Key PointsQuestion
Does intravenous (IV) acetaminophen administered prior to IV opioids reduce the total duration of IV opioids administered during a patient’s inpatient hospitalization?
Findings
In this comparative effectiveness research study including 893 293 hospitalized children, administration of IV acetaminophen prior to IV opioids was associated with a significant 15.5% reduction in total IV opioid duration when compared with administration of IV opioids alone.
Meaning
The results of this study suggest that IV acetaminophen administered prior to IV opioids should be considered in multimodal pain regimens because it may potentially reduce the total duration of IV opioids administered to hospitalized children.
Importance
Adoption of multimodal pain regimens that incorporate nonopioid analgesic medications to reduce inpatient opioid administration can prevent serious opioid-related adverse effects in children, including tolerance, withdrawal, delirium, and respiratory depression. Intravenous (IV) acetaminophen is in widespread pediatric use; however, its effectiveness as an opioid-sparing agent has not been evaluated in general pediatric inpatients.
Objective
To determine if IV acetaminophen administered prior to IV opioids is associated with a reduction in the total duration of IV opioids administered compared with IV opioids administered without IV acetaminophen in general pediatric inpatients.
Design, Setting, and Participants
This comparative effectiveness research study included data on pediatric inpatients from 274 US hospitals between January 2011 and June 2016 collected from a national database. Outcomes were compared with a propensity score–matched analysis of pediatric inpatients administered IV opioids without IV acetaminophen (control) and those administered IV acetaminophen prior to IV opioids (intervention). Data were analyzed from January 2020 through October 2021.
Exposures
Patients in the intervention group received IV acetaminophen prior to IV opioids. Patients in the control group received IV opioids without IV acetaminophen.
Main Outcomes and Measures
Total duration of all IV opioids administered during a patient’s hospitalization.
Results
Of 893 293 pediatric inpatients, a total of 104 579 were included in analysis (median [IQR] age, 1.3 [0-14.7] years; 59 806 [57.2%] female; 21 485 [21.5%] African American, 56 309 [53.8%] White), of whom 18 197 (2.0%) received IV acetaminophen, and 287 504 (34.0%) received IV opioids. After applying exclusion criteria, among patients who received IV acetaminophen, 1739 (10.8%) received IV acetaminophen prior to IV opioids within a median (IQR) treatment time of 1.5 (0.02-7.3) hours. After propensity score matching produced comparable groups in the control and intervention groups (with 839 patients in each group), the multivariable model estimated a 15.5% shorter duration of IV opioid use in the intervention group, with an absolute IV opioid reduction of 7.5 hours (95% CI, 0.7-15.8 hours).
Conclusions and Relevance
In this comparative effectiveness study, IV acetaminophen administered prior to IV opioids was associated with a reduction in IV opioid duration by 15.5%. Multimodal pain regimens that use IV acetaminophen prior to IV opioids could reduce IV opioid duration.
Opioid medications are a common therapeutic approach to alleviate pain in pediatric inpatients. A recent assessment of medication use in pediatric intensive care unit (ICU) patients found that 39.4% of all patients received opioid medications.1 While effective, opioid use may lead to adverse consequences including dependence, tolerance, and withdrawal, which can prolong ICU and hospital length of stay.2-6 Important short-term adverse effects include delirium, respiratory depression, oversedation, delayed gut motility, and urinary retention.6 Children experience these complications more frequently than adults, possibly because of developmental differences in metabolism, excretion, receptor subtypes, signal transduction, receptor induction, and cellular regulatory pathways.7-9
The importance and frequency of clinical opioid adverse effects and increased hospital length of stay has led to attempts to reduce opioid use. A prominent therapeutic approach uses multiple medications, most notably a nonopioid analgesic medication (with opioids reserved as second-line analgesic medications).10-12 Intravenous (IV) acetaminophen has been a common analgesic initiated prior to opioids in multimodal pain regimens with the purpose of reducing subsequent opioid requirements.13-16 However, assessments of the association between IV acetaminophen and opioid use in multimodal pain regimens have had conflicting results.13-15,17-21 In particular, randomized studies that compare treatment that initiates pain control with IV acetaminophen and supplements with opioids vs therapy initiated with opioids have been small with conflicting results.13,18,19,22 The aim of this analysis was to determine if the initiation of IV acetaminophen prior to IV opioids would result in a reduction in the total hospital duration of IV opioid use compared with IV opioid medications administered without IV acetaminophen in both operative and nonoperative pediatric inpatients in a national database. This analysis used a national database and propensity score matching.
For this comparative effectiveness study, we followed the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) reporting guideline for nonrandomized studies using large data sets.23 We defined the research question a priori, reported all research methodology, had no changes or modifications to our prespecified plan, and included interpretations to our findings in the discussion to aid in dissemination of this work to patient care and future research studies. The institutional review board at Children’s National Health System approved the study and granted a waiver of consent because data were deidentified.
The data set was derived from the Health Facts database (Cerner Corporation) that collects comprehensive deidentified clinical data on patient encounters from hospitals in the US with a Cerner data use agreement. Data are episodic and longitudinal and include date and time-stamped data including admission and demographic data, laboratory results, medication data derived from pharmacy records, diagnostic and procedure codes, vital signs, respiratory data, hospital outcome, and hospital and regional characteristics. Cerner Corporation has established Health Insurance Portability and Accountability Act compliance operating policies to establish deidentification of data. The database is representative of the US and inclusive of academic and nonacademic hospitals of varied sizes and locations, making it appropriate for comparative effectiveness research that is generalizable.24-27 The database has been used to study multiple aspects of pediatrics and pediatric medication practices.1,3,28-31 eAppendix 1 in the Supplement provides a detailed description of the data cleaning process, definitions, and hospital characteristics.
This assessment compared patients receiving IV opioids without IV acetaminophen (controls) to those receiving IV acetaminophen prior to IV opioids (intervention). The primary inclusion criteria were pediatric inpatients who received IV opioids between January 2011 and June 2016 with complete data on age, race, gender, temperature, International Classification of Diseases, Ninth Revision (ICD-9) or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnostic codes, and hospital and regional characteristics (Figure). Patients with incomplete data were excluded. Patients who received IV acetaminophen after IV opioids were also excluded because the treatment arm required IV acetaminophen to be administered prior to IV opioid medications. Ultimately, 274 hospitals donated data on 104 579 pediatric patients with complete data sets. January 2011 corresponded to the time IV acetaminophen became commercially available. Pediatric patients were defined as younger than 22 years at time of admission, consistent with the American Academy of Pediatrics’s definition of a pediatric patient.32
Variables and Outcome Measures
The variables included in the propensity score estimates consisted of age, race, gender, positive pressure ventilation, diagnostic category, operations category, temperature, admission year, hospital census region, hospital bed size, and hospital teaching status (Table 1; eFigure in the Supplement). Race was considered as a variable because previous studies have detailed differing opioid prescribing practices by comparing African American patients with White patients; race was stratified as African American, White, and other (including Asian, Asian and Pacific Islander, biracial, and missing). All variables included in the propensity score estimates were assessed prior to the start of follow-up, which was marked by the first dose of IV opioid in the control group or first dose of IV acetaminophen in the intervention group. Age was categorized into 4 groups: less than 2 years, 2 through 5 years, 6 through 12 years, and 13 up to 22 years. Positive pressure ventilation was identified from the Healthcare Common Procedure Coding System (HCPCS) and Current Procedural Terminology (CPT-4) codes; invasive and noninvasive positive pressure ventilation were assessed separately. Both the primary diagnosis and operative information were categorized by organ system. The primary diagnoses were categorized into 13 diagnostic groups from the ICD-9 and ICD-10 classifications.33 When the primary diagnostic group was diseases originating in childbirth or the perinatal period, the secondary and tertiary diagnostic codes were evaluated to classify the primary organ system of dysfunction. Operations were identified from ICD-9, ICD-10-Procedure Coding System, HCPCS, and CPT-4 codes. Initial temperature was used as a matching variable because IV acetaminophen is also used for fever. Hospital census region was the greatest level of regional data available in the database, represented by South, Midwest, West, or Northeast. Hospital bed size was categorized into 5 groups: less than 100, 100 to 199, 200 to 299, 300 to 499, and more than 500 beds. Teaching status was characterized as teaching hospital, nonteaching hospital, or unknown.
Medication data included the generic and brand name, national drug code, and time the medication was ordered and discontinued. Dosing was not evaluated because reliable per kilogram dosing information was not consistently available. Analgesic medications administered to patients were assessed individually and by medication class by linking the national drug code to the Multum classification (eAppendix 2 in the Supplement).34,35 Multum provides information about medications’ therapeutic action in 3 categories, from general mechanism of action to a specific therapeutic category. The duration of medication administration determined from pharmacy records was rounded to the nearest hour. If a single dose of medication was administered, the patient was considered to have received 1 hour of medication. If multiple orders of different IV opioid medications had overlapping administration times, the medication orders were summed and the overall length of administration was determined by the start and end time.
The primary outcome was IV opioid duration, with the first dose of IV opioid administration marking the start of the follow-up period. IV opioid duration was determined by the sum of all IV opioid durations in a patient’s hospitalization. If a patient was simultaneously receiving multiple different generic opioid medications, each medication course was summed to calculate the total duration. Cumulative duration was used as a measure of overall opioid receipt because per kilogram dosing was consistently unavailable.
A propensity score–matching analysis was performed to ensure balance between the control and intervention groups (eAppendix 2 in the Supplement). Propensity for receipt of IV acetaminophen was modeled using logistic regression for the following variables: age, race, gender, positive pressure ventilation, diagnostic category, operations category, temperature, admission year, census region, bed size, and teaching hospital status using data obtained prior to administration of IV acetaminophen or IV opioid. A 1-to-1 without replacement nearest-neighbor matching method was used. Forest plots were constructed to assess uniformity between the groups before and after matching (eFigure in the Supplement). Categorical variables were expressed as frequency and percentages and were compared using χ2 tests (Table 1). Odds ratios with 95% confidence intervals were calculated with a reference group.
Postmatching analyses assessed opioid duration via generalized linear models with log-linked γ distribution. A univariate analysis was first used to assess the association between each variable and opioid duration (Table 2). Those with significant differences were included in the multivariable model comparing the control and intervention groups with regard to IV opioid duration. We fitted a marginal model using hospital system identification numbers as a random effect to account for the clustered data structure. Compound-symmetry structure of covariance matrix was selected (which has constant variance and constant covariance), and empirical sandwich estimator was used to get standard errors of regression coefficients. We used the marginal model (generalized estimating equation type) because the goal was to estimate population-average effect rather than hospital-specific effect. The marginal model produced robust estimates regardless of the choice of covariance structure. P value for test of the random effect was <.001, indicating that the clustering effect was needed in the model. Length of stay was the only postbaseline characteristic included in the multivariable model, as it remained significantly different in the propensity-matched sample. Duration was log transformed to ensure normality. All statistical analyses were conducted using SAS software version 9.4 (SAS Institute). Significance was set to P < .05 in 2-sided tests.
IV opioid duration was evaluated in 104 579 pediatric inpatients from 274 hospitals with a median (IQR) age of 1.3 years (0-14.7 years); a total of 104 579 patients (57.2%) were female, 21 485 (21.5%) were African American and 56 309 (53.8%) were White. The post–propensity score sample included 1678 pediatric inpatients from 53 hospitals with a mean (SD) age of 13.9 (6.8) years, which included 796 (47.4%) female patients (Figure). A total of 893 293 pediatric inpatients were evaluated, of which 287 504 (34.0%) received IV opioids and 18 197 (2.0%) received IV acetaminophen. After excluding patients who did not receive IV opioids, patients without diagnostic information, and patients without hospital information, 118 908 pediatric inpatients received IV opioids, with 16 068 (13.5%) receiving IV acetaminophen. Among patients who received IV acetaminophen, 1739 (10.8%) received IV acetaminophen prior to IV opioids with a median (IQR) of 1.7 hours (0.03-8.4 hours) between IV acetaminophen administration and first dose of IV opioid. The 16 458 patients (89.2%) who received IV acetaminophen after their first dose of IV opioids were excluded from the final population of 104 579 pediatric inpatients who received IV opioids used for further analyses. When compared with those receiving IV opioids only in the univariate model, patients receiving IV acetaminophen followed by IV opioids were older (eg, ages 13 to 22 years: 59.1% [1027 patients] vs 56.4% [58 021 patients]; P < .001) and not mechanically ventilated (97.4% [1693 patients] vs 95.2% [97 858 patients]; P < .001); and were more likely to have a body temperature above 38° C (3.1% [54 patients] vs 1.7% [1706 patients]; P < .001); diagnoses in the musculoskeletal (7.5% [130 patients] vs 4.2% [4316 patients]; P < .001), digestive (19.8% [344 patients] vs 15.9% [16 334 patients]; P < .001), nervous (9.4% [163 patients] vs 6.7% [6582 patients]; P < .001), and endocrine systems (5.6% [198 patients] vs 4.1% [4250 patients]; P = .002); and musculoskeletal operations (7.5% [130 patients] vs 4.2% [4316 patients]; P < .001) (Table 1).
Propensity score estimates comparing patients administered IV opioid medications without IV acetaminophen (102 840 patients) and those administered IV acetaminophen followed by opioids (1912 patients) showed significant differences in most matching variables (Table 1; eFigure in the Supplement). Propensity score matching produced comparable groups with regard to matching variables, with a sample of 839 patients in each group. After matching, the predominant age group was between ages 13 and 22 years (996 patients [59.4%]), African American individuals represented 24.4% of the populations (572 patients), 796 patients (47.4%) were female, 31 (1.8%) received mechanical ventilator support, and 1534 (91.4%) had temperatures below 38.0° C prior to receipt of IV opioids or IV acetaminophen in the intervention and control groups. The 2 most common diagnostic categories were gastrointestinal disorders (323 patients [19.2%]) and injury and poisonings (336 patients [20.0%]), and the 2 most common operations were musculoskeletal (189 patients [11.3%]) and gastrointestinal (143 patients [8.5%]).
Prior to propensity score matching, the median (IQR) duration of IV opioid use in the control group was 30.5 hours (5.0-74.2 hours) and 29.4 hours (4.0-82.9 hours) in the intervention group (P = .65). After propensity score matching, median (IQR) duration of IV opioid use in the control group was 33.5 hours (5.4-74.0 hours) and for the intervention group was 27.7 hours (4.0-76.1 hours) (P = .41). The multivariable model after propensity score matching examined differences in IV opioid duration between the control and intervention groups. Significant univariate baseline variables established in a generalized linear mode were included in the multivariable model, which used health system identification numbers as a random effect to account for the clustered data structure (Table 2). We additionally controlled for hospital length of stay that was significantly different before and after propensity score matching (Table 3). After propensity score matching and adjusting for the aforementioned variables, there was a 15.5% shorter duration of IV opioid use in the intervention group vs the control group, an absolute reduction in IV opioid duration by 7.5 hours (95% CI, 0.7-15.8) in the intervention group when compared with the control group.
We assessed the efficacy of IV acetaminophen in reducing overall IV opioid use in pediatric inpatients using a propensity score–matched analysis from a large sample of a national database. To our knowledge, this is the first assessment of the opioid sparing association of IV acetaminophen in a general, real-world pediatric inpatient population. We found that IV acetaminophen administered prior to IV opioids was associated with a 15.5%, or 7.5-hour (95% CI, 0.7-15.8 hours), reduction in total IV opioid duration.
A propensity score–matched analysis is a practical and effective method to reduce selection bias in nonrandomized studies by matching the treatment and control groups for similar propensities for an intervention. In this analysis, they were matched for their propensity to receive IV acetaminophen. The covariates used to estimate the propensity score were age, race, gender, positive pressure ventilation, diagnostic category, operation category, and temperature. The propensity score was then used in a multivariable regression analysis to compare opioid durations when IV acetaminophen was used prior to opioids or not used.
The reduction in IV opioid duration in the group that received IV acetaminophen prior to IV opioid medications confirms several small pediatric and larger adult trials that reported a reduction in opioid utilization when opioids were preceded by IV acetaminophen.13,14,16,18,20,22,36,37 Prior pediatric trials of IV acetaminophen primarily focused on specific postoperative patient populations, such as spinal fusions and tonsillectomies, with only 1 trial focusing on nonoperative patients, a cohort of sickle cell patients.13-15,17 Our inclusion of both operative and nonoperative pediatric inpatients adds to the generalizability of the results. The results of the propensity score method support the general therapeutic approach of incorporating IV acetaminophen prior to IV opioid medications to achieve a reduction in overall opioid use. However, the results of this study may not be applicable to specific subpopulations of pediatric inpatients.
Reducing opioid medication administration can be beneficial in preventing drowsiness, postoperative nausea and vomiting, ileus, respiratory depression, bladder dysfunction, and prolonged immobilization in the short-term as well as long-term dependency.2,6,38,39 While opioids have been a mainstay of pain control, recommendations from numerous professional organizations have advocated multimodal pain control regimens such as the one tested in this analysis.4,40,41
This study had several limitations, some of which are associated with large data repositories. First, medication use was determined from pharmacy records, not assessed through patient medication administration records. Second, our primary outcome was duration of opioid use, not cumulative opioid dose, because weight-based dosing was not available. Third, the effectiveness of the therapeutic regimens was not assessed because pain scores were unavailable. Fourth, propensity score matching cannot account for unobserved variables, and it is possible that there remain unmeasured differences between the treatment arms that contribute to the observed findings. Fifth, while we believe the results are generalizable, they may not hold for all groups of patients.
To our knowledge, this is the first study to use a propensity score–matched analysis to evaluate the association of administering IV acetaminophen prior to IV opioid medications with opioid duration in pediatric inpatients. Our results found that IV acetaminophen was associated with an overall reduction in IV opioid duration, suggesting that there could be a benefit to introducing this medication early in multimodal pain regimens, with the ultimate goal of minimizing IV opioid exposure in pediatric inpatients.
Accepted for Publication: October 17, 2021.
Published: December 21, 2021. doi:10.1001/jamanetworkopen.2021.38420
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Patel AK et al. JAMA Network Open.
Corresponding Author: Anita K. Patel, MD, Division of Critical Care Medicine, Department of Pediatrics, Children’s National Medical Center, 111 Michigan Ave NW, Ste M4800, Washington, DC 20010 (apatel4@childrensnational.org).
Author Contributions: Drs Patel and Pollack had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Patel, Pollack.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Patel, Gai, Faruqe, Bost, Pollack.
Critical revision of the manuscript for important intellectual content: Patel, Gai, Trujillo-Rivera, Kim, Pollack.
Statistical analysis: Patel, Gai, Faruqe, Bost, Pollack.
Obtained funding: Patel, Pollack.
Administrative, technical, or material support: Patel, Faruqe, Kim.
Supervision: Patel, Pollack.
Conflict of Interest Disclosures: No disclosures were reported.
Funding/Support: Funding was provided, in part, by philanthropy from Mallinckrodt LLC, and by grants from the National Institutes of Health, National Center for Advancing Translational Sciences (Nos. Ul1TR001876 and KL2TR001877).
Role of the Funder/Sponsor: Neither Mallinckrodt LLC nor the National Center for Advancing Translational Sciences of the National Institutes of Health were responsible for or involved 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.
Disclaimer: Contents of the study are solely the responsibility of the authors and do not necessarily represent the official views of the National Center for Advancing Translational Sciences of the National Institutes of Health.
1.Patel
AK, Trujillo-Rivera
E, Faruqe
F,
et al. Sedation, analgesia, and neuromuscular blockade: an assessment of practices from 2009 to 2016 in a national sample of 66,443 pediatric patients cared for in the ICU.
Pediatr Crit Care Med. 2020;21(9):e599-e609. doi:
10.1097/PCC.0000000000002351Google ScholarCrossref 4.Harris
J, Ramelet
AS, van Dijk
M,
et al. Clinical recommendations for pain, sedation, withdrawal and delirium assessment in critically ill infants and children: an ESPNIC position statement for healthcare professionals.
Intensive Care Med. 2016;42(6):972-986. doi:
10.1007/s00134-016-4344-1PubMedGoogle ScholarCrossref 11.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. doi:
10.1093/bja/aeq406PubMedGoogle ScholarCrossref 13.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. doi:
10.1001/jama.2012.148050PubMedGoogle ScholarCrossref 15.Baichoo
P, Asuncion
A, El-Chaar
G. Intravenous acetaminophen for the management of pain during vaso-occlusive crises in pediatric patients.
P T. 2019;44(1):5-8.
PubMedGoogle Scholar 17.Hong
J-Y, Kim
WO, Koo
BN, Cho
JS, Suk
EH, Kil
HK. Fentanyl-sparing effect of acetaminophen as a mixture of fentanyl in intravenous parent-/nurse-controlled analgesia after pediatric ureteroneocystostomy.
Anesthesiology. 2010;113(3):672-677. doi:
10.1097/ALN.0b013e3181e2c34bPubMedGoogle ScholarCrossref 18.Rizkalla
N, Zane
NR, Prodell
JL,
et al. Use of Intravenous acetaminophen in children for analgesia after spinal fusion surgery: a randomized clinical trial.
J Pediatr Pharmacol Ther. 2018;23(5):395-404. doi:
10.5863/1551-6776-23.5.395PubMedGoogle Scholar 20.Jibril
F, Sharaby
S, Mohamed
A, Wilby
KJ. Intravenous versus oral acetaminophen for pain: systematic review of current evidence to support clinical decision-making.
Can J Hosp Pharm. 2015;68(3):238-247. doi:
10.4212/cjhp.v68i3.1458PubMedGoogle Scholar 21.Yung
A, Thung
A, Tobias
JD. Acetaminophen for analgesia following pyloromyotomy: does the route of administration make a difference?
J Pain Res. 2016;9:123-127. doi:
10.2147/JPR.S100607PubMedGoogle Scholar 23.Berger
ML, Mamdani
M, Atkins
D, Johnson
ML. Good research practices for comparative effectiveness research: defining, reporting and interpreting nonrandomized studies of treatment effects using secondary data sources: the ISPOR Good Research Practices for Retrospective Database Analysis Task Force report—part I.
Value Health. 2009;12(8):1044-1052. doi:
10.1111/j.1524-4733.2009.00600.xPubMedGoogle ScholarCrossref 27.Palmer
JB, Friedman
HS, Waltman Johnson
K, Navaratnam
P, Gottlieb
SS. Association of persistent and transient worsening renal function with mortality risk, readmissions risk, length of stay, and costs in patients hospitalized with acute heart failure.
Clinicoecon Outcomes Res. 2015;7:357-367. doi:
10.2147/CEOR.S82267PubMedGoogle Scholar 30.Kahn
AH, Gai
J, Faruqe
F, Bost
JE, Patel
AK, Pollack
MM. Pediatric mortality and acute kidney injury associated with chloride abnormalities in the intensive care unit.
J Pediatr Intensive Care. Published online November 23, 2020. doi:
10.1055/s-0040-1719172Google Scholar 34.Fung
KW, Kapusnik-Uner
J, Cunningham
J, Higby-Baker
S, Bodenreider
O. Comparison of three commercial knowledge bases for detection of drug-drug interactions in clinical decision support.
J Am Med Inform Assoc. 2017;24(4):806-812. doi:
10.1093/jamia/ocx010PubMedGoogle ScholarCrossref 36.Song
K, Melroy
MJ, Whipple
OC. Optimizing multimodal analgesia with intravenous acetaminophen and opioids in postoperative bariatric patients.
Pharmacotherapy. 2014;34(S1)(suppl 1):14S-21S. doi:
10.1002/phar.1517PubMedGoogle ScholarCrossref 37.Saurabh
S, Smith
JK, Pedersen
M, Jose
P, Nau
P, Samuel
I. Scheduled intravenous acetaminophen reduces postoperative narcotic analgesic demand and requirement after laparoscopic Roux-en-Y gastric bypass.
Surg Obes Relat Dis. 2015;11(2):424-430. doi:
10.1016/j.soard.2014.09.017PubMedGoogle ScholarCrossref 39.Sadhasivam
S, Chidambaran
V, Olbrecht
VA,
et al. Opioid-related adverse effects in children undergoing surgery: unequal burden on younger girls with higher doses of opioids.
Pain Med. 2015;16(5):985-997. doi:
10.1111/pme.12660PubMedGoogle ScholarCrossref 40.Barr
J, Fraser
GL, Puntillo
K,
et al; American College of Critical Care Medicine. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit.
Crit Care Med. 2013;41(1):263-306. doi:
10.1097/CCM.0b013e3182783b72PubMedGoogle ScholarCrossref 41.American Society of Anesthesiologists Task Force on Acute Pain Management. Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management.
Anesthesiology. 2012;116(2):248-273. doi:
10.1097/ALN.0b013e31823c1030PubMedGoogle ScholarCrossref