. Jr and Carolyn Bookout Presidential Distinguished Chair fund at the Houston Methodist Hospital Foundation.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Meeting Presentations: A research-in-progress scientific abstract was presented as a poster at the American College of Clinical Pharmacy Annual Meeting; October 19, 2020; virtual meeting. A late-breaking original research abstract of this study was presented at the American College of Clinical Pharmacy Annual Meeting; October 16, 2021; virtual meeting. A version of this abstract was published in the Journal of the American College of Clinical Pharmacy. Another abstract was presented as an oral presentation at the Rabies in the Americas meeting; October 28, 2021; virtual meeting.

Additional Contributions: The authors acknowledge Sandra Yu, RPh (Houston Methodist), Jennifer Zeien, PhD, MSN, RN, ACNS-BC (Houston Methodist), and Adebowale Adesanya, MSBI, BSRC (Houston Methodist), for their assistance with the electronic health record enhancement development. The authors acknowledge Roberta J. Bogany, MEd (Houston Methodist), for assistance with coordinating educational activities for emergency department nurses and physicians. The authors acknowledge graphic designer Rachael Whitehead (Academic Affairs, Houston Methodist Research Institute) for assistance with developing manuscript figures. The authors acknowledge Amanda Weiskoff, PhD (Academic Affairs, Houston Methodist Research Institute), for assistance with manuscript preparation. These contributors did not receive additional compensation for contributing to this project.

Additional Information: The data sets generated and/or analyzed during the current study are not publicly available due to privacy of protected health information.

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