A Post-Operative Pain Management Guideline for Opioid Exposed Neonates

Neonates are commonly prescribed opioids in the NICU for pain management. Prolonged opiate exposure can lead to increased drug tolerance and/or dependence, and result in higher total opiate exposure and suboptimal pain control. Evidence suggests that the use of a standardized pain management guideline can decrease provider opioid prescribing variability and lead to improved pain management. The objective of this project was to develop, pilot, and evaluate a standardized post-operative pain management guideline for the opioid exposed neonatal population. Criteria to categorize patients as "opioid exposed" was determined after completing a literature review and consulting with content experts. A retrospective chart review of 20 patients was completed to assess baseline opioid exposure and post-operative pain control. An evidence based guideline was developed to be trialed and implemented for "opioid exposed" neonates to improve post-operative pain control. Education regarding the guideline was provided to staff prior to the implementation. Following the trial of the guideline, a review of four charts was conducted to evaluate the use and adherence to the new guideline and to compare total opiate exposure and time to achieve pain control post-operatively before and after piloting the guideline. Total opioid exposure between the two groups was compared using descriptive statistics due to the small sample size of pilot patients. Results showed that the total mean opioid exposure and time to achieve pain control post-operatively decreased in the post-implementation group. However, total benzodiazepine and total dexmedetomidine exposure increased in the post-implementation group. Piloting an evidence-based guideline to standardize post-operative pain management for opioid exposed neonates resulted in a decrease in opioid exposure and time to achieve pain control post-operatively. Further studies with larger sample sizes are recommended in order to gain further knowledge on how to appropriately and effectively manage post-operative pain for opioid exposed neonates.

A Post-Operative Pain Management Guideline for Opioid Exposed Neonates Erin Pabst The University of Utah College of Nursing 1 Abstract Background: Neonates are commonly prescribed opioids in the NICU for pain management. Prolonged opiate exposure can lead to increased drug tolerance and/or dependence, and result in higher total opiate exposure and suboptimal pain control. Evidence suggests that the use of a standardized pain management guideline can decrease provider opioid prescribing variability and lead to improved pain management. The objective of this project was to develop, pilot, and evaluate a standardized post-operative pain management guideline for the opioid exposed neonatal population. Methods: Criteria to categorize patients as "opioid exposed" was determined after completing a literature review and consulting with content experts. A retrospective chart review of 20 patients was completed to assess baseline opioid exposure and postoperative pain control. An evidence based guideline was developed to be trialed and implemented for "opioid exposed" neonates to improve post-operative pain control. Education regarding the guideline was provided to staff prior to the implementation. Following the trial of the guideline, a review of four charts was conducted to evaluate the use and adherence to the new guideline and to compare total opiate exposure and time to achieve pain control post-operatively before and after piloting the guideline. Results: Total opioid exposure between the two groups was compared using descriptive statistics due to the small sample size of pilot patients. Results showed that the total mean opioid exposure and time to achieve pain control post-operatively decreased in the postimplementation group. However, total benzodiazepine and total dexmedetomidine 2 exposure increased in the post-implementation group. Conclusions: Piloting an evidence-based guideline to standardize post-operative pain management for opioid exposed neonates resulted in a decrease in opioid exposure and time to achieve pain control post-operatively. Further studies with larger sample sizes are recommended in order to gain further knowledge on how to appropriately and effectively manage post-operative pain for opioid exposed neonates. 3 Introduction Problem Description Critically ill neonates in the Newborn Intensive Care Unit (NICU) are regularly prescribed opioids for many reasons such as post-surgical pain management, procedural pain management, to provide sedation to manage agitation, and to facilitate optimal ventilation (Anand et al., 2010). Prolonged opiate exposure can lead to increased drug tolerance and/or dependence, and result in higher total opiate exposure as well as suboptimal pain control with subsequent surgical procedures (Galinkin & Koh, 2014; Lewis, Erfe, Ezell, & Gauda, 2015). Variation in pain management strategies due to differences in beliefs and attitudes between providers can further complicate effective management of neonatal post-surgical pain (Zhang & Sweitzer, 2008). Evidence suggests that the use of a standardized pain management guideline can decrease provider opioid prescribing variability and lead to improved pain management (Zhang & Sweitzer, 2008). Available Knowledge 4 Opioids are the most common drugs used for pain control in the neonatal population (Galinkin & Koh, 2014). Emerging research evaluating the effects of neonatal opioid exposure, particularly prolonged and/or excessive exposure, suggests that there are long term consequences (Attarian et al., 2014). One complication of prolonged opioid use is the development of opioid dependence and withdrawal symptoms after as little as seven days of use (Galinkin & Koh, 2014). This complication can lead to an extended hospital course due to the need for opioid weaning regiments (Rana et al., 2017). Opioid exposure may also alter basal pain processing and endogenous pain inhibitory pathways and make pain control more difficult to achieve (Zhang & Sweitzer, 2008). Long term or excessive opioid use can lead to poor developmental and cognitive outcomes (Attarian et al., 2014; Giordano et al., 2018; Schiller et al., 2018). In addition, a study conducted showed that opioid exposure leads to apoptosis of human neurons and microglial cells which may result in cognitive delays (Attarian et al., 2014). Behavioral development impairment has also been observed later in life of neonates that received prolonged opioid administration during infancy (Giordano et al., 2018). Extremely low birthweight infants that were exposed to opioids have been found to have worse cognitive index scores later in life (Kocek, Wilcox, Crank, & Patra, 2016). The increased opioid use has also led to an increased use of benzodiazepines as an adjunct therapy to help manage pain and sedation. Benzodiazepines, previously thought to be benign, have been observed to result in adverse effects in the neonatal population (Ng, Klinger, Shah, & Taddio, 2002). Prolonged benzodiazepine use has also been 5 correlated with abnormal brain and neural development (Duerden et al., 2016). Although the appropriate use and dosing of opioids in neonates is still under investigation, available evidence suggests that the use of a standardized pain management protocol may improve overall patient pain management by decreasing opioid prescribing variability between providers and improving the consistency of pain assessment (Furdon, Eastman, Benjamin, & Horgan, 1998; Rana et al., 2017). Rationale The Theory of Planned Behavior looks at the relationship between individuals' beliefs, attitudes, social norms, intentions, behavior, and their perceived control over that behavior (Rimer & Glanz, 2005). The implementation and long term success of a standardized pain management guideline is dependent on nursing acceptance and practice. By identifying and addressing potential barriers within the nursing community, such as negative attitudes or beliefs regarding neonatal pain management, it is more likely that a new guideline will be accepted and implemented. This will result in consistent pain assessments and the correct utilization of opioids by the nursing community to promote improved patient pain management and decreased opioid usage (Francis et al., 2004). Specific Aims The purpose of this project is to develop and implement a standardized postoperative pain management protocol in a quaternary regional children's hospital for neonates that have had previous opioid exposure to improve pain management and decrease opioid use. 6 Methods Context This quality improvement project was conducted in a quaternary level NICU at a large pediatric medical center in Salt Lake City, Utah. The NICU serves term and preterm infants with severe acute medical and surgical conditions. The referral area for this NICU includes the states of Idaho, Wyoming, Montana, and Nevada. The NICU has 52 beds and is staffed by neonatologists, neonatal fellows, neonatal nurse practitioners, residents, neonatal registered nurses, and respiratory therapists. A related quality improvement project addressing the use of a standardized post-operative pain management guideline for opioid-naïve neonates is also in process in this NICU. This project is complementary as it has the same goals to reduce opioid use/exposure and improve post-operative pain management in neonates. Intervention(s) This project focused on creating and implementing a standardized post-operative pain management guideline for opioid exposed neonates to improve patient pain control in the post-operative period and reduce overall opioid use. A project team was created that included the project lead, the medical director at the implementation site and content expert for this project, a Neonatal Nurse Practitioner (NNP), a neonatal hospital pharmacist, and an advanced surgical registered nurse. The first objective to this project was to identify criteria to categorize patients as "opiate exposed." An extensive literature review on the development of opioid tolerance/dependence and opioid exposure in the neonatal population was completed. 7 The findings were discussed with the NICU pharmacist and NICU medical director/content expert to develop the criteria to categorize the opioid exposed patients. The second objective was to develop a standardized post-operative pain management guideline. A literature review was conducted to examine published evidence based post-operative pain management guidelines for opioid exposed neonates as well as current strategies for non-pharmacologic pain management. Using these findings, the project team developed a guideline to manage post-operative pain in neonates that have had been identified as "opiate exposed". The third objective was to implement the post-operative pain management guideline. An order set for the guideline was developed and incorporated into the electronic ordering system used at the implementation site. This facilitated easy and efficient provider ordering and reinforced standardization of management between caregivers. The charge nurse group at the implementation site was educated about the new guideline at their monthly meeting. The NNP group was notified and educated via email. The guideline was tested on four pilot patients that met guideline criteria. Using the PDSA model the guideline was adjusted between pilot patients based on feedback from the providers and nurses that used the guideline. The project lead and/or the medical director were available throughout the pilot period for questions and assistance. The final objective was to evaluate the effectiveness and usability of the guideline. Prior to the pilot study period, a retrospective chart review was completed on 20 pre-implementation patients that met the established definition of "opioid exposed" to establish baseline. The variables that were collected included the patient encounter 8 number, date of birth, birth weight, gestational age at birth, days since last opioid dose prior to surgery, days since last consecutive opioid dosing period prior to surgery, number of consecutive days of opioid administration prior to surgery, the total cumulative opioid dose of opioids received in the consecutive period prior to surgery, surgery date, the total amount of opioids received in the post-operative period, preoperative benzodiazepine use, the total amount of benzodiazepines received in the postoperative period, pre-operative dexmedetomidine use, the total amount of dexmedetomidine received in the post-operative period, and time (in hours) to reach two consecutive Neonatal Pain Agitation and Sedation Scale (NPASS) scores less than three. The same data was collected on the pilot patients. After the pilot period, the pre and post implementation patients' data was compared to determine if there was a difference in total post-operative opioid exposure, total post-operative benzodiazepine administration, total post-operative dexmedetomidine administration, and time to achieve two consecutive NPASS pain scores of less than three between the two populations. All opioid exposure was converted into morphine milligram equivalents, all benzodiazepine administration was converted into milligrams per kilogram, and all dexmedetomidine administration was converted into micrograms per kilogram to establish consistency. Study of the Intervention(s) In order to assess the impact of this quality improvement project, criteria was established to identify infants that were "opioid exposed." The definition of "opioid exposed" that was used for this project is any infant who has received 10 or more consecutive days of scheduled opioid administration since birth. Neonates that did not 9 meet the "opioid exposed" criteria, had liver failure, or had a neurological disorder were excluded from the project. Retrospective pre-implementation and post- implementation chart review measured the impact and outcomes of this project. Specifically, the change in total opioid exposure, total benzodiazepine administration, total dexmedetomidine administration, and time to achieve two consecutive NPASS pain scores of less than three in the post-operative period of the pre- and post- guideline neonates were compared. Measures A retrospective chart review of pre-intervention neonates was performed to quantitatively determine the extent of opioid exposure prior to guideline implementation. The post-implementation data for each pilot patient was collected prospectively and recorded in an Excel spreadsheet. Opioid exposure was measured in oral morphine milligram equivalents (MME) with a cross tolerance reduction of 25%, benzodiazepine administration was measured in milligrams per kilogram, and dexmedetomidine administration was measured in micrograms per kilogram to establish consistency and allow valid comparison between infant groups. Analysis The data for this project was analyzed using descriptive statistics. Scatterplot and bar-graph diagrams were used to visualize the collected data and allow for easy comparison between pre- and post- intervention neonates as well as identify outliers in the pre- and post- implementation groups. Ethical Considerations A University of Utah Health Care Improvement Assessment Tool was completed 10 to determine whether this project qualified as research or quality improvement. The project met the criteria for quality improvement. Based on this classification a formal evaluation by the University of Utah Institutional Review Board was not required. There were no potential conflicts of interest. Results Prior to the start of the pilot study, a retrospective chart review of 20 patients was completed for analysis to determine a baseline "opioid exposed" population. The charts were collected on surgical patients who met the designated inclusion criteria from February 2019 to August 2019. Neonatal demographics were populated into an Excel spreadsheet. The mean number of consecutive days of opioid exposure prior to surgery was 22.7 days with the mean number of days between surgery and the consecutive opioid administration period being 47.2. The mean total amount of opioids received during the consecutive period in morphine milligram equivalents (MME) was 2935.3 with a mean maximum daily dose in MME of 161. Results from the retrospective chart reviews showed that in the post-operative period the mean opioid exposure in MME was 686.8, the mean benzodiazepine exposure was 0.7 milligrams per kilogram, and the mean dexmedetomidine exposure was 31.2 micrograms per kilogram. The mean time in hours to reach two consecutive NPASS scores of less than 3 in the post-operative period was 4.1. However, some pain assessment documentation was missing on two of the patients who were excluded which could cause skewed results for time to the NPASS score goal. The standardized post-operative pain management protocol was piloted on four 11 patients during November 2019 through February 2020. The pilot patients all met the "opioid exposed" criteria prior to surgery. Surgical patients managed with an alternative guideline were excluded. The mean number of consecutive days of opioid exposure prior to surgery was 21.5 days with the mean number of days between surgery and the consecutive opioid administration period being 45.3. The mean total amount of opioids received during the consecutive period in morphine milligram equivalents (MME) was 2716.8. The mean total opioid administration during the post-operative period was 456 MME. The mean total benzodiazepine administration during the post-operative period was 0.9 milligrams per kilogram. The mean total dexmedetomidine exposure during the post-operative period was 48.8 micrograms per kilogram. The mean time to reach two consecutive NPASS scores less than three was two hours. These results indicate there was a decrease in the mean opioid exposure with an increase in benzodiazepine and dexmedetomidine exposure in the post-operative period when using the standardized "opioid exposed" guideline. There was also a decrease in time to reach two consecutive NPASS scores of less than 3 in the post-operative period in the pilot patient group compared to the pre-implementation patients. Discussion Summary Despite increased understanding of neonatal pain and the effects of opioid administration, pain management for the opioid exposed neonate remains a challenge. The retrospective chart reviews on the pre-implementation patients showed significant previous prolonged iatrogenic opioid exposure with higher opioid administration and 12 NPASS scores in the post-operative period after subsequent surgery. The purpose of this project was to develop and implement a standardized post-operative pain management protocol for post-operative neonates with previous opioid exposure to improve pain management and decrease opioid use. Results of this project demonstrated that with a standardized pain management guideline, overall opioid exposure in the post-operative period decreased with an improvement in pain management as evidenced by a reduction in time to reach two consecutive NPASS scores of less than 3 post-operatively. This study was one of the first of its kind and explored previous iatrogenic opioid exposure and its effect on post-operative pain management in the NICU. Interpretation There are few studies that explore iatrogenic opioid exposure in neonates and the adverse effects that result from prolonged opioid use. There are even fewer studies that examine how iatrogenic opioid exposure and dependence in the NICU affect pain control for subsequent surgical procedures. Most articles focus on prenatal opioid exposure and the effects of Neonatal Abstinence Syndrome. The lack of relevant studies indicates the need for more research on the effects of prolonged opioid use in the NICU population. However, the lack of studies could be attributed to ethical limitations. Current literature provides evidence that having a standardized post-operative pain management guideline in place can increase consistency in the assessment of neonatal pain, decrease opioid use, and improve patient outcomes (Rana et al., 2017). Consistent with the literature, the results of this project showed a decrease in opioid use and improved patient NPASS scores in the post-operative period while using the 13 standardize pain management guideline. However, there was an increase in benzodiazepine and dexmedetomidine exposure in the post-operative period for the post-intervention group compared to the pre-implementation patients. This could be attributed to increased knowledge of registered nurses regarding the difference between pain and agitation assessments and how to properly use pharmaceuticals in response to these conditions. The preimplementation group's agitation could have been mistaken for pain and treated with opioids rather than with benzodiazepine or dexmedetomidine which could explain the lower benzodiazepine or dexmedetomidine exposure. In addition, the postimplementation group was immediately started on a dexmedetomidine drip postoperatively which would result in more time and exposure to dexmedetomidine compared to the pre-implementation group that was not routinely started on a dexmedetomidine drip. Although all the pilot patients qualified as "opioid exposed," patient 1 and 3 had higher opioid, benzodiazepine, and dexmedetomidine exposure prior to surgery compared to patients 2 and 4. Because patients 1 and 3 had higher pre-surgical exposure levels of these medications, they required more post-operative opioid, benzodiazepine, and dexmedetomidine medication to achieve optimal pain control. In addition, patients 1 and 3 were already receiving a morphine and dexmedetomidine drip prior to the start of their surgery which would explain their higher post-operative exposure levels. Limitations 14 Limitations to this study include the time constraints for collecting data on the targeted pilot patients for this guideline. This resulted in a very small sample size of postimplementation patients for comparison to the baseline group. In addition, this guideline was piloted and evaluated at a single Level IV NICU which also limited the data collected and the generalization to other NICUs due to the unique patient population at the pilot NICU site. Further staff education regarding consistent pain score charting is also necessary in order to accurately determine the establishment and maintenance of pain control during the post-operative period. Pain scoring was only documented every 1-4 hours by staff which could misrepresent the pain status of a patient during the postoperative period and the results of this project. Conclusions Piloting an evidence-based guideline to standardize post-operative pain management for opioid exposed neonates resulted in an increase in the consistency of neonatal pain assessment and a decrease in time to achieve pain control post-operatively. Post-operative opioid exposure was also decreased when using a standardized guideline. This project uncovered knowledge gaps, system inefficiencies, and barriers to the nursing work flow as it related to the protocol. Recognizing these barriers will facilitate additional staff education, improve system functions, and allow for modifications of the guideline to reach full implementation and integration into management and nursing workflow. 15 Acknowledgements I would like to acknowledge the efforts of Marilyn Rigby, APRN, NNP; Con Yee Ling, MD; and Kim Friddle, PhD, APRN, NNP-BC. As project chair, content expert, and program director they all provided invaluable guidance, advice, and mentorship. 16 References Anand, K. J. S., Wilson, D. F., Berger, J., Harrison, R., Meert, K. L., Zimmerman, J., … Nicholson, C. (2010). Tolerance and withdrawal from prolonged opioid use in critically ill children. Pediatrics, 125(5), e1208-e1225. Retrieved from http://doi.org.ezproxy.lib.utah.edu/10.1542/peds.2009-0489 Attarian, S., Tran, L. C., Moore, A., Stanton, G., Meyer, E., & Moore, R. P. (2014). The neurodevelopmental impact of neonatal morphine administration. 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Recognition and management of iatrogenically 17 induced opioid dependence and withdrawal in children. American Academy of Pediatrics, 133(1), 152-155. doi: 10.1542/peds.2013-3398 Giordano, V., Deindl, P., Fuiko, R., Unterasinger, L., Waldhoer, T., Cardona, F., … Olischar, M. (2018). Effect of increased opiate exposure on three years neurodevelopmental outcome in extremely preterm infants. Early Human Development, 123, 1-5. https://doi.org/10.1016/j.earlhumdev.2018.06.010 Kocek, M., Wilcox, R., Crank, C., & Patra, K. (2016). Evaluation of the relationship between opioid exposure in extremely low birth weight infants in the neonatal intensive care unit and neurodevelopmental outcome at 2 years. Early Human Development, 92, 29-32. Retrieved from https://doiorg.ezproxy.lib.utah.edu/10.1016/j.earlhumdev.2015.11.001 Lewis, T., Erfe, B. L., Ezell, T., & Gauda, E. (2015). Pharmacoepidemiology of opiate use in the Neonatal ICU: Increasing cumulative doses and iatrogenic opiate withdrawal. 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The Journal of Clinical Pharmacology, 58(S10), S140-S150. https://doi.org/10.1002/jcph.1139 Zhang, G. H., & Sweitzer, S. M. (2008). Neonatal morphine enhances nociception and decreases analgesia in young rats. Brain Research, 1199, 82-90. https://doi.org/10.1016/j.brainres.2007.12.043 19 Appendix A Figure 1. Opioid exposure of "opioid exposed" neonates prior to guideline Figure 2. Total opioid exposure in post-op period (pre-implementation) Figure 3. Total opioid exposure in post-op period (post-implementation) Figure 4. Total benzodiazepine exposure in post-op period (pre-implementation) Figure 5. Total benzodiazepine exposure in post-op period (post-implementation) 20 Figure 6. Total time to reach NPASS goal in hours (pre-implementation) Figure 7. Total time to reach NPASS goal in hours (post-implementation) SEDATION ALGORITHM Upon Arrival from OR Assess sedation with every pain score 21 PAIN ALGORITHM Upon Arrival From OR Hour 0‐2 post‐op Assess pain/sedation every 3‐4 hours Every 12 Hours 22 PCH NICU Post‐Op Pain Management Guideline for Opioid Exposed Patients Inclusion Criteria: ⦁ Infants with a history of >10 consecutive days of opioid use during hospital course OR with current morphine/fentanyl drip infusing. Exclusion Criteria: ⦁ ⦁ Morphine allergy, seizure or severe neurological disorder, liver failure, or physician request. Minimally painful procedures (i.e. bronchoscopy, laser eye surgery, cardiac catheterization). *Always provide developmental comfort measures and cue‐based care. Partner with parents/guardians about pain expectations, assessments and medications. ⦁ Before infant leaves for surgery ⦁ Medical team (MD, NNP, Resident, RN) to discuss appropriate pain management guideline to be ordered/initiated for patient ⦁ Early Extubation/Non‐ventilated ⦁ Ventilated ⦁ Opioid Exposed ⦁ NNP to discuss with bedside RN to determine the pain and sedation assessment goals for the patient ⦁ NNP to order appropriate power plan prior to patient leaving for OR ⦁ Bedside RN to discuss patient expectations with surgical team during hand off ⦁ Patient will return from OR intubated ⦁ Determine if IV Tylenol to be given in OR or in NICU upon arrival ⦁ Bedside RN ensure that IV Tylenol is at the bedside prior to patient return from OR ⦁ Bedside RN ensure that Morphine and Dexmedetomidine drips are at the 23 ⦁ bedside prior to patient return from OR Bedside RN ensure that correct guideline algorithm is at bedside for quick reference 24