Pain and Sedation Management: 2018 Update for

the Rogers’ Textbook of Pediatric Intensive Care

Tracie Walker, MD1; Sapna R. Kudchadkar, MD, PhD1–3

Objectives: To review important articles on pain, sedation, sleep, pediatric intensive care environment to promote sleep. (Pediatr
and delirium in the field of pediatric critical care published sub- Crit Care Med 2018; XX:00–00)
sequent to the fifth edition of the Rogers’ Textbook of Pediatric Key Words: children; delirium; intensive care units; pain; sedation;
Downloaded from http://journals.lww.com/pccmjournal by BhDMf5ePHKbH4TTImqenVOxbUnPuOlhihe1t+TODkkFVRn4j3Xeb9NjXmFmPcV3e on 10/25/2018

Critical Care. sleep

Data Sources: The U.S. National Library of Medicine PubMed was
searched for a combination of the term “pediatric” and the fol-
lowing terms: “sedation,” “sedation protocol,” “pain,” “pain score,”

T
“neuromuscular blockade,” “delirium,” and “sleep.” Titles and his article contributes to a series of updates for the fifth
abstracts resulting from the search were screened for full-text edition of the Rogers’ Textbook of Pediatric Intensive
review and potential inclusion. Authors also included recent key Care. The overall objective of this targeted review is to
articles they were aware of with direct relevance to the topics. update readers about key recent research that has furthered
Study Selection and Data Extraction: The authors selected articles our understanding and management of pain, sedation, sleep,
for inclusion based on their relevance and clinical significance if and delirium in the PICU since the publication of the fifth edi-
they were published subsequent to the fifth edition of the text- tion. The last 5 years have brought exciting new information
book. about pain and sedation assessment and protocols, safety and
Data Synthesis: Selected articles were grouped together by cate- efficacy of sedative-analgesic regimens, reversal of neuromus-
gories similar to specific sections of the pain and sedation chapter cular blockade (NMB), and sleep in the PICU. Additionally,
in the textbook and included pain, sedation, sleep, and delirium. there has been extraordinary progress since the fifth edition
Conclusions: Recent research into pediatric pain and sedation to elucidate the epidemiology and risk factors for delirium in
management has focused on optimizing the choice of sedative critically ill children in a wide spectrum of disease processes.
medications, in particular by increasing the use and understanding Given decreasing PICU mortality rates and increasing mor-
of nonopioid and nonbenzodiazepine options such as ketamine bidity rates, the focus of PICU care is shifting toward reducing
and alpha-2 agonists. Delirium has emerged as a significant mor- iatrogenic harm as a result of PICU care and improving long-
bidity in the critically ill pediatric patient, and recent articles have term outcomes for patients (1). Thus, an area of intense focus
concentrated on the use of validated screening tools to determine is long-term sedative and analgesic exposure in mechanically
the epidemiology and risk factors in specific populations, includ- ventilated patients and the risks associated with benzodiaz-
ing patients with cardiac disease and those receiving extracor- epine use in particular as it relates to delirium. When the fifth
poreal membrane oxygenation. A consistent theme in the most edition was published, validated screening tools had just been
recent literature is the role of titrated but effective sedation, quality established for recognition of delirium in critically ill pedi-
improvement to increase delirium recognition, and optimizing the atric patients, and this review will provide updates on what
we have learned thanks to the availability of these tools. Since
publication of the fifth edition, our field has also learned from
1
Department of Anesthesiology and Critical Care Medicine, Charlotte R.
Bloomberg Children’s Center, Johns Hopkins University School of Medi- the largest clinical trial of sedation protocolization in critically
cine, Baltimore, MD. ill children.
2
Department Pediatrics, Johns Hopkins University School of Medicine, The ICU Liberation movement and “ABCDEF” bundle (2),
Baltimore, MD. a multidisciplinary and integrated approach to improve out-
3
Department of Physical Medicine & Rehabilitation, Johns Hopkins Univer- comes in critically ill patients, has established the intercon-
sity School of Medicine, Baltimore, MD.
nection between assessing, treating, and managing pain (A),
The authors have disclosed that they do not have any potential conflicts
of interest. choice of sedation (C), and delirium monitoring and manage-
For information regarding this article, E-mail: [email protected] ment (D) (3). Reviewing new literature on both spontaneous
Copyright © 2018 by the Society of Critical Care Medicine and the World awakening and extubation readiness trials (B), early mobiliza-
Federation of Pediatric Intensive and Critical Care Societies tion (E), and family engagement (F) is outside the scope of this
DOI: 10.1097/PCC.0000000000001765 update, but it is important to consider how we may approach

Pediatric Critical Care Medicine www.pccmjournal.org 1

Copyright © 2018 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.
Unauthorized reproduction of this article is prohibited
 Walker and Kudchadkar

pain, sedation, and delirium management within the context critically ill children. Using both quantitative and qualitative
of ICU Liberation. At the time of this update, the most recent tools, Lafond et al (10) found that many undertreat pain out
clinical practice guidelines from the Society of Critical Care of concern for adverse effects of opioids or knowledge gaps
Medicine have added immobility and sleep disruption to pain, regarding pharmacokinetics.
agitation/sedation, and delirium as critical considerations for These recent studies highlight the wide variation in nursing
clinical care and research in the adult ICU (4). Although ICU assessment of pain and emphasize the need for standardiza-
Liberation began in adult ICUs, these same ABCDEF prin- tion. Keogh et al (11) showed that using practice guidelines
ciples are being progressively addressed in pediatric critical for analgesic management in critically ill children was feasible
care. While we await pediatric-specific guidelines, the litera- and led to an improvement in staff ’s understanding of pediat-
ture included in this review highlights increased attention by ric pain and its treatment. Implementation of the guidelines
our field to each of these areas and how their interplay impacts did lead to higher minimum and maximum dosages of mor-
short- and long-term outcomes in infants and children. phine and midazolam, but lower average length of continuous
Benzodiazepines have been established as an independent infusions, suggesting that the pain was adequately controlled
risk factor for delirium development in critically ill infants and with minimal risk of withdrawal. Future directions in pain
children. Thus, data regarding the use of medications other assessment of critically ill children should continue to focus on
than opiates and benzodiazepines for sedation are evolving improving consistency in assessment and alleviation of pain.
and comprise a substantial proportion of the recent literature.
Medications such as alpha-2 agonists and ketamine are gain- Sedation Assessment
ing popularity for use during procedural sedation, as well as Sedation should be goal-directed and customized for each
for longer term sedation management of the PICU patient. patient with consistent and reliable assessment methods. Since
Current evidence demonstrates their safety and efficacy when the publication of the fifth edition of the Rogers’ Textbook of
used at appropriate dosages. A major advance in NMB rever- Pediatric Critical Care, two additional sedation scales have been
sal has emerged with sugammadex. Emerging research in validated for use in children: the Richmond Agitation Sedation
the PICU is characterizing sleep in critically ill children and Scale (RASS) and the Pediatric Sedation State Scale (PSSS).
staff perceptions of the PICU environment for sleep hygiene. The RASS is a scoring system commonly used in adults
Finally, we are gaining new insights about the prevalence and that incorporates both agitation and sedation. It had not been
cost of delirium and its impact in different subsets of PICU previously validated for the pediatric population. The RASS
patients, including those undergoing cardiac surgery and those is unique because of its ability to assess awareness, which is
receiving extracorporeal membrane oxygenation (ECMO). important in the recognition of hypoactive and hyperac-
tive delirium. Kerson et al (12) tested this tool in 100 patient
encounters and from 50 unique patients aged 2 months to
PAIN AND SEDATION ASSESSMENT
21 years. Twenty-seven percent of the assessments were per-
Pain Assessment formed in mechanically ventilated patients; the remainder of
Critically ill children commonly experience pain secondary the children were breathing spontaneously. This criterion for
to trauma, medical procedures, invasive devices, and illness- inclusion is distinctive, as the commonly used State Behavioral
induced discomfort. Assessment of pain in pediatrics is chal- Scale is validated only in mechanically ventilated children (4).
lenging because of variability in cognition and development, The RASS score was compared with both a Visual Analog Scale
difficulty with communication, and the complex interplay (VAS), given by the bedside nurse for assessment of agitation,
between sedative and analgesic medications. Pain is a sub- and the University of Michigan Sedation Scale (UMSS), which
jective measure, and efforts to standardize assessments using was conducted by a researcher. The researchers found that
objective, noninvasive monitoring such as bispectral index or the RASS was highly correlated with both the VAS (Spearman
cutaneous conductance have been unsuccessful (5, 6). correlation coefficient, 0.8; p < 0.0001) and with the UMSS
Bedside nurses play a central role in assessing the pain of (weighted kappa, 0.9; p < 0.0001).
children, and current recommendations encourage the use The PSSS is a six-point scale developed to measure the
of validated pain scales to guide alleviation of pain (7). The effectiveness and quality of procedural sedation, including the
COMFORT Scale; Face, Legs, Activity, Cry and Consolability; control of pain, anxiety, movement, and adverse side effects
and the Multidimensional Assessment of Pain Scale are the in pediatric patients. The PSSS was shown to have respect-
three most commonly used pain assessment tools in the PICU able interrater and intrarater reliability as well as validity
setting and are recommended by the European Society of when compared with the Observational Scale of Behavioral
Paediatric and Neonatal Intensive Care (8). Recent studies, Distress-Revised scale (13). The scoring system differs from
however, suggest that bedside nurses do not consistently use other sedation scales because it allows for analysis of proce-
these assessment tools. In a study that used virtual humans dural conditions regardless of presence or absence of seda-
and written vignettes, PICU nurses used behavior as a primary tion. For example, this scale can be used when performing
indicator to assess and treat pain, even when the child was a lumbar puncture in a pediatric patient with distraction
mature enough to articulate (9). PICU nurses exhibit marked instead of pharmacologic sedation, and will alert the care-
variability in their assessment, beliefs, and response to pain in giver of any dangerous conditions such as unsafe movements.

2 www.pccmjournal.org XXX 2018 • Volume XX • Number XXX

Copyright © 2018 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.
Unauthorized reproduction of this article is prohibited
 Rogers’ Update

The development of the PSSS and the validation of the out that there was also no difference in emotional dysfunction.
RASS scoring system will help PICU providers to administer Therefore, they concluded that a sedation strategy allowing
optimal sedation and evaluate sedation status of patients who patients to be more awake was not harmful from a physical or
receive short-term procedural sedation or longer term seda- emotional perspective.
tion with or without an endotracheal tube. Daily sedation interruption was separately evaluated in a
multicenter randomized control trial in the Netherlands by
SEDATION: THE ROLE OF PROTOCOLS AND Vet et al (17). This trial was conducted from 2009 to 2014 and
included mechanically ventilated children in three PICUs. These
SEDATION INTERRUPTION
Sedation is a central component of PICU care meant to ensure patients, who were randomized to receive protocolized sedation
the comfort and safety of our patients. However, prolonged use with daily sedation interruptions or protocolized sedation only,
of sedation can lead to detrimental side effects such as respira- exhibited no difference in length of mechanical ventilation,
tory depression, constipation, tolerance, and physical depen- cumulative midazolam dose, or hospital length of stay. The
dence that can cause iatrogenic withdrawal when sedation is group without the daily sedation interruption did require more
no longer needed. Reports in the adult ICU literature are con- reintubations (3% vs 14%; p = 0.03). Interestingly, the authors
flicting with regard to improvement in mechanical ventilation did find a higher occurrence rate of mortality in the daily seda-
time and length of stay with the use of protocolized sedation tion interruption group (9% vs 0%; p = 0.03). The findings
(5). Studies evaluating this topic in PICUs were not available of this study differ from two earlier studies on daily sedation
at the time of the publication of the fifth edition of the Rogers’ interruption in PICU patients (18, 19). These previous stud-
Textbook of Pediatric Critical Care (14). ies showed that sedation interruptions led to diminished use of
The Randomized Evaluation of Sedation Titration for sedative medications, shorter mechanical ventilation time, and
Respiratory Failure (RESTORE) trial was an unblinded and shorter ICU stays. In the most recent study by Vet et al (17),
clustered randomized control trial involving 2,449 mechani- all patients were on a sedation protocol, whereas the previous
cally ventilated children in 31 U.S. PICUs from 2009 to 2013 studies used no sedation protocol. The authors speculate that
(15). PICUs randomized to the study group used a sedation the use of protocolized sedation itself outweighs the previously
protocol that incorporated arousal assessments, extubation seen benefits of a daily sedation interruption.
readiness tests, and adjustment and weaning of sedation as Although these two new additions to the literature did not
needed per assessment. Control PICUs managed sedation per provide us clear supporting evidence for the benefit of seda-
usual care without any protocolization. The RESTORE study tion protocolization, they do highlight the shift in thought
showed no difference between the two groups in the duration paradigm regarding sedation management in the PICU. The
of mechanical ventilation, inadequate pain or sedation man- new target has evolved to frequent tailoring of medications to
agement, iatrogenic withdrawal, or unplanned endotracheal or allow patients to be as awake and communicative as possible
invasive catheter removal. In exploratory analysis, the authors while balancing the need for pain management and anxioly-
did find that patients in the intervention group had fewer days sis. Each individual PICU must determine the best approach
of opioid administration (median 9 vs 10 d) and were exposed to achieve this goal in the setting of their own unit culture,
to fewer classes of sedative medication (median 2 vs 3) than whether through nurse-driven sedation protocols or frequent
the control groups. The intervention group was awake and bedside assessments by the care team. All in all, each patient’s
calm 86% of the time compared with 75% of the time for the sedation plan should be individualized and titrated for his/her
control group (p = 0.004); however the intervention group own clinical needs.
had more days with a pain score greater than 4 (60% vs 40%;
p ≤ 0.001). Investigators also found a higher occurrence rate of SEDATIVE MEDICATIONS IN THE PICU
postextubation stridor (7% vs 4%; p = 0.03) but no difference Sedation of the critically ill child can be a daunting task, espe-
in reintubation rates, and a lower risk of pressure ulcers (< 1% cially when attempting to achieve a balance among adequate
vs 2%) in the intervention group. The authors concluded that sedation, anxiolysis, and pain control while minimizing short-
the use of a nurse-implemented, goal-directed sedation proto- and long-term effects from these centrally acting medications.
col did not reduce the duration of mechanical ventilation and Substantial research has been conducted to target the utiliza-
acknowledged that the relationship between wakefulness, pain, tion of medications other than benzodiazepines and opiates
and agitation is complex. for PICU sedation since publication of the fifth edition. We
A subsequent analysis from the RESTORE study that highlight the most impactful studies in the following sections.
evaluated postdischarge outcomes showed no difference in
postdischarge morbidity between patients who received a Ketamine
goal-oriented sedation protocol and those who received usual Ketamine, a N-methyl-d-aspartate receptor antagonist, is a dis-
care (16). This study highlighted a significant physical mor- sociative anesthetic that also provides analgesia with minimal
bidity in patients recovering from acute respiratory failure, respiratory depression and stable hemodynamics. These prop-
with 19% experiencing a persistent decline in functional sta- erties have increased its popularity for use in procedural seda-
tus 6 months after discharge. Although there was no observed tion. Previous studies of ketamine’s safety have been limited to
physical benefit in the sedation protocol arm, the authors point the pediatric emergency department. The Pediatric Sedation

Pediatric Critical Care Medicine www.pccmjournal.org 3

Copyright © 2018 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.
Unauthorized reproduction of this article is prohibited
 Walker and Kudchadkar

Research Consortium (PSRC) published data on 22,645 seda- decrease respiratory drive. The disadvantage of this class is the
tions with ketamine outside of the operating room from 2007 possibility for bradycardia and hypotension, which may limit
to 2015 (20). The locations of the sedation events were primar- these medications as a first-line choice for sedation, particu-
ily in sedation or radiology suites (65%), with 12% occurring in larly in young infants and cardiac patients. Studies published
the emergency department and 7% in the PICU. Ketamine was since the fifth edition have focused on the safety profile of these
used as the sole medication in 17% of the cases; benzodiazepines drugs and indications for more widespread use.
and propofol were the most commonly coadministered agents Clonidine. Clonidine is available in multiple preparations,
(58% and 35%, respectively). The authors found a low occur- including nasal spray, oral liquids, oral tablets, oral transmuco-
rence rate of serious adverse events (SAEs, 2%) and an overall sal system, and rectal suspensions and is approved for IV use
adverse event (AE) rate of 7%. No patients died, although three in some countries. A systematic review in which Hanning et
in radiology/sedation suites had cardiac arrests, all related to al (24) compared the bioavailability and efficacy among the
laryngospasm. Dental procedures comprised a small propor- different formulations found the IV form to have the most
tion of the cases (0.6%) but did have a significantly higher risk predictable bioavailability. Given that clonidine has a long
of SAE. The coadministration of benzodiazepines was associ- half-life of 12–24 hours owing to its large volume of distribu-
ated with decreased odds of SAE and AE. Coadministration of tion, down titration can be difficult with any formulation. The
propofol, anticholinergics, or barbiturates was associated with authors concluded that additional work needs to be done on
significantly higher percentages of AEs and SAEs. The authors oral, nasal, and rectal suspensions.
also found a dose-dependent relationship. Dosages greater Studies on the efficacy of clonidine as an adjunctive seda-
than 2.5 mg/kg were associated with a significant increase in tion agent are limited. Hayden et al (25) performed a sys-
AE (7% vs 5%; p = 0.008), and dosages greater than 5 mg/kg tematic review to evaluate the efficacy of alpha-2 agonists for
were associated with a statistically higher percentage of AEs and sedation in the PICU. They found six randomized control tri-
SAEs. The dosage-based risk factor is in agreement with a meta- als that compared the use of an alpha-2 agonist with either
analysis on ketamine administered in the pediatric emergency another medication or a placebo. Three of the trials involved
department that found a total dose of greater than 5 mg/kg to clonidine—two which compared it with placebo and one
be associated with adverse respiratory events (21). which compared it with midazolam. The authors found that
The PSRC later performed a separate analysis of the out- clonidine had an opiate- and benzodiazepine-sparing poten-
comes associated with the use of ketamine and propofol in pedi- tial when used as an adjunctive sedation in the neonatal age
atric patients outside of the operating room (22). The cohort group only. This potential benefit was not supported in older
included 7,313 procedural sedations that occurred mainly in children and was not associated with a decrease in the duration
dedicated sedation or radiology units. Anticholinergics and of mechanical ventilation in any age group.
benzodiazepines were coadministered 14% and 41% of the Given clonidine’s long half-life, the potential for alterations
time, respectively. AEs occurred in 10% of sedations, and the in hemodynamics has been a concern, particularly in neonates.
SAE rate was 3%. This SAE, although low, is higher than that Kleiber et al (26) compared the use of an IV infusion of cloni-
for use of propofol (2%) or ketamine alone (2%). There were dine to midazolam as an adjunct to morphine in neonates after
no deaths and one cardiac arrest, and airway obstruction was cardiac surgery. Although the patients who received clonidine
the leading cause of SAE. The authors also found higher odds had a transient decrease in diastolic blood pressure 13% of the
of AE with the coadministration of anticholinergics, ASA sta- time and a maximal decrease in heart rate of 12%, the neo-
tus greater than or equal to III, and the primary diagnosis of a nates showed no signs of decreased cardiac output. Thus, these
gastrointestinal illness. changes seemed of minimal clinical importance. The authors
Studies of ketamine use exclusively in the PICU are lacking. concluded that the use of IV clonidine appears hemodynami-
However, the safety profile of ketamine use in other high-risk cally safe in the neonatal population, although a larger study
units (emergency department, sedation suite) depicts a low rate is warranted. Most recently, Kleiber et al (26) followed their
of SAEs, with laryngospasm being the most common event. neonatal study with an evaluation of hemodynamic tolerance
Therefore, ketamine use in the PICU setting has a substantial of clonidine in a broad population of PICU patients ages 0–18
role in procedural sedation and even sedation for mechanical years (27). They concluded that although clonidine adminis-
ventilation specifically in cases of severe bronchospasm or as tration was often associated with bradycardia and hypotension,
an adjunct for children who are difficult to sedate. However, those complications were rarely clinically significant despite a
the interaction of ketamine with other agents, including pro- high degree of illness severity.
pofol, must be considered with caution. Dexmedetomidine. Dexmedetomidine, an alpha-2 agonist
that was approved in 1999 for use in adults, has gained popu-
Alpha-2 Adrenergic Agonists larity in pediatrics given its continuous infusion form, titrat-
The alpha-2 agonists clonidine and dexmedetomidine have ability, and short half-life. At this time, dexmedetomidine is
become increasingly used for sedation in the PICU over the not approved for use in children in any country; however its
last decade (23). This class of medications mediates sleep, anal- off-label usage is increasing, particularly in the United States.
gesia, and sedation but does not provide amnesia. Alpha-2 ago- The PSRC performed a retrospective review to evaluate the
nists are an attractive choice for sedation because they do not safety of dexmedetomidine use for procedural sedation (28).

4 www.pccmjournal.org XXX 2018 • Volume XX • Number XXX

Copyright © 2018 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.
Unauthorized reproduction of this article is prohibited
 Rogers’ Update

Five percent of all sedations during the study period used dex- failure showed that it might prove beneficial as a periextuba-
medetomidine. Of those, dexmedetomidine was coadminis- tion agent by shortening the ventilator weaning process (31).
tered with benzodiazepines in 61% of cases, ketamine in 6% of In the pediatric congenital heart disease population, a meta-
cases, and opioids in 4% of cases. Most uses of dexmedetomi- analysis of outcomes showed that dexmedetomidine use was
dine for sedation were for radiologic imaging, given its limited associated with a shorter duration of mechanical ventilation,
analgesic properties. The overall AE rate was 4%, and the SAE reduced stress response, and lower risk of delirium (35).
rate was a very low 0.34%, with airway obstruction being the
most common. The rate of unexpected change in heart rate
NMB
or blood pressure of greater than 39% was 0.93%, and there
Reversal of NMB is often required to prevent postoperative
were no deaths or cardiac arrests in the patients who received
residual paresis and can facilitate quicker extubation times.
dexmedetomidine. The occurrence rate of clinically signifi-
Previously, acetylcholinesterase inhibitors were the only rever-
cant hypotension or bradycardia is reassuring and supported
sal agents available and were associated with muscarinic side
by other studies. For example, a meta-analysis that evaluated
effects and residual blockade in both adults and children (36).
the occurrence rate of bradycardia with dexmedetomidine use
Sugammadex, a modified gamma cyclodextrin, was
showed a wide range of 0–22% across previous studies, with an
approved by the Food and Drug Administration in December
average of 3% occurrence rate after meta-regression analysis (29).
of 2015 for the reversal of steroidal nondepolarizing NMB
Dexmedetomidine can be suitable in some settings as a pri-
agents such as rocuronium and vecuronium (37). This is a clin-
mary sedative agent and may be particularly useful as a sole
ically important development, as sugammadex acts more rap-
agent when short- or long-term sedation is required in non-
idly and effectively than neostigmine for full NMB reversal and
intubated patients. A recent review evaluating the use of intra-
does not have the associated muscarinic side effects that come
nasal dexmedetomidine for preprocedural sedation showed
with neostigmine. Sugammadex exerts its effect by forming a
that, compared with oral benzodiazepines, dexmedetomidine
tight water-soluble complex with the neuromuscular agent.
had a longer onset of effect but led to better overall sedative
It encapsulates the drug particles and prevents their binding
effects without respiratory depression (30). Data from the
to nicotinic receptors at the neuromuscular junction (38, 39).
RESTORE trial supports its use in low criticality patients (31),
A meta-analysis of sugammadex use in pediatric patients was
and Venkatraman et al (32) demonstrated dexmedetomidine
performed in 2016 (40). This review evaluated six randomized
to be effective as a single agent for sedation to facilitate toler-
control trials that included a total of 253 pediatric patients and
ance of pediatric noninvasive ventilation. During noninvasive
compared reversal by sugammadex, neostigmine, or placebo.
ventilation, the sole use of dexmedetomidine enabled the tar-
The authors found that when compared with placebo or neo-
geted sedation level in 83% of patients. Clinically significant
stigmine, sugammadex shortened the rocuronium-induced
hemodynamic changes were minimal and were responsive to a
NMB time, leading to faster extubations. There was no differ-
decrease in dexmedetomidine infusion, fluid bolus, or titration
ence between the two groups in the number or severity of AEs.
of the noninvasive ventilation. Additional studies that evalu-
The dosage of sugammadex is dependent on the patient’s train
ated prolonged use of dexmedetomidine as a primary agent
of four at the time of administration. Limited data are available
in noninvasive ventilation revealed predictable hemodynamic
for children under 2 years old. The dosage chart is included in
effects, with patients experiencing bradycardia and systolic
Table 1.
hypertension during the escalation phase (33). This retrospec-
Because sugammadex is cleared renally, its use is not rec-
tive review by Shutes et al (33) also highlighted the iatrogenic
ommended for a patient with creatinine clearance less than
withdrawal potential, as 25% of patients who received dexme-
30 mL/min. If readministration of rocuronium or vecuronium
detomidine for more than 96 hours experienced withdrawal.
is required after sugammadex administration, a clinical effect
The authors recommended the initiation of clonidine in this
may not be observed for 5 minutes to 24 hours; therefore, it
population.
is advised instead to use a nonsteroidal neuromuscular block-
A systematic review showed that when dexmedetomidine
ing agent. The development of sugammadex is momentous for
is used as an adjunctive medication, it can lead to decreased
select PICU patients who require rapid and effective reversal,
opioid administration; however this conclusion has not been
such as in the postoperative setting to facilitate extubation or
supported in all trials (25). The RESTORE trial concluded that
for rescue in the “can’t intubate, can’t ventilate” patient.
dexmedetomidine does not appear to have any added benefit
as a secondary agent and offers inadequate pain control and
sedation in these patients (31). WEANING OF OPIOIDS AND SEDATIVES
Given the absence of respiratory depression with dexme- Tolerance, dependence, and then subsequent withdrawal from
detomidine use, clinical benefits from improved respiratory sedative medications are an iatrogenic complications of many
strength have been suggested. A Cochrane review showed that critically ill children. Despite this common clinical problem,
dexmedetomidine reduced the duration of mechanical ven- there has been little consensus on the best practice approach
tilation and ICU stays in adult patients, and recent pediatric for weaning of sedative medications in long-term mechani-
literature supports this notion as well (34). A study evaluating cally ventilated children. Sanchez-Pinto et al (41) evaluated
the use of dexmedetomidine in children with acute respiratory the effects of an opioid weaning protocol on the opioid drug

Pediatric Critical Care Medicine www.pccmjournal.org 5

Copyright © 2018 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.
Unauthorized reproduction of this article is prohibited
 Walker and Kudchadkar

Recommended Sugammadex
TABLE 1. against noise and light outside of the room as well as privacy
Dosage for Reversal of Neuromuscular from a neighbor’s interventions. From a nurse’s perspective,
the use of private rooms is more conducive to promoting a
Blockade
good sleep environment for patients than the use of multi-
Recommended patient rooms (47). Future research is needed to evaluate the
Sugammadex Dose, interplays among the ICU environment, medication choices,
Train of Four Result mg/kg
patient activity, and sleep in pediatric critically ill patients.
Immediate/emergent reversal after 16
administration of neuromuscular
blockade (rocuronium 1.2 mg/kg) DELIRIUM IN THE PICU
Delirium, characterized by a fluctuating disturbance in aware-
1–2 twitches 4 ness, attention, and cognition, has been established as a signifi-
2–4 twitches 2 cant morbidity in the PICU (35–38). A recent multinational
point prevalence study found the prevalence of delirium in
critically ill children to be notably high at 25% (48). Prolonged
burden in PICU patients. Among 107 children (68 pre inter-
ICU stay of more than 6 days and mechanical ventilation
vention and 39 post intervention), they found that the use of
requirement increased the prevalence of delirium significantly
an opioid weaning protocol led to fewer days on opioids (23 d
to 38% and 53%, respectively. Patients in cardiac intensive
vs 17; p = 0.01) and a decrease in the total cumulative opioid
care exhibit an even higher prevalence, with one study show-
exposure without an increase in withdrawal symptoms. These
ing that the occurrence rate of delirium was 100% in cardiac
findings have been supported by previous studies (42), and the
ECMO patients and 49% in children who had undergone sur-
implementation of weaning protocols for opiates should be
gery requiring cardiac bypass (49, 50). Reported outcomes of
considered in all PICUs.
patients with delirium are concerning. Recent studies have
Of interest, the study by Sanchez-Pinto et al (41) did
found that the diagnosis of delirium is associated with a pro-
incorporate the novel approach of establishing a baseline
longed ICU stay and is a strong and independent predictor of
Withdrawal Assessment Tool (WAT)-1 score as a key compo-
mortality (51). Pediatric delirium can put a substantial burden
nent of the weaning protocol. The baseline WAT-1 score allows
on healthcare costs. Delirium has been associated with an 85%
for bedside caregivers to differentiate between withdrawal and
increase in PICU costs, with the cost increasing incrementally
overlapping clinical symptoms that could mimic and be mis-
with the number of days spent delirious (52).
interpreted as withdrawal thus leading to a prolonged wean.
Recognizing delirium in the pediatric population can be
Examples of these symptoms include baseline hypertonia,
challenging given the wide diversity of ages, developmental
hyperthermia, and persistent emesis. Recognizing and incor-
stages, and mix of hypoactive and hyperactive delirium. At the
porating an individual patient’s baseline symptoms can likely
time of publication of the fifth edition, the only validated tool
facilitate a shorter duration of sedative weaning.
for delirium screening in children less than 5 years old was the
Cornell-Assessment of Pediatric Delirium (CAPD). The pedi-
SLEEP IN THE PICU atric Confusion Assessment Method for ICU was previously
Restorative sleep is important for neuronal development, validated in critically ill children greater than 5 years old and
metabolism, and immune system function; however previous has been shown to have superior validity when compared with
studies have demonstrated significant sleep disturbances in the the Paediatric Anesthesia Emergence Delirium Scale (53, 54).
PICU (43–45). A prospective study recently evaluated tempo- The Preschool Confusion Assessment Method for the ICU
ral characteristics of the sleep electroencephalogram (EEG) in (psCAM-ICU) was most recently validated for use in children
mechanically ventilated PICU patients and confirmed a lack of 6 months to 5 years old (55). The psCAM-ICU screening tool
the normal ultradian variation and decreased slow wave sleep encompasses colored and mirrored cards to evaluate atten-
in critically ill children compared with that in healthy children tion and can detect both hypoactive and hyperactive delirium.
(46). In that study, eight PICU patients with respiratory failure Given that most children admitted to the PICU are under the
who required mechanical ventilation underwent limited mon- age of 5 years, having two validated tools, the psCAM-ICU and
tage EEG. The EEGs of the PICU patients were compared with CAPD, is crucial for accurate and efficient delirium screen-
those of eight age- and gender-matched healthy children. The ing. Implementation of an ICU bundle that includes delirium
typical patterns in δ or θ power spectral bands observed in screening, detection, and treatment has been shown to be fea-
the healthy subjects were entirely lacking in the PICU patients. sible and effective, decreasing delirium rates from 17% to 12%
Importantly, these children exhibited a behavioral state similar in one PICU (56).
to sleep (eyes closed, resting) while having an EEG that did not In light of the emerging literature regarding the high occur-
support restorative sleep. rence rate of delirium in our patients and the concern for asso-
The lack of organized and restorative sleep in the PICU ciated worse clinical outcomes, we must be cognizant of and
is multifactorial. Contributors include many modifiable fac- address modifiable risk factors. The delirium point prevalence
tors, such as medication choice, nighttime interventions, and study by Traube et al (48) showed an increased risk of delirium
environmental stimuli. Single patient rooms allow for a shelter with younger age (< 2 yr), need for vasoactive infusions, and

6 www.pccmjournal.org XXX 2018 • Volume XX • Number XXX

Copyright © 2018 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.
Unauthorized reproduction of this article is prohibited
 Rogers’ Update

the need for antiepileptic medication, all factors that are non- patients by minimizing modifiable risk factors for delirium
modifiable. However, the study also pointed out many iatro- should be advocated. In particular, an ICU delirium bundle
genic risk factors. The use of benzodiazepines, narcotics, and should be implemented universally, and the use of benzodiaze-
physical restraints was all strongly associated with delirium. pines and restraints, although many times medically necessary,
The concern for an association between benzodiazepine use should be limited when possible.
and subsequent delirium has heightened.
A recent retrospective study by Mody et al (57) found ben-
ACKNOWLEDGMENTS
zodiazepines to be an independent predictor of delirium in
We would like to thank Claire Levine, MS, in the Department
critically ill children. They reported a temporal, causal, and
of Anesthesiology and Critical Care Medicine at Johns Hop-
dose-dependent relationship between benzodiazepine expo-
kins for providing editorial assistance for this article.
sure and the development of delirium. Receipt of benzo-
diazepines more than doubled a child’s risk factor for being
delirious the following day (odds ratio [OR], 2.0; p < 0.001), REFERENCES
even after controlling for prior delirious status. In children 1. Pollack MM, Holubkov R, Funai T, et al; Eunice Kennedy Shriver
National Institute of Child Health and Human Development
who were not yet delirious, benzodiazepine exposure quadru- Collaborative Pediatric Critical Care Research Network: Pediatric
pled the chance of delirium (OR, 4.4; p ≤ 0.002), showing these intensive care outcomes: Development of new morbidities during
drugs to be independently associated with a transition from pediatric critical care. Pediatr Crit Care Med 2014; 15:821–827
2. Marra A, Ely EW, Pandharipande PP, et al: The ABCDEF bundle in
normal mental status to delirium. Similarly, analysis of data critical care. Crit Care Clin 2017; 33:225–243
from the psCAM-ICU validation study of preschool age chil- 3. Ely EW: The ABCDEF bundle: Science and philosophy of how
dren (58) showed that benzodiazepine exposure was indepen- ICU liberation serves patients and families. Crit Care Med 2017;
dently associated with the development of delirium (OR, 2.47; 45:321–330
p = 0.005). In children greater than 12 months old, both benzo- 4. Devlin JW, Skrobik Y, Gélinas C, et al: Clinical practice guidelines for
the prevention and management of pain, agitation/sedation, delirium,
diazepine exposure and delirium were significantly associated immobility, and sleep disruption in adult patients in the ICU. Crit Care
with a lower likelihood of ICU discharge (hazard ratio, 0.65; Med 2018; 46:e825–e873
p = 0.011). The conclusions from these recent studies suggest 5. Solana MJ, Lopez-Herce J, Fernandez S, et al: Assessment of pain in
critically ill children. Is cutaneous conductance a reliable tool?. J Crit
that a benzodiazepine-sparing approach may decrease the bur- Care 2015; 30:481–485
den of delirium in our PICU population. 6. Coleman RM, Tousignant-Laflamme Y, Ouellet P, et al: The use of the
At the time of this review, the most recent literature had bispectral index in the detection of pain in mechanically ventilated
explored risk factors for delirium in postoperative patients adults in the intensive care unit: A review of the literature. Pain Res
Manag 2015; 20:e33–e37
admitted to the PICU (59). Notably, total IV anesthesia
7. Harris J, Ramelet AS, van Dijk M, et al: Clinical recommendations
was associated with a lower risk of delirium development for pain, sedation, withdrawal and delirium assessment in critically ill
(p < 0.05). Additionally, a nested retrospective cohort study infants and children: An ESPNIC position statement for healthcare
demonstrated an independent association between blood professionals. Intensive Care Med 2016; 42:972–986
8. Harris J, Ramelet A-S, van Dijk M, et al: Clinical recommendations
transfusion and delirium development (adjusted OR, 2.16; for pain, sedation, withdrawal and delirium assessment in critically ill
95% CI, 1.38–3.37). infants and children: An ESPNIC position statement for healthcare
Another important and logical focus of the recent delirium professionals. Intensive Care Med 2016; 42:972–986
literature is the approach to treatment once delirium has been 9. LaFond CM, Vincent CVH, Corte C, et al: PICU nurses’ pain assess-
ments and intervention choices for virtual human and written vignettes.
diagnosed. Although the importance of using nonpharma- J Pediatr Nurs 2015; 30:580–590
cologic therapies as a first-line tactic is emphasized, the role 10. LaFond CM, Van Hulle Vincent C, Oosterhouse K, et al: Nurses’
of child psychiatry engagement and the safety and efficacy of beliefs regarding pain in critically ill children: A mixed-methods study.
antipsychotic therapy are growing areas of interest. In a case J Pediatr Nurs 2016; 31:691–700
11. Keogh SJ, Long DA, Horn DV: Practice guidelines for sedation and
series describing child psychiatry consultation in cases of delir- analgesia management of critically ill children: A pilot study evaluat-
ium, Barnes et al (60) found that over half of patients were ing guideline impact and feasibility in the PICU. BMJ Open 2015;
started on an antipsychotic medication before involvement of 5:e006428
child psychiatry. However, the involvement of the psychiatry 12. Kerson AG, DeMaria R, Mauer E, et al: Validity of the Richmond
Agitation-Sedation Scale (RASS) in critically ill children. J Intensive
team facilitated adjustment and weaning of medications after Care 2016; 4:65
discharge from the PICU. Slooff et al (61) reported first results 13. Cravero JP, Askins N, Sriswasdi P, et al: Validation of the Pediatric
from prospective, systematic monitoring of AEs in 13 patients Sedation State Scale. Pediatrics 2017; 139:e20162897
with confirmed delirium who were treated with a haloperidol 14. Brook AD, Ahrens TS, Schaiff R, et al: Effect of a nursing-implemented
sedation protocol on the duration of mechanical ventilation. Crit Care
dose titration protocol. Their study revealed a significant pro-
Med 1999; 27:2609–2615
portion of potential AEs despite low plasma concentrations 15. Curley MA, Wypij D, Watson RS, et al; RESTORE Study Investigators
and dosing within recommended ranges. and the Pediatric Acute Lung Injury and Sepsis Investigators Network:
Significant advances have been made over the past few years Protocolized sedation vs usual care in pediatric patients mechanically
ventilated for acute respiratory failure: A randomized clinical trial.
in our understanding of the epidemiology, recognition, asso- JAMA 2015; 313:379–389
ciated risk factors, treatment, and troublesome outcomes for 16. Watson RS, Asaro LA, Hertzog JH, et al; RESTORE Study Investigators
patients with delirium. Interventions to mitigate harm to our and the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI)

Pediatric Critical Care Medicine www.pccmjournal.org 7

Copyright © 2018 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.
Unauthorized reproduction of this article is prohibited
 Walker and Kudchadkar

Network: Long-term outcomes after protocolized sedation versus 38. Bom A, Bradley M, Cameron K, et al: A novel concept of reversing
usual care in ventilated pediatric patients. Am J Respir Crit Care Med neuromuscular block: Chemical encapsulation of rocuronium bromide
2018; 197:1457–1467 by a cyclodextrin-based synthetic host. Angew Chem Int Ed Engl
17. Vet NJ, de Wildt SN, Verlaat CW, et al: A randomized controlled trial 2002; 41:266–270
of daily sedation interruption in critically ill children. Intensive Care 39. Abrishami A, Ho J, Wong J, et al: Sugammadex, a selective rever-
Med 2016; 42:233–244 sal medication for preventing postoperative residual neuromuscular
18. Verlaat CW, Heesen GP, Vet NJ, et al: Randomized controlled trial of blockade. Cochrane Database Syst Rev 2009; (4):CD007362
daily interruption of sedatives in critically ill children. Paediatr Anaesth 40. Abrishami A, Ho J, Wong J, et al: Cochrane corner: Sugammadex,
2014; 24:151–156 a selective reversal medication for preventing postoperative residual
19. Gupta K, Gupta VK, Jayashree M, et al: Randomized controlled trial neuromuscular blockade. Anesth Analg 2010; 110:1239
of interrupted versus continuous sedative infusions in ventilated chil- 41. Sanchez-Pinto LN, Nelson LP, Lieu P, et al: Implementation of a risk-
dren. Pediatr Crit Care Med 2012; 13:131–135 stratified opioid weaning protocol in a pediatric intensive care unit. J
20. Grunwell JR, Travers C, McCracken CE, et al: Procedural sedation Crit Care 2018; 43:214–219
outside of the operating room using ketamine in 22,645 children: A 42. Robertson RC, Darsey E, Fortenberry JD, et al: Evaluation of an opi-
report from the Pediatric Sedation Research Consortium. Pediatr Crit ate-weaning protocol using methadone in pediatric intensive care unit
Care Med 2016; 17:1109–1116 patients. Pediatr Crit Care Med 2000; 1:119–123
21. Green SM, Roback MG, Krauss B, et al; Emergency Department 43. Dahl RE: Sleep and the developing brain. Sleep 2007; 30:1079–1080
Ketamine Meta-Analysis Study Group: Predictors of emesis and 44. Everson CA: Sustained sleep deprivation impairs host defense. Am J
recovery agitation with emergency department ketamine sedation: An Physiol 1993; 265:R1148–R1154
individual-patient data meta-analysis of 8,282 children. Ann Emerg 45. Kudchadkar SR, Aljohani OA, Punjabi NM: Sleep of critically ill chil-
Med 2009; 54:171.e–80.e1 dren in the pediatric intensive care unit: A systematic review. Sleep
22. Grunwell JR, Travers C, Stormorken AG, et al: Pediatric procedural Med Rev 2014; 18:103–110
sedation using the combination of ketamine and propofol outside 46. Kudchadkar SR, Yaster M, Punjabi AN, et al: Temporal characteristics
of the emergency department: A report from the Pediatric Sedation of the sleep EEG power spectrum in critically ill children. J Clin Sleep
Research Consortium. Pediatr Crit Care Med 2017; 18:e356–e363 Med 2015; 11:1449–1454
23. Kamat PP, Kudchadkar SR: IV Clonidine in the PICU: Time for dex- 47. Kudchadkar SR, Beers MC, Ascenzi JA, et al: Nurses’ perceptions of
medetomidine to share the limelight? Pediatr Crit Care Med 2018; pediatric intensive care unit environment and work experience after
19:792–794 transition to single-patient rooms. Am J Crit Care 2016; 25:e98–e107
24. Hanning SM, Orlu Gul M, Toni I, et al; CloSed Consortium: A mini- 48. Traube C, Silver G, Reeder RW, et al: Delirium in critically ill chil-
review of non-parenteral clonidine preparations for paediatric seda- dren: An International Point Prevalence Study. Crit Care Med 2017;
tion. J Pharm Pharmacol 2017; 69:398–405 45:584–590
25. Hayden JC, Breatnach C, Doherty DR, et al: Efficacy of α2-agonists 49. Patel AK, Biagas KV, Clark EC, et al: Delirium in the pediatric cardiac
for sedation in pediatric critical care: A systematic review. Pediatr Crit extracorporeal membrane oxygenation patient population: A case
Care Med 2016; 17:e66–e75 series. Pediatr Crit Care Med 2017; 18:e621–e624
26. Kleiber N, de Wildt SN, Cortina G, et al: Clonidine as a first-line seda- 50. Patel AK, Biagas KV, Clarke EC, et al: Delirium in children after car-
tive agent after neonatal cardiac surgery: Retrospective cohort study. diac bypass surgery. Pediatr Crit Care Med 2017; 18:165–171
Pediatr Crit Care Med 2016; 17:332–341 51. Traube C, Silver G, Gerber LM, et al: Delirium and mortality in criti-
27. Kleiber N, van Rosmalen J, Tibboel D, et al: Hemodynamic tolerance cally ill children: Epidemiology and outcomes of pediatric delirium.
to IV clonidine infusion in the PICU. Pediatr Crit Care Med 2018; Crit Care Med 2017; 45:891–898
19:e409–e416 52. Traube C, Mauer EA, Gerber LM, et al: Cost associated with pediatric
28. Sulton C, McCracken C, Simon HK, et al: Pediatric procedural seda- delirium in the ICU. Crit Care Med 2016; 44:e1175–e1179
tion using dexmedetomidine: A report from the Pediatric Sedation 53. Smith HA, Boyd J, Fuchs DC, et al: Diagnosing delirium in critically ill
Research Consortium. Hosp Pediatr 2016; 6:536–544 children: Validity and reliability of the Pediatric Confusion Assessment
29. Gong M, Man Y, Fu Q: Incidence of bradycardia in pediatric patients Method for the intensive care unit. Crit Care Med 2011; 39:150–157
receiving dexmedetomidine anesthesia: A meta-analysis. Int J Clin 54. Luetz A, Gensel D, Müller J, et al: Validity of different delirium assess-
Pharm 2017; 39:139–147 ment tools for critically ill children: Covariates matter. Crit Care Med
30. Jun JH, Kim KN, Kim JY, et al: The effects of intranasal dexmedetomi- 2016; 44:2060–2069
dine premedication in children: A systematic review and meta-analy- 55. Smith HA, Gangopadhyay M, Goben CM, et al: The Preschool Confusion
sis. Can J Anaesth 2017; 64:947–961 Assessment Method for the ICU: Valid and reliable delirium monitoring
31. Grant MJ, Schneider JB, Asaro LA, et al; Randomized Evaluation for critically ill infants and children. Crit Care Med 2016; 44:592–600
of Sedation Titration for Respiratory Failure Study Investigators: 56. Simone S, Edwards S, Lardieri A, et al: Implementation of an ICU
Dexmedetomidine use in critically ill children with acute respiratory bundle: An interprofessional quality improvement project to enhance
failure. Pediatr Crit Care Med 2016; 17:1131–1141 delirium management and monitor delirium prevalence in a single
32. Venkatraman R, Hungerford JL, Hall MW, et al: Dexmedetomidine for PICU. Pediatr Crit Care Med 2017; 18:531–540
sedation during noninvasive ventilation in pediatric patients. Pediatr 57. Mody K, Kaur S, Mauer EA, et al: Benzodiazepines and development
Crit Care Med 2017; 18:831–837 of delirium in critically ill children: Estimating the causal effect. Crit
33. Shutes BL, Gee SW, Sargel CL, et al: Dexmedetomidine as single Care Med 2018; 46:1486–1491
continuous sedative during noninvasive ventilation: Typical usage, 58. Smith HAB, Gangopadhyay M, Goben CM, et al: Delirium and benzo-
hemodynamic effects, and withdrawal. Pediatr Crit Care Med 2018; diazepines associated with prolonged ICU stay in critically ill infants
19:287–297 and young children. Crit Care Med 2017; 45:1427–1435
34. Cruickshank M, Henderson L, MacLennan G, et al: Alpha-2 agonists 59. Meyburg J, Dill ML, Traube C, et al: Patterns of postoperative delirium
for sedation of mechanically ventilated adults in intensive care units: in children. Pediatr Crit Care Med 2016; 1:128–133
A systematic review. Health Technol Assess 2016; 20:v-xx, 1–117
60. Barnes SS, Grados MA, Kudchadkar SR: Child psychiatry engage-
35. Pan W, Wang Y, Lin L, et al: Outcomes of dexmedetomidine treatment ment in the management of delirium in critically ill children. Crit Care
in pediatric patients undergoing congenital heart disease surgery: A Res Pract 2018; 2018:9135618
meta-analysis. Paediatr Anaesth 2016; 26:239–248
61. Slooff VD, van den Dungen DK, van Beusekom BS, et al: Monitoring
36. Baxter MR, Bevan JC, Samuel J, et al: Postoperative neuromuscular func- haloperidol plasma concentration and associated adverse events in
tion in pediatric day-care patients. Anesth Analg 1991; 72:504–508 critically ill children with delirium: First results of a clinical protocol
37. Kovac AL: Sugammadex: The first selective binding reversal agent for aimed to monitor efficacy and safety. Pediatr Crit Care Med 2018;
neuromuscular block. J Clin Anesth 2009; 21:444–453 19:e112–e119

8 www.pccmjournal.org XXX 2018 • Volume XX • Number XXX

Copyright © 2018 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.
Unauthorized reproduction of this article is prohibited