BACKGROUND AND OBJECTIVES:

Opiate use in neonates can affect clinical outcomes after surgery and may alter future neurodevelopment. We implemented a multimodal opioid reduction strategy in our NICU for infants undergoing nonemergent gastrointestinal surgery.

METHODS:

After multiple stakeholder’s meetings, our opioid reduction intervention included giving neonates postoperative standing intravenous acetaminophen every 6 hours for 48 hours, a standardized postsurgical sign-out with the NICU team in which pain control was directly addressed, and a series of postsurgical pain education seminars with NICU providers. To assess the impact of our quality improvement project, we used process control charts to investigate trends in postoperative opioid use in our preintervention (January 2012 to April 2016) and postintervention (May 2016 to September 2019) cohorts.

RESULTS:

A total of 77 infants were included in the study (40 in the preintervention cohort and 37 in the postintervention cohort). Patient characteristics were equivalent. The intervention significantly reduced the trend in postoperative morphine equivalents (median: 7.96 mg/kg in preintervention cohort versus 0.095 mg/kg in postintervention cohort; P < .0001). The Neonatal Pain, Agitation, and Sedation Scale pain scores and safety profiles were equivalent in both groups. The intervention was also associated with a 24-hour reduction in postoperative ventilation time (P < .048) and a 7-day reduction in the use of total parenteral nutrition (P < .017).

CONCLUSIONS:

Standing intravenous acetaminophen coupled with provider education can successfully reduce opioid use in postsurgical neonates. Given the concern for opioid exposure in neonatal neurodevelopment as well as clinical benefits of reduced opioids, similar strategies for opioid reduction may prove useful at other institutions.

More than 4000 neonates undergo surgery annually in the United States.1  For these patients, the use of opioids for postoperative pain control and sedation over a prolonged NICU stay can result in high cumulative doses.24  There is growing evidence that neonates treated with high doses of opiates may have diminished neurodevelopment scores as well as social sequalae in early childhood.5,6  Additionally, opioid administration can have negative clinical effects, including respiratory suppression and delayed bowel motility.79 

The success of enhanced recovery protocols and opioid reduction strategies in adult surgery has led to interest in applying the principals of standardized postoperative protocols in children.10,11  However, there are few studies in neonatal surgical populations in which opioid reduction through different analgesic strategies is addressed. The studies that do exist have revealed mixed results.12  In a randomized control trial of infants aged 0 to 2 months, rectal acetaminophen did not reveal an opioid reduction effect.13  The same group later reduced opiate use in children <1 year old undergoing noncardiac surgery using postoperative intravenous (IV) acetaminophen.14  A separate group reduced opioid use in a surgical NICU population by implementing procedural pain guidelines for neonatal providers.15  Little work has been done to address opiate reduction in neonates undergoing gastrointestinal surgery with a multimodal approach.

Given the potential clinical as well as neurodevelopmental benefits, we implemented a quality improvement project to reduce the use of opiates in neonates admitted to our NICU undergoing nonemergent gastrointestinal surgery. On the basis of previous interventions in similar patient populations, we hypothesized that postoperative pain management education to NICU providers, a postsurgical pain management regimen on NICU admission, standing postoperative IV acetaminophen as the primary pain control, and guidelines on the use of continuous opiate infusions would reduce opiate usage while not increasing pain scores in neonates. With this multitiered intervention, we sought to reduce postoperative opioid use in neonates undergoing gastrointestinal surgery by 50% over a 2-year time period.

Our medical center includes an academic, tertiary care hospital that represents the major referral center of our region. The hospital includes a 51-bed, level IV NICU and a pediatric surgery group that performs the complete range of neonatal procedures. In early 2015, we noted that the mainstay of postoperative pain control in neonates was fentanyl-based infusions regardless of the surgery or the initial Neonatal Pain, Agitation, and Sedation Scale (N-PASS) score. We also found that IV acetaminophen was not approved at our institution because of perceived high costs and was only used sporadically as a “rescue” medication when a patient was in a pain crisis. This led to high cumulative doses of postoperative opioids in our surgical neonatal population and potential oversedation.

We began our quality improvement project in late 2015 with an initial collaborative team meeting with representatives from the pediatric surgery, pediatric anesthesia, and neonatal intensivist teams (interventions and time line listed in Table 1). The group agreed to address postoperative opioid use in neonates with a multimodal approach. First, we agreed to standardize our postoperative pain control regimen to include standing IV acetaminophen and to reduce postoperative opioid infusions. We worked directly with pharmacy representatives to obtain IV acetaminophen approval in postoperative neonates. In May 2016, we successfully began administering IV acetaminophen in the NICU. During the same time period (May 2016), we began holding postoperative pain management seminars for NICU providers at nursing staff meetings as well as at NICU and/or surgery licensed independent practitioner conferences, discussing our initiative to reduce opioid use. Key aspects of the education session included the clinical benefits of reduced opioid use and our strategy to reduce continuous opioid infusions and use nonopioid alternatives for postsurgical pain management. Lastly, postoperative pain management strategies for each patient were discussed at a standardized NICU postsurgical handoff attended by anesthesia, surgery, and NICU team members.

TABLE 1

Interventions and Implementation Period for Opioid Reduction Strategy

InterventionIntervention OverviewImplementation Period
Initial collaborative meeting(s) Representatives from pediatric surgery and pediatric anesthesia and neonatologists to discuss project goals and implementation strategy October 2015 to April 2016 
Order set (intervention A) Approval of IV acetaminophen and reduction of postoperative opioid infusions May 2016 
Education sessions (intervention B) Postoperative pain management seminars at nurse staff meetings and NICU and/or surgery conferences May 2016 (current) 
Standardized handoff (intervention C) Standardized NICU postsurgical handoff attended by anesthesia, surgery, and NICU staff May 2016 (current) 
InterventionIntervention OverviewImplementation Period
Initial collaborative meeting(s) Representatives from pediatric surgery and pediatric anesthesia and neonatologists to discuss project goals and implementation strategy October 2015 to April 2016 
Order set (intervention A) Approval of IV acetaminophen and reduction of postoperative opioid infusions May 2016 
Education sessions (intervention B) Postoperative pain management seminars at nurse staff meetings and NICU and/or surgery conferences May 2016 (current) 
Standardized handoff (intervention C) Standardized NICU postsurgical handoff attended by anesthesia, surgery, and NICU staff May 2016 (current) 

The intervention was centered on standing IV acetaminophen administration as the primary pain management tool. Acetaminophen was dosed by postnatal age and weight. For neonates <28 days old (minimum: 32 weeks’ gestational age), 12.5 mg/kg of IV acetaminophen was administered every 6 hours for 8 doses. A maximum dose of 50 mg/kg per day from all sources of acetaminophen was implemented. For infants >28 days old, 15 mg/kg of IV acetaminophen was given every 6 hours for 9 doses, with a maximum daily dose of 60 mg/kg per day. Intermittent IV fentanyl was similarly weight based at 1 to 5 µg/kg and made available on an as-needed basis. If pain control was not considered adequate by the bedside nurse and NICU practitioner, then a fentanyl infusion was started.

We examined all infants admitted to our NICU with nonemergent gastrointestinal study from January 2012 to September 2019. Our intervention evaluation period began in May 2016. Baseline data on patients from January 2012 to April 2016 (preintervention cohort) were obtained by retrospective chart review; data on patients from May 2016 to September 2019 (postintervention cohort) were obtained prospectively.

Patients in either cohort were included if they were admitted to the NICU at the time of surgery and underwent a nonurgent gastrointestinal operation (included pathology and operations are listed in Supplemental Table 5). Patients with comorbid conditions of prematurity and cardiac anomalies were included in the analysis. Neonates of all ages and weights were included. Patients who underwent thoracic cases, congenital diaphragmatic hernia repair, or emergent operations (eg, emergent Ladd’s procedure for volvulus) were excluded. They were also excluded if they had a terminal disorder unrelated to their direct surgical pathology.

The primary outcome measure of our intervention was cumulative postoperative opioid use, whereas the primary balancing measure was individual pain scores over the first 48 postoperative hours. Secondary outcomes included clinical and postoperative outcomes to reveal the safety of our intervention. Postoperative bronchial pneumonia, sepsis, and surgical-site infection were considered positive if listed as the primary diagnosis by either the NICU team or pediatric surgery team and if the patient received treatment of at least 5 days’ duration for the infection. Postoperative acute kidney injury (AKI) was defined by using the Kidney Disease: Improving Global Outcomes definition as anything greater than a 1.5-fold increase or >0.3-mg/dL rise in serum creatinine levels from a preoperative baseline (stage 1 and above).16  Postoperative acute hepatic injury was defined as a 10-fold increase in either alanine aminotransferase or aspartate transaminase levels from preoperative baseline levels.

Morphine equivalents were calculated by individual conversion of all opioid sources, including oral doses, to morphine equivalents and then by summing across the respective time period. The majority of postoperative opioids were administered as fentanyl, which was converted from 1 μg of IV fentanyl to 0.1 mg of IV morphine equivalents. The N-PASS is a validated tool used to determine sedation and agitation levels in infants who are critically ill by using a composite assessment of crying, behavior, facial expression, extremity tone, and vital signs.17  The score ranges from −10 (deep sedation) to +10 (extreme pain and/or agitation). The same N-PASS scoring system was used across our study period.

Process control charts were created for our primary and secondary outcomes, including cumulative postoperative opiates, use of postoperative opioid infusions, and median N-PASS scores. For continuous outcome variables, individuals and moving range (X and mR) charts of individual patient data were used. The centerline and upper and lower confidence levels were fixed after the first 25 data points (preintervention cohort) to determine if a shift occurred after our opioid reduction intervention. Nelson rules were used to determine if our process revealed a shift after our intervention.18  For our binary postoperative opioid infusion variable, we plotted a run chart of the proportion of patients who received an opioid infusion by subgroups of 5. Process control figures were created by using the QIMacros package (KnowWare International, Inc, Denver, CO) in Microsoft Excel 2016 (Microsoft Corporation, Redmond, WA).

Patient demographics and clinical outcomes were additionally summarized by using mean and SD for parametric data and median and interquartile range (IQR) for nonparametric data. Student’s t test, Wilcoxon rank test, and Fisher’s exact test were used to determine the significance between the pre- and postintervention cohorts. All tests were considered 2-sided, and a P value of .05 was considered significant. SAS version 9.4 (SAS Institute, Inc, Cary, NC) was used for all analysis.

Formal approval was sought and obtained from our institutional review board before proceeding with our study intervention (University of Virginia Institutional Review Board 12351).

Seventy-seven neonates were included in the study: 40 in the preintervention group and 37 in the postintervention group. Patient characteristics, by cohort, are included in Table 2. The 2 groups were appropriately matched, and there was no statistical difference in the preoperative data we collected, including age; weight; appearance, pulse, grimace, activity, and respiration (Apgar) score; and American Society of Anesthesiologists classification. The most common indications for surgery were intestinal atresia, sequela of necrotizing enterocolitis, Hirschsprung disease, and anorectal malformations.

TABLE 2

Patient Characteristics in Opioid Reduction Post- and Preintervention Cohorts

Patient CharacteristicPreintervention Group, n = 40Postintervention Group, n = 37Statistical Significance, P
Gestational age at birth, wk, mean (SD) 33.29 (6.14) 34.03 (6.34) .601 
Age at operation, d, median (IQR) 15.5 (4.5–77.5) 14 (5–94) .850 
Birth wt, kg, mean (SD) 2.13 (1.19) 2.11 (1.35) .445 
Wt at operation, kg, mean (SD) 2.80 (0.81) 3.03 (0.78) .204 
Sex (female), n (%) 20 (50.0) 22 (59.4) .494 
1-min Apgar score, median (IQR) 7 (5.5–8) 7 (4–8) .323 
5-min Apgar score, median (IQR) 8 (7–9) 9 (7.5–9) .454 
American Society of Anesthesiologists score, median (IQR) 3 (2–3) 3 (3–3) .937 
Cardiac anomaly, n (%) 5 (12.5) 5 (13.5) .895 
Ventilator dependency at operation, n (%) 3 (7.5) 4 (10.8) .614 
Patient CharacteristicPreintervention Group, n = 40Postintervention Group, n = 37Statistical Significance, P
Gestational age at birth, wk, mean (SD) 33.29 (6.14) 34.03 (6.34) .601 
Age at operation, d, median (IQR) 15.5 (4.5–77.5) 14 (5–94) .850 
Birth wt, kg, mean (SD) 2.13 (1.19) 2.11 (1.35) .445 
Wt at operation, kg, mean (SD) 2.80 (0.81) 3.03 (0.78) .204 
Sex (female), n (%) 20 (50.0) 22 (59.4) .494 
1-min Apgar score, median (IQR) 7 (5.5–8) 7 (4–8) .323 
5-min Apgar score, median (IQR) 8 (7–9) 9 (7.5–9) .454 
American Society of Anesthesiologists score, median (IQR) 3 (2–3) 3 (3–3) .937 
Cardiac anomaly, n (%) 5 (12.5) 5 (13.5) .895 
Ventilator dependency at operation, n (%) 3 (7.5) 4 (10.8) .614 

Statistical significance determined by either Wilcoxon rank test or Student’s t test, as appropriate.

Postoperative opioid use was significantly reduced in the postintervention group, as revealed by the reduction in mean opioid rates in the X and mR control charts after the intervention (Fig 1). By direct cohort analysis, the median postoperative morphine equivalent dose was reduced from 7.96 mg/kg (IQR: 3.31–15.40) to 0.095 mg/kg (IQR: 0.0–0.25) in the postintervention group (P < .0001) (Table 3). The result appears to be, in part, due to the decrease in the proportion of children receiving continuous postoperative opioid infusions (Fig 2) (13.5% in postintervention group versus 87.5% in preintervention group; P < .0001). Importantly, the N-PASS scores were equivalent in the 2 cohorts across the study period, with no changes in the X and mR charts after the intervention (Fig 3).

FIGURE 1

A and B, X and mR process control charts of cumulative postoperative morphine equivalents (milligrams per kilogram). The x-axis represents individual patient data, which are chronologically ordered by date of surgery. The centerline and confidence intervals are set from the first 25 data points in the preintervention cohort. The intervention period began in May 2016, which is delineated by a blue vertical line. UCL, upper control limit.

FIGURE 1

A and B, X and mR process control charts of cumulative postoperative morphine equivalents (milligrams per kilogram). The x-axis represents individual patient data, which are chronologically ordered by date of surgery. The centerline and confidence intervals are set from the first 25 data points in the preintervention cohort. The intervention period began in May 2016, which is delineated by a blue vertical line. UCL, upper control limit.

Close modal
TABLE 3

Pain Control Data in Opioid Reduction Post- and Preintervention Cohorts

Pain Control CategoryPreintervention Group, n = 40Postintervention Group, n = 37Statistical Significance, P
Intraoperative morphine equivalents, mg/kg, median (IQR) 0.296 (0.027–0.570) 0.305 (0.039–0.770) .675 
Postoperative morphine equivalents, mg/kg, median (IQR) 7.964 (3.312–15.401) 0.095 (0.0–0.248) <.0001* 
Patients placed on postoperative opioid infusion, n (%) 35 (87.5) 5 (13.5) <.0001* 
Patient who received no postoperative opioids, n (%) 4 (10.0) 13 (35.1) .0079* 
Postoperative midazolam equivalents, mg/kg, median (IQR) 0.0 (0.0–0.156) 0.0 (0.0–0.0) .0142* 
Postoperative acetaminophen, mg/kg, median (IQR) 0.0 (0.0–122.45) 226.77 (89.65–289.52) <.0001* 
N-PASS pain scale, n 39 32 — 
 0–24 h, median (IQR) 0 (0–1) 0 (0–1) .891 
 24–48 h, median (IQR) 0 (0–1) 0 (0–1) .382 
 Maximum, median (IQR) 5 (1–6) 3 (1–5) .468 
Pain Control CategoryPreintervention Group, n = 40Postintervention Group, n = 37Statistical Significance, P
Intraoperative morphine equivalents, mg/kg, median (IQR) 0.296 (0.027–0.570) 0.305 (0.039–0.770) .675 
Postoperative morphine equivalents, mg/kg, median (IQR) 7.964 (3.312–15.401) 0.095 (0.0–0.248) <.0001* 
Patients placed on postoperative opioid infusion, n (%) 35 (87.5) 5 (13.5) <.0001* 
Patient who received no postoperative opioids, n (%) 4 (10.0) 13 (35.1) .0079* 
Postoperative midazolam equivalents, mg/kg, median (IQR) 0.0 (0.0–0.156) 0.0 (0.0–0.0) .0142* 
Postoperative acetaminophen, mg/kg, median (IQR) 0.0 (0.0–122.45) 226.77 (89.65–289.52) <.0001* 
N-PASS pain scale, n 39 32 — 
 0–24 h, median (IQR) 0 (0–1) 0 (0–1) .891 
 24–48 h, median (IQR) 0 (0–1) 0 (0–1) .382 
 Maximum, median (IQR) 5 (1–6) 3 (1–5) .468 

Statistical significance determined by either Wilcoxon rank test or Student’s t test as appropriate. —, not applicable.

*

Denotes statistical significance.

FIGURE 2

Run chart of the proportion of patients who received a postoperative opioid infusion in subgroups (n = 5). The x-axis represents individual subgroups, which are chronologically ordered by date of surgery. The intervention period began in May 2016, which is delineated by a blue vertical line and highlights the first postintervention cohort.

FIGURE 2

Run chart of the proportion of patients who received a postoperative opioid infusion in subgroups (n = 5). The x-axis represents individual subgroups, which are chronologically ordered by date of surgery. The intervention period began in May 2016, which is delineated by a blue vertical line and highlights the first postintervention cohort.

Close modal
FIGURE 3

A and B, X and mR process control charts of the median postoperative N-PASS score from 0 to 48 hours. The x-axis represents individual patient data, which are chronologically ordered by date of surgery. The centerline and confidence intervals are set from the first 25 data points in the preintervention cohort. The intervention period began in May 2016, which is delineated by a blue vertical line. LCL, lower control limit; UCL, upper control limit.

FIGURE 3

A and B, X and mR process control charts of the median postoperative N-PASS score from 0 to 48 hours. The x-axis represents individual patient data, which are chronologically ordered by date of surgery. The centerline and confidence intervals are set from the first 25 data points in the preintervention cohort. The intervention period began in May 2016, which is delineated by a blue vertical line. LCL, lower control limit; UCL, upper control limit.

Close modal

There were no statistical differences in surgical morbidity or mortality or in medical complications, including sepsis, AKI, liver injury, or pneumonia, by cohort analysis (Table 4). Postoperative intubation was reduced by 24 hours in our postintervention group (4 hours [IQR: 0.0–20.0] compared with 28.5 hours [IQR: 0.0–96.0]; P = .048). In addition, the intervention correlated with a reduction in postoperative length of total parenteral nutrition (TPN) from 14.75 days (IQR: 6.75–23.75) to 7.0 days (IQR: 3.5–15.0) (P = .017). There was no statistical difference in postoperative length of stay (P = .380).

TABLE 4

Postoperative Outcomes and Safety Profile in Opioid Reduction Post- and Preintervention Cohorts

Clinical ParameterPreintervention Group, n = 40Postintervention Group, n = 37Statistical Significance, P
Total LOS, d, median (IQR) 45.5 (17–121.5) 36 (14–115) .438 
Postoperative LOS, d, median (IQR) 22 (11–37.5) 19 (8–35) .380 
Postoperative intubation, h, median (IQR) 28.5 (0.0–96.0) 4 (0.0–20.0) .048* 
Postoperative TPN, d, median (IQR) 14.75 (6.75–23.75) 7 (3.5–15.0) .017* 
30-d mortality, % — 
SSI, n (%) 3 (7.5) 1 (2.7) .343 
AKI, n (%) 1 (2.5) .333 
Acute postoperative hepatic injury, % — 
Sepsis, n (%) 2 (5.0) 2 (5.4) .936 
Pneumonia, n (%) 2 (5.0) .168 
Unplanned reoperation, n (%) 2 (5.0) 2 (5.4) .936 
Unplanned readmission, n (%) 4 (10.0) 3 (8.1) .773 
Clinical ParameterPreintervention Group, n = 40Postintervention Group, n = 37Statistical Significance, P
Total LOS, d, median (IQR) 45.5 (17–121.5) 36 (14–115) .438 
Postoperative LOS, d, median (IQR) 22 (11–37.5) 19 (8–35) .380 
Postoperative intubation, h, median (IQR) 28.5 (0.0–96.0) 4 (0.0–20.0) .048* 
Postoperative TPN, d, median (IQR) 14.75 (6.75–23.75) 7 (3.5–15.0) .017* 
30-d mortality, % — 
SSI, n (%) 3 (7.5) 1 (2.7) .343 
AKI, n (%) 1 (2.5) .333 
Acute postoperative hepatic injury, % — 
Sepsis, n (%) 2 (5.0) 2 (5.4) .936 
Pneumonia, n (%) 2 (5.0) .168 
Unplanned reoperation, n (%) 2 (5.0) 2 (5.4) .936 
Unplanned readmission, n (%) 4 (10.0) 3 (8.1) .773 

Statistical significance determined by either Wilcoxon rank test, Student’s t test, or Fisher’s exact test, as appropriate. LOS, length of stay; SSI, surgical-site infection; —, not applicable.

*

Denotes statistical significance.

Our opioid reduction strategy reduced postoperative opioid administration in neonates undergoing nonemergent gastrointestinal surgery. Provider education coupled with delivering postoperative analgesia with standing IV acetaminophen as the primary postoperative pain modality led to a 98% reduction in opiate use. In addition, 35% of neonates in our postintervention group did not receive a single postoperative opioid dose. Despite reducing opioid use, N-PASS scores remained identical in the pre- and postintervention groups. This suggests that there was no difference in the efficacy of postoperative pain control. Intraoperative dosing of opiates was not changed. This was not the focus of our intervention because our anesthesia colleagues believe that delivering opiate analgesia intraoperatively allows for a smooth transition after emergence from anesthesia without a significant pain crisis.

The cause of opiate reduction in our postintervention group is likely multifactorial. We undertook a team approach to managing pain instead of relying on the individual provider’s discretion on a pain control regimen. This led to a reduction in the heterogeneity of our practice, as appreciated by the significant variability in the preintervention period compared with the relative consistency in the postintervention period of our X and mR charts (Fig 1). IV acetaminophen administered as a standing medication was an effective substitute to the standard opioid infusions previously used at our institution. Reducing the use of opioid infusions as a primary pain control modality was likely responsible for the large effect size seen in our quality improvement intervention. Interestingly, although it was not the main aspect of our intervention, by standardizing the postoperative pain protocol, we also significantly reduced the use of postoperative benzodiazepines for sedation.

Multiple investigations have been performed to evaluate the use of acetaminophen on postoperative pain management in children. However, various administration routes, different patient populations (including varying ages), and different surgeries have led to heterogenous results. Several studies have revealed no effect on opioid reduction after interventions that included acetaminophen administration.13,1921  In a patient population similar to that in our own investigation, a group performed a randomized study of rectal acetaminophen in infants (0 to 2 month old) undergoing major thoracic (noncardiac) or abdominal surgery.13  The group did not find an opioid sparing effect from the intervention, although the acetaminophen administration was in addition to a continuous morphine infusion, which may have mitigated the beneficial effects of acetaminophen. It is also notably different from our study, in which acetaminophen was the primary postoperative pain management medication, with opioids used as a rescue medication.

Other studies have revealed reduced opioids in pediatric and neonatal populations with acetaminophen administration.14,15,22,23  In a randomized trial of 71 infants <1 year of age undergoing major thoracic (noncardiac) or abdominal surgery, investigators demonstrated that IV acetaminophen reduced cumulative postoperative morphine by 66%.14  The group further demonstrated that pain scores were equivalent in both groups and that the intervention was safe. Because of these findings, we selected IV acetaminophen as our primary pain management medication.

An important part of our protocol was the provider education meetings on pain control and our post procedure provider sign-out. This has been suggested to be helpful in other studies. Authors noted that implementing procedural pain guidelines in a surgical NICU population for infants reduced cumulative morphine equivalent doses by ∼50%.15  In addition, an investigation of a nurse-managed comfort protocol in ventilated neonates was also found to reduce overall opioid use.24 

We found similar postoperative and clinical outcomes between our pre- and postintervention group, suggesting our intervention was safe for neonates. There were no differences in liver or kidney injury. Postoperative infections were similar, and there were no 30-day postoperative mortalities in either cohort. Multiple investigations have revealed an appropriate safety profile of therapeutically dosed acetaminophen in neonates and children.2528  We closely evaluated any potential hepatic injury in our postintervention group. However, we did not find any cases of clinically significant hepatic injury, including no instances of postoperative transaminitis (transaminase level >100 U/L) after acetaminophen administration.

The significant reduction of postoperative opioid use in our study appears to correlate with a reduction in postoperative ventilation, which was reduced by ∼24 hours in our postintervention group. Similarly, postoperative TPN administration was also reduced by ∼7 days in our postintervention group. These findings are similar to those found in the Neurologic Outcomes and Pre-emptive Analgesia in Neonates (NEOPAIN) trial, in which authors reported a significant increase in ventilation days and TPN requirement in ventilated preterm infants randomly assigned to receive preemptive morphine treatment.9  Importantly, there were no new major NICU interventions instituted during the time period that could directly account for the reduced ventilator days and TPN.

The biggest challenge of our quality improvement project was getting IV acetaminophen approved by the pharmacy team. Given concern for the price of the medication, IV acetaminophen could originally only be ordered on an individual basis through a pharmacist at our institution. We were able to overcome this by first presenting our proposed protocol to the pain subcommittee at our institution. With their involvement, we found that we could reuse a single bottle of IV acetaminophen (1000-mg vial) for multiple postoperative doses. This brought the overall cost of the intervention down.

The next challenge was to work with our bedside providers to explain our goal of reducing opiate use while still adequately controlling pain. We had multiple meetings discussing postoperative pain management. We discussed the clinical benefits and better safety profile of reduced opioid use. There was some initial reluctance because opiates have been the primary analgesic for the past few decades. However, obtaining IV acetaminophen approval allowed for a primary substitute for pain control and helped with acceptance and participation from all providers.

Limitations to our study include our nonrandomized, single-institution study design. However, given the robust effect on opioid reduction after our pharmacologic and education-based intervention, we believe our intervention will be applicable to other institutions and clinical scenarios. We purposely used a simultaneous, bundled intervention to reduce opioids in neonates; as such, it was not possible to separate the individual effect of these interventions. Additionally, the nursing staff, who are responsible for determining the neonate’s pain score and administering available opioid boluses, received specific education and were made aware of our desire to reduce opiate use. This could potentially lead to a bias in underreporting pain scores. However, the nursing staff was encouraged to report pain scores honestly and to use available opiates when they felt that pain was not controlled. Lastly, the neonatal patient population is clinically heterogenous. To address this, we limited our intervention to elective gastrointestinal surgery, although validating these results in other large-volume centers remains necessary.

Future directions for our project include investigating additional interventions that may reduce postoperative opioid use in neonates, such as the integration of regional blocks. We are also currently expanding our protocol to include other nonverbal children undergoing elective surgery, including patients with thoracic cases and non-NICU populations. Lastly, we are currently working on a formalized enhanced recovery protocol for neonates undergoing elective gastrointestinal surgery that involves pre-, intra-, and postoperative phases of care.

Neonates are a vulnerable patient population. With potential adverse effects of opiate use on their neurodevelopment, as well as the known side effects of slower gastrointestinal motility and respiratory depression, it is essential to limit opioids in these postoperative patients. A protocol of provider education, standing IV acetaminophen, and reduction of the use of routine postoperative opioid infusions has aided in reducing the use of opiates. This appears to aid in reducing length of intubation and need for TPN. We believe similar interventions may be equally effective at other institutions and in other postoperative neonatal populations.

We thank Dr Eric Schneider in the Department of Surgery for his expert assistance in study design and statistical analysis. We also thank the entire Neonatal Care Team that was essential in implementing this clinical improvement initiative.

Dr Grabski was responsible for the study design, data collection, data analysis, and initial draft of the manuscript; Dr Vavolizza was responsible for primary data collection, data analysis, and assistance on drafting the manuscript; Ms Lepore was responsible for conceptualization of the project, project design, interpretation of data, and critical review of the manuscript; Drs Levin and Rasmussen were responsible for conceptualization of the project, supervising data collection, interpretation of data, and critical review of the manuscript; Dr Swanson conceptualized the initial study design, interpreted the results, and was responsible for critical review of the manuscript for important intellectual content; Dr McGahren assisted in supervision of data collection, assisted analysis and interpretation of data, and critically reviewed the manuscript; Dr Gander was responsible for original conception and design, oversaw acquisition and primary analysis of the data, and drafted the initial manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: Supported by The National Cancer Institute Training grant (T32 CA163177). Funded by the National Institutes of Health (NIH).

     
  • AKI

    acute kidney injury

  •  
  • Apgar

    appearance, pulse, grimace, activity, and respiration

  •  
  • IQR

    interquartile range

  •  
  • IV

    intravenous

  •  
  • N-PASS

    Neonatal Pain, Agitation, and Sedation Scale

  •  
  • TPN

    total parenteral nutrition

  •  
  • X and mR

    individuals and moving range

1
Sømme
S
,
Bronsert
M
,
Morrato
E
,
Ziegler
M
.
Frequency and variety of inpatient pediatric surgical procedures in the United States
.
Pediatrics
.
2013
;
132
(
6
).
2
Hall
RW
,
Shbarou
RM
.
Drugs of choice for sedation and analgesia in the neonatal ICU [published correction appears in Clin Perinatol. 2009;36(2):xvii]
.
Clin Perinatol
.
2009
;
36
(
1
):
15
26
3
Lago
P
,
Frigo
AC
,
Baraldi
E
, et al
.
Sedation and analgesia practices at Italian neonatal intensive care units: results from the EUROPAIN study
.
Ital J Pediatr
.
2017
;
43
(
1
):
26
4
Berde
CB
,
Jaksic
T
,
Lynn
AM
,
Maxwell
LG
,
Soriano
SG
,
Tibboel
D
.
Anesthesia and analgesia during and after surgery in neonates
.
Clin Ther
.
2005
;
27
(
6
):
900
921
5
Ferguson
SA
,
Ward
WL
,
Paule
MG
,
Hall
RW
,
Anand
KJ
.
A pilot study of preemptive morphine analgesia in preterm neonates: effects on head circumference, social behavior, and response latencies in early childhood
.
Neurotoxicol Teratol
.
2012
;
34
(
1
):
47
55
6
Steinhorn
R
,
McPherson
C
,
Anderson
PJ
,
Neil
J
,
Doyle
LW
,
Inder
T
.
Neonatal morphine exposure in very preterm infants-cerebral development and outcomes
.
J Pediatr
.
2015
;
166
(
5
):
1200
1207.e4
7
Bellù
R
,
de Waal
K
,
Zanini
R
.
Opioids for neonates receiving mechanical ventilation: a systematic review and meta-analysis
.
Arch Dis Child Fetal Neonatal Ed
.
2010
;
95
(
4
):
F241
F251
8
Boom
M
,
Niesters
M
,
Sarton
E
,
Aarts
L
,
Smith
TW
,
Dahan
A
.
Non-analgesic effects of opioids: opioid-induced respiratory depression
.
Curr Pharm Des
.
2012
;
18
(
37
):
5994
6004
9
Anand
KJ
,
Hall
RW
,
Desai
N
, et al.;
NEOPAIN Trial Investigators Group
.
Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial
.
Lancet
.
2004
;
363
(
9422
):
1673
1682
10
Thiele
RH
,
Rea
KM
,
Turrentine
FE
, et al
.
Standardization of care: impact of an enhanced recovery protocol on length of stay, complications, and direct costs after colorectal surgery [published correction appears in J Am Coll Surg. 2015;220(5):986]
.
J Am Coll Surg
.
2015
;
220
(
4
):
430
443
11
Martin
LW
,
Sarosiek
BM
,
Harrison
MA
, et al
.
Implementing a thoracic enhanced recovery program: lessons learned in the first year
.
Ann Thorac Surg
.
2018
;
105
(
6
):
1597
1604
12
Shinnick
JK
,
Short
HL
,
Heiss
KF
,
Santore
MT
,
Blakely
ML
,
Raval
MV
.
Enhancing recovery in pediatric surgery: a review of the literature
.
J Surg Res
.
2016
;
202
(
1
):
165
176
13
van der Marel
CD
,
Peters
JW
,
Bouwmeester
NJ
,
Jacqz-Aigrain
E
,
van den Anker
JN
,
Tibboel
D
.
Rectal acetaminophen does not reduce morphine consumption after major surgery in young infants
.
Br J Anaesth
.
2007
;
98
(
3
):
372
379
14
Ceelie
I
,
de Wildt
SN
,
van Dijk
M
, et al
.
Effect of intravenous paracetamol on postoperative morphine requirements in neonates and infants undergoing major noncardiac surgery: a randomized controlled trial
.
JAMA
.
2013
;
309
(
2
):
149
154
15
Rana
D
,
Bellflower
B
,
Sahni
J
, et al
.
Reduced narcotic and sedative utilization in a NICU after implementation of pain management guidelines
.
J Perinatol
.
2017
;
37
(
9
):
1038
1042
16
Khwaja
A
.
KDIGO clinical practice guidelines for acute kidney injury
.
Nephron Clin Pract
.
2012
;
120
(
4
):
c179
c184
17
Hillman
BA
,
Tabrizi
MN
,
Gauda
EB
,
Carson
KA
,
Aucott
SW
.
The Neonatal Pain, Agitation and Sedation Scale and the bedside nurse’s assessment of neonates
.
J Perinatol
.
2015
;
35
(
2
):
128
131
18
Nelson
LS
.
The Shewhart control chart—tests for special causes
.
Journal of Quality Technology
.
1984
;
16
(
4
):
238
239
19
Bremerich
DH
,
Neidhart
G
,
Heimann
K
,
Kessler
P
,
Behne
M
.
Prophylactically-administered rectal acetaminophen does not reduce postoperative opioid requirements in infants and small children undergoing elective cleft palate repair
.
Anesth Analg
.
2001
;
92
(
4
):
907
912
20
Morton
NS
,
O’Brien
K
.
Analgesic efficacy of paracetamol and diclofenac in children receiving PCA morphine
.
Br J Anaesth
.
1999
;
82
(
5
):
715
717
21
Korpela
R
,
Silvola
J
,
Laakso
E
,
Meretoja
OA
.
Oral naproxen but not oral paracetamol reduces the need for rescue analgesic after adenoidectomy in children
.
Acta Anaesthesiol Scand
.
2007
;
51
(
6
):
726
730
22
Korpela
R
,
Korvenoja
P
,
Meretoja
OA
.
Morphine-sparing effect of acetaminophen in pediatric day-case surgery
.
Anesthesiology
.
1999
;
91
(
2
):
442
447
23
Maund
E
,
McDaid
C
,
Rice
S
,
Wright
K
,
Jenkins
B
,
Woolacott
N
.
Paracetamol and selective and non-selective non-steroidal anti-inflammatory drugs for the reduction in morphine-related side-effects after major surgery: a systematic review
.
Br J Anaesth
.
2011
;
106
(
3
):
292
297
24
Fleishman
R
,
Zhou
C
,
Gleason
C
,
Larison
C
,
Myaing
MT
,
Mangione-Smith
R
.
Standardizing morphine use for ventilated preterm neonates with a nursing-driven comfort protocol
.
J Perinatol
.
2015
;
35
(
1
):
46
51
25
Anderson
BJ
,
van Lingen
RA
,
Hansen
TG
,
Lin
YC
,
Holford
NH
.
Acetaminophen developmental pharmacokinetics in premature neonates and infants: a pooled population analysis
.
Anesthesiology
.
2002
;
96
(
6
):
1336
1345
26
Palmer
GM
,
Atkins
M
,
Anderson
BJ
, et al
.
I.V. acetaminophen pharmacokinetics in neonates after multiple doses
.
Br J Anaesth
.
2008
;
101
(
4
):
523
530
27
Allegaert
K
,
Rayyan
M
,
De Rijdt
T
,
Van Beek
F
,
Naulaers
G
.
Hepatic tolerance of repeated intravenous paracetamol administration in neonates
.
Paediatr Anaesth
.
2008
;
18
(
5
):
388
392
28
Chen
L
,
Zhang
M
,
Yung
J
,
Chen
J
,
McNair
C
,
Lee
KS
.
Safety of rectal administration of acetaminophen in neonates
.
Can J Hosp Pharm
.
2018
;
71
(
6
):
364
369

Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

Supplementary data