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Pediatr Crit Care Med. Author manuscript; available in PMC 2021 September 01.
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Published in final edited form as:

Pediatr Crit Care Med. 2020 September ; 21(9): e599–e609. doi:10.1097/PCC.0000000000002351.

Sedation, Analgesia and Neuromuscular Blockade: an

Assessment of Practices from 2009-2016 in a National Sample of
66,443 Pediatric Patients Cared for in the Intensive Care Unit.
Anita K Patel, MD,
Department of Pediatrics, Division of Critical Care Medicine, Children’s National Health System
and George Washington University School of Medicine and Health Sciences
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Eduardo Trujillo-Rivera, PhD,

George Washington University School of Medicine and Health Sciences

Farhana Faruqe, MS,

Children’s National Health System

Julia Heneghan, MD,

Department of Pediatrics, Division of Critical Care Medicine, Children’s National Health System
and George Washington University School of Medicine and Health Sciences

T. Elizabeth Workman, PhD,

George Washington University School of Medicine and Health Sciences

Qing Zeng-Treitler, PhD,

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George Washington University School of Medicine and Health Sciences

James Chamberlain, MD,

Department of Pediatrics, Division of Emergency Medicine, Children’s National Health System
and George Washington University School of Medicine and Health Sciences

Hiroki Morizono, Ph.D.,

Department of Genomics and Precision Medicine, GWU School of Medicine and Health Sciences

Dongkyu Kim, Ph.D.,

Department of Pediatrics, Children’s National Health System and George Washington University
School of Medicine and Health Sciences

James E. Bost, PhD,

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Children’s National Health System and George Washington University School of Medicine and
Health Sciences

Murray M. Pollack, MD
Department of Pediatrics, Division of Critical Care Medicine, Children’s National Health System
and George Washington University School of Medicine and Health Sciences

Correspondence to: Anita K Patel, MD, Children’s National Medical Center, 111 Michigan Ave NW Suite MZ4800, Washington,
DC 20010, Telephone: 202-476-6817, [email protected].
Conflict of Interest: There are no conflicts of interest to report for any authors of this manuscript.
 Patel et al. Page 2

Abstract
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Objectives: To describe the pharmaceutical management of sedation, analgesia, and

neuromuscular blockade medications administered to children in Intensive Care Units (ICUs).

Design: A retrospective analysis using data extracted from the national database Health Facts®
(Cerner Corporation, Kansas City, MO).

Setting: 161 ICUs in the United States with pediatric admissions.

Patients: Children in ICUs receiving medications from 2009 to 2016.

Exposure/Intervention: Frequency and duration of administration of sedation, analgesia, and

neuromuscular blockade medications.

Measurements and Main Results: Of 66,443 patients with a median age of 1.3 years (IQR
0-14.5); 63.3% (n = 42,070) received non-opioid analgesic, opioid analgesic, sedative and/or
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neuromuscular blockade medications consisting of 83 different agents. Opioid and non-opioid

analgesics were dispensed to 58.4% (n = 38,776) of which non-opioid analgesics were prescribed
to 67.4% (n = 26149). Median duration of opioid analgesic administration was 32 hours (IQR
7-92). Sedatives were dispensed to 39.8%% (n = 26,441) for a median duration of 23 hours (IQR
3-84), of which benzodiazepines were most common (73.4%, n =19,426). Neuromuscular
blocking agents were dispensed to 17.3% (n =11,517) for a median duration of 2 hours (IQR
1-15).Younger age was associated with longer durations in all medication classes. A greater
proportion of operative patients received these medication classes for a longer duration than non-
operative patients. A greater proportion of patients with musculoskeletal and hematologic/
oncologic diseases received these medication classes.

Conclusion: Analgesic, sedative and neuromuscular blocking medications were prescribed to

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63.3% of children in ICUs. The durations of opioid analgesic and sedative medication
administration found in this study can be associated with known complications, including
tolerance and withdrawal. Several medications dispensed to pediatric patients in this analysis are
in conflict with FDA warnings, suggesting that that there is potential risk in current sedation and
analgesia practice that could be reduced with practice changes to improve efficacy and minimize
risks.

Keywords
Sedation; Analgesia; Neuromuscular Blockade; Pediatrics; Pediatric Critical Care

Introduction:
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Numerous factors determine the practice of sedation, analgesia, and neuromuscular

blockade. In pediatric intensive care, age-related differences in perception and expression of
pain and anxiety, individual needs, therapeutic goals and the interaction of critical illness
physiology with medications result in diverse practice patterns that vary according to
physician preferences, training experience, and geography.1,2 Additionally, the treatment of
pain and alleviation of anxiety continue to undergo an evolution. For example, historical
perspectives from the 1960’s and 1970’s suggested that young children could not localize or

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 Patel et al. Page 3

remember painful stimuli, and therefore did not require analgesia to the same degree as
adults.3,4,5 Current practices focus on maximizing pain relief and treating anxiety consistent
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with a universal recognition that children experience pain and anxiety.6

Medications used for pain, sedation and neuromuscular blockade may alter risk profiles for
hemodynamic and respiratory instability affecting the course of critical illness, including the
duration of mechanical ventilation, unconsciousness, and dependency. These medications
are associated with serious critical care complications, including withdrawal, delirium and
immobility that can contribute to post-intensive care myopathy.7–9 Inadequate treatment of
pain can lead to a heightened inflammatory response as well as an exaggerated response to
future painful stimuli. 6,10–15 Pain and sedation medications can be useful to pre inadvertent
removal of invasive devices such as endotracheal tubes, and central venous catheters, and to
maintain ventilator synchrony.
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Data regarding the practice of administering sedation, analgesia and neuromuscular

blockade to pediatric patients during the course of critical illness has been primarily derived
from surveys, small trials, and two multi-institutional trials designed to determine the
efficacy and safety of protocol-driven, nurse-directed sedation practice.1,16–20 Evidence-
based guidelines for sedation, analgesia and neuromuscular blockade administration in
pediatrics are lacking.21,22 Our aim was to describe the practice patterns and pharmaceutical
management of sedation, analgesia, and neuromuscular blockade medications administered
to children in ICUs utilizing an electronic health record (EHR)-derived national database.

Methods:
Database
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The dataset was derived from the Health Facts® (Cerner Corporation, Kansas City, MO)
database that collects comprehensive clinical data on patient encounters from hospitals in the
United States with a Cerner data use agreement. Health Facts® is a voluntary program to
facilitate the capture of patient data from the EHR since 2000 from more than 500 hospitals.
Health Facts® provides episodic and longitudinal, date and time-stamped data from
affiliated patient care locations including admission and demographic data, care-setting
characteristics, laboratory results, medication data derived from pharmacy records,
microbiology results, diagnostic and procedure codes, vital signs, respiratory data, and
hospital outcome, providing a temporal relationship between treatment patterns and clinical
information. Cerner Corporation has established Health Insurance Portability and
Accountability Act compliance operating policies to establish de-identification of Health
Facts®.
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The Health Fact’s® database is representative of the nation, inclusive of academic and non-
academic hospitals of varied sizes and locations.23,24,25,26 The varied patient population in
the Health Fact’s® database has been used to develop major advances in clinical
medicine23,24,25,26, including the APACHE score.27 Data is captured directly from the EHR,
and therefore required cleaning prior to analysis. Data cleaning included eliminating data
inconsistent with valid entries, including but not limited to duplicate or null values,
admission times of zero, spurious or absent age values, and/or lab or vital sign values outside

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of the range of physiologic possibility. Notably, not all data were available for all patients.
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Further details about data processing are in Appendix 1.

All children in ICUs who received medications during their ICU admission were included in
this analysis. Pediatric patients were defined as < 22 years of age at time of admission,
consistent with the American Academy of Pediatrics’ definition of a pediatric patient and
patient’s routinely cared for in pediatric ICUs.28 Pediatric age cohorts used for age-related
analyses were based on the World Health Organization position paper on age categories for
the administration of medications.29 Children cared for in ICUs were identified by
associating the ICU care setting with laboratory, medication or discharge orders. This cohort
included patients from161 hospitals. If a patient had more than 1 ICU admission, medication
information was combined and analyzed at the patient level. Neonatal intensive care unit
patients were excluded. Details of the definitions, identification of ICU patients, and
cleansing and reliability checks are in Appendix 1. The dates of the dataset used for this
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analysis were from January 2009 to June 2016.

Data Elements
Descriptive data consisted of age, gender, diagnostic information, and procedures. The
primary diagnosis for each patient was categorized into 17 diagnostic groups from the
ICD9-10 classifications.30,31 When the primary diagnostic group was Diseases Originating
in Childbirth, the Perinatal Period, or Congenital Diseases, the secondary and tertiary
diagnostic codes were evaluated to classify the primary system of physiological dysfunction/
reason for admission (Table 1). Positive pressure ventilation and operations organized by
organ system were identified from procedure codes (ICD-9, ICD-10-PCS, HCPCS, and
CPT-4), detailed in Table 1.
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Medication data included generic and brand names, and the national drug code (NDC). The
times a medication was ordered and discontinued were determined from pharmacy records.
If multiple doses of a medication or medication class occurred concomitantly, the overall
length of administration was determined by the start and end time. If one dose of medication
or medication class was ordered in an hour period of time, the patient was considered to
have received one hour of medication. Reliable per kilogram dosing information was not
consistently available. Therefore dosing was not evaluated. Each medication was linked to
Cerner Multum™, an industry standard for medication classification, using the NDC.32,33 A
total of 96% of the NDC codes were classified into Multum™ classes, and the remaining
medications were classified by the authors (AP, MP, JC) into the existing Multum™ classes.
The classes analyzed for this assessment included non-opioid analgesics, opioid analgesics,
sedatives, general intravenous (IV) anesthetics, and neuromuscular blockers. Propofol and
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ketamine, which are classified as anesthetic agents, were analyzed as sedative medications
because of their predominant clinical use in the ICU.

Statistical Analysis:
Patient, medication, diagnostic and procedure data were summarized using descriptive
statistics. Continuous variables are expressed as medians with 25-75th percentile
interquartile ranges (IQR). Data for medication classes and generic medications included the

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number of patients, age distributions and durations of administration during their ICU
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admission. The Wilcoxon rank sum test was used to compare continuous measures and the
chi-squared test was used to compare categorical measures. The Kruskal-Wallis test was
used for comparing multiple groups. When the Kruskal-Wallis test was significant, the
analysis was followed with paired comparisons using the Wilcoxon rank sum test. Durations
of medication administration were controlled for ICU length of stay by determining the
proportion of time each patient received each medication class during their ICU admission.
The software utilized was R version 3.5.1.34,35,36,37,38,39 All statistical analyses were
performed by E.T.R.

Results
At total of 66,443 children utilizing 518,711 days of ICU care had medications dispensed to
them while in the ICU. Table 1 describes the patient characteristics between patients who
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received sedation, analgesia and neuromuscular blockade and those who did not. Overall, the
median age was 1.3 years (IQR 0 – 14.5 years) and the predominant age group was < 1
month (37.7%) with 12.5% of patients (n = 8,279) between 18 and <22 years old. Median
ICU length of stay was 2.8 days (IQR 1.2 – 7.3 days). Overall hospital mortality rate was
2.3%. A total of 59.5% of patients (n = 39,551) had diagnostic information with the
predominant primary diagnoses involving the respiratory system and injury and poisonings.
Of the 9,693 patients with operative data, cardiovascular, digestive, and respiratory system
operations were the most common. Positive pressure ventilation was received by 14.5%
(n=9,634).

A total of 63.3% (n=42,070) of ICU patients received non-opioid analgesic, opioid

analgesic, sedative and/or neuromuscular blockade medications consisting of 83 different
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generic medications (Table 2). Figure 1 is a Venn diagram of the overlap of usage among the
medication classes. A total of 34.1% of patients received medications in only one
medication class, with non-opioid analgesic medications being the most common. The
second and third largest groups of patients receiving combinations of medication classes
were patients receiving all four classes (18.6%) and three classes (16.2%).

Non-opioid and opioid analgesic medications were dispensed to 58.4% (n=38,776) of

patients with 70.7% receiving non-opioid acetaminophen preparations, 67.4% receiving
opioid-based medications, and 25.7% receiving non-steroidal anti-inflammatory agents
(Table 2). Patients less than 1 month received the smallest proportion of opioid (21.1%) and
non-opioid (15.1%) analgesic medications. Patients >13 years received the highest
percentage of opioid analgesics (52.7%). Of the patients receiving opioid analgesic
medications, fentanyl was most commonly dispensed (63.0%, n=17,428) followed by
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morphine (60.7%, n=17,142) and hydromorphone (12.1%, n=3731). Median durations of

administration were less than 2 days for all opioid analgesics except methadone. However, a
substantial number of patients received opioid analgesics for relatively long periods (75th
percentile = 92 hours). For example, the median duration of administration of fentanyl was
15 hours but the IQR was 2 hours to 81 hours. Methadone was prescribed for a longer
duration of administration than the shorter acting opioid analgesics (median 73 hours; IQR
27 −182 hours).

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Sedatives (Table 2) were dispensed to 39.8% (n=26,441) of ICU patients. Benzodiazepines

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were the most commonly administered sedative class (73.5% of patients receiving sedatives,
n=19,426), followed by ketamine and propofol (39.6%, n =10,477), and miscellaneous
sedatives inclusive of antihistamines and dexmedetomidine (28.1%, n =7,455). Patients less
than 1 month received the lowest proportion of sedative medications (15.7%), whereas
those13 years to 21 years received the highest proportion (43.7%). Midazolam was the most
commonly dispensed sedative (52.3% of patients receiving sedatives, n = 14,395), followed
by lorazepam (35.4%, n=9,362) and propofol (29.1%, n=8,792). Similar to opioid analgesic
medications, the median duration of administration for sedatives was less than 2 days with
wide variability among the specific agents. For example, the median duration of use of
lorazepam was 23 hours (IQR 3- 91 hours) compared to propofol with a median of 2 hours
(IQR 1-15 hours).

Neuromuscular blocking medications were dispensed to 17.3% (n =11,517) of ICU patients

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consisting of six generic agents. Rocuronium was the most common agent (53.9% of
patients receiving neuromuscular blocking medications, n=6,209), followed by vecuronium
(51.2%, n=5,897) and succinylcholine (18.2%, n=2099). The smallest proportion of
neuromuscular blockade medications were dispensed to patients less than 1 month (8.7%)
and the highest proportion were dispensed to patients between the ages of 1month to 2 years.
Unlike analgesics and sedatives, neuromuscular blocking medications were administered for
short periods of time with less variability. Most agents were used for a median of 3 hours or
less. Cisatracurium had the longest duration of administration (median 18.5 hours) and the
most variability of the neuromuscular blocking medications (IQR 1-68 hours).

Of the 14.5% (n = 9,634) of patients treated with positive pressure ventilation, all received
an opioid analgesic for a median duration of 41 hours (IQR 9-111 hours) with fentanyl and
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morphine being the most common. A total of 95% (9,152) received a sedative medication for
a median duration of 29 hours (IQR 4-107 hours), with midazolam and lorazepam being the
most common. Neuromuscular blocking agents were dispensed for 53.3% (n = 5,134) with a
median duration of 2 hours (IQR 1-15 hours) (Table 4).

Operative patients (n=9692) received proportionally more non-opioid analgesic, opioid

analgesic, sedative and neuromuscular blockade medications with longer durations of
administration than non-operative patients (Figure 2, Table 3). Operative patients received a
greater proportion of opioid analgesic medications (60.0%, n=5,411) than non-opioid
analgesic medications (48.0%, n=4,657). This pattern was not observed in the non-operative
patients where non-opioid analgesic medications (60.1%, n=34,119) were prescribed more
frequently than opioid analgesic medications (36.5%, n=20,738) (Table 3).
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Younger age was significantly (p<0.005) associated with longer durations of administration,
even when controlling for ICU length of stay (Table 4). Patients <1 month of age had the
longest (p<.05) opioid analgesic (median 62 hours, IQR 10 −183 hours) and sedative
(median 57 hours, IQR 5-202 hours) durations of medication administration. Patients 1
month-2 years had the longest neuromuscular blocking agent use (median 3 hours, IQR 1-27
hours, p<.05), with the <1 month group having the second longest duration of
administration. The oldest age group (13-22 years) had the shortest duration of opioid

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analgesic, sedative and neuromuscular blocking agent durations of administration (p <

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0.005).

The highest proportion of patients receiving analgesic, opioid analgesic, sedative, and
neuromuscular blocking agents had primary diagnoses involving musculoskeletal
dysfunction or hematology/oncology diagnoses (Figure 3 and Supplemental Table 3).
Patients with dermatologic and not otherwise specified diagnoses were least likely to receive
any of the studied medication classes. The highest proportion of all medication classes were
used in the 13 to < 22 year old patients across all diagnostic groups.

Discussion
This was the first application of a large, national database to determine the spectrum of
sedative, analgesic, and neuromuscular blockade medications used in pediatric patients cared
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for in the ICU. Prior national and international observational studies had either small
populations, examined a protocol intervention, or relied on physician and nurse surveys on
medication preferences and practices. 1,17–20,40,41,42

Analgesic and sedative medication use in children in ICUs is common. Analgesic and
sedative agents were dispensed to 58.4% and 39.8% of patients receiving medications,
respectively, with 64.9% of these patients receiving both medication classes. Opioid
analgesics were prescribed to 67.4% of those receiving analgesics, with fentanyl and
morphine being the most common agents. Benzodiazepines were the most frequently
dispensed sedative medications, with midazolam being the most common. In a recent
pediatric ICU survey, 72% of respondents reported that opioid and benzodiazepine
medications were the most commonly administered with fentanyl and midazolam as the
preferred agents.18 Neuromuscular blocking agents were dispensed to 17.3% of the cohort,
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all of whom also received either analgesics and/or sedatives. A European study of neonatal
ICUs reported a 5.3% rate of neuromuscular blockade, similar to the 8.7% rate found in the
less than 30 day old patients in this analysis.43

A substantial proportion of patients received medications for prolonged time periods. For
example, 25% of patients less than 2 years of age received opioid analgesics and sedatives
for greater than 5 days, durations associated with complications including tolerance,
withdrawal, and delirium.7,22,44–46 Similarly, neuromuscular blocking agents were generally
used for less than 2 hours , but 25% of children < 2 year of age received neuromuscular
blockade for greater than 27 hours, durations that increase the risk for myopathy and are
associated with prolonged mechanical ventilation.47,48
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There was a significant diversity of pharmacologic practice regarding specific medications.

Overall, 49 different opioid and non-opioid analgesic medications, 28 different sedative
medications, and 6 different neuromuscular blocking medications were dispensed. Children
in ICUs often have unique pharmacodynamics and individualized pain and sedation
requirements, so the diversity of practice is expected. However, some of the agent choices is
notable. For example, ketorolac was used in only 8.2% of patients older than 6 months
although it has a pain relief profile comparable to opioids and can reduce overall opioid

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consumption in multi-modal pain regimens .49,50 Ketorolac and other NSAIDs have
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limitations including contraindication in children less than 6 months and a risk of kidney
injury. Fentanyl, which has a similar analgesic profile as morphine, was used with a similar
frequency as morphine despite an increased risk of tolerance and withdrawal.51,52,53 A
possible benefit to fentanyl use is its favorable hemodynamic profile including a reduced risk
of histamine release.54

The FDA has warnings concerning some common pharmacologic practices found in this
study. A recent warning was issued against use of general anesthetics (propofol, ketamine)
and sedatives (benzodiazepines) in children under 3 years old due to their possible negative
effect on the developing brain.55 Benzodiazepines, propofol and ketamine were used in
17.5%, 19.4% and 8.2% respectively in children under 2 years old. Additionally, propofol
was the third most common sedative medication used in this pediatric population
(administered to 13.2% of patients), despite the FDA “black box” warning concerning the
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potentially lethal propofol related infusion syndrome (PRIS).56,57,58

Studies utilizing large data repositories such as the Health Facts® database have limitations.
First, medication use was implied from pharmacy records, not assessed through individual
patient records. Second, weight-based dosing was not available which may have added
further practice variability. Third, the database did not explicitly identify pediatric ICUs,
requiring the identification of children in ICUs using age and general ICU labels. Fourth, the
data analyzed are from 2009 to June 2016, and therefore may affect generalizability to
current medication practices. Lastly, since 40.5% of patients did not have diagnostic data,
there could be a bias in the assessments based on diagnoses.

Conclusion
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This study of analgesics, sedatives, and neuromuscular blockade practices demonstrates both
substantial diversity as well as commonalities in prescribing patterns. These medications are
often necessary adjuncts to critical care management to maintain physiologic stability. While
most medications were dispensed for relatively short time periods, a substantial proportion
of patients received durations of medications that can be associated with serious
complications. Some medication practices were in conflict with FDA warnings. These data
suggest there are risks in current sedation and analgesia practices that could be reduced with
practice changes to improve efficacy and minimize risks.

Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
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Acknowledgments
Financial Support

Funding was provided, in part, by Mallinckrodt LLC, and by Awards Ul1TR001876 and KL2TR001877 from the
National Institutes of Health, National Center for Advancing Translational Sciences. Its contents are solely the
responsibility of the authors and do not necessarily represent the official views of the National Center for
Advancing Translational Sciences or the National Institutes of Health.

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 Patel et al. Page 9

“Copyright form disclosure: Drs. Patel, Workman, Chamberlain, and Morizono’s institutions received funding from
Awards Ul1TR001876 and KL2TR001877 from the National Institutes of Health (NIH) National Center for
Author Manuscript

Advancing Translational Sciences. Drs. Patel, Trujillo-Rivera, Zeng-Treitler, Chamberlain, Morizono, Bost, and
Pollack’s institutions received funding from Mallinckrodt Pharmaceuticals. Drs. Patel, Workman, Zeng-Treitler,
Chamberlain, Morizono, Kim, and Pollack received support for article research from the NIH. Drs. Morizono and
Bost received support for article research from and Mallinckrodt Pharmaceuticals. The remaining authors have
disclosed that they do not have any potential conflicts of interest.”

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Figure 1:
Venn Diagram of Patients Receiving Non-Opioid Analgesic, Opioid Analgesic, Sedative and
Neuromuscular Blockade Medications (N = 42,070)
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 Patel et al. Page 13
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Figure 2.
Non-Opioid Analgesic, Opioid Analgesic, Sedative and Neuromuscular Blockade
Medications by Age
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Figure 3.
a – e. Patients Receiving Non-Opioid Analgesic, Opioid Analgesic, Sedative and
Neuromuscular Blockade Medications for Diagnostic Categories (n = 39,514). Pairwise
comparisons of the proportion of medication classes administered between each diagnostic
group are significantly different (p<0.05). Pairwise comparisons are detailed in
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Supplemental Appendix 3.
1. P<0.05 for comparison of proportions in different diagnostic groups.

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Table 1.

Characteristics for Children in ICUs Receiving Medications (n = 66,443)

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Patients who Received Non- Patients who did not receive Non- Significance level (1)
Opioid Analgesic, Opioid Opioid Analgesic, Opioid
Analgesic, Sedative and NMB Analgesic, Sedative and NMB (n
Characteristics (n=42,070) = 24,373)
Age in Years (Median (IQR) 5.3 (0.2-16.9) 0.003 (0.001-2.4) p < 0.005
Age Groups (N (%))
< 1 months 8887 (21.1) 16158 (66.3) p < 0.005
>= 1mo- < 2 years 7868 (18.7) 1923 (7.9) p < 0.005
>= 2 - <6 years 4738 (11.3) 1167 (4.8) p < 0.005
>= 6 - <13 years 5301 (12.6) 1562 (6.4) p < 0.005
>= 13 - <22years 15276 (36.3) 3563 (14.6) p < 0.005
Female (N (%)) 19195 (45.6) 11628 (47.7) p < 0.005
Race (N, (%))
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Caucasian 22216 (52.8) 11885 (48.8) p < 0.005

African American 12191 (29.0) 7248 (29.7) p < 0.005
Unknown/Other 7663 (19.4) 5240 (21.5) p < 0.005
ICU Length of Stay (median (IQR) 2.8 (1.3-7.5) 2.9 (1.2-7.1) p < 0.005
Hospital Mortality (N (%)) 1335 (3.2) 185 (0.8) p < 0.005
Diagnostic Categories (N (%)) (2)
Respiratory System 4808 (19.3) 1798 (12.3) p < 0.005
Injury and Poisoning 3845 (15.5) 932 (6.4) p < 0.005
Endocrine, Nutrition, and Immunity 2617 (10.5) 2130 (14.6) p < 0.005
Central Nervous System 2640 (10.6) 578 (3.4) p < 0.005
Circulatory System 1722 (6.9) 764 (5.2) p < 0.005
Gastrointestinal System 1585 (6.4) 539 (3.7) p < 0.005
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Infection and Parasitic Diseases 1775 (7.1) 597 (4.1) p < 0.005
Hematology and Oncology 1505 (6.1) 380 (2.6) p < 0.005
Genitourinary System 643 (2.6) 259 (1.8) p < 0.005
Musculoskeletal System 740 (2.9) 74 (0.5) p < 0.005
Dermatological System 335 (1.3) 444 (3.0) p < 0.005
Psychiatric 498 (2.0) 218 (1.5) p < 0.005
Diseases Not Otherwise Specified 2172 (8.7) 5916 (40.4) p < 0.005
Operations by Organ System (N (%)) (3)
Cardiovascular Operations 3604 (8.6) 449 (1.8) p < 0.005
Digestive System Operations 1482 (3.5) 57 (0.2) p < 0.005
Respiratory Operations 1139 (2.7) 51 (0.2) p < 0.005
Musculoskeletal Operations 826 (2.0) 21 (0.1) p < 0.005
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Nervous System Operations 692 (1.6) 15 (0.1) p < 0.005

Integumentary Operations 346 (0.8) 16 (0.1) p < 0.005
Otolaryngology Operations 293 (0.7) 15 (0.1) p < 0.005
Genitourinary Operations 253 (0.6) 26 (0.1) p < 0.005
Lymphatic Operations 143 (0.3) 9 (0.0) p < 0.005

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Patients who Received Non- Patients who did not receive Non- Significance level (1)
Opioid Analgesic, Opioid Opioid Analgesic, Opioid
Analgesic, Sedative and NMB Analgesic, Sedative and NMB (n
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Characteristics (n=42,070) = 24,373)

Ophthalmology Operations 95 (0.2) 5 (0.0) p < 0.005
Endocrine Operations 83 (0.2) 7 (0.0) p < 0.005
Positive Pressure Ventilation (N, (%))(3) 7182 (17.1) 2452 (10.1) p < 0.005

Abbreviations: ICU =Intensive Care Unit; NMB = Neuro Muscular Blockade; IQR = Interquartile range.
1.
Univariate comparisons.
2.
Diagnostic Categories were available for 39,514 patients, and missing for 26,929. The primary diagnostic code was used for categorization (see
methods). The percentages are shown for the sample with diagnostic information.
3.
Procedures were available from 23,935 patients, and unavailable in 42,508 patients. The percentages are shown are from the total sample.
Procedure codes indicating positive pressure ventilation including: Continuous Invasive Mechanical Ventilation, Non-Invasive Mechanical
Ventilation, Continuous positive airway pressure ventilation, Assistance with Respiratory Ventilation, Intermittent Positive Airway Pressure
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Table 2.

Frequency and Duration of the Most Common Non-Opioid Analgesic, Opioid Analgesic, Sedative and
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Neuromuscular Blockade Medications (N = 66,443)

Medication Class Overall N (%) Age <1mo N Age 1mo - <2 Age 2 yrs - <6 Age 6 yrs - <13 Age 13 yrs -
Duration (%) Duration yrs N (%) yrs N (%) yrs N (%) <22 yrs N (%)
(hours, (IQR)) (hours, (IQR)) Duration Duration Duration Duration
(hours, (IQR)) (hours, (IQR)) (hours, (IQR)) (hours, (IQR))
1 38776 (58.4) 3783 (15.1) 5909 (60.4) 3466 (58.7) 3741 (54.5) 9876 (52.4)
Non-Opioid Analgesic
26 (7-69) 36 (10-98) 31 (8-86) 23 (5-61) 24 (6-60) 23 (6-52)
Acetaminophen 27397 (41.2) 4399 (17.6) 6258 (63.9) 3589 (60.8) 3843 (56.0) 9308 (49.4)
27 (10-73) 16 (0-73.5) 25 (5-76) 19 (2-54) 19 (2-53) 20 (3-49)
Ibuprofen 5436 (8.2) 340 (1.4) 1551 (15.8) 1313 (22.2) 1254 (18.3) 2374 (12.6)
30 (10-76)) 29 (7-50) 16 (1-56) 11 (1-45) 11 (1-42) 7 (1-33)
Ketorolac 2728 (4.1) 49 (0.2) 353 (3.6) 429 (7.3) 602 (8.8) 2000 (10.6)
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23 (7-45) 1 (0-2) 11 (1-27) 8 (1-26) 9 (1-28) 2 (1-22)

Aspirin 1553 (2.3) 215 (0.9) 406 (3.6) 274 (4.6) 260 (23.5) 798 (42.4)

45 (15-101) 74 (14-346) 34 (6-92) 26 (3-70) 23.5 (3.8-57) 18.5 (2-48)

2 26149 (39.4) 5295 (21.1) 4047 (41.3) 2192 (37.1) 2872 (41.8) 9931 (52.7)
Opioid Analgesic
32 (7-92) 62 (10-183) 42 (9-119 24 (5-68) 25 (5.8-65.3) 23 (5-57)
Fentanyl 17428 (26.2) 4560 (18.2) 3508 (44.6) 1613 (27.3) 2032 (29.6) 5715 (30.3)
15 (2-81) 19 (1-124) 6 (1-74.3) 2 (1-28) 2 (0-19) 2 (1-16)
Morphine 17142 (25.8) 3553 (14.2) 2901 (36.9) 1717 (29.1) 2413 (35.2) 6558 (34.8)
26 (6-69) 38 (3-119) 21 (2-61) 14 (1-43) 17 (2-46) 15 (2-43)
Hydromorphone 3731 (5.6) 92 (0.4) 127 (1.6) 129 (2.2) 312 (4.5) 3071 (16.3)
19 (2-51) 47 (1-345) 19 (1-79.5) 4 (1-31) 3.5 (1-27) 7 (1-35)
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Acetaminophen- 3159 (4.8) 40 (0.2) 295 (3.7) 314 (5.3) 468 (6.8) 2502 (13.3)
Hydrocodone
32 (16-58) 16 (0-62.3) 24 (6-44.5) 12 (1-32) 9 (0-30.3) 9 (1-29)
Oxycodone 2722 (4.1) 35 (0.1) 234 (3.0) 204 (3.5) 414 (6.0) 1835 (9.7)
26 (6-69) 30 (1-56.5) 21.5 (1-64) 10 (1-40.3) 13 (1-41) 15 (1-44.5)
Acetaminophen- 1652 (2.5) 32 (0.2) 51 (0.7) 57 (1.0) 166 (2.4) 1695 (9.0)
Oxycodone
27 (9-62) 1 (0-10) 1 (0-11.5) 4 (1-15) 4 (1-25) 9 (1-29)
Acetaminophen- 1383 (2.1) 56 (0.2) 449 (5.7) 448 (7.6) 399 (5.8) 392 (2.1)
Codeine
24 (8-51) 26 (7-71.5) 15 (1-41) 8 (1-28.3) 6 (1-28) 6 (0-26)
Meperidine 1230 (1.9) 11 (0.0) 35 (0.4) 51 (0.9) 97 (1.4) 1405 (7.5)
11 (2-40) 1 (0-14) 1 (0-6) 1 (0-2) 1 (0-4) 1 (0-6)
Methadone 1148 (1.7) 305 (1.2) 472 (6.0) 145 (2.5) 90 (1.3) 136 (0.7)
73 (27-182) 92 (30-236) 57 (17-154) 47 (12-98) 57 (16-140) 42 (6.3-143)
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3 26441 (39.8) 3923 (15.7) 4026 (41.1) 2328 (39.4) 2723 (39.7) 8225 (43.7)
Sedatives
23 (3-84) 57 (5-202) 30 (5-120) 16 (2-55) 15 (3-44) 15 (3-44)
Midazolam 14395 (21.7) 3070 (12.3) 3107 (31.7) 1702 (28.8) 1901 (27.7) 4615 (24.5)
7 (2-69) 10 (1-114) 7 (1-77) 2 (1-22) 1 (0-12) 1 (0-6)

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Medication Class Overall N (%) Age <1mo N Age 1mo - <2 Age 2 yrs - <6 Age 6 yrs - <13 Age 13 yrs -
Duration (%) Duration yrs N (%) yrs N (%) yrs N (%) <22 yrs N (%)
(hours, (IQR)) (hours, (IQR)) Duration Duration Duration Duration
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(hours, (IQR)) (hours, (IQR)) (hours, (IQR)) (hours, (IQR))

Lorazepam 9362 (14.1)) 1984 (7.9) 2222 (22.7) 1095 (18.5) 1197 (17.4) 3749 (19.9)
23 (3-91) 28 (1-150) 22 (2-100) 11 (1-45) 9 (1-45) 10 (1-41)
Propofol 8792 (13.2) 1083 (4.3) 1478 (15.1) 1042 (17.6) `1422 (20.7) 3767 (20.0)
2 (1-15) 1 (0-1) 1 (0-2) 1 (0-5) 1 (0-4.8) 2 (1-17)
Diphenhydramine 6896 (10.4) 176 (0.1) 760 (7.8) 816 (13.8) 1208 (17.6) 3936 (20.9)
15 (3-46) 7 (0.8-66) 5 (1-36) 5 (1-40.5) 9 (1-42) 7 (1-30)
Ketamine 2800 (4.2) 381 (1.5) 754 (7.7) 474 (8.0) 490 (7.1) 701 (3.7)
2 (1-6) 1 (0-2) 1 (0-4) 1 (1-4) 1 (0-4) 1 (0-3)
Phenobarbital 2622 (3.9) 1179 (4.7) 743 (7.6) 265 (4.5) 237 (3.5) 198 (1.1)
57 (16-188) 74 (9-233) 31 (3-123) 17 (2-52) 34 (9-84) 26.5 (2-90)
Diazepam 2188 (3.3) 37 (0.1) 235 (2.4) 293 (5.0) 542 (7.9) 1081 (5.7)
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37 (11-90) 6 (1-72) 4 (1-39) 6 (1-36) 18 (2-45) 17 9(1-42)

Dexmedetomidine 2003 (3.0) 213 (0.9) 607 (6.2) 313 (5.3) 329 (4.8) 541 (2.9)
24 (7-52) 5 (0-44) 23 (1-50) 14 (1-33) 6 (1-30) 10 (1-32)
Neuromuscular 11517 (17.3) 2189 (8.7) 2287 (23.4) 909 (15.4) 1005 (14.6) 2440 (13.0)
Blocking Agents
2 (1-15) 3 (1-27) 4 (1-34) 2 (1-18) 2 (1-7) 2 (1-4)
Rocuronium 6209 (9.3) 1270 (5.1) 1555 (15.9) 600 (10.2) 790 (1.2) 1994 (10.6)
1 (1-2) 1 (0-1) 1 (1-2) 1 (0-2) 2 (0-3) 1 (0-2)
Vecuronium 5897 (8.9) 1757 (7.0) 1675 (17.1) 642 (10.9) 650 (9.5) 1173 (6.2)
3 (1-28) 3 (1-27) 3 (1-30) 2 (1-20) 4 (1-49.5) 1 (0-4)
Succinylcholine 2099 (3.2) 209 (0.8) 321 (3.3) 19 (3.2) 239 (3.5) 1139 (6.0)
1 (1-2) 1 (0-1) 1 (0-1) 1 (1-1) 1 (1-7.3) 1 (0-1)
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Pancuronium 758 (1.1) 243 (1.0) 240 (2.5) 90 (1.5) 76 (1.1) 109 (0.6)
1 (1-16) 1 (1-18) 1 (1-20) 1 (1-3) 1 (0-1) 1 (1-2)
Cisatracurium 730 (1.1) 151 (0.6) 211 (2.1) 79 (1.3) 95 (1.4) 194 (1.0)
18.5 (1-68) 1 (0-3) 16 (2-59) 10 (1-73.5) 1 (0-2) 1 (1-10.3)
Atracurium 182 (0.3) 9 (0.0) 40 (0.4) 10 (0.2) 21 (0.3) 102 (0.5)
3 (1-45) 1 (1-2) 31 (1-60.3) 2 (0.3-3.8) 1 (1-7) 2 (1-5)

1.
Other medications included naproxen (n=452), Indomethacin (n=56), sumatriptan (n=30), meloxicam (n=9), apap/dichloralphenazone/
isometheptene (3), caffeine-ergotamine (n=2), caffeine-ergotamine (n=2), acetaminophen/butalbital/caffeine (1), choline salicylate-magnesium
salicylate (1), diclofenac (n=1), nabumetone (n=1), naratriptan (n=1), piroxicam (n=1), rizatriptan (n=1), zolmitriptan (n=1), and
dihydroergotamine (1).
2.
Other medications included nalbuphine (n=1047), butorphanol (n=593), remifentanil (n=550), alfentanil (n=406), sufentanil (n=309), tramadol
(n=270), codeine (n=109), belladonna-opium (33), bupivacaine-fentanyl (30), tapentadol (n=25), opium (n=11), buprenorphine-naloxone (11),
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fentanyl-ropivicaine (7), buprenorphine (n=6), acetaminophen-tramadol (4), hydrocodone-ibuprofen (2), and meperidine-promethazine (2), aspirin-
oxycodone (1), and bupivacaine-hydromorphone (1).
3.
Other medications included zolpidem (n=1229), chloral hydrate (n=1195), clonazepam, (n=715), pentobarbital, (n=470) Hydroxyzine (n=438),
alprazolam (n=369), temazepam (n=207), and clobazam (n=151).

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Table 3.

Frequency and Duration of Non-Opioid Analgesic, Opioid Analgesic, Sedative and Neuromuscular Blockade
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Medications in Operative/Non-Operative, and Ventilated/Non-Ventilated Patients.

Medication Class Operative(1) (n = Non-Operative(1) Positive Pressure No Positive Pressure

9693) (n = 56750) Ventilation(2) (n = Ventilation(2) (n =
9634) 56,809)

Non-Opioid Analgesic N% 4657 (48.0) 34119 (60.1) 9634 (100) 29142 (51.3)
(hours, IQR) 52 (20-132) 23 (5-57) 38 (11-97) 22 (5-52)
Opioid Analgesic N% 5411 (60.0) 20738 (36.5) 9634(100) 16515 (29.1)
(hours, IQR) 50 (17-127) 25 (5-74) 41 (9-111) 23 (5-66)
Sedatives N% 4526 (51.6) 21915 (38.6) 9152 (95.0) 17289 (30.4)
(hours, IQR) 40 (6-134) 18 (3-64) 29 (4-107) 16 (3-55)
Neuromuscular N% 2926 (36.6) 8591 (15.1) 5134 (53.3) 6383 (11.2)
Blocking Agents
(hours, IQR) 2 (1-22.8) 2 (1-10) 2 (1-15) 2 (1-12)
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1.
P< 0.005 for both proportions and durations for each medication class.
2.
P<0.005 for both proportions and durations for each medication class.
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Table 4:

Differences in the Duration of Administration of Non-Opioid Analgesic, Opioid Analgesic, Sedative and
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Neuromuscular Blockade Medications to Children in ICUs by Age.

Variable Age <1mo Age 1mo - <2 Age 2 yrs - <6 Age 6 yrs - <13 Age 13 yrs - Significance
yrs yrs yrs <22 yrs 1
Level

Median ICU LOS (IQR 4.8 (2.0 – 1.6 (0.3 – 4.9) 0.9 (0.2 – 2.3) 1.1 (0.3 – 2.5) 1.2 (0.4-2.4) p < .005
days) 11.8)
Median Hospital LOS 8.1 (3.8 - 2.8 (1.50 - 5.0 (2.3-13.0) 3 (1.5 - 6.4) 3.3 (1.7-6.8) p < .005
(IQR) days) 21.3) 5.9)
Death Rate (95% CI) 2.6% (2.6, 2.7% (2.6, 2.2% (1.9, 2.4) 1.6% (1.4, 1.8) 1.9% (1.9, NS
2.7) 2.9) 2.0)
Median Sedative 57 (5-202) 30 (5-120) 16 (2-55) 19 (3-59) 15 (3-44) p < .005
Duration (IQR, hours)
Median Opioid 62 (10-183) 42 (9-119) 24 (5-68) 25 (5.8-65.3) 23 (5-57) p < .005
Analgesic Duration
(IQR, hours)
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Median Neuromuscular 3 (1-27) 4 (1-34) 2 (1-18) 2 (1-7) 2 (1-4) p < .005

Blockade Duration (IQR,
hours)

1.
Kruskal-Wallis test
2.
Pairwise comparisons of durations of administration are in Supplemental Table 3.
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