Seminars in Pediatric Surgery 28 (2019) 33–42

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Seminars in Pediatric Surgery

journal homepage: www.elsevier.com/locate/sempedsurg

Analgesia, sedation, and delirium in pediatric surgical critical care

Megan E. Cunningham a, Adam M. Vogel a,b,∗
a
Texas Children’s Hospital, Division of Pediatric Surgery, Department of Surgery, 6701 Fannin Street, Houston, TX 77030, USA
b
Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA

a r t i c l e i n f o a b s t r a c t

Keywords: The alleviation of discomfort and distress is an essential component of the management of critically ill
Analgesia surgical patients. Pain and anxiety have multifocal etiologies that may be related to an underlying disease
Sedation
or surgical procedure, ongoing medical therapy, invasive monitors, an unfamiliar, complex and chaotic
Delirium
environment, as well as fear. Pharmacologic and non-pharmacologic therapies have complex risk benefit
Anxiolysis
Critical care profiles. A fundamental understanding of analgesia, sedation, and delirium is essential for optimizing
Surgery important outcomes in critically ill pediatric surgical patients. There has been a recent emphasis on goal
directed, evidence based, and patient-centered management of the physical and psychological needs of
these children. The purpose of this article is to review and summarize recent advances and describe
current practice of these important subjects in the pediatric surgical intensive care environment.
© 2019 Elsevier Inc. All rights reserved.

Introduction advances in pain management, the incidence of moderate to severe

Analgesia, sedation, and delirium are complex topics that in-
tertwine during the management of critically ill surgical patients.
The administration of analgesic and sedative agents to reduce pain
and anxiety comes with side effects that may include delirium and
withdrawal.1 On the other hand, inadequate pain control and in-
creased anxiety may also lead to delirium.2,3 In recent years, there
has been an increased emphasis within the critical care and sur-
gical communities on the relationship between analgesia, seda-
tion, and anxiolysis and important outcomes such as mortality, the
duration of mechanical ventilation, and intensive care length of
stay.4,5
pain remains high in post-operative children.16–18
There are three major pain pathways: somatic, visceral, and
neuropathic. Somatic pain is usually “sharp” and well localized.
Visceral pain is experienced by internal organs and tends to be
vague and may be referred to other body regions. Neuropathic
pain is a result of direct neuronal injury and may be described as
a burning sensation.8 In many cases, trauma and disease may be
found as the source of pain, but not always. Because of this, it is
necessary to assess pain according to the patient’s subjective expe-
rience. This is not always a straightforward task with children.
Assessment

The continuum of pain expression across pediatric age ranges

Analgesia
Significance
Pain control in post-operative patients is an essential compo-
nent of recovery.6 Uncontrolled post-operative pain has been as-
sociated with both negative physiological and psychological out-
comes in children and adults.7–11 Decreased immune responses,
poor sleep, decreased physical function, anxiety, chronic persis-
tent post-surgical pain (CPSP), and future psychiatric problems
are all associated with poorly controlled pain.8 , 12–15 Despite many
∗
Corresponding author.
E-mail addresses: mecunnin@texaschildrens.org (M.E. Cunningham), amvogel
@texaschildrens.org (A.M. Vogel).
has been well described.14 Infants may have an intense cry, body
rigidity, poor oral intake, and hypersensitivity/irritability. Toddlers
may push away the stimuli, guard painful body regions, cry in-
tensely, or exhibit regressive behavior. Preschool age children start
to verbalize pain and may push away the painful stimuli or thrash
their arms and legs to get away. School age children are able to
use objective scales to describe pain and may exhibit stalling to
prevent pain. They often have muscle rigidity and body stiffness
while in pain. Adolescents are able to localize pain and may have
changes in sleep and appetite. They may also show regressive be-
havior while in pain.14 Pediatric pain assessment tools have been
validated in neonates as young as 23 weeks gestational age and
extend up to the adolescent age group.19,20
The neonatal pain, agitation and sedation scale (N-PASS) is a
pain assessment tool validated for assessing acute and prolonged

https://doi.org/10.1053/j.sempedsurg.2019.01.006
1055-8586/© 2019 Elsevier Inc. All rights reserved.
34 M.E. Cunningham and A.M. Vogel / Seminars in Pediatric Surgery 28 (2019) 33–42

Table 1 ketorolac), acetaminophen, gabapentin, and local anesthetics (e.g.

Faces, Legs, Activity, Cry, Consolability scale (FLACC).
levobupivacaine and ropivacaine). A multimodal approach to pain
Faces Score management, which may include regional analgesia, has been
0 = No particular expression or smile shown to be superior to single agent therapy in the acute setting
1 = Occasional grimace or frown, withdrawn, disinterested in both adults and children.31–33
2 = Frequent to constant quivering chin, clenched jaw
Legs
0 = Normal position or relaxed Regional anesthesia
1 = Uneasy, restless, tense
2 = Kicking or legs drawn up
Regional anesthesia is the loss of sensation to a localized
Activity
0 = Lying quietly, normal position, moves easily
area of the body as the result of an anesthetic applied to the
1 = Squirming, shifting back and forth, tense nerves supplying that region. There are several types of regional
2 = Arched, rigid, or jerking anesthesia including epidural block, spinal block, and a multitude
Cry of peripheral nerve blocks. Few studies have focused on regional
0 = No cry (awake or asleep)
anesthesia in critically ill post-operative patients. What has been
1 = Moans or whimpers, occasional complaint
2 = Crying steadily, screams or sobs, frequent complaints studied is promising but is in further need of high quality evidence
Consolability concerning safety and efficacy.34 The European Society of Regional
0 = Content and relaxed Anaesthesia and Pain Therapy, along with the American Society of
1 = Reassured by occasional touching, hugging, or being talked to.
Regional Anesthesia and Pain Medicine, have released recommen-
Distractible.
2 = Difficult to console or comfort
dations concerning this type of analgesia in pediatric patients.35
Peripheral nerve blocks have been applied to nerve bun-
dles anywhere from the head to the toe. A systematic re-
view of randomized controlled trials for regional anesthesia
pain in neonates and infants. It has been shown to correlate with
showed limited data concerning efficacy and safety for many
the bedside nurse’s subjective pain and agitation score.19–21 The
anatomical regions.34 Abdominal wall blocks, performed at the
Faces, Legs, Activity, Cry, and Consolability (FLACC) tool was de-
ilioinguinal/iliohypogastric nerve, rectus sheath, and transverse ab-
signed to assess pain in children between the ages of 2 months
dominus plane (TAP) under image guidance, have become increas-
and 7 years based on behavioral observations (Table 1). It has been
ingly common in pediatric general surgery. While many peripheral
validated in multiple settings including the pediatric intensive care
blocks are a one-time application, they may also be applied con-
unit (ICU) and has also correlated with the nurses’ global ratings
tinuously in post-operative patients by means of a slow release de-
of pain.22 A revised version of the FLACC score (r-FLACC) has been
vice.36
created for and validated in children with cognitive impairment
Finally, central nerve blocks provide anesthesia to large body
and was shown to have a higher clinical utility in this population
regions starting at a specific spinal level. They may be used as al-
(Table 2).23
ternatives or adjuncts to general anesthesia in certain patient pop-
Face scales are commonly used for pain assessment in older
ulations including infants and adolescents.37 Spinal blocks are gen-
children. In a systematic review looking at published pediatric
erally administered prior to surgery and provide analgesia for a
faces tools, only four had undergone extensive psychometric test-
limited amount of time. Nociception and motor function are hin-
ing.24 The Wong-Baker Faces Pain Rating Scale (WBFPRS) was de-
dered in the lower limbs and trunk. If the anesthetic moves up the
termined to be preferred by children, but the Faces Pain Scale–
spinal canal, it may result in respiratory difficulties due to block-
Revised (FPS-R) was recommended for clinical use due to its utility
ade of intercostal motor neurons.37 Hypotension may also result
and psychometric features.24
from sympathetic blockade, but is less common in young children
Finally, the verbal numeric scale, also known as the numeric
compared to adults.37 The injection of opioids with a local anes-
rating scale (NRS) is a commonly used pain assessment tool in the
thetic agent has been used to extend analgesia in adults, but is
adult population and has also been validated for acute pain assess-
less commonly performed in children.30,37 Unfortunately, the fail-
ment in older children (≥ 8 years).25 The scale ranges from 0–10
ure rate for this procedure may be as high as 28%.37 The epidural
with 0 indicating “no pain” and 10 indicating a patient’s “worst
nerve block differs from the spinal in that the anesthetic agent sits
pain”.26 For an individual to use this scale, they must be able to
within the epidural space; drugs are continuously infused via an in
abstractly convert a state of being into a numerical value. This lim-
situ catheter. Opioids may be added to the epidural to extend anal-
its its applicability to populations with a certain degree of cogni-
gesia. While this method of blockade is usually less potent than
tive development and cognitive clarity.27 When compared to other
a spinal, patients may still experience similar side effects includ-
pediatric pain assessment tools, it has been shown to correlate
ing pruritus.30 Infection from the infusion catheter is rare and can
best at high numerical values, but as the numbers become lower,
usually be detected by local signs of inflammation at the inser-
the correlation dwindles.25,26,28 As a results, there is skepticism as
tion site.38 Additionally, these blocks are not performed in children
to the clinical applicability of this scale.29
with any suspicion of coagulopathy due to bleeding concerns.

Management
Pain can be managed in many different ways by altering the
physiology of central and peripheral nerve receptors.30 When the
body is injured, such as in invasive surgery and trauma, it pro-
duces a stress response that includes nociception, inflammation,
and the release of catecholamines. Because of the complex interac-
tion between pain transmission and the stress response, different
methods of pain control can alter systemic processes such as heart
rate and pulmonary vascular resistance.30 Pharmacologic analgesic
agents include narcotics (e.g. morphine and hydromorphone),
nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g. ibuprofen and
Narcotics
Opioids are a class of analgesic drug that bind to a multitude
of opioid receptors (e.g. mu, delta and kappa). Pain relief is ex-
perienced when the opioids penetrate the blood brain barrier and
bind to receptors within the central nervous system.39 Clinical opi-
oids, such as morphine, fentanyl, hydromorphone, methadone, hy-
drocodone, and oxycodone have varying degrees of affinity for the
mu receptor.40,41 Drug potency is described in terms of morphine
milligram equivalents and is helpful when converting between two
opioids or from one route of administration to another.41
 M.E. Cunningham and A.M. Vogel / Seminars in Pediatric Surgery 28 (2019) 33–42 35

Table 2
(Revised) Faces, Legs, Activity, Cry, Consolability scale (R-FLACC).

Faces Score

0 = No particular expression or smile

1 = Occasional grimace or frown, withdrawn, disinterested; appears sad or worried
2 = Consistent grimace or frown; frequent/constant quivering chin, clenched jaw; distressed-looking face; expression of fright or panic
Individualize behavior:
Legs
0 = Normal position or relaxed; usual tone & motion to limbs
1 = Uneasy, restless, tense; occasional tremors
2 = Kicking, or legs drawn up; marked increase in spasticity, constant tremors or jerking
Individualized behavior:
Activity
0 = Lying quietly, normal position, moves easily; Regular, rhythmic respirations
1 = Squirming, shifting back and forth, tense or guarded movements; mildly agitated (e.g. head back and forth, aggression); shallow, splinting
respirations, intermittent sighs.
2 = Arched, rigid or jerking; severe agitation; head banging; shivering (not rigors); breath holding, gasping or sharp intake of breaths, severe splinting
Individualized behavior:
Cry
0 = No cry/verbalization
1 = Moans or whimpers; occasional complaint; occasional verbal outburst or grunt
2 = Crying steadily, screams or sobs, frequent complaints; repeated outbursts, constant grunting
Individualized behavior:
Consolability
0 = Content and relaxed
1 = Reassured by occasional touching, hugging or being talked to. Distractible.
2 = Difficult to console or comfort; pushing away caregiver, resisting care or comfort measures
Individualized behavior:

While the administration of opioids to post-operative children
in the ICU is common, precautionary measures for adverse reac-
tions must be taken. Just as drugs activate opioid receptors within
the brain, they also activate the same receptors peripherally. The
most common side effects of opioids in children are vomiting, pru-
ritus and constipation.42 Respiratory depression is uncommon but
can be life threatening, especially in the very young. Several ac-
tions can be taken to lessen these adverse reactions including drug
titration, the use of multimodal analgesia, continuous infusions of
an opioid antagonist and side-effect specific prophylaxis.42
Administrative route
ing intermittent intravenous opioid dosing to continuous dosing in
children between the ages of 0 and 4 years.46,47
Intermittent dosing of opioids can either be controlled by the
nurse according to pain assessment tools or by the patient us-
ing a patient-controlled analgesia (PCA) device. Use of a PCA de-
vice is considered the mainstay for acute post-operative pain man-
agement in children ages 6 and older.48 PCA’s have been shown
to reduce overall opioid consumption and provide improved pain
scores.49,50 With a PCA, the patient receives a programmed dose
of analgesia by pressing a button. Continuous infusions may be
programmed in addition to bolus doses and a lock-out mechanism
prevents overdosing.50 PCA by proxy has been studied with mixed
results concerning safety.50

The route of opioid administration may be chosen according to

Neuropathic pain
pain severity, the duration of expected discomfort, and enteral sta-
tus. Single dose oral analgesia provides pain relief for an extended
With the push to reduce narcotic use in post-operative patients,
amount of time compared to analgesia given as a single dose intra-
a number of non-opioid analgesics have been explored. Unfortu-
venously. On the other hand, oral medications takes time to reach
nately, the evidence concerning the safety and efficacy for many of
their full effect; pain relief with intravenous administration is gen-
these agents is limited, especially in children. In a meta-analysis
erally quite rapid. Many children may be required to fast post-
published in 2017 by Zhu et al., acetaminophen, NSAIDs dex-
operatively thus making oral medications a poor choice for pain
amethasone, ketamine, clonidine, and dexmedetomidine showed
control. Moreover, these often cause nausea and vomiting which
promise in decreasing post-operative pain when given periopera-
may complicate bioavailability. Intramuscular injections and rectal
tively.51 Several other agents, including gabapentin and pregabalin
suppositories containing analgesic agents are not normally consid-
have shown limited to no benefit in acute post-operative pain con-
ered first tier options due to pain associated with the injection and
trol, although their addition to multimodal pain regimens may be
their “invasive” nature, respectively.
increasing, particularly to facilitate opioid sparing.52–54 In adults,
Intravenous opioids can be given continuously, as needed,
gabapentin and pregablin may be used as first line agents for neu-
or via patient-controlled devices. Continuous administration is
ropathic pain along with tricyclic antidepressants.55,56 There are
common in critically ill and severely injured pediatric patients.43
only a few case reports and case series that have assessed the use
With this mode of delivery, medication doses can be titrated
of gabapentin and pregabalin in treating neuropathic pain in chil-
according to the patient’s degree of pain. However, the longer a
dren.57–59
patient receives a continuous infusion the more likely they are
to need increasing doses of analgesia due to opioid tolerance.43
Importantly, adverse events with continuous infusions are low.44 Withdrawal
In neonates, continuous infusion has been shown to be favorable
to bolus dosing with respect to the severity of respiratory sup- Assessment
pression it may cause, although it may be associated with longer The long-term and extensive use of narcotics and other anal-
durations of mechanical ventilation.45 Studies have demonstrated gesic medications may result in withdrawal if they are not reduced
mixed results with respect to optimal pain control when compar- in an appropriate manner. Withdrawal symptoms are classified into
36 M.E. Cunningham and A.M. Vogel / Seminars in Pediatric Surgery 28 (2019) 33–42
Table 3
Withdrawal Assessment Tool- Version 1 (WAT-1).
Assessment
Information from patient record (previous 12 h)
Any loose/watery stools
Any vomiting/wretching/gagging
Body Temperature >37.8 °C
2 min pre-stimulus observation
State
Tremor
Any sweating
Uncoordinated/repetitive movements
Yawning or sneezing
1 min stimulus observation
Startle to touch
Muscle tone
Post-stimulus recovery
Time to gain calm state i.e. SBS ≤ 0 < 2 min = 0, 2–5 min = 1, > 5 = 2
SBS- state behavioral scale
three categories which include central nervous system (CNS) stim-
ulation, gastrointestinal disturbance, and sympathetic nervous sys-
tem activation.60,61 The common symptoms of narcotic withdrawal
in the pediatric population include diarrhea, diaphoresis, fever and
vomiting.62 Symptoms are highest on the second day of drug ta-
pering and generally decrease thereafter.62 The incidence of with-
drawal in children receiving continuous opioid infusions for > 5
days has been shown to be as high as 53%.60,63 Factors that pre-
dict withdrawal are the duration of opioid use and total opioid
dosage.60
There are several scales that have been created to assess opi-
oid withdrawal in children.1,64,65 The Withdrawal Assessment tool-
1 (WAT-1) is a well validated scoring system that was designed
for clinical simplicity and applicability (Table 3).66,67 The Wat-1
is composed of 11 withdrawal symptoms that are to be assessed
twice daily. A score of ≥ 3 on a 12 point scale is considered to
be positive for withdrawal. In neonates, the Finnegan scoring tool
evaluates 21 clinical signs of withdrawal and is commonly em-
ployed to assess neonatal abstinence syndrome (NAS). Performing
assessments every 4 h, a score of greater than 12 on two consec-
utive assessments or greater than 8 on three consecutive assess-
ments, is consistent with withdrawal.
Management
The principle strategy for the management of withdrawal
symptoms is the slow tapering of the offending agent. Studies
have shown that with tapering alone, time to complete drug
discontinuation lasts anywhere from 2–4 weeks.61 As a result,
hospital length of stay may be prolonged when all other discharge
criteria are met. Transition from intravenous opioid administration
to a long-acting opioid agonist or partial agonist such as extended-
release morphine, extended-release oxycodone and methadone
decreases hospital length of stay and the duration of opioid taper-
ing.68–70 Alternatives agents that have been studied for withdrawal
prevention include buprenorphine, clonidine, dexmedetomidine,
gabapentin, propofol, and propoxyphene.70–72 While many of
these agents show promise, there is limited data concerning
their use in the post-operative pediatric critical care patient.
Robust clinical trials are needed to ascertain their safety and use
profile.
Some alternative strategies to prevent opioid tolerance and thus
the likelihood of withdrawal include nurse-led sedation protocols,
the use of multimodal analgesia including regional anesthesia, and
daily sedation vacations.70 There are also early studies looking
into the addition of NMDA and opioid antagonists, nitrous oxide
Grading Score
No = 0, Yes = 1
No = 0, Yes = 1
No = 0, Yes = 1
SBS ≤ 0 or asleep/awake/calm = 0
SBS ≥ + 1 or awake/distressed = 1
None/mild = 0, moderate/severe = 1
No = 0, Yes = 1
None/mild = 0, moderate/severe = 1
None or 1 = 0, ≥2 = 1
None/mild = 0, moderate/severe = 1
Normal = 0, Increased = 1
synthase inhibitors, and selective serotonin-reuptake inhibitors
along with opioid therapy that may also prevent tolerance.70
Similar to the other withdrawal strategies, high quality clinical
trials are needed before their use will be widely adopted.
Sedation/Anxiolysis
Significance
Sedation in critically ill pediatric patients is an essential com-
ponent of care. Sedation aids in recovery by reducing agitation,
protecting indwelling/intravenous catheters and drains, allowing
invasive procedures, and aiding synchronization with mechani-
cal ventilation. While the need for sedation is well understood
amongst providers, optimal levels of sedation are only achieved
50% of the time.73
Optimal sedation is defined as a state in which the patient is
somnolent, is responsive to the environment but is untroubled by
it and only moves in a limited manner.74 For children within the
intensive care unit, that means they are sleepy but easily aroused,
they are tolerant of therapeutic procedures, and they breathe in
synchrony with the mechanical ventilator.75 Over-sedation may re-
sult in prolonged mechanical ventilation, delirium, and drug tol-
erance, while undersedation may lead to loss or displacement of
intravenous access and drains, self-extubation, and anxiety.76
The use of standardized sedation practices with validated seda-
tion scales has been strongly recommended by international so-
cieties, but actual implementation varies between hospitals and
clinicians.77 While there is a high level of evidence for sedation
guidelines in adults, those in children are lacking.78 To date, only
a single randomized control trial has been published concerning
the use of a sedation protocol within the pediatric intensive care
unit (PICU).77,79 In an international survey on the topic, only 29%
of respondents had access to and regularly used a sedation scoring
system, while only 27% had a written PICU sedation protocol.
Assessment
Similar to pain assessment tools, there are several sedation
assessment tools that have been validated for use in critically-ill
pediatric patients. One of the earliest validated tools was the
COMFORT scale which assessed both sedation and pain.80 The
original version has six behavioral and two physiologic measures.
Since then, several modified versions have been released. The most
utilized of the modified COMFORT scales is the COMFORT-Behavior
 M.E. Cunningham and A.M. Vogel / Seminars in Pediatric Surgery 28 (2019) 33–42 37

Table 4
State Behavioral Score (SBS).

Score Description Definition

−3 Unresponsive No spontaneous respiratory effort

No couch or coughs only with suction
No response to noxious stimuli
Unable to pay attention to care provider
Does not distress with any procedure (including noxious)
Does not move
−2 Responsive to stimuli Spontaneous uet supported breathing
Coughs with suction/repositioning
Responds to noxious stimuli
Unable to pau attention to care provider
Will distress with a noxious procedure
Does not move/occasional movement of limbs and shifting of position
−1 Responsive to gentle touch or voice Spontaneous but ineffective nonsupported breaths
Coughs with suction/repositioning
Responds to touch/voice
Able to pay attention but drifts off after stimulation
Distress with procedures
Able to calm with comforting touch or voice when stimulus removed
Occasional movement of limbs or shifting of position
0 Awake and able to calm Spontaneous and effective breathing
Coughs when repositioned/occasional spontaneous cough
Responds to voice/no external stimulus is required to elicit response
Spontaneously pays attention to care provider
Distresses with procedures
Able to calm with comforting touch or voice when stimulus removed
Occasional movement of limbs or shifting of position/increased movement (restless/squirming)
+1 Restless and difficult to calm Spontaneous effective breathing/having difficulty breathing with ventilator
Occasional spontaneous cough
Responds to voice/no external stimulus is required to elicit response
Drifts off/spontaneously pays attention to care provider
Intermittently unsafe
Does not consistently calm, despite 5-min attempt/unable to console
Increased movement (restless, squirming)
+2 Agitated May have difficulty breathing with ventilator
Coughing spontaneously
No external stimulus required to elicit response
Spontaneously pays attention to care provider
Unsafe (biting endotracheal tube, pulling of catheters, cannot be left alone)
Unable to console
Increased movement (Restless, squirming, or thrashing side-to-side, kicking legs)

scale which excludes the two physiologic measures.81 When look-
ing at all of the versions of the COMFORT scale, there is moderate
to excellent construct validity for sedation assessment and it can
be used in children from birth to 18 years.82 The European Society
of Paediatric and Neonatal Intensive Care (ESPNIC) recommends
the use of the COMFORT scale, the COMFORT-Behavioral scale, or
State Behavioral Scale (SBS) to assess for sedation as a Grade A
recommendation.5
The SBS was designed to assess the level of sedation in me-
chanically ventilated pediatric patients from 6 weeks to 6 years of
age (Table 4).83 The scale contains seven state/behavioral measures
which are grouped into 5 profiles on a bipolar scale (−2 to +2),
where the negative numbers equate to a less active states and the
more positive numbers equate to more active states. It is suggested
that the level of sedation be assessed at the beginning of every
shift and at least ever four hours thereafter, depending on the pa-
tient’s need.
Another sedation scale that has been validated for use in
the critically ill pediatric population is the Richmond Agitation-
Sedation Scale (RASS) (Table 5). This scale was originally published
in 2002 for use in adult intensive care patients.84 Similar to the
SBS, it is a bipolar scale (−5 to +4). The RASS assessment contains
three steps which includes observation, verbal stimulation and tac-
tile stimulation of the patient. In children, it has been validated
for use from two months of age to adulthood. It may also be used
in both mechanically ventilated and spontaneously breathing pa-
tients.85
Management
There are several classes of sedating drugs utilized within the
pediatric ICU and there are varying degrees of evidence supporting
their long-term safety and efficacy. The most commonly used
sedating agents are benzodiazepines, with midazolam being the
medication of choice.75,86 Of the sedating agents, midazolam is
also the best studied.78 This drug class acts on receptor com-
plexes that activate GABA inhibitory neurotransmitters resulting
in sedation, amnesia, and anxiolysis. Importantly, it does not
provide analgesia.87 The benefits of midazolam are its quick
onset of action and short half-life, but several adverse effects
can manifest. Slow-wave and non-REM sleep are affected by
benzodiazepines thus increasing the risk of delirium. Midazo-
lam also has an active metabolite that may accumulate in renal
patients.87 Lorazapam is a medium-acting benzodiazepine that
has been used as an alternative to midazolam due to its more
stable dosing. Similar to its short-acting cousin, lorazepam may
cause delirium. It may also result in metabolic acidosis and renal
tubular necrosis with extensive use due to its diluent propylene
glycol.76,88
Ketamine, a non-competing NMDA receptor antagonist gener-
ally been used as a second line agent produces sedation, analgesia,
and amnesia together with a central dissociative affect.78 Adverse
events may with ketamine include myocardial collapse in patients
with depleted catecholamine stores, hallucinations, and increased
intracranial pressure.75 Animal studies have raised concern
38 M.E. Cunningham and A.M. Vogel / Seminars in Pediatric Surgery 28 (2019) 33–42

Table 5
Richmond Agitation-Sedation Scale (RASS).

Score Term Description

+4 Combative Overtly combative, violent, immediate danger to staff

+3 Very agitated Pulls or removes tube(s) or catheter(s), aggressive
+2 Agitated Frequent non purposeful movement, fights ventilator
+1 Restless Anxious but movements not aggressively vigorous
0 Alert and calm
−1 Drowsy Not fully alert but has sustained awakening (eye opening/contact) to voice (≥ 10 s)
−2 Light sedation Briefly awakens to voice with eye contact ( < 10 s)
−3 Moderate sedation Movement or eye opening to voice (but not eye contact)
−4 Deep sedation No response to voice but movement or eye opening to physical stimulation
−5 Unarousble No response to voice or physical stimulation

regarding neurotoxicity and this has led to certain limitations
regarding its long-term clinical application.89
Barbiturates, like benzodiazepines, result in an increase in GABA
neurotransmission. They are also considered a second line therapy
for sedation when alternative drugs fail. Phenobarbital has been
shown to cause increased complications such as blood pressure
instability, over-sedation, drug interactions, and neurologic seque-
lae in pediatric ICU patients when infused continuously.90 Because
barbiturates have a high lipid solubility, their half-life is long and
this may contribute to the development of adverse events.75
Chloral hydrate is one of the oldest sedatives to be used clini-
cally and was initially discovered in 1832.91 It is absorbed through
mucosal membranes and can be given either orally or per rectum.
In children, it is most commonly used for short-term procedural
sedation (e.g. imaging studies), but it has also been studied for
prolonged sedation in critically ill children.92 When given along
with promethazine, it has been shown to provide adequate se-
dation more often than a continuous infusion of midazolam.93
Caution should be taken when it is administered to infants and
neonates as they have an increased risk of developing metabolic
acidosis and hyperbilirubinemia. This agent should also be avoided
in patients with renal and hepatic dysfunction.91
Propofol, another sedative that involves GABA receptor activa-
tion, has been described in several studies involving the pediatric
critical care population.78,94 Despite these studies, only 2% of
providers utilize propofol in their initial sedation regimen.86 It is
most commonly utilized in post-operative critical care patients
and is suggested as an adjunct when weaning from mechanical
ventilation (“propofol washout”) and for use at night to promote
restorative sleep.76 While the drug has a short half-life thereby
providing a quick recovery time, its long term use in children is
not recommended due to the risk of propofol infusion syndrome
(PRIS). PRIS results in metabolic acidosis, hyperlactatemia, hyper-
lipidemia, rhabdomyolysis, and myoglobinuria that subsequently
leads to renal, hepatic, and cardiac failure.95 It is recommended
that the maximum dose of propofol be no greater than 4 ml/kg/h,
with maximum infusion times no greater than 24 h due to the
increased risk of PRIS.96
Anxiety management
Adequate sedation serves to mitigate deleterious emotional
states such as agitation and anxiety. Anxiety in the intensive care
setting has been shown to occur in as many as 89% of mechani-
cally ventilated adults.97 Because of the neurodevelopmental state
of children and the way they interact with their environment, anx-
iety may be even higher in this population. The lack of validated
anxiety assessment tools for children has been a barrier to fully
grasping the impact it plays in the pediatric ICU.97–99
Pharmacological agents such as alpha-2 agonists have been
increasingly utilized to reduce anxiety and produce sedation in
intensive care patients.100 In adults, two of these agents are
clinically approved, dexmedetomidine and clonidine. In children,
only dexmedetomidine has been approved for sedation, but cloni-
dine is still widely used.99,101 Both agents work by suppressing
neurotransmission from the locus ceruleus in the brain which re-
sults in anxiolysis, sedation, and analgesia.102,103 Unlike many other
sedating agents, respiratory depression is minimal.100 The amnes-
tic properties of alpha-2 agonists are also much less pronounced
thus resulting in a state of conscious sedation.100
While the studies concerning its safety and efficacy in chil-
dren are quite limited, clonidine has been shown to reduce the
need for opioids and benzodiazepines in neonates; dexmedetomi-
dine has been shown to reduce mechanical ventilation time in chil-
dren post-operatively.104–106 Hemodynamic instability is the most
commonly encountered side effect. Dexmedetomidine may cause
hypertension and bradycardia, especially after a bolus dose, while
clonidine may cause hypotension.99,100
A non-pharmacologic alternative for anxiety reduction in criti-
cal post-operative patients is the use of music therapy. Traditional
music therapy involves exposure of the patient to music, either
passively or actively, according to the patient’s state of devel-
opment and taste, during a designated period of time.107 Music
therapy has been shown to improve physiologic parameters such
as heart rate and respiratory rate by reducing the sympathetic
response.107–109 It has also been shown to reduce pain scales in
post-operative pediatric cardiac patients.108 Alternatively, massage
therapy has also been shown to reduce anxiety scores and overall
benzodiazepine use in post-operative pediatric cardiac patients.110
Further high quality data is needed to fully understand the im-
pact of non-pharmacologic therapy on anxiety in this vulnerable
population.
Delirium
Significance
Delirium is a well described phenomenon in the intensive care
population. It is defined as a disturbance in attention, awareness,
and cognition over a short period of time that is not explained
by a pre-existing neurocognitive disorder or a decreased level of
arousal attributed to a medical condition, intoxication, withdrawal,
or a medication side effect.111 The occurrence of delirium in adult
ICU patients has been reported to affect 16–89% of patients and is
more common in the elderly and in those with pre-existing cogni-
tive decline.2,112 Research in pediatric delirium is in evolution. The
most recent data suggests a prevalence of 13–28% in pediatric crit-
ical care patients, but this may grossly underrepresent its actual
prevalence.113
The impact of delirium on the hospitalized patient is vast.
It has been shown to be associated with longer lengths of ICU
stay, longer mechanical ventilation times, higher hospital costs,
 M.E. Cunningham and A.M. Vogel / Seminars in Pediatric Surgery 28 (2019) 33–42
Table 6
Cornell Assessment of Pediatric Delirium (CAPD).
Rass score: (if − 4 or −5 do not proceed)
Never 4
Does the child make eye contact with caregiver?
Are the child’s actions purposeful?
Is the child aware of his/her surroundings?
Does the child communicate need and wants?
Never 0
Is the child restless?
Is the child inconsolable?
Is the child underactive- very little movement while awake?
Does it take the child a long time to respond to interactions?
and higher mortality rates.2,114 In a prospective longitudinal study,
delirium in children was shown to be a strong independent
predictor of mortality.114 Not only does delirium impact the child,
but it may also impact the parent, as some children present with
impaired responsiveness, lack of caregiver recognition, and devel-
opmental regression.3 The morbidity of delirium does not stop
at discharge but may manifest as post-traumatic stress, depres-
sion, anxiety, and changes in future cognitive function.3 Children
at highest risk of delirium are male, those who have pre-existing
cognitive delay, and patients who are mechanically ventilated.115
Assessment
In recent years, several tools have been created and validated
to assess delirium in ICU patients. The Confusion Assessment
Method for the Intensive Care Unit (CAM-ICU) is one of the ear-
liest delirium assessment tools for adult critical care patients. It
has been well researched and shows a high specificity for delir-
ium.116 The CAM-ICU objectively assesses the 4 clinical features of
altered mental status, inattention, altered level of consciousness,
and disorganized thinking in a hierarchal fashion. Each clinical fea-
ture may either be positive or negative using specific assessment
tools.117
There have been two modified CAM-ICU scales for use in the
pediatric population. The first was designed for children greater
than 5 years of age and is referred to as the pediatric-CAM-ICU (P-
CAM-ICU) scale.118 The second is a tool designed for infants and
children aged 6 months to 5 years and is called the PreSchool-
CAM-ICU (PS-CAM-ICU) scale.119 Both scales use the same template
as the original CAM-ICU but the objective assessment tools have
been adjusted to the developmental level of each age group.120
Another pediatric delirium assessment tool used to assess crit-
ically ill patients is the Cornell Assessment of Pediatric Delirium
(CAP-D) scale (Table 6).121 It is an alteration of the Pediatric Anes-
thesia Emergence Delirium Scale (PAED) which was created for
children emerging from procedural anesthesia.122 The CAP-D ver-
sion has eight questions that are scored numerically depending on
the answer of “never, rarely, sometimes, often, and always”. The
first four questions are scored from 4 to 0 and the second four
questions are scored from 0 to 4. Compared to the PAED scale, the
CAP-D has two additional elements that aid in assessing hypoactive
and mixed-type delirium.
Management
While the consequences of delirium during hospitalization are
detrimental, management strategies are only in the early stages
of development. In 2013, the American College of Critical Care
Medicine updated their guidelines for pain, agitation, and delirium
in adult ICU patients.123 From these guidelines, the ABCDEF bundle
was created by an interprofessional group of critical care practi-
tioners. Each letter stands for a step in care; Assess, prevent and
39
Rarely 3 Sometimes 2 Often 1 Always 0 Score
Rarely 1 Sometimes 2 Often 3 Always 4 Score
manage pain, Both spontaneous awakening trials and spontaneous
breathing trials, Choice of analgesia and sedation, Delirium: assess,
prevent and manage, Early mobility and exercise, and Family en-
gagement and empowerment. The philosophy behind the ABCDEF
bundle is that intensive care practices should be designed not
only to help a patient recover from their acute illness but also to
prevent the iatrogenic sequelae of care by “liberating” them from
the ICU environment.4
Each element of the bundle has been chosen based upon prac-
tices that have demonstrated patient safety and patient-centered
outcomes when applied alone. Since the release of the ABCDEF
bundle, studies in adults have shown excellent results in sev-
eral domains including ventilator days, ICU length of stay, hospital
length of stay, delirium free days, and in-hospital mortality.124,125
While results are positive, the actual application of the bundle re-
mains sub-par. In a global survey that had respondents from 47
countries, only 57% implemented the ABDEF bundle.126 Of those
who responded positively to prescribing specific elements within
the bundle, a portion of them did not have adequate resources for
actual implementation.
In the pediatric population, studies looking at outcomes con-
cerning the implementation of the ABCDEF bundle are scarce. Dur-
ing development of the bundle, nine pediatric ICU’s participated in
the ICU Liberation and THRIVE initiative.4 While the results from
the initiative are yet to be published, the Mayo Clinic pediatric ICU
site reported decreased mechanical ventilation days, ICU length of
stay, hospital length of stay, and improved pediatric overall perfor-
mance categories and functional status scale scores.127 In a study
that looked at the implementation of an ICU bundle to reduce
delirium in pediatric patients, delirium was reduced in a stepwise
manner over time.128
Environment
The environment plays a significant role in either reducing or
exacerbating delirium. Sleep disturbance caused by disruptions in
the circadian rhythm act as an exacerbating element.129 Many fac-
tors within the ICU may lead to sleep disturbance including bright
lights and elevated noise levels during the night.130 Simple inter-
ventions that have been shown to improve sleep quality include
the use of bright lights during the day and dim lights at night, as
well as eye masks and ear plugs for nighttime use.130–132
Child life specialists also play an important role in managing
delirium in critically-ill pediatric patients. While there are no
studies looking specifically at the reduction in delirium, the pro-
vision of coping mechanisms for pain and anxiety may accomplish
just that.133 The primary role of these specialists is to provide op-
portunities for play, age appropriate information, and therapeutic
relationships that enhance the patient experience.134 While the
intensive care patient often has physical and cognitive limitations,
these specialists are taught how to provide coping techniques in
all areas of care.
40 M.E. Cunningham and A.M. Vogel / Seminars in Pediatric Surgery 28 (2019) 33–42
Melatonin
Melatonin is produced by the pineal gland and has many func-
tions including the regulation of the circadian rhythm, the mod-
ulation of seasonal changes, as well as acting as an antioxidant
and anti-inflammatory agent.135–137 Melatonin can be given ex-
ogenously and has been shown to have sedative, anxiolytic, and
analgesic properties.135 Endogenous melatonin may be reduced in
critically ill patients, especially in the post-operative population.138
Only a single study has directly assessed the effect of a melatonin
agonist on delirium. In this study, the number of elderly patients
who developed delirium was significantly reduced.139 There have
been several other studies looking at melatonin on sleep in the
ICU.137 One study demonstrated that subjects given melatonin had
longer total sleep time, increased REM, shorter sleep onset latency,
and subjectively better sleep when compared to patients receiving
no intervention or those provided with ear plugs and eye masks.140
Antipsychotics
The administration of antipsychotic pharmacologic therapy
plays an unquestionable role in the management of delirium.111 In
adults, haloperidol is commonly used for aggressive or nonrespon-
sive delirious behavior.141 The drug has also been used in children
but has an increased risk of extrapyramidal symptoms, making it
a less than ideal choice.142 Atypical antipsychotics such as risperi-
done, olanzapine, and quetiapine have been shown to have a lower
burden of side effects than haloperidol.141 In one study investi-
gating the prescribing practices for pediatric ICU patients that re-
ceived a psychology consult, 81% were prescribed an antipsychotic
for delirium. This study reported no adverse effects and only one
child went home with the prescription.143 In a similar study, the
use of atypical antipsychotics for delirium was associated with re-
duced delirium scores without documented side effects.144 More
robust studies are needed to assess the true safety and efficacy of
antipsychotic agents in the critical pediatric population.
Summary
In critically ill, post-operative, pediatric patients, analgesia, se-
dation, and delirium represent complex yet extremely important
aspects of care. While the literature is diverse and expanding for
adults, studies concerning best practices in children are lacking.
Appropriate pain control, optimal sedation, and the identification
and treatment of delirium in the intensive care environment re-
duces morbidity and mortality. Indeed, the proper management of
these conditions may be just as critical to the patient as the main-
tenance of proper tissue perfusion and ventilation. Additional clin-
ical trials are sorely needed to establish the efficacy and safety of
medication regimens and non-pharmacological therapies.
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