Analgesia and Sedation in Hospitalized Children: by Elizabeth J. Beckman, Pharm.D., BCPS, BCCCP, BCPPS

Analgesia and Sedation
in Hospitalized Children
By Elizabeth J. Beckman, Pharm.D., BCPS, BCCCP, BCPPS
Reviewed by Julie Pingel, Pharm.D., BCPPS; and Brent A. Hall, Pharm.D., BCPPS
Learning Objectives
1. Evaluate analgesics and sedative agents on the basis of drug mechanism of action, pharmacokinetic principles, adverse
drug reactions, and administration considerations.
2. Design an evidence-based analgesic and/or sedative treatment and monitoring plan for the hospitalized child who is
postoperative, acutely ill, or in need of prolonged sedation.
3. Design an analgesic and sedation treatment and monitoring plan to minimize hyperalgesia and delirium and optimize
neurodevelopmental outcomes in children.
Introduction
Abbreviations in This Chapter
Pain, anxiety, fear, distress, and agitation are often experienced by
GABA γ-Aminobutyric acid
children undergoing medical treatment. Contributory factors may
ICP Intracranial pressure
include separation from parents, unfamiliar surroundings, sleep dis-
PAD Pain, agitation, and delirium turbance, and invasive procedures. Children receive analgesia and
PCA Patient-controlled analgesia sedatives to promote comfort, create a safe environment for patient
PICU Pediatric ICU and caregiver, and increase patient tolerance to medical interven-
PRIS Propofol-related infusion tions such as intravenous access placement or synchrony with
syndrome
mechanical ventilation. However, using these agents is not without
Table of other common abbreviations. risk. Many of the agents used for analgesia and sedation are con-
sidered high alert by the Institute for Safe Medication Practices
because of their potential to cause significant patient harm, given
their adverse effects and the development of tolerance, dependence,
and withdrawal symptoms. Added layers of complexity include the
ontogeny of the pediatric patient, ongoing disease processes, and
presence of organ failure, which may alter the pharmacokinetics and
pharmacodynamics of these medications. Therefore, the pharma-
cist’s role is vital in forming the best and safest comfort plan and
environment for the patient and provider.
Review of Medications
The primary pillars for safe and effective analgesia and sedation in
children are using the lowest effective dose (Table 1-1) with the wid-
est therapeutic index and minimizing adverse effects (Table 1-2). In
addition, the pharmacokinetic changes that children undergo across
the developmental spectrum must be considered, as must how these
will affect each child’s drug exposure.
Opioid Analgesics
Fentanyl, morphine, and hydromorphone are the most commonly
used parenteral opioid agents in the hospital. Other synthetic
PedSAP 2017 Book 3 • Sedation and Analgesia 7 Analgesia and Sedation in Hospitalized Children
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Table 1-1. Initial Doses of Opioids and Sedatives in Children
Intermittent Dose Continuous Intravenous Infusiona
Chloral hydrate PO: 0.5–5 mcg/kg N/A
Clonidine PO: 0.5–5 mcg/kg N/A
Dexmedetomidine IN: 1–4 mcg/kg 0.2–0.7 mcg/kg/hr

IV: 0.5–1 mcg/kg
Etomidate IV: 0.1–0.3 mg/kg N/A
Fentanyl IN: 1–2 mcg/kg 0.5–2 mcg/kg/hr

IV: 0.5–3 mcg/kg
Hydromorphone IV: 0.01–0.02 mg/kg 0.003–0.005 mg/kg/hr
Ketamine IM: 5–10 mg/kg 0.3–0.6 mg/kg/hr

IN: 3–5 mg/kg (5–10 mcg/kg/min)
IV: 0.5–3 mg/kg
PO: 5–8 mg/kg
Lorazepam IV: 0.05–0.1 mg/kg 0.05 mg/kg/hr

PO: 0.05 mg/kg
Midazolam IM: 0.05–0.15 mg/kg 0.03–0.12 mg/kg/hr

IN: 0.2–0.3 mg/kg
IV: 0.05–0.1 mg/kg
PO: 0.25–0.5 mg/kg
Morphine IV: 0.03–0.2 mg/kg 0.01–0.04 mg/kg/hr
Pentobarbitalb IM: 2–6 mg/kg 0.5–1 mg/kg/hr

IV: 1–2 mg/kg
PO/PR: 1.5–6 mg/kg
Propofol IV: 0.5–2 mg/kg 1.2–4.8 mg/kg/hr

(20–80 mcg/kg/min)
a
Actual infusion rates may exceed listed values as infusions are titrated to effect.
b
Higher loading doses (5–10 mg/kg) may be used to induce pentobarbital coma.
IM = intramuscularly; IN = intranasally; IV = intravenously; N/A = not applicable; PO = orally; PR = rectally.
parenteral opioids such as sufentanil and remifentanil are and peripheral nervous system. However, these opioids, even
also used, but typically not outside the operating room. when used at high doses, do not induce the deep level of
Meperidine is another synthetic opioid with a long history unconsciousness or amnesia necessary for general anes-
of use in analgesia. However, data do not support the supe- thesia, but they may cause transient euphoria and sedation
riority of meperidine to any other opioid for analgesia, and (Butterworth 2013b). Analgesia-based sedation is gaining
meperidine may place the patient at risk of exposure to momentum as a sedation strategy in adult ICUs because it
the neurotoxin normeperidine (Buck 2011). The American is recommended by the American College of Critical Care
Academy of Pediatrics (AAP), American Pain Society, and Medicine publication titled “Clinical Practice Guidelines for
Institute for Safe Medication Practices have recommended on the Management of Pain, Agitation, and Delirium [PAD] in
against the routine use of meperidine for analgesia (ISMP Adult Patients in the Intensive Care Unit” (Barr 2013).
2007; AAP 2001). Oral opioid analgesics are also used for Opioid adverse effects include respiratory depression,
analgesia in the hospital setting. These agents are often used constipation, nausea, vomiting, and pruritus. Pruritus is
in the less critically ill patient (e.g., hemodynamically stable) more likely with morphine because histamine release is not
when it is clinically appropriate to transition to the enteral commonplace with synthetic and semisynthetic opioids like
route and a longer-acting analgesic option is desired. fentanyl and hydromorphone. In addition, histamine release
Fentanyl, morphine, and hydromorphone are μ-opioid from morphine may induce hypotension and potentially exac-
receptor agonists that produce analgesia through the central erbate reactive airway disease in susceptible patients. Rigid
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Table 1-2. Opioid and Sedative Effects
Analgesia Sedation Amnesia Anxiolysis Respiratory Effects Hemodynamic Effects
Chloral hydrate X X
Clonidine X X X
Dexmedetomidine X X X X
Etomidate X
Fentanyl X Xa X
Hydromorphone X Xa X
Ketamine X X X Xb X
Lorazepam X X X X X
Midazolam X X X X X
Morphine X X a
X X
Pentobarbital X X X X
Propofol X X X X
a
Opioids have transient sedating properties.
b
Ketamine may induce hypoventilation with high intravenous doses.
chest syndrome is a rare phenomenon that has been associ- spasms of the respiratory muscles leading to insufficient res-
ated with the rapid infusion of high-dose fentanyl (e.g., greater pirations and inability to ventilate the patient through artificial
than 5 mcg/kg) in adults, but rigid chest syndrome has also means. To reverse this syndrome, neuromuscular blockade
been reported at lower fentanyl doses in neonates and infants must be introduced to paralyze the chest wall muscles and
(Dewhirst 2012). Rigid chest syndrome is characterized by allow for effective respirations (Weaver 2016). Case reports
have also described success with naloxone in reversing this
syndrome (Coruh 2013). Naloxone is a competitive opioid
antagonist that reverses the effects of opioids. Naloxone’s
Baseline Knowledge Statements
effects are dose-dependent, in which low doses (less than
Readers of the chapter are presumed to be familiar 0.05 mg/kg) are used for opioid-induced pruritus and partial
with the following: reversal and larger doses (0.1 mg/kg) are used for full opioid
• Pharmacokinetic and pharmacodynamic changes reversal for intoxication.
in children
Sedatives
Table of common laboratory reference values.
Benzodiazepines
Benzodiazepines potentiate the binding of the inhibitory neu-
Additional Readings
rotransmitter γ-aminobutyric acid (GABA), which promotes
The following free resources have additional back- GABA A postsynaptic receptor opening to chloride ions, thus
ground information on this topic: hyperpolarizing the cell membrane and preventing the gen-
• American Academy of Pediatrics (AAP). Guidelines eration of an action potential. Sedation, hypnosis, muscle
for Monitoring and Management of Pediatric relaxation, anxiolysis, and anticonvulsant effects are medi-
Patients Before, During, and After Sedation for ated through this mechanism.
Diagnostic and Therapeutic Procedures: Update Midazolam is a short-acting benzodiazepine that is com-
2016. monly used as both procedural and long-term sedation. With
• ICU Delirium and Cognitive Impairment Study continuous exposure to midazolam, the half-life and dura-
Group. ABCDEFs of Prevention and Safety [home-
tion of action become prolonged (Patel 2011). The anxiolytic
page on the Internet].
effect is ideal for treating the anxious and uncooperative
• Society of Critical Care Medicine. ICU Liberation child and allows for anterograde amnesia, thus inhibiting the
Collaborative [homepage on the Internet].
formation of memory after administration. This property may
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be desired in children undergoing procedures and interven- may occur. Barbiturates used at anesthetic doses may induce
tions deemed traumatic; however, it may also contribute to laryngospasm and coughing, as well as depress the respira-
adverse psychological events later because of the patient’s tory drive, thus requiring close observation both during and
inability to recall logical and sequential memories (Trevor after administration (Mihic 2011). Cardiac adverse events may
2015). Lorazepam is an intermediate-acting benzodiazepine occur because of the cardiac depressant and vasodilating
similar to midazolam in sedative, anxiolytic, amnestic, and properties of barbiturates. With pentobarbital, hypotension
hypnotic properties. Unlike midazolam, however, lorazepam may be further exacerbated by the 40% propylene glycol dilu-
is formulated in propylene glycol. Propylene glycol may accu- ent (Butterworth 2013a).
mulate when lorazepam is used as a continuous infusion at
Propofol
high doses and in the presence of renal failure (Horinek 2009;
Chicella 2002). Toxicity manifests as hyperosmolar meta- Propofol is a rapid-acting hypnotic and sedative agent with
bolic acidosis, lactic acidosis, hypotension, seizures, and no analgesic properties that increases the binding affinity of
cardiac arrhythmias (Horinek 2009). GABA (Mihic 2011). Propofol is labeled for inducing anesthe-
The benzodiazepines’ dose-dependent adverse drug events sia in patients older than 3 years and maintaining anesthesia
involve the respiratory and cardiovascular systems. Respiratory in patients older than 2 months. Propofol is primarily used
depression is increased with benzodiazepine use in children. for short-term sedation in pediatric patients. Propofol has
Particularly, hypnotic doses of benzodiazepines may decrease also been used to facilitate extubation in children previously
the muscle tone of the upper airway, which may exacer- receiving other respiratory-depressing agents (Teng 2011;
bate a preexisting breathing pattern such as obstructive Sheridan 2003; Cray 2001).
sleep apnea. Combining a benzodiazepine with other respi- Propofol’s adverse effects on the respiratory and cardio-
ratory-depressing agents such as opioids further increases vascular system are significant. Propofol may induce apnea,
the risk of adverse respiratory events. The decrease in but likely not respiratory depression, and is less likely to incite
peripheral vascular resistance from benzodiazepine adminis- bronchospasm than barbiturates (Patel 2011). These respira-
tration may lead to hypotension in children (Mihic 2011). The tory effects favor propofol use in the peri-extubation setting.
hypnotic effect of benzodiazepines does not allow for Cardiovascular effects of propofol include hypotension and
restorative sleep, which also may contribute to future adverse decreased cardiac output from a decrease in systemic vascu-
psychological events if used repeatedly or continuously lar resistance and cardiac contractility (Butterworth 2013a).
(Trevor 2015). Flumazenil competitively inhibits benzodi- The cardiac effects are often related to the dose and rate of
azepines at the GABA/benzodiazepine receptor complex to administration. An isotonic fluid bolus, decrease in infusion
reverse sedative and respiratory adverse effects. Flumazenil rate, or smaller propofol bolus dose may help alleviate the
has dose-dependent effects much like naloxone and should hemodynamic adverse effects. Propofol is a 10% oil-in-water
be given in small aliquots (0.01 mg/kg or smaller) until the emulsion containing a lipid component composed of egg lec-
desired resolution of adverse effects. ithin and soybean oil that should be avoided in patients with
egg and soy allergies.
Barbiturates Propofol-related infusion syndrome (PRIS) has been
Barbiturates as a drug class have sedative, hypnotic, and described in children and adults who have been exposed to
anticonvulsant properties through a mechanism similar to high doses (greater than 83 mcg/kg/minute or 5 mg/kg/hour)
benzodiazepines, but barbiturates prolong the opening of and prolonged infusions (greater than 48 hours). The patho-
the chloride channel. Barbiturates have a narrow therapeutic physiology of PRIS has been postulated to be mitochondrial
index, making it difficult to achieve an anticonvulsive effect toxicity because of direct inhibition of aerobic phosphory-
without some degree of CNS depression and thus expanding lation, respiratory chain uncoupling, and inhibition of fatty
the use of these agents into the sedation arena. Pentobarbital, acid oxidation. Features of PRIS include unexplained meta-
methohexital, and thiopental are the three barbiturate agents bolic acidosis, hyperkalemia, rhabdomyolysis, hepatomegaly,
used most commonly for sedation. Pentobarbital is consid- triglyceridemia, arrhythmia, and cardiovascular collapse.
ered a short-acting barbiturate and has been used for many Metabolic acidosis (77%) and arrhythmias (66%) are common
years for pediatric sedation. Methohexital and thiopental are in PRIS. Dose-related adverse effects manifest as cardiac
considered ultra-short-acting barbiturates that are used to failure, metabolic acidosis, fever, and hypotension. In a recent
induce anesthesia. However, thiopental is no longer available meta-analysis, infusions greater than 48 hours were associ-
because the sole manufacturer has discontinued the product ated with arrhythmias, and over 96 hours of exposure was
in the United States and Canada. associated with rhabdomyolysis and hypertriglyceridemia,
Barbiturates have many adverse effects involving the CNS, irrespective of dose. Emerging case report data suggest that
respiratory system, and cardiovascular system. The hypnotic even short durations of moderate doses (less than 67 mcg/
effects of barbiturates may last a few hours, but prolonged kg/minute or 4 mg/kg/hour) result in PRIS, which is a thresh-
impairment of fine motor skills and alterations in cognition old lower than the FDA warning label (Krajčová 2015).
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Ketamine would be unfavorable in patients with pulmonary hyperten-
Ketamine is a unique rapid-acting sedative agent with sion, though a recent pediatric study showed little change in
analgesic properties. Ketamine is chemically similar to phen- pulmonary hemodynamics when a ketamine bolus dose was
cyclidine, which explains the untoward psychotogenic effects used in a multimodal anesthesia approach in children with
described with ketamine use (Patel 2011). The anesthetic pulmonary hypertension (Friesen 2016).
effects are mediated from the noncompetitive antagonism Ketamine preserves the laryngeal reflexes and allows
of the N-methyl- D -aspartate receptor, which ultimately inhib- spontaneous respirations, making it favorable for procedural
its the activity of the excitatory neurotransmitter glutamate. sedation. However, with the rapidly administered, large intra-
Delta- and mu-opioid receptor agonism contributes to ket- venous doses used in anesthesia induction, ketamine may
amine’s analgesic property, whereas liberation of dopamine induce transient hypoventilation and even apnea. In addi-
and norepinephrine contributes to its adverse effects (Sleigh tion, ketamine is a potent bronchodilator. Bronchodilation is
2014). Ketamine’s dissociative and analgesic effects can thought to be the result of catecholamine release, inhibition of
begin at subanesthetic doses, whereas its psychotogenic vagal tone, and direct smooth muscle relaxation (Patel 2011).
reactions increase in severity with higher serum concentra- This property makes ketamine a logical choice for sedating a
tions achieved by anesthetic doses (Mion 2013). patient with bronchospasm. Ketamine causes excessive sal-
Emergence delirium is the psychotogenic phenomenon ivation, though recent reports have recommended against
described as combativeness and disorientation. Delirium using an anticholinergic agent to antagonize the sialagogue
is estimated to affect 2% of ketamine-treated patients. (Sahyoun 2012; Deasy 2010). A large prospective study of
However, the incidence of unpleasant sensation and dreams over 900 children who underwent ketamine sedation without
is estimated to be as high as 10% (Sahyoun 2012). According adjunctive atropine found excessive salivation as an uncom-
to several studies, post-recovery agitation appears not to mon adverse effect of ketamine. Only 3.2% of patients were
be attenuated by premedication with benzodiazepines, as reported to have transient airway complications (e.g., desatu-
previously thought; instead, airway events and oxygen desat- ration), and 4.2% required intervention with suctioning (Brown
urations increased (Sahyoun 2012; Deasy 2010; Krauss 2006). 2008).
Agitation and emotional liability are also adverse effects of
ketamine; ketamine should be avoided in patients with a sig- α-Adrenergic Agonists
nificant psychiatric history (Sahyoun 2012). Clonidine and dexmedetomidine are both selective agonists
Unlike other sedative agents discussed, ketamine may of the α 2-adrenergic receptor in the locus ceruleus from which
cause elevations in blood pressure and heart rate because the sedative-hypnotic properties originate as well as in the
of stimulation of catecholamine release and inhibition of spinal cord, which contributes to the analgesic properties.
catecholamine reuptake. Ketamine is a negative inotrope Dexmedetomidine differs from clonidine in its receptor affin-
with vasodilating properties, but the indirect sympathomi- ity and selectivity. Clonidine has a selectivity ratio of 200:1 for
metic activity preserves cardiac output (Patel 2011). Because the α 2- versus the α1-receptor, whereas dexmedetomidine is
of this, ketamine is accepted as an ideal choice in patients 8 times more selective than clonidine and has a selectivity
with hemodynamic instability, but perhaps a poor choice for ratio of 1620:1 for the α 2-receptor (Capino 2016; Phan 2008).
patients with traumatic brain injury and elevated intracranial Both clonidine and dexmedetomidine have been used for
pressure (ICP). However, the “catecholamine surge” theory short- and long-term sedation, and clonidine has been used
was debunked after a recent meta-analysis showed no differ- as an adjuvant to analgesia and for opioid and dexmedetomi-
ence in ICP or mean arterial pressure with ketamine compared dine withdrawal symptoms (Capino 2016).
with opioids. Literature supports ketamine’s cardiovascular Dexmedetomidine offers arousable sedation, which differs
neutrality and suggests its safety in patients with elevated from the level of consciousness induced by the previously
ICP (Wang 2014). However, ketamine’s cardiopulmonary inter- discussed agents. Sedation from dexmedetomidine is similar
actions should be considered in children with heart failure to that from natural sleep, and dexmedetomidine’s sedative
or pulmonary hypertension. Negative inotropic effects and properties do not reliably induce amnesia. In addition, dex-
increased myocardial oxygen demand from ketamine admin- medetomidine allows for spontaneous respiration, which
istration is not advantageous in the failing heart. In a patient is advantageous in patients without an artificial airway or
with compromised left ventricular dysfunction, ketamine- mechanical ventilation support.
induced systemic vascular resistance may increase afterload, The adverse effects of the α-agonists are rather limited
thus impairing cardiac output. One adult study reported that to the effects mediated by the adrenergic receptor. A dose-
patients with catecholamine-dependent heart failure had limiting adverse effect is bradycardia and hypotension
a 21% drop in cardiac index with ketamine infusions (Christ facilitated by the inhibition of norepinephrine release from
1997). Reports are conflicting on the increase in pulmonary α 2A-adrenergic stimulation in the central and peripheral
arterial pressure and pulmonary vascular resistance with nervous system (Capino 2016; Phan 2008). Hypertension
ketamine administration. Increases in these parameters can present with bolus dosing or higher infusion doses
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of dexmedetomidine, which cause stimulation of the α 2B- to substantiate the claim in children and the unknown mag-
adrenergic receptors in the periphery (Kamibayashi 2000). nitude of adrenal suppression, the consensus panel for
pediatric shock recommends avoiding etomidate in the
Chloral Hydrate hemodynamically unstable child (Brierley 2009).
Chloral hydrate is a sedative-hypnotic drug that was first Other notable adverse effects of etomidate include myo-
discovered in the 1830s. Its usefulness for sedation was doc- clonic movements, nausea, vomiting, and hiccups. The
umented as early as 1869 (Gauillard 2002). Chloral hydrate myoclonic movements may be attenuated with premedica-
has primarily been used in non-painful diagnostic procedures tion with opioids or benzodiazepines. Etomidate is formulated
such as electroencephalography, MRI, and pulmonary func- in 35% propylene glycol, which contributes to pain with injec-
tion tests (Sahyoun 2012). Chloral hydrate’s sedative effects tion (Patel 2011).
are thought to be GABA mediated. Chloral hydrate is metab-
olized by alcohol dehydrogenase to the active metabolites Ontogeny Considerations
trichloroethanol and trichloroacetic acid. The active metabo- Children undergo many pharmacokinetic alterations as they
lites have prolonged half-lives compared with the parent drug grow and mature. Drug distribution changes, hepatic enzy-
(8 hours and 67 hours vs. 1 hour, respectively) (Gauillard 2002). matic capacity matures, and renal function develops. The
Chloral hydrate, which preceded the Federal Food, Drug, expression of P-glycoprotein, cell membrane efflux transport
& Cosmetic Act (FD&C) of 1938, has never undergone the protein, plays an important role in opioid movement across
rigorous safety and efficacy trials expected of drugs on the the blood-brain barrier. A recent publication described the
U.S. pharmaceutical market. Therefore, chloral hydrate is ontogeny of P-glycoprotein in the human brain. P-glycoprotein
considered an FDA-unapproved drug, and commercially avail- has been detected as early as 8–12 weeks’ gestation, with
able chloral hydrate products are no longer manufactured. the quantity increasing with advancing age. Adult values of
Compounding chloral hydrate from the pharmaceutical grade P-glycoprotein in the brain were achieved by 3–6 months of
powder is still occurring and permitted under the FD&C sec- age. This finding is significant for opioid exposure in the neo-
tion 503A (ISMP 2016). natal period, which is when these drugs may concentrate
Safety of chloral hydrate use in children is of concern. in the brain from the lower expression of this protein (Lam
Extemporaneously prepared products introduce another 2015). In a study of children younger than 3 years receiving
avenue for medication errors with non-standardized con- intravenous morphine after surgery, changes in volume of
centrations and preparations. A 2000 review of pediatric distribution and elimination of morphine metabolites were
adverse events from sedatives showed that chloral hydrate observed. The volume of distribution of morphine almost dou-
contributed to 21% of the severe adverse effects (e.g., bled from birth to 6 months of age, when adult values were
severe neurological injury, death) reported in children achieved (1.2 L/kg vs. 1.9 L/kg). Formation of metabolites
(Coté 2000). Dose-dependent hypotension and ventricular by glucuronidation is also affected by age, with morphine-3-
arrhythmiashave beenreportedwithoverdoses.Chloral hydrate– glucuronide and morphine-6-glucuronide achieving 80% of
associated respiratory depression or airway obstruction lead- adult values by 6 months of age. Metabolite clearance of both
ing to respiratory arrests has been reported in the literature. entities had a maturation half-life of 129 days and reached
The long half-lives of the active metabolites create the poten- 80% of adult values by 6 months and 96% of adult values
tial for prolonged sedation and respiratory adverse events, by 1 year, which mimics the glomerular filtration matura-
creating an unsafe environment for the patient without an tion trajectory (Bouwmeester 2004). The biotransformation
artificial airway or mechanical ventilation (ISMP 2016). capacities of all the phase I and II hepatic enzymes mature
at different rates. For example, CYP3A4 is responsible for pri-
Etomidate marily metabolizing midazolam. The fetal liver has very little
Etomidate is an ultra-short-acting, non-barbiturate hypnotic CYP3A4 but does have CYP3A7, which has a lower magnitude
drug with GABA-like effects. Etomidate has a rapid onset, of catalytic activity. A lower clearance of midazolam would be
short duration of action, and few cardiac and respiratory expected in an infant because of immature CYP3A4 enzyme
adverse effects, making it ideal for inducing anesthesia and activity. However, examination of data showed no significant
rapid sequence intubation. Etomidate is more cardiac neutral change in hepatic clearance with age (Björkman 2006).
than barbiturates or propofol. Small changes in heart rate, Pharmacogenomic contributions to the ontogenic
blood pressure, and cardiac output are noted but are hemo- alterations in drug disposition, drug response, and clini-
dynamically insignificant, making etomidate a good choice cal application are incomplete and not yet fully elucidated
for patients with hemodynamic instability. Little respiratory (Leeder 2010). Describing the clinical impact of genetic poly-
depression and apnea is associated with etomidate com- morphisms on the phase I and phase II enzymes is a prime
pared with other agents (Patel 2011). example of applying this information. The study of CYP2D6
Etomidate-associated adrenal suppression has evoked has shown many polymorphisms that influence ultra-
much controversy in the critical care area. With little evidence metabolism and poor metabolism of certain medications.
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A current pediatric example is codeine, which is metabo- 2016). A 2010 survey on pediatric pain management queried
lized to morphine by CYP2D6. Patients who are considered members of the American Society for Pediatric Anesthesia,
ultra-metabolizers of codeine create a toxic environment of of whom over half reported a formal pediatric pain service
supratherapeutic morphine concentrations. Conversely, poor staffed by either a physician or a nurse. Freestanding chil-
metabolizers of codeine are at risk of therapeutic failure dren’s hospitals and hospitals with more than 150 pediatric
(Gammal 2016). beds had formalized pain services, which helps address the
Joint Commission recommendation (Nelson 2010).
Obesity Considerations
Childhood obesity rates are reaching endemic proportions Combination Therapies
in the United States, with one in six children or adolescents The recently published clinical practice guideline for man-
affected (CDC 2016). Developmental changes that influence aging postoperative pain strongly recommends the use of
drug pharmacokinetics in children are well described, but multimodal pain treatment. Multimodal therapy uses more
drug pharmacokinetics in obesity is not well understood. than one medication with synergistic or additive analgesic
Obesity presents a challenge to the delivery of safe and effec- properties. This therapy includes medications given by dif-
tive medication in children, especially with drugs that have ferent administration routes by local, regional, and neuraxial
narrow therapeutic windows such as some sedatives and anesthetic techniques as well as integration of nonpharma-
analgesics. cologic treatments (Chou 2016).
The pharmacokinetic profile in obesity includes a greater Acetaminophen and NSAIDs decrease opioid needs and
total lean mass and higher volume of distribution of lipophilic postoperative pain when used in combination. This com-
agents like fentanyl and propofol. Patients with obesity have bination strategy for postoperative analgesia is strongly
increased circulating blood volume and higher cardiac output, recommended by several national pain societies and anes-
which may explain their increased hepatic and renal blood thesia groups, though no preference has been given to
flow. Increased organ size and perfusion culminate in higher intravenous versus enteral (Chou 2016).
hepatic drug extraction and glomerular hyperperfusion. With Recently making its way to the U.S. market, intravenous
many of the equations available for creatinine clearance acetaminophen offers favorable pharmacodynamics with
based on body measurements in children, the true glomerular analgesic onset in less than 10 minutes and CNS concen-
filtration rate of children with obesity is likely underestimated, trations peaking at 1 hour after administration. One study
which may lead to suboptimal dosing (Vaughns 2015). described the use of intravenous acetaminophen in children
Aside from the pharmacokinetic considerations in chil- younger than 2 years undergoing bladder surgery. Patients
dren with obesity, choosing the appropriate and optimal received an admixture of intravenous acetaminophen and
dosing weight is perplexing. Given the options of total body fentanyl administered by a patient-controlled analgesia (PCA)
weight, lean body weight, ideal body weight, and adjusted infusion device. Compared with the fentanyl-only group, the
body weight for weight-based dosing, a practitioner is acetaminophen/fentanyl PCA group had decreased fentanyl
faced with a challenge and little evidence to guide decision- use on postoperative days 1 and 2. In addition, the rates of
making. A decision support tool was published to assist with vomiting and sedation were higher in the fentanyl-only group
weight-based dosing in critically ill patients with obesity. The (Hong 2010a). Of interest, a recent randomized, double-blind,
algorithm considers the information available in primary lit- placebo-controlled trial of children and adolescents undergo-
erature as well as volume of distribution, therapeutic window ing surgery for scoliosis repair found no difference in opioid
of the specific drug, and the risk of over- or undertreating requirement in the first 24 hours postoperatively, regardless
to create a recommended dosing scheme on the basis of of whether the children received intravenous acetaminophen
ideal, adjusted, or total body weight. According to the tool, at 90 mg/kg/day or placebo. However, the acetaminophen
dexmedetomidine, ketamine, lorazepam, midazolam, and group had improved analgesia, as reported in lower visual
morphine should be dosed on the basis of ideal body weight analog scale (VAS) pain scores, compared with the pla-
and then titrated to effect. Fentanyl should be dosed on an cebo group. The rate of nausea and vomiting did not differ
adjusted body weight, whereas total body weight dosing has between the two groups. The authors cited the study limita-
been proposed for propofol and pentobarbital (Ross 2015). tions as the small sample size (n=36), the conservative power
calculation, and the use of oxycodone PCA in the acetamino-
phen group for general discomfort instead of for severe pain
Postoperative Analgesia (Hiller 2012).
Pain is often viewed as the fifth vital sign because it is appli- Many of the modern analgesic combination studies use
cable to all patients and should be assessed often. The Joint intravenous acetaminophen as the non-opioid agent as sub-
Commission has recommended that pain assessment and jects are recruited from the preoperative, intraoperative,
treatment be outlined in institution-specific policies that cen- and immediate postoperative setting. A recent systematic
ter on individual patient and patient population needs (Baker review that compared the efficacy of intravenous and oral
01_1_Beckman.indd 13 11-09-2017 16:45:26

acetaminophen in adults found no strong evidence to sup- to demand injections for pain relief. The bolus dose on a
port intravenous acetaminophen over oral acetaminophen PCA is typically offered in smaller doses and at a greater
(Jibril 2015). A randomized controlled study compared intra- frequency than intravenous push opioid doses, which leads
venous with rectal acetaminophen in children undergoing to overall lower opioid drug use with PCA. Continuous infu-
adenotonsillectomy. Both groups had similar fentanyl use sions can be maintained through setting a basal rate on the
postoperatively; however, the rectal acetaminophen group PCA, but this mode is not recommended in the opioid-na-
had longer duration of analgesia before the first rescue dose ive patient (Chou 2016). Some children may not understand
request (median time to rescue dose, rectal: 10 hours; intrave- the push-button concept for analgesia. Use of PCA-by-proxy
nous: 7 hours; p=0.01) (Capici 2008). A retrospective study of (e.g., nurse or parent) has been proposed to expand PCA
infants undergoing a laparoscopic pyloromyotomy assessed use. In a 2010 survey of U.S. hospitals with members of the
the efficacy of rectal versus intravenous acetaminophen. Society for Pediatric Anesthesia, 96% of institutions sur-
Both groups had similar postoperative pain scores, post- veyed had PCA availability, and 59% had no age restrictions
anesthesia care unit time, and hospital length of stay. for independent use. Of the 38% (95 of 252) of institutions
However, the number of additional acetaminophen doses that authorized PCA-by-proxy, 50 allowed nurse-only proxy,
given differed (intravenous group 4.4 ± 5.6 doses vs. rectal 39 allowed a parent or nurse proxy, and 5 allowed parent-
group 3.5 ± 3.7 doses) (Yung 2016). only proxy (Nelson 2010). Some safety concerns of PCA use
The combination of acetaminophen and NSAIDs appears in children stem from the infusion device and drug delivery.
to be favorable in postoperative analgesia. Using a com- It is recommended to use smart pump technology with drug
bination of intravenous acetaminophen and intravenous libraries that offer dose error reduction software, as well as
ketorolac was investigated for possible fentanyl-sparing limit the available concentrations, and create labeling on the
effects during pediatric inguinal hernia repair. Children drug product that matches the medication administration
5 years and younger were assigned to receive either record (ISMP 2008).
intravenous acetaminophen/ketorolac or placebo intra-
operatively. The combination group used significantly Assessment and Monitoring
fewer fentanyl doses and a less-cumulative fentanyl dose Monitoring of analgesics should include observing for toxici-
than the placebo group. Not surprisingly, sedation and ties as well as treatment efficacy. Continuous or intermittent
vomiting were more prolific in the placebo group (seda- monitoring of vital signs to identify respiratory depression
tion 55.6% vs. 25.0%; vomiting 33.3% vs. 10.7%; p<0.05) and hemodynamic compromise is common with the use of
(Hong 2010b). A 2010 meta-analysis explored combination parenteral opioids. From the Society for Pediatric Anesthesia
acetaminophen/NSAIDs versus acetaminophen alone. Of survey, about 78% (196 or 252) of respondents provided
the 20 studies and 1852 patients reviewed, 606 (33%) were routine monitoring to all patients receiving intravenous opi-
children. Combination therapy was preferred to acetamin- oids, regardless of age. The most common monitoring tool
ophen alone, with a 35% reduction in pain scores and a used was pulse oximetry, followed by ECG (Nelson 2010).
38% reduction in supplemental analgesic requirements. In The 2016 American Pain Society guidelines do not recom-
another meta-analysis, results were similar when compar- mend which mechanical monitoring device to use because
ing acetaminophen/NSAIDs with NSAIDs alone. Of the 14 supporting data are lacking. Pulse oximetry in a patient with
studies and 1129 patients reviewed, 268 patients (24%) were oxygen supplementation is not very sensitive for hypoventi-
children. Pain scores and supplemental analgesic require- lation; however, capnography may offer greater sensitivity
ments were reduced in the combination group by 37% and for detecting opioid-induced hypoventilation and resulting
31%, respectively (Ong 2010). This assimilation of data sug- hypercarbia. However, neither of these mechanical monitor-
gests that combination acetaminophen and NSAID therapy ing devices should take the place of periodic assessments of
more dramatically affects the ability to achieve postopera- alertness, hypoventilation, and hypoxia by a medical profes-
tive analgesia than monotherapy. sional (Chou 2016). Sedation scales can evaluate the patient’s
level of sedation after receiving an opioid. The Pasero Opioid-
Pain Medication Delivery Devices Induced Sedation Scale has been validated for assessing
Many delivery devices are available for parenteral pain med- sedation during opioid administration in adult patients, but
ications. These devices, developed for the adult patient, not in children (Pasero 2009). Other sedation scales may be
have expanded use in pediatric patients. Intravenous deliv- used (e.g., Ramsay scale, COMFORT); however, these scales
ery of opioids by PCA infusion device has increased patient evaluate other elements that are not specific to opioid-
satisfaction in postoperative pain management compared induced sedation.
with intramuscular therapies (ASA 2004). Postoperative The gold standard for monitoring the effectiveness of pain
pain management guidelines recommend PCA when paren- medication is patient self-assessment. The premise of these
teral opioids are needed in adults and children. This delivery scales is assigning a numeric value to the perception of pain,
device increases patient satisfaction with the quick access such as designating 0 as “no pain” and 10 as “worst pain
01_1_Beckman.indd 14 11-09-2017 16:45:27

imaginable,” as presented with the 10-point numeric rating analgesic administered and the expected achievement
scale. Self-assessment is a good tool to detect the presence and duration of effects. The frequency of assessment will
of pain as well as the perceived intensity of pain. However, be patient-dependent, considering the source of pain, ade-
pain self-assessment can be challenging in some pediat- quacy of initial pain relief with medication, and medication
ric patients because of their limited ability to communicate adverse effects (Chou 2016). Documenting pain assess-
or comprehend as a result of age or disability. Several non- ment in hospitalized children improves pain management
verbal self-assessment pain scales, such as the VAS, Bieri (McGrath 2013).
Faces Pain Scale Revised, and Wong-Baker FACES scale, can
be used in any age- and developmentally appropriate child
(Table 1-3). Children as young as 6 years may reliably use the Procedural Sedation
“FACES” assessment, and children older than 8 years can Procedural sedation is used for various reasons, includ-
typically rate their pain on a numeric scale (McGrath 2013). ing ensuring patient safety by modifying patient behavior
Observational pain assessments may also be used, but these or movement to allow for completion of procedures, con-
are not preferred to self-assessment scales. Observational trol of anxiety, curtailment of psychological trauma, and
pain scales are used in sedated patients or those who are minimization of physical pain and discomfort. If the dispo-
too young or cognitively inappropriate to describe pain. sition allows, the goal of procedural sedation is to return
Examples of observational pain scales include the Neonatal the child to a state in which discharge from medical care
Pain, Agitation, and Sedation Scale (N-PASS); Face, Legs, is safe. Medications with short duration and few post-pro-
Activity, Cry, and Consolability scale (FLACC); and Nonverbal cedure sequelae are ideal to accomplish a safe discharge.
Pain Scale. Observational scales best identify the presence of Historically, anesthesia providers have performed procedural
pain rather than its intensity because pain-induced behaviors sedation. More recently, credentialing of practitioners such
and physiological responses are not linked to pain intensity as emergency medicine physicians and intensivists to man-
(Wells 2008). age airways, ventilation, and cardiovascular adverse events
In addition to quantifying or qualifying pain with a sub- has increased the number of procedures that can be per-
jective or behavioral scoring tool, other elements must be formed. Procedural sedation is now often performed in clinic
included in the assessment. Having the patient or care- areas, sedation suites, ED, and treatment rooms instead of
giver describe the onset, location, quality, and intensity of the operating theater. Providing these services is not with-
pain is as important as clarifying the factors that aggra- out risks to the patient; however, the AAP has guidelines for
vate or relieve pain and the previous treatments that have monitoring and treating pediatric patients undergoing proce-
been successful or unsuccessful. Setting the expectation dures (Coté 2016).
of pain relief is imperative because achieving a “zero” pain Pediatric patients undergoing painful or prolonged pro-
score may not be possible in some cases, and attempts to cedures may benefit from a medication that contains both
attain this goal may lead to medication overuse and adverse sedative and analgesic properties. When choosing an agent
effects. Timing of assessments should be based on the for sedation, the route of administration, onset of action,
Table 1-3. Comparison of Pain Assessment Instruments
Instrument Population Validated Pain State Type of Assessment Type of Scale
FLACC Children, all ages Acute, surgical Observational Behavioral, physiological
FPS-R ≥ 4 yr Acute, surgical Self Pictorial
N-PASS Neonates Acute, surgical Observational Behavioral, physiological
NVPS Children, all ages Acute, surgical Observational Behavioral, physiological
NRS ≥ 6 yr Acute, surgical, Self Numeric

chronic
VAS ≥ 6 yr Acute, surgical, Self Numeric

chronic
Wong-Baker FACES ≥ 4 yr Acute, surgical Self Pictorial
FLACC = Face, Legs, Activity, Cry, and Consolability scale; FPS-R = Faces Pain Scale Revised; N-PASS = Neonatal Pain, Agitation, and
Sedation Scale; NRS = numeric rating scale; NVPS = Nonverbal Pain Scale; VAS = visual analog scale.
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Table 1-4. Levels of Sedation
Level of Sedation Stimulus Response Airway Patency Ventilation Hemodynamics
Minimal (“anxiolysis”) Verbal and tactile Unaffected Unaffected Maintained
Moderate (“conscious sedation”) Verbal and tactile Unaffected Unaffected Maintained
Deep Noxious tactile Affected Affected Maintained
General anesthesia None Affected Affected Impaired
duration of action, and adverse effect profile must be con- more-frequent arrhythmias, suggesting that atropine admin-
sidered. The level of sedation desired is another important istration provides a safer intubation environment (Jones
element in agent selection (Table 1-4). 2013). Intravenous lidocaine is used as an adjuvant in intubat-
ing a patient with neurological injury. Intravenous lidocaine is
thought to blunt the sympathomimetic response from intu-
Indications for Use
bation and preserve cerebral perfusion. A systematic review
Rapid Sequence Intubation
has shown equivocal results when comparing intravenous
Rapid sequence intubation originated in the ED as a way to lidocaine-pretreated and lidocaine-untreated patients with
handle the airway of a patient in extremis with an unknown traumatic brain injury in hemodynamics, ICP reduction, or
aspiration risk. The goal is to induce unresponsiveness and overall neurological outcome (Bucher 2015). At this time, no
muscular relaxation as quickly as possible in order to con- data support intravenous lidocaine as an intubation adjuvant
trol the airway (Bledsoe 2004). Benzodiazepines, ketamine, in a neurologically injured patient.
etomidate, quick-acting opioids (e.g. fentanyl), and rapid-
acting neuromuscular blocking agents are preferred because Non-painful Procedures
of their favorable pharmacodynamic profiles of quick onset Procedural sedation is used for non-painful procedures such
and short duration of action. Hemodynamic stability will as radiologic imaging, echocardiograms, and auditory testing.
contribute to the selection of agents, and the agents with car- Previously, agents such as benzodiazepines and barbiturates
diovascular neutrality (e.g., ketamine, etomidate, fentanyl) were the only available medication, leading to delayed recov-
will likely be preferred for a patient with compromised hemo- ery periods. With the introduction of dexmedetomidine and
dynamics. The NEAR III investigators reported the intubation propofol, recovery time has been shortened.
practices in children younger than 16 years and described Because imaging is being pushed to the outpatient areas,
etomidate (64%) and succinylcholine (53%) as the most com- children undergoing these procedures most likely do not
mon induction agent and paralytic used, though there was have an artificial airway for mechanical ventilation; therefore,
a trend toward not using a neuromuscular blocking agent using an agent that allows spontaneous respirations such
in children younger than 2 years (39%). Premedication with as dexmedetomidine is a favorable choice for sedation. A
the intubation adjuvants atropine or lidocaine had decreased 2015 meta-analysis compared dexmedetomidine with propo-
from previous years (Pallin 2016). fol for procedural sedation in 337 children undergoing MRIs.
Although little evidence supports adjuvants to blunt Children who received dexmedetomidine had a longer mean
hemodynamic response with intubation, these adjuvants recovery time with a pooled mean difference of 10.7 minutes
may be used in some institutions and in certain patient between the groups (95% CI, 4.26–17.13; p<0.05). The dex-
populations. Use of intravenous atropine during intubation medetomidine group had a delayed discharge time weighted
conserves the heart rate by antagonizing acetylcholine in mean difference of 12.7 minutes (95% CI, 8.1–17.37; p<0.05)
the sinoatrial node, which helps combat the vagal-mediated compared with the propofol group. However, despite the
bradycardia that can be induced by inserting a laryngo- delays in the dexmedetomidine group, both groups had sim-
scope or using succinylcholine. The anticholinergic effects ilar duration of sedation for the procedure. As for effects on
of atropine can help curtail secretions from succinylcho- the respiratory and cardiovascular system, minimum heart
line or ketamine (Bledsoe 2004). The expert opinion from rate did not differ between the two groups, but the dexmede-
the pediatric shock group recommends using ketamine tomidine group had higher minimum mean arterial pressure
with adjuvant atropine for intubation of critically ill children and respiratory rates (Fang 2015). Concurrent use of dex-
(Brierley 2009). More recently, in a study of over 300 neona- medetomidine and midazolam was compared with propofol
tal and pediatric intubations, fewer bradyarrhythmias were for maintaining anesthesia in a small group of children (n=40)
noted with atropine administration (OR 0.14; 95% CI, 0.06– undergoing an MRI. Dexmedetomidine/midazolam resulted in
0.35; p<0.05). Lack of atropine administration resulted in a delayed time to full responsiveness compared with propofol
01_1_Beckman.indd 16 11-09-2017 16:45:27

alone (44 vs. 29 minutes; p<0.05). Similarly, the time to dis- Painful Procedures
charge from the hospital was delayed in the combination Procedural sedation for painful procedures has created a
group (95 vs. 79 minutes; p<0.05). The dexmedetomidine/ use for ketamine because of its analgesic properties and
midazolam group had lower heart rates and higher systolic favorable pharmacodynamics. The Pediatric Sedation
blood pressures (p<0.05), but respiratory rates or respiratory Research Consortium published an observational review
events did not differ between the two groups (Heard 2008). of 22,000 children younger than 21 years who received ket-
As more procedures are being completed in the ambulatory amine for procedural sedation outside the operating room.
setting, intravenous access may be limited. Therefore, alter- Intravenous ketamine was used 92% of the time, and intra-
native routes of administration such as oral or intranasal may muscular ketamine was used 5.6% of the time. Almost 70% of
be more feasible. In 2015, a systematic review investigated the procedures were classified as painful. Although no anal-
non-intravenous routes of sedation for children younger than gesic therapy was captured in the study, other sedatives were
19 years undergoing imaging. Intranasal midazolam was co-administered (anticholinergics 19.8%, benzodiazepines
studied for procedural use in children during CT. Intranasal 57.9%, propofol 35.4%). Adverse events were reported in 7.3%
midazolam 0.5 mg/kg with intranasal ketamine 5 mg/kg had of patients, with severe adverse events occurring in 1.7%
83% achievement of desired sedation level. Monotherapy with of the study group. Severe adverse events were defined as
0.4 mg/kg of intranasal midazolam achieved sedation in 75% airway obstruction, laryngospasm, emergency airway inter-
of the tested population. Comparing 0.2 mg/kg of intrana- vention, aspiration, or cardiac arrest. Evaluation through
sal midazolam with oral chloral hydrate showed that chloral logistic regression revealed that the physical location of
hydrate achieved the desired level of sedation more often the procedure appeared to be an independent risk factor
than a single dose of intranasal midazolam, likely because of for adverse events, with the ED having the lowest odds (OR
the less-than-optimal midazolam dose (93% vs. 40%, p<0.05) 0.71; 95% CI, 0.57–0.88) and dental suites having the highest
(Thomas 2015). In a study comparing intranasal dexmedeto- odds (OR 3.75; 95% CI, 1.74–8.06) of an adverse event. A pri-
midine with oral midazolam in children younger than 5 years mary cardiac diagnosis also increased the odds of having any
undergoing a CT scan, the dexmedetomidine group met the adverse event (OR 2.38; 95% CI, 1.64–3.46). Both propofol and
sedation goal 67% of the time, compared with 24% in the oral anticholinergic use were independent risk factors for severe
midazolam group (p<0.05). The scan times were similar in adverse events (propofol 5.36; 95% CI, 4.08–7.05; anticholin-
both groups, and no adverse events were reported with either ergics 2.92; 95% CI, 2.35–3.63) (Grunwell 2016).
therapy. Both groups had similar sedation scores 10 and Ketamine has been compared with other procedural seda-
20 minutes after administration, but the dexmedetomidine tives. Ketamine was prospectively compared with ketamine/
group had a higher sedation score at the time of the CT scan, propofol for children with isolated orthopedic injuries under-
which is consistent with the half-life and duration of action of going procedural sedation. Monotherapy with ketamine had a
dexmedetomidine. The lower level of sedation in the midazo- prolonged median sedation time (16 minutes vs. 13 minutes)
lam group may explain the larger number of rescue ketamine and a median recovery time (12 minutes vs. 10 minutes), as
doses given compared with the dexmedetomidine group well as more adverse effects (49% vs. 25%) than ketamine/
(22 vs. 10 doses, p<0.01). Parental satisfaction was more propofol. However, the ketamine monotherapy group received
favorable in the intranasal dexmedetomidine group but did not 1 mg/kg of ketamine, whereas the ketamine/propofol group
achieve statistical significance (Ghai 2016). When comparing received 0.5 mg/kg of each drug, which may have contributed
oral midazolam with oral chloral hydrate for sedated transt- to the incongruent results (Shah 2011). Ketamine/midazolam
horacic echocardiograms, midazolam offered a 40-minute has also been prospectively evaluated against midazolam/
faster recovery than chloral hydrate (p<0.05). However, chlo- fentanyl for procedural sedation and analgesia in pediatric
ral hydrate provided a deeper level of sedation so that a more orthopedic emergencies. The ketamine/midazolam group had
comprehensive evaluation could be completed. No hemody- less hypoxia (45.2% vs. 76.6%, p<0.05), shorter hypoxic epi-
namic compromise was noted in this study (Thomas 2015). sodes, and lower pain scores than the midazolam/fentanyl
Similarly, two different doses of intranasal dexmedetomidine group. However, the ketamine/midazolam group had a higher
(2 mcg/kg and 3 mcg/kg) were compared with oral chloral incidence of adverse effects (51.6% vs. 6.7%, p<0.05) (Cevik
hydrate for sedation during transthoracic echocardiograms 2013). A study of pediatric burn patients who were randomized
in children younger than 3 years. Rescue medication was to receive either ketamine/propofol or ketamine/dexmedeto-
rarely needed, with 4% or less of the patients receiving addi- midine showed no difference in sedation scores, Sao2 values,
tional sedation medications. Heart rate was decreased in all and diastolic blood pressures. Systolic blood pressures were
groups, with a 22% decrease in the chloral hydrate group, a increased in the ketamine/dexmedetomidine group (p<0.05),
27% decrease in the 2-mcg/kg dexmedetomidine group, and and respiratory depression was noted in the ketamine/prop-
a 23% decrease in the 3-mcg/kg dexmedetomidine group ofol group but not the ketamine/dexmedetomidine group
(p=0.21). The mean time to discharge did not differ between (13.3% vs. 0%, p<0.05). In addition, recovery took longer in the
the groups (p=0.18) (Miller 2016). ketamine/dexmedetomidine group (36 vs. 27 minutes, p<0.05)
01_1_Beckman.indd 17 11-09-2017 16:45:27

(Canpolat 2012). Fentanyl/etomidate versus ketamine/ of the patient, thus avoiding the respiratory adverse events
midazolam was studied for procedural sedation and analge- often associated with propofol use (Kamat 2015).
sia in children undergoing orthopedic reductions. Etomidate/
fentanyl produced higher distress and pain scores, according Assessment and Monitoring
to parental and physician observations (p<0.05). However, eto- Monitoring of patients receiving procedural sedation should
midate/fentanyl had shorter sedation time (49 vs. 77 minutes, be focused on maintaining the patient’s airway, breath-
p<0.05) and recovery time (24 vs. 61 minutes, p<0.05) than ing, and circulation. The AAP has published guidelines
ketamine/midazolam. More adverse drug events (e.g., pain at for equipment and personnel requirements according to
injection site, myoclonus) and respiratory events occurred in the level of sedation obtained. Monitoring should always
the etomidate/fentanyl group (Jayaram 2010). include pulse oximetry, telemetry, and blood pressure mea-
Propofol has been studied in many combinations for pro- surement at designated intervals intra- and post-procedure.
cedural sedation in children. One study randomized children Capnography is recommended in moderate sedation and
undergoing procedural sedation in the interventional radiol- required in deep sedation. Rescue carts stocked with age-
ogy suite to receive either propofol/fentanyl or propofol/ and size-appropriate airway equipment and medications
fentanyl plus ketamine. Adding ketamine to the propofol/ are required to be available. Patients should be observed by
fentanyl group led to fewer propofol boluses to maintain trained personnel (i.e., anesthesiologist, trained physician,
sedation (p<0.05) and fewer oxygen desaturations (p=0.05) or advanced practice provider) who can perform interven-
(Erden 2009). In children with acute lymphoblastic leuke- tions to keep the airway patent and address hypoventilation
mia, similar desired levels of sedation and analgesia were and hemodynamic instability. In addition, patients should
achieved in both the propofol/alfentanil and the propofol/ be observed before and after they emerge from sedation for
ketamine groups. In contrast, the propofol/alfentanil group drug-related adverse effects and should receive treatment
had a significant increase in cardiorespiratory adverse accordingly (Coté 2016).
effects compared with the propofol/ketamine group, per-
haps because of opioid exposure (p<0.05) (Chiaretti 2010). Prolonged Sedation
Monotherapy with propofol resulted in more oxygen desat- Critically ill children often require prolonged sedation to meet
urations (p=0.05), more hypotensive episodes (p<0.05), and therapeutic goals and to enhance healing. Sedation, like anal-
increased propofol exposure (p<0.05) when concomitant ket- gesia, can decrease the physiological stress response and
amine was not given (Chiaretti 2011). decrease the body’s metabolic demand. In addition, pro-
In 2015, the Pediatric Sedation Research Consortium longed sedation decreases physiological stress by inducing
explored propofol use for pediatric procedural sedation amnesia, alleviating agitation, and reducing consciousness.
performed by pediatric intensivists. Of the 91,189 propofol Adequate sedation creates a safe environment for patient
procedures conducted in children, 52% of the population used and caregiver, permits ventilator synchrony, and allows for
propofol boluses alone, and almost 41% used a propofol bolus other therapeutic interventions and monitoring. Selection
plus an infusion. Concurrent medications included lidocaine of agents for prolonged sedation should consider the dura-
(35%), opioids (23%), benzodiazepines (16%), and ketamine tion of expected sedation, goal level of sedation (e.g., light vs.
(4%). The adverse event rate was 5%, and the severe adverse deep sedation), clinical status, organ function of the patient,
event rate was 2.2%, with most adverse events being airway and anticipated adverse effects.
patency and ventilation events. The multivariable logistical Data supporting preferred agents for prolonged use
regression showed that lower respiratory tract infections (OR in children are lacking. According to a 2014 international
2.8; 95% CI, 2.39–3.28) and the physical location of the pro- survey, practice varies greatly across the globe. In mechan-
cedure were independent risk factors for adverse events. The ically ventilated children, fentanyl was the most prescribed
most adverse events were found in dental suites with an odds opioid infusion (66%), and midazolam was the first-line sed-
ratio of 8.46 (95% CI, 4.1–17.49), followed by cardiac catheter- ative (86%). Propofol and dexmedetomidine were commonly
ization units (OR 2.62; 95% CI, 1.57–4.36), with the pediatric associated with administration restrictions because of their
ICU (PICU) (OR 1.38; 95% CI, 1.20–1.58) and EDs (OR 1.01; 95% potential for severe adverse effects and elevated drug cost,
CI, 0.44–2.29) having the lowest odds for adverse events. In respectively (Kudchadkar 2014).
addition, using propofol plus four other medications increased A systematic review of PICU prolonged sedation practices
the risk of adverse events by 3 times that of patients receiv- found 39 studies with fairly poor quality evidence, each with a
ing propofol plus three or fewer medications (propofol plus different sedation regimen. Heterogeneity of measured seda-
four medications OR 5.83; propofol + three medications or tion end points, non-standardized dosing, and lack of safety
less OR 1.17–1.76, p<0.05). Painful procedures appeared to be end points were identified. Midazolam was the most studied
protective, with an odds ratio of 0.73 (95% CI, 0.68–0.78). It of the sedatives, with an increased interest in dexmedetomi-
was hypothesized that the lack of analgesic effect of propofol dine (Hartman 2009). Most agents used in prolonged sedation
allowed the presence of pain to stimulate the respiratory drive are typically given as continuous infusions. However, a 1999
01_1_Beckman.indd 18 11-09-2017 16:45:27

study showed the successful transition of midazolam infu- One institution has published its experience with a PICU
sions to scheduled enteral lorazepam to achieve adequate nurse-driven sedation protocol. The length of PICU stay
sedation of mechanically ventilated children. This study decreased by a median of 1 day, total sedation days decreased
found that 80% of the midazolam infusions were discontinued by 2 days, and lorazepam infusions for sedation were almost
within 3 days of initiating lorazepam, with remaining patients eliminated compared with the observation group (Deeter
having the infusion rate reduced by over 50%. A cost savings 2011). Although initially successful, a review of practice
over $42,000 occurred with benzodiazepine transition in this 4 years after protocol implementation showed an increase
15-month investigation. This study is significant because it in PICU length of stay and sedation days. An increased use
shows the effect of capitalizing on drug pharmacokinetics to of dexmedetomidine was noted, and use of benzodiazepines
achieve the desired goal (Lugo 1999). remained similar to use at implementation levels (Yaghmai
2016).
Sedation Strategies The RESTORE study addressed gaps in the literature
Unlike the adult population, the pediatric critically ill pop- regarding prolonged sedation in children. This is the larg-
ulation has no comprehensive pain and sedation guideline est pediatric sedation study to date, enrolling almost 2500
to consult. The relative paucity of data likely contributes to patients with acute respiratory failure between 17 intervention
the absence of recommendations. The adult PAD guidelines institutions and 14 control institutions. The study objective
do not specifically address practice standards of manag- was to compare a nurse-driven, goal-oriented, sedation pro-
ing sedation, analgesia, and delirium in critically ill children. tocol with standard of care. The protocol was very complex
The guidelines may be used as a resource to stimulate pedi- and considered pain, sedation, and withdrawal assessments
atric PAD research, assist in creating pediatric protocols as well as scheduled arousal assessments (e.g., sedation
to treat pain and agitation, and prevent and treat delirium “holiday”) and extubation readiness tests, when deemed
(Barr 2013). appropriate. The primary objective of decreasing the days on
Patient Care Scenario

M.N., a 5-year-old boy (height 43 inches [108 cm], weight 60 pressure ventilation with heliox. Despite all of the inter-
kg) with uncontrolled severe persistent asthma, is admit- ventions, his oxygenation and ventilation is compromised;
ted to the PICU with a severe acute asthma exacerbation. hence, the decision is made to place an endotracheal
He is receiving continuous inhaled albuterol at 10 mg/hour tube and initiate mechanical ventilation. Rapid sequence
and methylprednisolone 60 mg intravenously daily. He still intubation is initiated with fentanyl, etomidate, and succin-
has retractions of accessory muscles, prolonged expira- ylcholine, and an endotracheal tube is successfully placed.
tory phase, and decreased air movement at the bases of What would be an appropriate continuous infusion regimen
both lungs. A dose of magnesium sulfate (2000 mg intra- to provide analgesia and sedation for this child receiving
venously × 1) is given and initiated on noninvasive positive mechanical ventilation?
Answer
Several options can be used for analgesia and seda- which would explain its success in patients with asthma.
tion in this child. However, morphine should be avoided. Dexmedetomidine, because of its lack of interference with
Morphine should not be used because of the potential for the respiratory drive, may prove advantageous as a sed-
histamine release exacerbating airway bronchospasm. ative in a patient with asthma and allowance for native
Fentanyl or hydromorphone would be reasonable options respiratory drive to stay intact. Midazolam and prop-
for analgesia in a patient with asthma. Fentanyl might ofol would be options in this child as well because they
be the best choice because of its shorter half-life, but its would provide titratable sedation (e.g., from light to deep)
high volume of distribution and lipophilicity may not be if the situation continued to deteriorate (e.g., continuous
desirable in this child with obesity. As for sedatives, dex- neuromuscular blockade is introduced). Midazolam and
medetomidine, midazolam, ketamine, and propofol are all propofol are not without risks; both adversely affect the
reasonable options. Ketamine is the only drug with data cardiorespiratory system, and propofol has the risk of
to support its use for sedating patients with asthma. One PRIS with high doses and long durations of use. One other
retrospective study reported that intravenous ketamine layer of complexity in this sedation conundrum is the
given at 2 mg/kg × 1, followed by an infusion at 20–60 mcg/ dosing of these agents in a child with obesity. Ketamine,
kg/minute, improved ventilation (e.g., improved partial dexmedetomidine, and midazolam should be dosed on
pressure of oxygen/fraction of inspired oxygen ratio, lung ideal body weight, whereas fentanyl uses an adjusted
compliance). Ketamine has bronchodilator properties, body weight for dosing.
1. Youssef-Ahmed MZ, Silver P, Nimkoff L, et al. Continuous infusion of ketamine in mechanically ventilated children with refractory
bronchospasm. Intensive Care Med 1996;22:972-6.
2. Ross EL, Heizer J, Mixon MA, et al. Development of recommendations for dosing of commonly prescribed medications in critically ill
obese children. Am J Health Syst Pharm 2015;72:542-56.
01_1_Beckman.indd 19 11-09-2017 16:45:27

mechanical ventilation in the intervention group was unmet analyses show the negative impact of sedative-hypnotic reg-
(median 6.5 vs. 6.5 days, p=0.61). However, the intervention imens on clinical outcomes and patient quality of life (Barr
group did have fewer opioid days (9 vs. 10 days, p<0.05) and 2013). However, no pediatric analgosedation studies have
less exposure to different sedative classes (two vs. three been published to date; therefore, this strategy for prolonged
classes, p<0.05) than the standard-of-care patients. In addi- sedation should not be considered standard of practice in
tion, the intervention group spent more time awake and calm children.
than the control group (86% vs. 75% of the day, p<0.05). The
intervention group reported more days of pain scores at or Monitoring and Assessment
above 4 (50% vs. 23%, p<0.05) and more agitation (60% vs. Similar to monitoring analgesia, observing for drug toxicities
40%, p<0.05) than the standard-of-care group. The authors and adverse events as well as assessing the efficacy of ther-
concluded that alertness resulted in more reported pain and apy is imperative in monitoring prolonged sedation. Heart
agitation, but also reaffirmed that having an arousable and rate, heart rhythm, respiratory rate, blood pressure, and oxy-
calm, critically ill, mechanically ventilated child is achievable hemoglobin saturations must be monitored continuously
(Curley 2015). or often. Further monitoring with laboratory values such as
A secondary analysis of this RESTORE data set investi- blood gases, serum electrolyte panels, and hepatic or renal
gated the role of dexmedetomidine in sedating critically ill function tests may be needed, depending on the sedatives
children. Almost 50% of the control group (n=596) received being used.
dexmedetomidine, with 11% (n=138) receiving dexmede- Many assessment tools are available to evaluate the
tomidine as the primary sedative agent, 23% (n=280) as a level of consciousness in a sedated patient. Several of the
secondary agent, and 15% (n=178) as a peri-extubation pediatric assessment tools for sedation are borrowed from
agent. In the intervention group, 23% of the population adult versions, but with additional age- and development-
(n=287) received dexmedetomidine, with only 55 of the sub- appropriate anchor points (Table 1-5). All sedation scales
jects receiving it per protocol as a peri-extubation agent. assess the level of consciousness through a series of
Increasing the use of dexmedetomidine as a primary and questions, observations, and exposure to noxious and non
secondary agent was a general trend during the study. -noxious stimuli at dedicated time intervals. The Ramsay
Children in the control group who received dexmedetomi- scale is a 6-point scoring system designed as a test of
dine as a peri-extubation agent had the shortest duration arousal and responsiveness in adults, though it has not
of mechanical ventilation (median 4.4 days) compared with been validated in children (Ramsay 1974). The University
when dexmedetomidine was used as the primary agent of Michigan Sedation Scale is a five-level observational
(median 5 days) and secondary agent (median 9.9 days). tool validated for short, procedural-related observations
This discrepancy may be explained by the secondary agent with limited applicability in prolonged sedation scenarios
group having higher severity of illness scores and more (Malviya 2002). The Richmond Agitation-Sedation Scale
severe lung disease. The dexmedetomidine for peri-extuba- (RASS) is 10-point scoring tool commonly used in pedi-
tion and primary agent groups had similar median opioid and atric patients, but until recently, it had been validated
benzodiazepine cumulative drug exposure (opioids: 12.5 vs. only in critically ill adults (Kerson 2016; Ely 2003; Sessler
12.8 mg/kg; benzodiazepines: 13.1 vs. 9.7 mg/kg). However, 2002). The RASS, favored for its clear and easily navi-
the secondary group had a markedly higher median expo- gated assessment, encompasses the entire spectrum
sure of opioids (53.2 mg/kg) and benzodiazepines (42.3 mg/ of consciousness from deeply sedated to very agitated
kg). The authors concluded that peri-extubation dexmede- (Kerson 2016). The State Behavioral Scale (SBS) is an eight-
tomidine helps facilitate ventilator weaning. In addition, dimension assessment tool that provides up to five levels to
dexmedetomidine as a primary agent is better used in the each dimension assessment (Curley 2006). The COMFORT
less critically ill patient than in the severely critically ill scale, a five-level, nine-dimension tool that evaluates dis-
patient. Secondary use of dexmedetomidine did not offer tress in PICU patients, has come under scrutiny because
much clinical benefit, according to the results of this suba- of the physiological variables included in the assessment
nalysis (Grant 2016). (Ambuel 1992). The COMFORT-behavior scale was created
Another sedation strategy in its infancy is analgoseda- to remove the physiological variables (heart rate, blood
tion. This analgesia-based sedation is aligned with the adult pressure) that were previously included in the COMFORT
PAD guidelines, which recommend minimizing sedatives assessment. Heart rate and blood pressure were removed
such as benzodiazepines to help decrease the risk of delir- because they poorly correlated with the behavioral assess-
ium. Untreated or undertreated pain in critically ill adults ment, especially in a hemodynamically unstable patient
has been identified as a cause of agitation, and optimizing receiving vasoactive infusions (Ista 2005). These assess-
comfort with an analgesic seems appropriate. Although ments all have an observational component of the scoring
the evidence is of moderate quality in adults, analgoseda- tool, but some introduce an intervention before the obser-
tion is a compelling sedative-sparing strategy as more data vation. This progressive stimulus is necessary to complete
01_1_Beckman.indd 20 11-09-2017 16:45:27

Table 1-5. Comparison of Sedation Scales
Validated Population Domains for Assessment

Name of Instrument Age Patient Variables Consciousness Agitation Respiratory Pain
COMFORT Newborn – 17 yr + ventilator X X X X
± ventilator
COMFORT-B Newborn – 18 yr X X X X
± sedatives
± ventilator
Ramsay Adults X X
+ sedatives
Adults ± ventilator
RASS X X X
2 mo – 21 yr ± sedatives
+ ventilator
SBS 6 wk – 6 yr X X X
+ sedatives
UMSS 4 mo – 5 yr + sedatives X X
COMFORT-B = COMFORT-behavior; RASS = Richmond Agitation-Sedation Scale; SBS = State Behavioral Scale; UMSS = University of
Michigan Sedation Scale.
the evaluation for the Ramsay scale and SBS. However, the that tolerance has a decreasing clinical effect with pro-
provocation may not be desirable, especially if assessing an longed exposure. In addition, opioid-induced hyperalgesia
already agitated or hemodynamically tenuous patient. differs from allodynia because allodynia describes a painful
response induced by normally innocuous stimuli (Roeckel
Untoward Effects of 2016). There is only one published report of opioid-induced
Analgesia and Sedation hyperalgesia in a child. The patient with polyarticular juve-
When recalling the untoward effects of analgesia and seda- nile idiopathic arthritis was experiencing refractory pain
tion, hemodynamic compromise, respiratory depression, with escalating opioid doses and allodynia. With a taper and
opioid-induced constipation, and nausea and vomiting eventual discontinuation of the opioids, pain alleviation was
come to mind. Iatrogenic withdrawal syndrome is also of reported (Vijayan 2012).
concern with prolonged, continuous exposure to these Prevention and treatment of hyperalgesia is not well
agents (e.g., opioids, benzodiazepines, barbiturates, and understood. Some approaches to relieve symptoms have
dexmedetomidine). Abrupt discontinuation after such been documented in case reports. Removing the offend-
exposure may activate this withdrawal syndrome. Other ing opioid, rotating to a different opioid, and using a
chapters in this series will examine iatrogenic withdrawal longer-acting opioid have been executed with success.
syndrome. Other than acute adverse drug events and with- Adding low-dose ketamine (0.25–5 mg/kg), an N-methyl-d-
drawal, exposure to analgesics and sedatives has many aspartate (glutamate) receptor antagonist, has also been
protracted effects. successful in some cases (Anand 2010). With the paucity
of pediatric hyperalgesia literature, this phenomenon is
Hyperalgesia not currently recognized as an issue in pediatric patients.
However, with its increased recognition in adult patients
Opioid-induced hyperalgesia has been described in both
and the changing landscape for analgesia and analgoseda-
human and animal models with various types of pain.
tion, the conversation about opioid-induced hyperalgesia
Hyperalgesia is an increased sensitivity to pain, and in opioid-
will likely increase.
induced hyperalgesia, opioids are thought to worsen pain
through a paradoxical response to painful stimuli (Roeckel
2016). The mechanism is theorized to be from sensitization Delirium
of the primary afferent neurons, enhanced glutamate release Delirium is acute brain dysfunction manifested by changes
at the primary afferent neurons, hyperexcitability of the neu- and fluctuations in cognition and attention. Symptoms mani-
rons, and release of excitatory neurotransmitters (Anand fest as hyperactive (e.g., restless, agitated, emotional liability),
2010). Hyperalgesia is a clinical diagnosis of increased hypoactive (e.g., somnolence, withdrawal from environment),
pain perception despite increasing opioid exposure. Opioid- or mixed delirium. Delirium is recognized as an adverse con-
induced hyperalgesia differs from opioid tolerance, given sequence of critical illness in adults and children alike. The
01_1_Beckman.indd 21 11-09-2017 16:45:27

Figure 1-1. Evaluation of potential explanations for delirium.
Information from Pediatric Road Map.
largest pediatric delirium study had a point prevalence of cost reflecting this trend as well (median $2645 vs. $1701;
25% across all studied institutions and a median institutional p<0.05) (Traube 2016). Delirium significantly affects the
prevalence of 23.3% (interquartile ratio 20%–35.4%, p=0.038) health care system.
(Traube 2017). Several risk factors have been identified (e.g., To prevent or treat delirium, a clinician must be able to
severity of illness, exposure to certain medications, and dis- recognize the signs and symptoms. The gold standard for
ruption of sleep-wake cycles) (Silver 2015) (Figure 1-1). In the diagnosing delirium is an evaluation completed by a psychi-
point prevalence study, medications appeared to contribute atrist. However, psychiatry resources are not available in all
to delirium, with narcotics, benzodiazepines, and antiepileptic locations at all times. Therefore, bedside tools were devel-
drugs identified. Age younger than 2 years (adjusted OR 0.7; oped to allow non-psychiatry clinicians to complete the
95% CI, 0.5–1), use of physical restraints (adjusted OR 4; 95% CI, delirium assessment (Table 1-6). The Delirium Rating Scale,
2–7.7), and use of vasopressors (adjusted OR 2.4; 95% CI, 1.5– 1988 (DRS-88) was the first tool for hospitalized patients to
3.8) were also identified as contributing factors. After 5 days detect hyperactive delirium symptoms (Trzepacz 1988). This
in the PICU, prevalence increased from 20% to 37% (p<0.001) scale was revised in 1998 to help discern between delirium
(Traube 2017). and psychiatric disorders (Trzepacz 2001). The Pediatric
Adult delirium data analyses have shown negative Anesthesia Emergence Delirium (PAED) tool was created to
long-term consequences in critical care survivors result- detect postoperative emergence delirium in children but was
ing in cognitive dysfunction, increased length of stay, and not applied to other hospitalized children (Sikich 2004). In
even mortality, as well as an increased financial burden to 2008, the adult confusion assessment method for ICU (CAM-
the health care system (Barr 2013). In a recent study, total ICU) tool was adapted for critically ill pediatric patients and
costs of a PICU stay were higher in children who had delir- renamed the pediatric confusion assessment method for
ium at any time during admission than in those who did not ICU (pCAM-ICU). This was the first pediatric bedside tool
(median $18,831 vs. $4802; p<0.05), with the daily PICU that could detect symptoms of delirium in patients 5 years
01_1_Beckman.indd 22 11-09-2017 16:45:32

Table 1-6. Comparison of Pediatric Delirium Screening Tools
DRS-88 DRS-R-98 PAED pCAM-ICU psCAM-ICU CAPD
PICU population Med/surg Med/surg Med/surga Med/surg, Med/surg, General

(n) (154) (154) (154) cardiac (68) cardiac (300) (111)
Age (yr) 1–17 1–17 1–17 ≥5 0.5–5 Birth – 21 yr
Include mechanical
No No No Yes Yes Yes
ventilation?
Include developmental delay? No No No No No Yes
Hyperactive Hyperactive Hyperactive

Type of delirium Hyperactive Hyperactive Hyperactive
Hypoactive Hypoactive Hypoactive
No. of questions or domains 10 16 5 4 4 8
Administering provider Psychiatrist Psychiatrist Anesthesia Bedside b

Bedside b
Bedsideb
a
Included postoperative patients, not PICU patients.
b
Bedside provider includes nurse, advanced practice provider, and physician.
CAPD = Cornell Assessment of Pediatric Delirium; DRS-88 = Delirium Rating Scale, 1988; DRS-R-98 = Delirium Rating Scale, Revised,
1998; IRR = interrater reliability; PAED = Pediatric Anesthesia Emergence Delirium; pCAM-ICU = pediatric confusion assessment
method for the ICU; psCAM-ICU = preschool confusion assessment method for the ICU.
and older (Smith 2011). To fill the age gap left by the first ver- literature; however, well-designed, well-controlled trials are
sion of the pCAM-ICU, the preschool confusion assessment lacking to support the safe and effective use of these agents.
tool for ICU (psCAM-ICU) was validated in children 6 months These medications are not without acute risk, most notably
to 5 years of age (Smith 2016). The Cornell Assessment of QT prolongation, dystonic reactions, and neuroleptic malig-
Pediatric Delirium (CAPD) is an adaption of the PAED with nant syndrome. Therefore, if pharmacologic treatment of a
additional questions to detect hypoactive delirium. The pediatric patient for delirium becomes an intention, this deci-
CAPD includes developmental anchor points for all ages, sion should be entered into thoughtfully and with a specific
negating an age limitation (Traube 2014). A recent publica- monitoring plan outlined.
tion showed much overlap in the symptoms of delirium and
iatrogenic drug withdrawal syndrome in children. Although Neurodevelopmental Outcomes
these screening tools help assign objectivity to the assess- Currently, neurodevelopmental outcomes of children exposed
ment, the syndromes are not mutually exclusive, and the to short- and long-term analgesics and sedatives are unknown.
authors warn providers not to overlook the clinical context A growing body of literature aims to describe the effect of
(Madden 2017). drug exposure on a child’s motor and cognition development.
Prevention and treatment of delirium are evolving. The In a study of infants younger than 8 weeks with periopera-
adult PAD guidelines recommend normalizing patient tive analgesia and sedation exposure, drug exposure was
environments, promoting sleep, and performing early mobi- not associated with negative neurodevelopmental outcomes
lization. One center showed that the incidence of delirium in 2 years after cardiac surgery (Guerra 2011). Mechanically ven-
the PICU decreased from 19.3% to 11.8% with the successive tilated preterm infants with a median gestational age of 29
rollout of delirium screening, sedation, and early-mobilization weeks who received morphine had a decreased IQ early in life,
protocols (Simone 2017). The PAD guidelines recommend but by 5 years of age, this effect had disappeared (de Graaf
against pharmacologic therapy for preventing or treating 2011). In a neuropsychological follow-up study of childhood
delirium because data are sparse to support medication use meningococcal survivors exposed to analgesia and seda-
(Barr 2013). Prevention of delirium has been investigated in tion in the PICU, the children had poor test outcomes at least
the pediatric anesthesia literature with respect to anesthesia 4 years after admission. Full-scale IQ, verbal and vocabulary
emergence, as well in the adult critically ill population with IQ, and visual attention and executive functioning were all
dexmedetomidine use. Treating the symptoms of delirium adversely affected (p<0.05). A multivariate analysis showed
with typical antipsychotics (e.g., haloperidol) and atypical that opioids were associated with the poor cognitive out-
antipsychotics (e.g., risperidone, quetiapine, olanzapine) has comes after controlling for many confounding factors (van
been reported in both the adult and the pediatric delirium Zellem 2014).
01_1_Beckman.indd 23 11-09-2017 16:45:32

Figure 1-2. The ABCDEF care bundle.
One limitation to studying neurocognitive outcomes is understanding the ontogeny of the disposition and clearance
the heterogeneity of the pediatric population, which may mechanisms in pediatric patients as well as how obesity and
preclude classifying patients into homogeneous groups for other illnesses contribute to medication pharmacokinetics.
more in-depth investigation. In addition, follow-up may be Analgesics and sedatives carry a high risk of patient harm
more difficult because many childhood hospitalizations are
acute and limited and do not require recurring care. There
is a growing interest in the pediatric critical care discipline
Practice Points
to address the unanswered questions of growth and devel-
• Each analgesic and sedative medication has a unique phar-
opment after critical illness and interventions, including
macokinetic profile. The agent-specific adverse events with
prolonged analgesia and sedation. Some children’s hospitals administration (e.g., fentanyl and rigid chest syndrome,
are responding to this need by creating longitudinal clinics to propofol and PRIS) and the ways in which to alleviate and
assist with follow-up. avoid them must be understood and appreciated.
Another initiative that is growing to address neurocogni- • Appreciation of the developmental changes in children is
important in order to optimize analgesia and sedation and
tive patient outcomes is the development of the ABCDEF care
avoid toxicities that may lead to serious adverse effects.
bundle in the ICU setting (Figure 1-2). Each arm of bundle can
• Obesity complicates drug dosing of these high-risk med-
help to reduce and prevent delirium, and enhance rehabilita- ications; thus, dosing on the basis of ideal, adjusted, or
tion of the adult ICU patient. The combination of all the arms total body weight must be considered.
of ABCDEF care bundle is thought to optimize the climate • Combination or multimodal analgesic therapy is preferred
for successful ICU liberation. Pediatric centers are actively for postoperative analgesia.
• Self-reported pain assessment is preferred to observa-
working to implement similar bundles; therefore, pediatric
tional pain assessment tools.
data supporting ABCDEF care bundles are forthcoming.
• When choosing sedatives for procedural sedation, onset
and duration of action are important, as are the adverse
Conclusion effects on the cardiorespiratory system. If there is a poten-
tial to adversely affect hemodynamics, respiratory drive, or
Providing hospitalized children with safe, effective, and
airway patency, patients must be sedated in a safe environ-
appropriate analgesia and sedation is complex. However, ment with appropriate rescue equipment and providers who
provision of analgesia and sedation is necessary to meet are skilled in managing cardiorespiratory emergencies.
the expectations of the patient and caregiver in pain relief • Sedation and delirium assessments are available for
and level of sedation as well as to optimize the healing children. Practitioners must understand the limitations of
these tools to make appropriate assessments.
environment. Challenges with providing this care include
01_1_Beckman.indd 24 11-09-2017 16:45:34

if used inappropriately. Pharmacists must be the health care Butterworth JF. Intravenous anesthetics. In: Butterworth
providers to create the analgesic and sedation plan because JF, Mackey DC, Wasnick JD, eds. Morgan & Mikhail’s
of their extensive training in pharmacology and medication Clinical Anesthesiology, 5th ed. New York: McGraw-Hill,
2013a:chap 9.
safety management.
Butterworth JF. Analgesic agents. In: Butterworth JF,
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Self-Assessment Questions
1. A 14-year-old boy presents to the pediatric ED after being A. Morphine
ejected from a motor vehicle during a crash. There is con- B. Fentanyl
cern for traumatic brain injury and suspected elevated C. Midazolam
intracranial pressure. The patient’s Glasgow Coma Scale D. Dexmedetomidine
score is 8. Vital signs are heart rate 102 beats/minute,
5. One pediatric intensivist is adamant about using atro-
blood pressure 82/46 mm Hg, and respiratory rate
pine as a pretreatment for intubating all infants. Which
6 breaths/minute. Rapid sequence intubation will be per-
one of the following statements best supports the con-
formed. Which one of the following is the best sedative to
sensus of the validity of this practice?
recommend for this patient?
A. Evidence does not support the use of atropine in any
A. Etomidate
situation.
B. Lidocaine
B. Atropine decreases bradycardic events with
C. Midazolam
intubation.
D. Propofol
C. No increase in arrhythmias was noted in the
2. A 6-year-old girl with medulloblastoma is undergoing an untreated atropine group.
MRI of the head today in the outpatient radiology suite. D. Adverse effects of atropine outweigh the benefit of
She is hemodynamically stable, with no signs or symp- using it during intubation.
toms of infection, and has her tunneled central venous
6. A 5-year-old girl (height 47 inches [120 cm], weight 40 kg)
line in place. Her allergies include eggs and peanuts.
is admitted to the PICU after cardiac arrest at home. She
The family says that she has high anxiety in closed, dark
is noted to have seizure activity after return of spontane-
spaces and is requesting medication to alleviate her anx-
ous circulation. Her seizures are refractory to first- and
iety. The sedation team physician wants this patient to
second-line therapies, so she is going to be initiated on
remain extubated during the procedure. Which one of the
pentobarbital to induce burst suppression on the electro-
following is best to recommend for this patient?
encephalogram. The medical team asks which weight to
A. Propofol 250-mcg/kg/minute intravenous infusion use to dose her pentobarbital. The usual starting pento-
B. Midazolam 0.2 mg/kg intranasally barbital dose is a bolus of 5 mg/kg, followed by infusion
C. Midazolam 0.5 mg/kg intranasally plus ketamine at 1 mg/kg/hour. Which one of the following is the most
5 mg/kg intranasally appropriate pentobarbital dose for this patient?
D. Midazolam 0.1 mg/kg intravenously plus
A. 90 mg × 1, followed by 18-mg/hour infusion
dexmedetomidine 0.5 mcg/kg/hour intravenous
B. 120 mg × 1, followed by 24-mg/hour infusion
infusion.
C. 150 mg × 1, followed by 30-mg/hour infusion
3. An 18-month-old boy is admitted to the pediatric ICU D. 200 mg × 1, followed by 40-mg/hour infusion
(PICU) with a metabolic crisis of a known fatty acid oxi-
7. A 5-month-old infant (weight 6 kg) with trisomy 21
dation disorder. He is hemodynamically unstable and
presents after an atrioventricular canal repair. He tran-
receiving a dopamine infusion through a peripheral
sitioned out of the operating room on a 2-mcg/kg/hour
venous line. A central venous line will be placed by the
fentanyl infusion. The nurse reports that he is very agi-
PICU team. Which one of the following is the best option
tated and irritable and moving all of his extremities on
for procedural sedation in this patient?
the current fentanyl dose. He is receiving a low dose of
A. Etomidate milrinone but no other vasoactive agents. He remains
B. Ketamine tachycardic, but his vital signs are otherwise within nor-
C. Midazolam mal range. The medical team would like to extubate him
D. Propofol in 24 hours but would like to offer additional sedation in
the interim. Which one of the following infusions is best
4. A 14-month-old boy is admitted to the PICU with respi-
to recommend for this patient?
ratory syncytial virus bronchiolitis and acute respiratory
failure. He is placed on mechanical ventilation and remains A. Increased fentanyl
hemodynamically stable without the need for vasoactive B. Dexmedetomidine
support. Because of ventilation issues, this patient needs C. Midazolam
to be initiated on a continuous neuromuscular blockade D. Pentobarbital
infusion to facilitate ventilator synchrony. Which one of
the following sedatives is best for this patient?
01_1_Beckman.indd 29 11-09-2017 16:45:35

8. A 13-year-old female adolescent was admitted with sep- 12. An 8-year-old boy with acute myeloid leukemia presents
tic shock and acute respiratory failure and is now off to the ED with febrile neutropenia, septic shock, and
vasopressors. She is being transitioned off fentanyl and respiratory failure. The decision is made to intubate this
dexmedetomidine infusions after being sedated and on patient and place him on mechanical ventilation. The boy
the ventilator for 4 days. Which one of the following most is intubated with rapid sequence intubation using fenta-
increases this patient’s risk of delirium? nyl, etomidate, and succinylcholine. Which one of the
following adverse effects would be most likely after this
A. Age
patient's rapid sequence intubation drug exposures?
B. Dexmedetomidine infusion
C. Duration of stay A. Tachycardia
D. Use of vasopressors B. Hypertension
C. Adrenal suppression
9. A 9-year-old girl is transitioning off a fentanyl infusion
D. Hyperventilation
after being sedated and on the ventilator for 8 days. Meth-
adone has been initiated for withdrawal attenuation.
Other pertinent medications include oral ciprofloxa- Questions 13–15 pertain to the following case.
cin for treatment of a UTI, intravenous famotidine for J.M. is an 8-year-old, mechanically ventilated boy with trisomy
stress-related mucosal disease, and intravenous ondan- 21. He is admitted to the PICU with acute respiratory failure.
setron as needed for nausea and vomiting (one dose in The nurse reports increased agitation despite escalating con-
24 hours). She is awake in the evenings, asleep through- tinuous infusion of both the opioid and the benzodiazepine,
out the daytime, and less engaged with her environment with extra bolus doses given of each.
and her family. She becomes combative with the bedside 13. J.M.’s medical team has high suspicion for delirium.
caregivers at times. The medical team is concerned for Which delirium screening tool would be most appropri-
delirium. Which one of the following is best to recom- ate for J.M.?
mend for this patient?
A. PAED (Pediatric Anesthesia Emergence Delirium)
A. Provide an atypical antipsychotic B. Cornell Assessment of Pediatric Delirium (CAPD)
B. Institute day- and nighttime activity schedule C. Preschool confusion assessment method for ICU
C. Add a dexmedetomidine infusion (psCAM-ICU)
D. Add lorazepam intravenously as needed D. Delirium Rating Scale, 1988 (DRS-88)
10. A patient has opioid-induced pruritus with intravenous 14. Which one of the following pain scales would be most
morphine for postoperative pain management. Which appropriate for J.M.?
one of the following is best for this patient?
A. VAS
A. Initiate diphenhydramine B. FACES
B. Change to intravenous fentanyl C. N-PASS
C. Change to enteral morphine D. FLACC
D. Initiate a dexmedetomidine infusion
15. Which one of the following sedation scales would be
11. A 16-year-old male adolescent is admitted to the PICU most appropriate for J.M.?
after a motor vehicle crash with a traumatic brain injury.
A. University of Michigan Sedation Scale
He is 24 hours into sedation with propofol so that fre-
B. Richmond Agitation-Sedation Scale (RASS)
quent neurological examinations can be done. Which
C. State Behavioral Scale (SBS)
one of the following monitoring values would be most
D. N-PASS
appropriate to detect the life-threatening adverse event
of propofol-related infusion syndrome at this time?
A. Serum phosphorus
B. Arterial blood gas
C. Creatine phosphokinase
D. Serum triglycerides
01_1_Beckman.indd 30 11-09-2017 16:45:35

Analgesia and Sedation in Hospitalized Children: by Elizabeth J. Beckman, Pharm.D., BCPS, BCCCP, BCPPS

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Analgesia and Sedation

01_1_Beckman.indd 7 11-09-2017 16:45:26

Intermittent Dose Continuous Intravenous Infusiona

Chloral hydrate PO: 0.5–5 mcg/kg N/A

Clonidine PO: 0.5–5 mcg/kg N/A

Dexmedetomidine IN: 1–4 mcg/kg 0.2–0.7 mcg/kg/hr

Etomidate IV: 0.1–0.3 mg/kg N/A

Fentanyl IN: 1–2 mcg/kg 0.5–2 mcg/kg/hr

Hydromorphone IV: 0.01–0.02 mg/kg 0.003–0.005 mg/kg/hr

Ketamine IM: 5–10 mg/kg 0.3–0.6 mg/kg/hr

Lorazepam IV: 0.05–0.1 mg/kg 0.05 mg/kg/hr

Midazolam IM: 0.05–0.15 mg/kg 0.03–0.12 mg/kg/hr

Morphine IV: 0.03–0.2 mg/kg 0.01–0.04 mg/kg/hr

Pentobarbitalb IM: 2–6 mg/kg 0.5–1 mg/kg/hr

Propofol IV: 0.5–2 mg/kg 1.2–4.8 mg/kg/hr

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Analgesia Sedation Amnesia Anxiolysis Respiratory Effects Hemodynamic Effects

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Table 1-3. Comparison of Pain Assessment Instruments

Instrument Population Validated Pain State Type of Assessment Type of Scale

FLACC Children, all ages Acute, surgical Observational Behavioral, physiological

FPS-R ≥ 4 yr Acute, surgical Self Pictorial

N-PASS Neonates Acute, surgical Observational Behavioral, physiological

NVPS Children, all ages Acute, surgical Observational Behavioral, physiological

NRS ≥ 6 yr Acute, surgical, Self Numeric

VAS ≥ 6 yr Acute, surgical, Self Numeric

Wong-Baker FACES ≥ 4 yr Acute, surgical Self Pictorial

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Level of Sedation Stimulus Response Airway Patency Ventilation Hemodynamics

Minimal (“anxiolysis”) Verbal and tactile Unaffected Unaffected Maintained

Moderate (“conscious sedation”) Verbal and tactile Unaffected Unaffected Maintained

Deep Noxious tactile Affected Affected Maintained

General anesthesia None Affected Affected Impaired

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Patient Care Scenario

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Validated Population Domains for Assessment

COMFORT Newborn – 17 yr + ventilator X X X X

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DRS-88 DRS-R-98 PAED pCAM-ICU psCAM-ICU CAPD

PICU population Med/surg Med/surg Med/surga Med/surg, Med/surg, General

Age (yr) 1–17 1–17 1–17 ≥5 0.5–5 Birth – 21 yr

Include developmental delay? No No No No No Yes

Hyperactive Hyperactive Hyperactive

No. of questions or domains 10 16 5 4 4 8

Administering provider Psychiatrist Psychiatrist Anesthesia Bedside b

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