European Journal of Pediatrics (2023) 182:2013–2026

https://doi.org/10.1007/s00431-023-04905-5

REVIEW

Analgesia and sedation in critically ill pediatric patients: an update

from the recent guidelines and point of view
Maria Cristina Mondardini1 · Francesca Sperotto2 · Marco Daverio3 · Angela Amigoni3

Received: 18 December 2022 / Revised: 14 February 2023 / Accepted: 26 February 2023 / Published online: 9 March 2023
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2023

Abstract
In the last decades, the advancement of knowledge in analgesia and sedation for critically ill pediatric patients has been
conspicuous and relevant. Many recommendations have changed to ensure patients’ comfort during their intensive care unit
(ICU) stay and prevent and treat sedation-related complications, as well as improve functional recovery and clinical outcomes.
The key aspects of the analgosedation management in pediatrics have been recently reviewed in two consensus-based docu-
ments. However, there remains a lot to be researched and understood. With this narrative review and authors’ point of view,
we aimed to summarize the new insights presented in these two documents to facilitate their interpretation and application
in clinical practice, as well as to outline research priorities in the field.
Conclusion: With this narrative review and authors’ point of view, we aimed to summarize the new insights presented
in these two documents to facilitate their interpretation and application in clinical practice, as well as to outline research
priorities in the field.

What is Known:
• Critically ill pediatric patients receiving intensive care required analgesia and sedation to attenuate painful and stressful stimuli.
• Optimal management of analgosedation is a challenge often burdened with complications such as tolerance, iatrogenic withdrawal syndrome,
delirium, and possible adverse outcomes.
What is New:
• The new insights on the analgosedation treatment for critically ill pediatric patients delineated in the recent guidelines are summarized to
identify strategies for changes in clinical practice.
• Research gaps and potential for quality improvement projects are also highlighted.

Keywords Analgesia · Sedation · Withdrawal · Delirium · Pediatric intensive care unit (PICU) · Neonatal intensive care
unit (NICU)

Abbreviations
ANI Analgesia Nociception Index
BIS Bispectral index
Communicated by Daniele De Luca. CAPD Cornell Assessment of Pediatric Delirium
* Angela Amigoni
ECMO Extra corporeal membrane oxygenation
[email protected] IWS Iatrogenic withdrawal syndrome
NIPE Newborn Infant Parasympathetic Evaluation
1
Pediatric Anesthesia and Intensive Care Unit, Department Index
of Woman’s and Child’s Health, IRCCS University Hospital
of Bologna Policlinico S. Orsola, Bologna, Italy
NMBA Neuromuscular blocking agent
2
NSAID Non-steroidal anti-inflammatory drug
Cardiovascular Critical Care Unit, Department of Cardiology,
Boston Children’s Hospital, Harvard Medical School,
pCAM-ICU Pediatric confusion assessment method for
Boston, MA, USA the intensive care unit
3
Pediatric Intensive Care Unit, Department of Women’s
pEEG Processed electroencephalogram
and Children’s Health, University Hospital of Padua, Padua, PICU Pediatric intensive care unit
Italy

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2014 European Journal of Pediatrics (2023) 182:2013–2026

PK Pharmacokinetic The choice of the drug also depends on the intrinsic anal-
RRT​ Renal replacement therapy gesic properties and pharmacokinetics (PK) of each drug [7].
SOS-PD Sophia Observation Withdrawal The amount of analgesics required may vary substantially
Symptoms–Pediatric Delirium Scale from patient to patient and in the same patient throughout
the disease, requiring individualized and dynamic prescrip-
tions. Additionally, the drug dose–response in pediatrics
Optimal care for critically ill pediatric patients admitted is particularly difficult to be estimated due to genotyping
to the intensive care unit (ICU) includes protection from variability and PK differences across ages; additionally, sig-
several sources of pain and stress. In the last decades, the nificant variation exists in the setting of organ dysfunction,
awareness of the need to ensure patients’ comfort has grown use of extracorporeal circuits (i.e., extracorporeal membrane
among health professionals and has been recently enhanced oxygenation (ECMO) or renal replacement therapy (RRT)),
by new insights in the field. The key aspects of the anal- and multiple drug interactions [8, 9].
gosedation management in pediatric ICU have been recently Currently, the first choice for analgesia in the PICU is
delineated in two important consensus-based documents, the mostly an opioid, with fentanyl and morphine being the most
2022 Society of Critical Care Medicine Clinical Practice frequently used. A recent European international survey que-
Guidelines on Prevention and Management of Pain, Agita- rying 215 European PICUs showed that fentanyl is the most
tion, Neuromuscular Blockade, and Delirium in Critically Ill used first-line opioid (51% of centers), followed by morphine
Pediatric Patients With Consideration of the ICU Environ- (29%), sufentanil (15%), and remifentanil (1%) [10]. Another
ment and Early Mobility [1] and the Recommendations for large survey from the USA showed that 72% of participants
analgesia and sedation in critically ill children admitted to chose an opioid as a first choice — most frequently fenta-
intensive care unit [2], from the Italian Society of Neonatal nyl [11]. The best opioid for each patient is usually chosen
and Pediatric Anesthesia and Intensive Care (SARNePI). based on the intrinsic PK profile of the drug, as well as on
With this review and point of view, we aim to summarize specific advantages and disadvantages: for example, mor-
the new insights presented in these two documents, facilitate phine adds more sedative than analgesic effects compared
their interpretation and application, and outline research pri- to fentanyl, while the latter has less hemodynamic impact
orities in the field (Table 1). [12, 13]. Remifentanil, due to its rapid metabolism and short
recovery profile, has been proposed to be used close to a
planned extubation, possibly leading to a quicker and more
How to protect patients from pain? The best predictable extubation time [14]. However, conclusive evi-
analgesic has not been established yet dence on how to identify the best opioid are lacking, and
future studies are needed to clarify this topic.
Pediatric patients in the ICU are routinely exposed to pain In neonates receiving mechanical ventilation, controver-
and discomfort. Additionally, it has been showed that sies exist on the use of a continuous infusion of opioids;
repeated painful events in neonates may impact neuronal there are currently concerns about both short-term adverse
development causing primary brain dysmaturation, with effects such as prolonged duration of mechanical ventila-
associated short- and long-term neurodevelopmental impair- tion, hypotension, and low tolerance to enteral nutrition and
ment [3, 4]. Ensuring adequate pain control is therefore long-term adverse outcomes as motor, cognitive, or behav-
considered a priority in critically ill pediatric patients [1, ioral impairment. The predisposition of preterm neonate to
2]. Pain-free patients require fewer sedative drugs, which drug accumulation should also be considered. Therefore,
have more stable hemodynamics and overall better outcome, continuous opioids infusion should be administered only at
especially when nonpharmacological interventions are in low doses and when pain and discomfort are confirmed by
place and when parental presence is allowed [5]. clinicians using validated tools [15–17]. Short-acting opi-
The predicted pain intensity based on severity of illness oids, such as fentanyl or remifentanil, are ideal agents for
and the actual measured pain assessed by validated tools neonatal endotracheal intubation, via both intravenous or
are the most important factors to guide clinicians towards intranasal route [18]. For painful procedures, propofol has
the optimal drug and dose selection. However, as a recent recently been proposed as a single agent for its dual GABA
survey confirmed, there is variability between neonatologists agonist and NMDA antagonist effects; however, results of
and pediatric intensivists on different treatment approaches, a recent multicenter study (NEOPROP-2) highlight the dif-
choice of drug (i.e., single or multiple agents), and adminis- ficulty of achieving effective analgosedation without the
tration strategy (i.e., continuous vs as needed). To overcome occurrence of sustained hypotension [19].
this variability in care, the authors suggest closer collabora- Paracetamol and non-steroidal anti-inflammatory drugs
tion between these two groups of health professionals and (NSAIDs) can contribute to the treatment of severe acute
the development of shared guidelines [6]. pain as adjuvants, although their opioid-sparing effect in the

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European Journal of Pediatrics (2023) 182:2013–2026 2015

Table 1  Most important research and knowledge gapsidentified by recent guidelines

RESEARCH PRIORITIES IN CHILDREN

The best analgesic
To identify the criteria for selecting the most appropriate analgesic for each pediatric
critically ill patient.
Light sedation strategies
To compare clonidine versus dexmedetomidine for light sedation in pediatric critically
ill patients.
patient
PICU patients and approaches for
achieving optimal analgosedation in these patients.
Analgesia and sedation monitoring
To identify the most important barriers for the systematic application of alidated cales for the
analgosedation monitoring and develop quality-improvement initiatives to address them.
NMBAs
To identify the appropriate monitoring tool to optimize sedation in PICU patients
reated with neuromuscular blockers.
Neurodevelopmental disability

the monitoring of analgosedation and IWS in PICU.

Sleep-wake cycle

Delirium
To identify the best pharmacologic treatments for severe cases of delirium.

Weaning strategy
To compare different weaning modalities for opioids and benzodiazepines, but also for
dexmedetomidine, propofol, and ketamine.
Early mobilization
To identify the most important barriers for the implementation of an early mobilization
protocol and to develop quality-improvement initiatives to address them.
Parental participation
To identify effective interventions to involve parents in the PICU care and promote
well-being.

RESEARCH PRIORITIES IN NEONATES

Nonpharmacologic interventions
To standardize methodological approaches to nonpharmacological interventions,

Oral sucrose administration

To investigate the long-term effects of repetitive and prolonged oral sucrose use on
neurobehavioral development.
Pharmacologic interventions
To develop physiologically based pharmacokinetic models to predict neonatal drug
metabolism and optimize doses.
Pharmacologic interventions for prolonged stress

infusion of ketamine and dexmedetomidine in neonates.

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2016 European Journal of Pediatrics (2023) 182:2013–2026

setting of acute postoperative pain is still discussed [20, 21]. there have not been definitive causal evidence in humans, the
Among interventional analgesic approaches, neuraxial tech- FDA warning significantly influenced daily clinical practice
niques and continuous peripheral blocks have been indicated on administration of sedatives in NICUs and PICUs. Current
for the treatment of localized pain, such as in the setting of guidelines strongly suggest reducing any benzodiazepine use,
burn injuries or regional ischemia [1, 22]. especially in the form of continuous infusion, and carefully
considering dosages and duration of treatment [1, 2].
Alpha-agonists (i.e., dexmedetomidine and clonidine)
Light sedation should be preferred. are indicated as an effective alternative choice, particularly
But is it true for every setting? What are in post-surgical patients and in less complex cases [1, 37].
the available strategies to achieve it? To date, data on the use of dexmedetomidine as a first-line
strategy in the PICU are limited [38–42]. Its use has been
The last updated guidelines [1, 2] and previous consen- described as a postoperative sedation strategy in critically
sus statements [23, 24] outline a novel pharmacological ill pediatric patients undergoing cardiac surgery [39], as
approach directed towards a light sedation and predomi- a single continuous sedative infusion in patients undergo-
nantly analgesia-based treatment (Tables 2 and 3). A large ing noninvasive ventilation [40, 41], and as an adjuvant for
pediatric study evaluating the post-discharge functional out- concomitant sedation with opioids and benzodiazepines
come in critically ill children treated with this approach ver- [42]. Moreover, preclinical data showed that, in neonates,
sus the usual care showed that functional outcome was com- dexmedetomidine might have a neuroprotective role on the
parable between the two groups, with no long-term harms immature brain, especially after hypoxic–ischemic injury
found in the light sedation group [25]. One of the expected [43]. While the results are promising in terms of efficacy
outcomes from this novel approach is also the reduction and safety, many aspects on dexmedetomidine remain to
in number and severity of sedation-related adverse events be investigated, especially regarding its use for a long-term
[26–28]. In fact, deeply sedated and often immobilized sedation in the PICU and the development of tolerance and
patients are at higher risk of physical and mental impair- withdrawal syndrome [44].
ment, which often delay and compromise the full recovery Intravenous infusion of clonidine may be considered as an
[29, 30]. However, we should also recognize that changes effective and cheaper alternative to dexmedetomidine [45,
of the usual practice in favor to a new approach represent 46], and two recent observational studies have provided
a challenge on many levels. For example, there will be a reassurance on its hemodynamic profile [47, 48]. However,
need to change routine habits, mindset, and organization, to date, no study has directly compared dexmedetomidine
which include the establishment of a more effective nurse- versus clonidine infusions in pediatric critically ill patients,
to-patient ratio and the introduction of parental presence so the relative benefits of an alpha agonist compared to the
where not already in place. Additionally, sedation manage- other are still to be defined.
ment in some specific clinical settings, such as in patients
with sepsis or supported with extracorporeal treatments, still
constitutes a gray area of knowledge, and data supporting What is the definition of difficult‑to‑sedate
light sedation in these conditions are currently missing [31]. patient? How can we select the best
To achieve the desired level of sedation, the choice of the adjuvant in this setting?
optimal sedative is crucial, along with its dose titration. The
previously mentioned European survey showed that 71% of To date, there is no clear definition of difficult-to-sedate
centers use a midazolam infusion as a first choice, in combi- patient in the PICU [49]. Is difficult sedation a problem
nation with opioids [10]. However, recent evidences showed related to the maximum dosages reached to obtain a desired
benzodiazepine to be associated with increased incidence of sedation level or rather an issue related to the number of
delirium and potential negative impact on the brain develop- drugs? Patients can manifest a difficult-to-sedate status in
ment [32, 33]. Anand et al. documented early brain injuries the presence of risk factors including cognitive developmen-
including intraventricular hemorrhage and periventricular tal delay, severity of illness, and invasiveness of treatments
leukomalacia in preterm neonates who received a mida- [49]. Similarly, to a standardized definition, diagnostic and
zolam infusion [34]. Duerden et al. showed a correlation treatment approaches are missing, and currently, they vary
between the midazolam dose and reduction in hippocampal among centers [50, 51].
volume [35]. In 2017, in light of new evidence of sedative- The difficult-to-sedate patient often requires multiple adju-
associated neurotoxicity in animal models, the US Food and vants to be added to its sedation plan. Dexmedetomidine,
Drugs Administration (FDA) issued a drug safety warning for ketamine, and propofol have been described among possible
prolonged or multiple use of anesthetics and sedative medica- choices [42, 52, 53]. A recent multicenter prospective study
tions in children younger than 3 years of age [36]. Although not yet included in the guidelines showed that, among 163

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Table 2  Analgesic and sedative pharmacological characteristics

Analgesic Therapeutic indications EV bolus dose Continuous infusion Onset Offset

Fentanyl Postoperative pain, moderate Neonate 0.5–2 mcg/Kg Neonate 0.3–3 mcg/Kg/h 1–2 min 30–60 min
to severe pain, elective Children 1–5 mcg/Kg Children 1–5 mcg/Kg/h Slower in neonate
neonatal endotracheal
intubation
Morphine Postoperative pain, moderate Neonate 10–30 mcg/Kg Neonate 5–20 mcg/Kg/h 5–15 min 360–480 min
to severe pain, increase Children 100 mcg/Kg Children 5–30 mcg/Kg/h Slower in neonate
ventilator synchrony,
sedation, decrease of
cerebral metabolic demand
Remifentanil Postoperative pain, moderate Neonate 0.1–1 mcg/Kg Neonate 0.25 mcg/Kg/min 1 min Rapid, does not
to severe pain, pre- Children 1–3 mcg/Kg Children depend on dose
extubation time, elective (over 1 min) 0.2–2 mcg/Kg/min or duration
neonatal endotracheal
intubation
Sufentanil Postoperative pain, moderate Children 0.5–5 mcg/Kg Children 0.05–4 mcg/Kg/h Rapid 50 min
to severe pain
Paracetamol Opioid-sparing effects Neonate 7.5–10 mg/Kg 5–10 min 4–6 h
for severe pain, like Children 15 mg/Kg
postoperative pain, (over 15 min)
neonatal intestinal
surgery, effective in mild
to moderate pain
Non-steroidal Postoperative pain, opioid- Children 5–10 min 4–6 h
anti-inflammatory sparing effects, effective Ketorolac 0.15–0.5 mg/Kg
drugs (NSAIDs) in mild to moderate pain every 6 h (max 48 h)
Ketoprofen 1 mg/Kg every
8h
Sedative Therapeutic Indications EV bolus dose Continuous Infusion Onset Offset

Dexmedetomidine Pain relief, opioid-sparing, Neonate Neonate 0.1–0.5 mcg/Kg/h 15–20 min 120–180 min
anxiolysis, sedation Children 1mcg/Kg Children 0.1–1.4 mcg/Kg/h
without impact on (> 10 min)
respiratory drive, sedation
in noninvasive/invasive
mechanical ventilation
Clonidine Pain relief, opioid-sparing, Neonate Neonate 30–60 min
anxiolysis, sedation, Children 3mcg/Kg Children 0.3–2 mcg/Kg/h
noninvasive/invasive
mechanical ventilation
Midazolam Sedation during mechanical Neonate 50–200 mcg/Kg Neonate 1–2 min 30–60 min
ventilation Children 50–200 mcg/Kg 0.25–1 mcg/Kg/min
(over 3 min) Children
0.5–3.3 mcg/Kg/min
Ketamine Sedation and analgesia for Neonate 0.25–1 mg/Kg Neonate 5–10 mcg/Kg/min 1–2 min 15–30 min
invasive procedure, sedation Children 1–4 mg/Kg Children 5–50 mcg/Kg/min
for prolonged stress
Propofol Hypnotic Sedation for Neonate 0.7–2.5 mg/Kg Children 0.3–4 mg/Kg/h 1 min 13 min
procedure, sedation for Children 1.5–4 mg/Kg
prolonged stress

patients who received a continuous infusion of dexmedetomi- a favorable short-term safety profile, with however no data
dine in the PICU, 42% used it as an adjuvant for opioid/ben- on long-term outcomes [52, 54, 55]. Currently, few data are
zodiazepine sparing and 8% for failure of other conventional available on the use of ketamine in newborns and its short-
drugs; the study also showed that dexmedetomidine may be and long-term adverse effects [56]. Some older classes of
considered both effective in ensuring comfort and safe in sedative agents, like barbiturates, have also been proposed
terms of short-term outcomes [42]. Similarly, retrospective as adjuvants, especially to avoid the use of propofol and its
and prospective data on ketamine showed good efficacy and risk of possible related infusion syndrome [1].

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2018 European Journal of Pediatrics (2023) 182:2013–2026

Table 3  Analgesic and sedative side effects and potential long-term outcome
Analgesic Side effects Potential long-term outcome

Fentanyl Respiratory depression, chest wall rigidity Cerebellar volume growth reduction, sensory, motor and
cognitive impairments
Morphine Respiratory depression, hypotension, retention urinary, No detrimental long-term neurological effects have been
gastrointestinal dysmotility, spasm of the ductus biliary confirmed
Remifentanil Apnea, chest wall rigidity, rapid tachyphylaxis
Sufentanil Apnea, chest wall rigidity, hypotension, bradycardia
Paracetamol Rare, risk of liver injury
Non-steroidal anti- Renal injury, gastrointestinal injury, bleeding events
inflammatory drugs
(NSAIDs)
Sedative Side effects Potential long-term outcome

Dexmedetomidine Hypotension, bradycardia Neuroprotection

hypertension, hypo/hyperglycemia,
atrio-ventricular block
Clonidine Hypotension, bradycardia,
hypertensive rebound
Midazolam Hypoventilation, bradycardia, hypotonia. Hypotension Outcomes of intraventricular hemorrhage,
and decreased mean cerebral blood flow from bolus periventricular leukomalacia. Hippocampal growth
reduction, lower neurocognitive scores
Ketamine Sialorrhea, delirium, hallucinations, hypertonia Neurotoxic to developing brain in absence of noxious
stimuli
Propofol Hypotension, metabolic acidosis, hyperkalemia,
rhabdomyolysis,
bradycardia, apnea

Analgesia and sedation monitoring: New diagnostic methods to monitor pain

validated tools are available and should be and sedation: how technology contributes
used to guide our sedation plan to pain and sedation assessment

The regular assessment of pain, sedation, delirium, and iat- The assessment of pain is challenging due to its multidimen-
rogenic withdrawal syndrome (IWS) through specific and sional and subjective nature. Pain, discomfort, and stress
validated tools is universally recognized as a pivotal compo- promote a change in the cardiac autonomic control, such as
nent to guide clinicians during the analgosedative treatment an increase in the heart rate, and peripheral vasoconstriction,
[23]. Much has been done in recent years to disseminate and pupillary dilatation, and an increase in galvanic skin response.
implement the monitoring of analgosedative scores and to In parallel, an increase in the sympathetic activity levels and
optimize the adherence for their use in daily clinical prac- the corresponding decrease in the parasympathetic ones
tice. Table 4 summarizes some of the most commonly used mediate the response to stimuli. In recent years, research has
pain and sedation assessment tools [57–71]. Two multicenter focused on investigating new strategies to analyze indicators
surveys involving 161 PICUs around the world [72] and of nociception and to identify new parameters to measure pain
215 European PICUs [10], respectively, showed that pain severity. Heart rate variability has shown good potential and is
and sedation are regularly monitored in a high percentage expressed as Analgesia Nociception Index (ANI) for patients
of PICUs, with a rate ranging from 81 to 91% [10, 72] for over 2 years of age and Newborn Infant Parasympathetic Eval-
pain and 84 to 87% [10, 72] for sedation assessment. Still, uation Index (NIPE) for newborns and infants up to 2 years of
a lot has still to be done in terms of monitoring of sedation- age. However, few pediatric studies have been conducted, and
related complications, as IWS and delirium: indeed, only further validation is needed [74]. Skin conductance may be
44% to 58% of the PICUs responding to the survey assess used; however, it may be altered by many confounders (i.e.,
delirium [72, 73] and only 62% monitor signs of IWS. Clari- sweating, electrode dislocation, wire stretching) [75]. Pupil-
fying the reasons that hinder the use of assessment tools lometry may be also be considered in children, particularly in
despite proven benefits can contribute to the development nonverbal populations; however, given the lack of trials, no
of quality improvement initiatives. high-level evidence can be determined yet [76]. The use of

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European Journal of Pediatrics (2023) 182:2013–2026 2019

Table 4  Pain and sedation assessment tools for neonatal and pediatric patients

Pain scales
Name/acronym Age range Setting use Indicators
Neonatal Infant Pain Scale/NIPS Preterm and term neonate Acute procedural pain Behavioral signs, physiological
[57] signs
Premature Infant Pain Profile/PIPP/ Preterm and term neonate Acute procedural pain Behavioral signs, physiological
PIPP-Revised [58, 59] signs
Douleur Aiguë Nouveau-né/DAN Preterm and term neonate Acute procedural pain Behavioral signs
[60]
Cry, requires oxygen, increased Infants with gestational age of Postoperative pain Behavioral signs, physiological
vital signs, expression, sleepless- 32–36 weeks signs
ness/CRIES [61]
Échelle Douleur Inconfort Preterm and term neonate Prolonged pain Behavioral signs
Nouveau-Né/EDIN [62]
Face, Legs, Activity, Cry, Consol- 2 months to 7 years of age Acute, postoperative pain Behavioral signs, consolability
ability/FLACC [63]
Wong–Baker Faces Pain Rating 3–18 years of age Acute procedural pain, postopera- Self-reporting pain assessment
Scale [64] tive pain
Numeric rating scale/NRS [65] >=7 years of age Acute procedural pain, postopera- Self-reporting pain assessment
tive pain
Pain and sedation scales
Name/acronym Age range Setting use Indicators
Neonatal Pain Agitation and Seda- 0–100 days Acute and prolonged pain, sedation Behavioral signs, physiological
tion Scale/N-PASS [66] signs
COMFORTneo [67] Preterm and term neonate Prolonged pain, sedation Behavioral signs
COMFORT [68] Preterm, term infants until 18 years Prolonged pain, sedation Behavioral signs, physiological
of age signs
COMFORT Behavior Scale/COM- Preterm, term infants until 18 years Acute and prolonged pain, sedation Behavioral signs
FORT-B [69] of age
Sedation scales
Name/acronym Age range Setting use Indicators
State Behavioral Scale/SBS [70] 1 month to 6 years of age Sedation, ventilated patient Behavioral signs
Richmond Agitation–Sedation 2 months to 21 years of age Sedation, ventilated patient Behavioral signs
Scale/RASS [71]

processed electroencephalogram (pEEG) monitoring, such as discomfort due to muscle blockade or being over-sedated
bispectral index (BIS) or S­ edline®, are recommended in adults [1, 2, 80, 81]. Unfortunately, current validated comfort and
to monitor the level of sedation, particularly in the operatory sedation scales are not applicable, and the assessment of
room; unfortunately, pEEG is not validated in patients with vital signs only is likely to be insufficient given their depend-
less than 1 year, and pediatric literature is currently scarce [77, ence on hemodynamics and medications. To date, guidelines
78]. To date, no clear evidence on the clinical impact of these do not recommend the use of specific tools in these patients,
technologies is available, and their use in daily clinical practice other than a processed electroencephalography [2]. Further
remains limited. Therefore, no definitive recommendations can studies on this population are highly needed to help optimize
be made at present. their sedation status and outcomes.

Patients treated with neuromuscular The difficult‑to‑be‑understood patients:

blocking agents: still a closed box children with intellectual disability. How can
we evaluate their sedation level?
Patients treated with neuromuscular blockades are at high
risk of adverse outcomes [79]. The existing literature is lack- Although multiple efforts have been made to develop and
ing in terms of offering guidance on how to assess seda- validate pain and sedation monitoring tools for children, it is
tion levels in patients receiving neuromuscular blocking essential to note that some patients still remain orphan of dedi-
agents (NMBAs), which are at risk of either not expressing cated tools or evidence-based guidance for the analgosedation

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2020 European Journal of Pediatrics (2023) 182:2013–2026

monitoring, such as patients with neurocognitive delay. In fact, of the analgosedation plan in response to changing patient
there is currently no standard validated tool for the sedation needs and therapeutic programs (Fig. 1).
monitoring in this population which would include a caregiver
assessment on patient’s state or a weighted response based on
the cognitive status, and further research effort should focus The sleep–wake cycle is important. How
on this topic. Similarly, while for delirium, the Cornell Assess- to preserve it in the PICU?
ment of Pediatric Delirium (CAPD), thanks to its anchor
points, may be applied to patients with neurodevelopmental The quality of sleep in critically ill children has been recently
delay [82], a dedicated validated tool is missing for the assess- investigated through dedicated research [86, 87]. Sleep is the
ment of IWS in these patients. predominant state for neonates and should be protected as a
basic tenet for healthy brain development. Sleep characteris-
tics change over time according to the neurological matura-
Analgosedation protocols: are they useful? tion process. The sleep cycle is completely disrupted in PICU
Likely a rhetorical question — protocols patients [88]. Benzodiazepines and opioids do not promote
are important and should be considered restorative sleep pattern; rather, they are among the major
a priority risk factors for sleep disorders [86]. Currently, only dexme-
detomidine has been shown to preserve the normal sleep
The benefit of the use of an analgosedation protocol has architecture [89]. Bundles of care acting on environmental
been an object of debate. A large study comparing protocol- and behavioral elements have been reported to promote sleep,
ized analgosedation versus usual care found no difference in but there is no trial comparing the different strategies [11].
outcome measures such as duration of mechanical ventila- How to promote physiological sleep in the child admitted
tion, PICU length of stay, and sedation-related complica- to PICU often remains a challenging “real-life” issue, and
tions [13]. However, other before-and-after studies evaluat- research would focus on this topic to help find more answers.
ing the effect of the implementation of an analgosedation
protocol showed an improvement in comparable outcome
measures [83–85]. These mixed results may be related to Delirium occurs frequently in the PICU.
different study settings, to the existence of different usual Which are the preventive strategies
care practice and/or protocols, or the adoption of different available? Is dexmedetomidine a possible
outcome measures. Outcome measures should also take into prevention or treatment strategy?
consideration patients’ comfort, quality of life, and func-
tional status. The introduction of a sedation protocol has Another topic of growing interest is the diagnosis and man-
been shown to reduce delays in providing patient comfort, agement of delirium, an acute brain dysfunction that occurs
to increase the likelihood to systematically monitor signs commonly in PICU [90]. The stress generated by the severity
of IWS and delirium, and to promote interprofessional col- of the disease can unmask patients with cognitive limited
laborations [5, 73]. Of course, protocols could not be static reserves, such as younger patients; this risk factor, along with
but should rather be dynamic and emphasize the flexibility the nonfamiliarity of the environment, the use of drugs such

Fig. 1  Diagram illustrating a

step-by-step strategy for achiev-
ing optimal analgosedation in a
critically ill patient

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European Journal of Pediatrics (2023) 182:2013–2026 2021

as benzodiazepines, the lack of a sleep–wake cycle, and the methadone over other weaning strategies [106]. Overall,
presence of uncontrolled pain can synergistically take part in studies on the discontinuation modalities of opioid and ben-
the etiological process for the development of this condition zodiazepines and discontinuation of other sedatives such as
[91–93]. The most frequent type of delirium in pediatric age dexmedetomidine, propofol, or ketamine and studies on fur-
is the hypoactive form, which is difficult to recognize [91]. ther weaning strategies are highly needed to better define the
In last years, efforts have been made to raise the awareness optimal IWS prevention strategies.
on PICU delirium and disseminate the validated tools for
its monitoring [1, 2, 23], as the pediatric confusion assess-
ment method for the intensive care unit (pCAM-ICU) [94], Immobility causes harm, which needs to be
the CAPD [95], and the Sophia Observation Withdrawal prevented. Is this always possible?
Symptoms–Pediatric Delirium Scale (SOS-PD) [96]. The
key concept for the prevention of delirium includes a regular Prolonged over-sedation and immobility have been proven to
assessment throughout the PICU stay, as well as the reduction cause muscle wasting and weakness, which are listed among
of modifiable risk factors that include restraints, immobility, the most important PICU complications impacting func-
disturbed sleep, and benzodiazepines use [90]. The off-label tional outcome [107]. Rehabilitation and mobilization are
use of antipsychotics should be reserved for cases refractory essential in the healing process and should be applied early
to nonpharmacological treatments [97]. Dexmedetomidine and frequently according to the recent recommendations
reduce the point prevalence and shorten the time to delir- [108–110]. However, among the 215 PICUs that responded
ium resolution in adults [98, 99]; however, to date, only one to the aforementioned survey, only 77 (36%) had a mobiliza-
observational study showed a reduction in the CAPD score tion protocol implemented [73]. The development of an early
and prevalence with dexmedetomidine in pediatrics [42]. mobilization culture may be hindered by physicians’ concern
Overall, high-evidence trials for the treatment of delirium in about the risk of device removal and patient instability, as
children are missing. well as by the excessive workloads, limited space, poorly
educated and trained staff, and limited resources.
The same concept may be true for nonpharmacologi-
Iatrogenic withdrawal syndrome: a frequent cal treatments, which, despite general recognition of their
complication that should be avoided. Is usefulness, continue to play a minor role in PICU patients’
there a suggested opioid/benzodiazepine management [111]. In infants, non-nutritive sucking, swad-
weaning strategy? Is that necessary dling, skin-to-skin contact, and facilitated tucking may
only for opioids and benzodiazepines? attenuate physiologic and behavioral response to mild pain-
ful procedures [112]; similarly, oral sucrose (0.1 mL at 24%
Prolonged analgosedation and high cumulative doses can lead solution) reduces behavioral responses to minor acute pain
to the development of dependence, tolerance, and IWS [100]. [113]. However, given the potential adverse effects of high
IWS has been well documented for opioids and benzodiaz- cumulative doses of glucose especially in preterm infants,
epines [101], but it has also been described for dexmedeto- attention must be paid to the daily number of administrations
midine [102] and — by limited case reports — for other seda- (suggested < 10 times) [113]. Overall, strategies to facilitate
tives such as propofol [103]; conversely, IWS has not been the implementation of these interventions and standardized
described for ketamine. Overall, IWS has been associated approaches should be further investigated.
with prolonged PICU stay and worse clinical outcome [101].
The most important current recommendation for pre-
venting IWS is a gradual weaning of opioids and benzo- Communication with parents is crucial. How
diazepines, especially for patient who received ≥ 5 days of can we improve it?
infusion [2, 7, 104]. Indications on the modality of weaning
have been only suggested for opioids and benzodiazepines Parents’ involvement is essential to keep pediatric patients
but never been validated; it is therefore still subject to physi- comfortable in an unfamiliar environment and to reduce
cian’s preference and therefore high-practice variability [3, parents’ anxiety and stress [1]. Unfortunately, too often cli-
105]. Another proposed strategy to facilitate the weaning nicians do not involve adequately family in the care of the
of opioids and benzodiazepines is the switch to enterally child. This may due to practice variation, but also to intrin-
administered longer half-life molecules, like methadone sic staffing and space limitations. Parents are therefore too
and lorazepam. For methadone, wide variability in dose often just observers in the process of care, feeling scared,
conversion from morphine and fentanyl has been reported, and useless [114]. Improving parents’ comfort is possible
along with variability in methadone wean duration. How- through ensuring appropriate and comprehensible informa-
ever, no evidence to date has been identified to recommend tion and heeding their opinion [115]. Similarly, empowering

13
2022 European Journal of Pediatrics (2023) 182:2013–2026

parents’ participation is possible by encouraging them to 5. Balit CR, LaRosa JM, Ong JSM, Kudchadkar SR (2021) Seda-
interact and provide pleasant touch to their child, as well as tion protocols in the pediatric intensive care unit: fact or fiction?
Transl Pediatr 10:2814–2824. https://d​ oi.o​ rg/1​ 0.2​ 1037/t​ p-2​ 0-3​ 28
playing and talking with them [116]. In addition, especially 6. Borenstein-Levin L, Hochwald O, Ben-Ari J, Dinur G, Littner
during long-term analgesia and sedation, it is necessary to Y, Eytan D, Kugelman A, Halberthal M (2022) Same baby, dif-
describe the risk of developing IWS and delirium to avoid a ferent care: variations in practice between neonatologists and
lack of parental alliance when these serious and unexpected pediatric intensivists. Eur J Pediatr 181:1669–1677. https://​doi.​
org/​10.​1007/​s00431-​022-​04372-4
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important aspects of care. Perinatol 46:673–692. https://​doi.​org/​10.​1016/j.​clp.​2019.​08.​004
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10. Daverio M, von Borell F, Ramelet A-S, Sperotto F, Pokorna
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Authors’ contributions All authors contributed to the narrative review gesia, and neuromuscular blockade: an assessment of practices
conception and design. The first draft of the manuscript was written by from 2009 to 2016 in a national sample of 66,443 pediatric patients
the first author (MCM), and all authors commented on previous versions cared for in the ICU. Pediatr Crit Care Med 21:e599–e609. https://​
of the manuscript. All authors read and approved the final manuscript. doi.​org/​10.​1097/​PCC.​00000​00000​002351
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patients. Eur J Pediatr 170:477–481. https://​doi.​org/​10.​1007/​
Consent for publication N/A. s00431-​010-​1312-6
15. McPherson C, Haslam M, Pineda R, Rogers C, Neil JJ, Inder TE
Competing interests The authors declare no competing interests. (2015) Brain injury and development in preterm infants exposed
to fentanyl. Ann Pharmacother 49:1291–1297. https://d​ oi.o​ rg/1​ 0.​
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