D DAVID PUBLISHING. 1. Introduction. Shannon Inglet 1, Michael Curcio 2 and Lada Radetic 3

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1 Journal of Pharmacy and Pharmacology 6 (2018) doi: / / D DAVID PUBLISHING Evaluation of Opioid Reversal with Naloxone before and after Implementation of a Computerized Physician Order Entry System at a Tertiary Medical Center Shannon Inglet 1, Michael Curcio 2 and Lada Radetic 3 1. Intermountain Medical Center, Department of Pharmacy, Murray, UT 84107, USA. 2. College of Pharmacy, Roseman University, South Jordan, UT 84095, USA 3. College of Pharmacy, University of Utah, Salt Lake City, UT 84112, USA Abstract: Objectives: Opioid medications consistently rank among the drugs most frequently associated with adverse events. We reviewed cases of naloxone administration to assess our opioid prescribing and administration practices before and after implementation of a computerized provider order entry (CPOE) system. Our primary measure was the rate of opioid reversal with naloxone in the two time periods. Methods: We systematically reviewed all cases of naloxone administration at our institution from March 2016 through May 2016 (before period) compared with cases from October 2017 through December 2017 (after period). Results: In the before period, 0.58% of patients who received an opioid required reversal with naloxone compared with 0.16% in the after period (p < 0.001). Subject demographics such as age, sex, BMI, and serum creatinine were not significantly different between the two groups. Similarly large proportions of patients in the before and after groups had at least 2 risk factors for over-sedation (79.5% and 75%, respectively, p = 0.17). More than 84% and 61% of patients in the before and after groups, respectively, did not have documentation of an opioid on the admission medication history, suggesting they were opioid-naïve (p = 0.10). Per our institution s policy on range orders, nurses should begin with the lowest prescribed opioid dose; this policy was followed in 58.3% in the before period and 69.2% in the after period (p = 0.36). Conclusions: Doses of naloxone that were required for opioid reversal were significantly reduced after implementation of a CPOE system. Our opioid-reversal rate was comparable to similar studies; however, secondary endpoints indicate that opioid prescribing and administration habits may not account for patient-specific risk factors for over-sedation. Key words: opioid, naloxone, over-sedation, patient safety. 1. Introduction Opioid medications consistently rank among the drugs that are most frequently associated with adverse events [1]. Literature suggests that the frequency of opioid-induced respiratory depression is less than 1% overall; however, it is dependent upon the setting and population being investigated [2-4]. One large retrospective review of adverse drug reactions estimated that 16% of all inpatient adverse events are due to opioids [5]. In severe cases of opioid-induced respiratory depression, naloxone, an opioid antagonist, Corresponding author: Shannon Inglet, PharmD, BCPS, research fields: clinical Pharmacist and medication safety. is used as a reversal agent [6]. Naloxone is a pure opioid antagonist which competitively binds central nervous system receptors, displacing opioids and rapidly reversing opioid effects [6]. This makes naloxone administration an ideal surrogate marker for evaluating opioid use that leads to respiratory depression [7]. Additionally, there is abundant evidence that computerized provider order entry (CPOE) systems improve patient safety and reduce the rate of adverse drug events [8, 9, 10]. We reviewed cases of naloxone administration to assess our opioid prescribing and administration practices before and after implementation of a CPOE system at our facility. Our primary measure was the

2 198 Evaluation of Opioid Reversal with Naloxone before and after Implementation of a rate of opioid reversal with naloxone in the two time periods. Secondary endpoints included demographic information, proportion of patients who had at least 2 known risk factors for over-sedation, proportion of patients with opioids on their admit medication history, cumulative 24-hour opioid amount in morphine milligram equivalents (MMEs) given prior to reversal, rate at which nurses followed our health system s Range Orders Procedure, and number of submissions to our institution s internal event reporting system describing opioid reversal between the two time periods. 2. Materials and Methods We systematically reviewed all cases of naloxone administration at our institution from March 2016 through May 2016, before implementation of a CPOE system, and from October 2017 through December 2017, after the implementation of CPOE, and allowing for over 2 months for staff to become accustomed to the new system. Cases stemming from outpatient opioid use were excluded. Patients who did not receive opioids outside of the operating room (OR) were also excluded (Fig. 1). Risk factors for over-sedation were defined as those included in the Joint Commission Sentinel Event Alert on the safe use of opioids in hospitals [1]. (Table 1). Twenty-four hour cumulative morphine equivalents were determined using the Hopkins Opioid Conversion Program online calculator [11] in order to provide consistency and prevent calculation errors. Statistical analyses were conducted using IBM SPSS, version 10 (IBM, Armonk, NY). A 2-sample test of proportions was used to analyze the primary endpoint. Discrete variables were analyzed using Fisher s exact test. Continuous data were analyzed using a student t-test and Wilcoxon-rank sum test, as appropriate. Statistical significance was set a priori at Results In the before period, 0.58% of patients who received an opioid required reversal with naloxone compared with 0.16% in the after period (p < 0.001). Subject demographics such as age, sex, BMI, and serum creatinine were not significantly different between the two groups. (Table 2). Similarly large proportions of patients in the before and after groups had at least 2 risk factors for over-sedation (79.5% and 75%, respectively, Before: Mar - May 2016: 82 naloxone doses administered After: Oct. - Dec. 2017: 85 naloxone doses administered 33 excluded for offsite overdose 51 excluded for offsite overdose 10 patients did not receive opioids outside the OR 21 patients did not receive opioids outside the OR 39 patients included 13 patients included

3 Evaluation of Opioid Reversal with Naloxone before and after Implementation of a 199 Fig. 1 Methods. Table 1 Before and After CPOE Implementation Comparison. Variable Before (n = 39) After (n = 13) p-value Proportion of patients requiring opioid reversal with naloxone 0.58% 0.16% P < Range Orders Procedure followed 53.8% 69.2% P = 0.36 Patients with 2 risk factors for over-sedation 79.5% 75% P = 0.17 No home opioid documented 84.6% 87.8% P = 0.10 Multiple opioids prescribed 41% 84.6% P = MMEs in past 24 hours (median) P = 1.0 Table 2 Patient demographics. Variable Before (n = 39) After (n = 13) p-value Sex (female) 22 (56.4%) 6 (46.2%) 0.75 Post-operative status 23 (59%) 7 (53.8%) 0.99 Age, median (Q1 Q3) 66 (54 76) ( ) 0.24 BMI, median (Q1 Q3) ( ) ( ) 0.46 Serum creatinine, median (Q1 Q3) 1.03 ( ) 1.06 ( ) 0.83 Patients excluded from study due to off-site overdose 33/82 (40.2%) 51/85 (60%) 0.02 p = 0.17). The majority of patients requiring opioid reversal did not have documentation of an opioid on their admission medication history, suggesting they were opioid-naïve (84% and 61% of patients in the before and after groups, respectively, p = 0.10). The median MMEs given in the 24 hours preceding naloxone administration was 39.9 mg in the before period and 42.4 mg in the after period (p = 1.0). Per our institution s policy on range orders, nurses should begin with the lowest prescribed opioid dose; this policy was followed in 58.3% in the before period and 69.2% in the after period (p = 0.36). Naloxone administration has historically been used as a surrogate marker for overall event reporting [12]. We reviewed all event reports submitted during the two study periods and found that 3 corresponded to opioid reversal in the before period and 7 in the after period, so it may be that our total event reporting rate is between 6 29%. There were no deaths resulting from opioid overdose in our sample population. 4. Discussion In our review, we found that our institution s rate of opioid reversal with naloxone was significantly reduced after implementation of a CPOE system. There may be multiple reasons for this. First, the functionality of our CPOE system required that our Range Orders Procedure be changed from allowing a maximum dose to be up to 4 times the minimum dose, to only allowing the maximum dose to be 2 times the minimum. Second, our CPOE system facilitates the use of pre-built opioid and analgesic regimens and supports assignment of priority of use when multiple analgesics are prescribed, guiding the prescriber toward potentially more conservative dosing and reducing ambiguous orders. Third, the CPOE system requires nursing to chart the patient s respiratory rate and degree of sedation with every dose of an opioid administered, possibly improving the quality of patient monitoring. This third explanation may be the most contributory because the cumulative MMEs given to patients in the before and after period did not significantly change. Our overall rate of naloxone administration for opioid reversal, both before and after CPOE, is comparable to other studies in the published literature [2-4, 13] Neil, et al. found a naloxone administration rate of 0.51% in hospitalized patients across 2 Canadian acute care centers [13]. In their study of post-operative patients, Gordon, et al. found a naloxone administration rate of 0.53% [3]. Interestingly, Khelemsky, et al. found a naloxone administration rate of just 0.1% in post-operative patients in their 13-year

4 200 Evaluation of Opioid Reversal with Naloxone before and after Implementation of a review [4]. Our investigation adds to this body of research by evaluating naloxone administration among all inpatients receiving opioids in a large, metropolitan U.S. hospital. There is also ample evidence describing CPOE systems impact on patient safety and adverse drug events, but not specific to opioid safety [8, 9, 10]; our results also provide insight into this important issue. While most of our secondary endpoints were not significantly different, we did see improved compliance with our Range Orders Procedure, which is likely due to education efforts that coincided with our CPOE system implementation. We also found that the majority of patients requiring naloxone did not have an opioid documented as a home medication, and most patients also had at least 2 risk factors for over-sedation. Thus, there may be opportunities to improve both provider-prescribing and nursing-administration practices at our institution in order to maximize both patient comfort and safety. Moving forward, we will look for opportunities to utilize our CPOE system to find new ways to improve pain management and develop pain treatment protocols that include multimodal analgesic options. One additional and unexpected finding was that the number of patients who were excluded from our study due to offsite overdoses significantly increased by nearly 20% (p = 0.02). This may be reflective of the worsening opioid and heroin crisis in our community. Centers for Disease Control and Prevention (CDC) data show a dramatic increase in the rate of drug overdose deaths in the United States since 1999, and in October 2017, the president declared this trend a public health emergency [14]. Data are not yet available for 2017, but in 2016, our state ranked 20 th in the nation for drug overdose deaths, with 22.4 per 100,000 deaths [15]. Using naloxone administration as a surrogate marker for overall event reporting has revealed that our reporting rate may be between 6 29%, which is higher than other estimates in the literature [16]. The increase in event reporting from the before and after periods may be attributable to recent efforts made to improve our culture of safety. Our hospital system has launched a Zero Harm initiative in 2015, which has provided education and tools for staff to voice safety concerns. In 2016, every staff member attended a 3-hour error-prevention technique training as part of this initiative. Empowering staff members to promote safety was expected to increase our event reporting rate. Our study has several limitations. First, by design, it is a single-center, retrospective study which included a span of only 3 months in the before and after periods. The patient population of our institution is homogeneous, primarily Caucasian, so it is difficult to extrapolate our results to other ethnicities and demographics. However, by limiting the time-frame, we were able to conduct a thorough and systematic chart review with well-defined endpoints, which prevented data omissions. Second, because the computer systems in the before and after periods were different, so were the data sources for drug utilization. Our chart review validated the data, but we cannot say definitively that there are no data omissions. Third, we set a low threshold for identifying risk factors for over-sedation. These risk factors are those defined by the Joint Commission which preserves external validity, but, by contrast, Pawakauskas, et al, using the same criteria, found that patients requiring opioid reversal had an average of 5 risk factors [2]. We also made assumptions based on surrogate markers: the lack of an opioid on an admission medication history may be indicative of opioid naivety, and the number of internal event reports describing naloxone administration was presumed to correlate to overall event reporting. The strengths of our study include, first, our systematic methodology. We were able to conduct a thorough chart review of all patients who received naloxone and identify specific, objective endpoints. Our broad inclusion criteria also enabled us to minimize selection bias and identify general trends in

5 Evaluation of Opioid Reversal with Naloxone before and after Implementation of a 201 prescribing and administration across disciplines. We also utilized an online calculator to determine 24-hour cumulative MMEs [8], which prevented calculation errors and provided consistency among the four data reviewers. 5. Conclusions Doses of naloxone that were required for opioid reversal were significantly reduced after implementation of a CPOE system. Our opioid-reversal rate was comparable to similar studies; however, secondary endpoints indicate that opioid prescribing and administration habits may not account for patient-specific risk factors for over-sedation. Further research is needed to evaluate opioid prescribing and administration behaviors in patients who did not require opioid reversal to determine causality rather than association. These results may serve as an impetus for improvements in quality and patient safety. References [1] Joint Commission. Sentinel event alert: safe use of opioids in hospitals, issue 49, August (accessed Jul 2016). [2] Pawasauskas, J., Stevens, B., Youssef, R., et al Predictors of Naloxone Use for Respiratory Depression and Oversedation in Hospitalized Adults. Am. J. Health Syst. Pharm. 71 (9): [3] Gordon, D. B., and Pellino, T. A Incidence and Characteristics of Naloxone Use in Postoperative Pain Management: A Critical Examination of Naloxone Use as a Potential Quality Measure. Pain Manag. Nurs. 6 (1): [4] Khelemsky, Y., Kothari, R., Campbell, N., et al Incidence and Demographics of Post-Operative Naloxone Administration: A 13-Year Experience at a Major Tertiary Teaching Institution. Pain Physician 18 (5): e [5] Davies, E. C., Green, C. F., Taylor, S., et al Adverse Drug Reactions in Hospital Inpatients: A Prospective Analysis of 3695 Patient Episodes. PLos One. 4 (2): e4439. [6] Narcan (Naloxone Hydrochloride) Injection Solution. Lake Forest, IL: Hospira, Inc., [7] IHI Trigger Tool for Measuring Adverse Drug Events. Institute for Healthcare Improvement Web Site. Updated: Accessed: August 11, [8] Prewitt, J., Schneider, S., and Horvath, M PCA Safety Data Review after Clinical Decision Support and Smart Pump Technology Implementation. J. Patient Saf. 9 (2): [9] Acheampong, F., Anto, B. P., and Koffuor, G. A Medication Safety Strategies in Hospitals A Systematic Review. Int. J. Risk Saf. Med. 26 (3): [10] Abramson, E. L., and Kaushal, R Computerized Provider Order Entry and Patient Safety. Pediatr Clin North Am. 59 (6): [11] Hopkins Opioid Conversion Program. The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins online calculator. Updated: Accessed: July-August [12] Beaudoin, F. L., Merchant, R. C., Janicki, A., et al Preventing Iatrogenic Overdose: A Review of In-Emergency Department Opioid-Related Adverse Drug Events and Medication Errors. Ann. Emerg. Med. 65 (4): [13] Neil, K., Marcil, A., Kosar, L., et al Retrospective Analysis of Opioid Medication Incidents Requiring Administration of Naloxone. Can. J. Hosp. Pharm. 66 (5): [14] Schuchat, A., Houry, D., and Jr. Guy, G. P New Data on Opioid Use and Prescribing in the United States. JAMA. doi: /jama [15] Drug Overdose Death Data. Centers for Disease Control and Prevention. Web Site. Updated: December 19, Accessed: February 12, [16] Harper, M. L., and Helmreich, R. L Advances in Patient Safety: From Research to Implementation (Volume 3: Implementation Issues). Rockville (MD): Agency for Healthcare Research and Quality (US).