ICU care bundles, including the ICU Liberation ABCDEF bundle, provide a new paradigm for liberating critically ill patients from mechanical ventilation (MV) and ICU environment, while optimizing post-ICU outcomes (
1 , ). Despite growing appreciation of this bundled patient care approach, PICU sedation and analgesia practices remain highly variable ( 2 ). Although valuable, previous pain/agitation/delirium guidelines ( 3–5 6 , ) have provided only limited guidance in the areas of prevention and management strategies for these conditions. 7
The American College of Critical Care Medicine (ACCM) supports the development of new and revised guidelines and clinical practice variables for the critical care practitioner. This document is the culmination of efforts solicited by the ACCM to review and develop guidelines for the identification, assessment, monitoring, and/or management of pain, sedation, neuromuscular blockade, withdrawal, and delirium in critically ill infants and children. The recommendations and good practice statements approved by the taskforce are presented in
and are summarized in a “flowchart” format in Table 1 for ease of use. The Pain, Agitation, Neuromuscular Blockade, and Delirium in critically ill pediatric patients with consideration of the PICU Environment and Early Mobility (PANDEM) guideline is intended to apply to all infants and children admitted to the medical/surgical/cardiac PICU and not routinely to those infants admitted to a neonatal ICU (NICU). The reader is additionally referred to the Figure 1 Supplemental Digital Content (SDC, ) which provides further detail informing recommendations, ancillary pharmacology detail, and discussions of questions for which available data were inadequate to make formal recommendations. https://links.lww.com/PCC/B920
Table 1. -
Summary of Recommendations
Strength of Recommendation
Quality of Evidence
We suggest that, in critically ill pediatric patients 6 yr old and older who are capable of communicating, pain assessment via self-report be routinely performed using the Visual Analog Scale, Numeric Rating Scale, Oucher Scale, or Wong-Baker Faces pain scale. Conditional
We recommend the use of either the Faces, Legs, Activity, Cry, and Consolability or COMFORT-B scales for assessing pain in non-communicative critically ill pediatric patients. Strong
We recommend the use of observational pain assessment tools rather than vital signs alone for assessment of postoperative pain in critically ill pediatric patients. Strong
We suggest the use of observational pain assessment tools rather than vital signs alone for assessment of procedure-related pain in critically ill pediatric patients. Conditional
We recommend that IV opioids be used as the primary analgesic for treating moderate to severe pain in critically ill pediatric patients. Strong
We recommend the addition of an adjunct NSAID (IV or oral) to improve early postoperative analgesia in critically ill pediatric patients. Strong
We suggest the addition of an adjunct NSAID agent (IV or oral) to decrease opioid requirements in the immediate postoperative period in critically ill pediatric patients. Conditional
We suggest the addition of adjunct acetaminophen (IV or oral) to improve early postoperative analgesia in critically ill pediatric patients. Conditional
We suggest the addition of adjunct acetaminophen (IV or oral) to decrease opioid requirements in the immediate postoperative period in critically ill pediatric patients. Conditional
We recommend that music therapy be offered to augment analgesia in critically ill postoperative pediatric patients. Strong
recommend that nonnutritive sucking with oral sucrose be offered to neonates and young infants prior to performing invasive procedures. Strong
We recommend the use of the COMFORT-B Scale or the State Behavioral Scale, to assess level of sedation in mechanically ventilated pediatric patients. Strong
We suggest the use of the Richmond Agitation-Sedation Scale to assess level of sedation in mechanically ventilated pediatric patients. Conditional
We suggest that all pediatric patients requiring MV are assigned a target depth of sedation using a validated sedation assessment tool at least once daily. Conditional
We suggest the use of protocolized sedation in all critically ill pediatric patients requiring sedation and/or analgesia during MV. Conditional
5) The addition of daily sedation interruption to sedation protocolization
is not suggested due to lack of improvement in outcomes. Conditional
6) During the periextubation period when sedation is typically lightened,
we suggest the following bundle strategies to decrease risk of inadvertent device removal: a) Assign a target depth of sedation at increasing frequency to adapt to changes inpatient clinical status and communicate strategies to reach titration goal. b) Consider a sedation weaning protocol. c) Consider unit standards for securement of endotracheal tubes and safety plan. d) Restrict nursing workload to facilitate frequent patient monitoring, decrease sedation requirements, and risk of self-harm. Conditional
We suggest the use of alpha 2-agonists as the primary sedative class in critically ill pediatric patients requiring MV. Conditional
We recommend that dexmedetomidine be considered as a primary agent for sedation in critically ill pediatric post-operative cardiac surgical patients with expected early extubation. Strong
We suggest the use of dexmedetomidine for sedation in critically ill pediatric postoperative cardiac surgical patients to decrease the risk of tachyarrhythmias. Conditional
We suggest that continuous propofol sedation at doses less than 4 mg/kg/hr (67 µg/kg/min) and administered for less than 48 hr may be a safe sedation alternative to minimize the risk of propofol-related infusion syndrome development. Conditional
11) Short term (< 48 hr) continuous propofol sedation may be a useful adjunct during the periextubation period to facilitate weaning of other analgosedative agents prior to extubation.
We suggest consideration of adjunct sedation with ketamine in patients who are not otherwise at an optimal sedation depth. Conditional
13) During the periextubation period when sedation is typically lightened,
we suggest the following bundle strategies to decrease risk of inadvertent device removal: 12) Assign a target depth of sedation at increasing frequency to adapt to changes inpatient clinical status and communicate strategies to reach titration goal. c) Consider a sedation weaning protocol. e) Consider unit standards for securement of endotracheal tubes and safety plan. d) Restrict nursing workload to facilitate frequent patient monitoring, decrease sedation requirements, and risk of self-harm. Conditional
We suggest that train-of-four monitoring be used in concert with clinical assessment to determine depth of neuromuscular blockade. Conditional
We suggest using the lowest dose of NMBAs required to achieve desired clinical effects and manage undesired breakthrough movement. Conditional
3) Electroencephalogram-based monitoring may be a useful adjunct for assessment of sedation depth in critically ill pediatric patients receiving NMBAs.
We suggest that sedation and analgesia should be adequate to prevent awareness prior to and throughout NMBA use. Conditional
We recommend routine use of passive eyelid closure and eye lubrication for the prevention of corneal abrasions in critically ill pediatric patients receiving NMBAs. Strong
recommend use of the preschool and pediatric Confusion Assessment Methods for the ICU or the Cornell Assessment for Pediatric Delirium as the most valid and reliable delirium monitoring tools in critically ill pediatric patients. Strong
We recommend routine screening for ICU delirium using a validated tool in critically ill pediatric patients upon admission through ICU discharge or transfer. Strong
3) Given low patient risk, and possible patient benefit to reduce the incidence and/or decrease duration or severity of delirium
we suggest the following non-pharmacologic strategies: optimization of sleep hygiene, use of interdisciplinary rounds, family engagement on rounds, and family involvement with direct-patient care. Conditional
We suggest performing EM, when feasible, to reduce the development of delirium. Conditional
We recommend minimizing benzodiazepine-based sedation when feasible in critically ill pediatric patients to decrease incidence and/or duration or severity of delirium. Strong
We suggest strategies to minimize overall sedation exposure whenever feasible to reduce coma and the incidence and/or severity of delirium in critically ill children. Conditional
We do not suggest routine use of haloperidol or atypical antipsychotics for the prevention of or decrease in duration of delirium in critically ill pediatric patients. Conditional
We suggest that in critically ill pediatric patients with refractory delirium, haloperidol or atypical antipsychotics be considered for the management of severe delirium manifestations, with consideration of possible adverse drug effects. Conditional
We recommend a baseline electrocardiogram followed by routine electrolyte and QTc interval monitoring for patients receiving haloperidol or atypical antipsychotics. Strong
We recommend use of either the Withdrawal Assessment Tool-1or Sophia Observation Scale for the assessment of IWS due to opioid or benzodiazepine withdrawal in critically ill pediatric patients. Strong
We suggest routine IWS screening after a shorter duration (3–5 d) when higher opioid or benzodiazepine doses are used. Conditional
3) Until a validated screening tool is developed, monitoring for IWS from alpha
2-agonists should be performed using a combination of associated symptoms (unexplained hypertension or tachycardia) with adjunct use of a validated benzodiazepine or opioid screening tool. Good practice
We suggest that opioid related IWS be treated with opioid replacement therapy to attenuate symptoms, irrespective of preceding dose and /or duration or opioid exposure. Conditional
5) Benzodiazepine-related IWS should be treated with benzodiazepine replacement therapy to attenuate symptoms, irrespective of preceding dose and/or duration of benzodiazepine exposure.
2-agonist–related IWS should be treated with IV and/or or enteral alpha 2-agonist replacement therapy to attenuate symptoms, irrespective of preceding dose and/or duration of alpha 2-agonist exposure. Good practice
We suggest use of a standardized protocol for sedation/analgesia weaning to decrease duration of sedation taper and attenuate emergence of IWS. Conditional
We suggest facilitation of parental or caregiver presence in the PICU during routine care and interventional procedures to a) provide comfort to the child, b) decrease parental levels of stress and anxiety and c) increase level of satisfaction of care. Conditional
We suggest offering patients the use of noise reducing devices such as ear plugs or headphones to reduce the impact of non-modifiable ambient noise ( conditional, low-level evidence). Conditional
We suggest that PICU teams make environmental and/or behavioral changes to reduce excessive noise and therefore improve sleep hygiene and comfort, in critically ill pediatric patients. Conditional
We suggest performing EM to minimize the effects of immobility in critically ill pediatric patients. Conditional
We suggest the use of a standardized EM protocol that outlines readiness criteria, contraindications, developmentally appropriate mobility activities and goals, and safety thresholds guided by the multidisciplinary team and family decision-making. Conditional
COMFORT-B = COMFORT Behavior, EM = early mobility, IWS = iatrogenic withdrawal syndrome, MV = mechanical ventilation, NMBA = neuromuscular blocking agent, NSAID = nonsteroidal anti-inflammatory drug.
Schematic summary of the key Pain, Agitation, Neuromuscular Blockade, and Delirium in critically ill pediatric patients with consideration of the PICU Environment and Early Mobility (PANDEM) recommendations and representation of the interplay between sedative and analgesic choice on unintended but related outcomes. BRAIN MAPS = Bring oxygen, Remove/Reduce deliriogenic drugs, patient Atmosphere, Immobilization, New organ dysfunction, Metabolic disturbances, Awake, Pain, Sedation, CAPD = Cornell Assessment of Pediatric Delirium, COMFORT-B = COMFORT-Behavior, EEG = electroencephalogram, ETT = endotracheal tube, FLACC = Faces, Legs, Activity, Cry, and Consolability, IWS = iatrogenic withdrawal syndrome, MV = mechanical ventilation, NMBA = neuromuscular blocking agent, NSAID = nonsteroidal anti-inflammatory drug, pCAM-ICU = pediatric Confusion Assessment Method for the ICU, PRIS = propofol-related infusion syndrome, psCAM-ICU = preschool Confusion Assessment Method for the ICU, RASS = Richmond Agitation-Sedation Scale, SBS = State Behavioral Scale, SOS = Sophia Observation Scale, TOF = train-of-four, WAT-I = Withdrawal Assessment Tool-1.
The pediatric guideline taskforce was formed in 2009 consisting of multidisciplinary experts in the comprehensive clinical care of critically ill pediatric patients, with specific attention to seven domains of critical care including pain, sedation/agitation, iatrogenic withdrawal, neuromuscular blockade, delirium, PICU environment (family and sleep hygiene), and early mobility (EM). The pediatric taskforce leadership team was composed of the cochairs, subgroup leaders, methodologist(s), librarian(s), and SCCM staff.
Subgroups created actionable Population, Intervention, Comparison, and Outcome (PICO) (
) questions and nonactionable or descriptive questions that are clinically relevant for care of critically ill pediatric patients. MeSH terms (medical subheadings) were chosen, and a hospital-based medical librarian performed an initial literature search restricted to a period from 1990 to 2018, querying electronic databases including PubMed and the Cochrane Library. An updated search was completed by a SCCM-appointed medical information specialist, focusing on the period from January 2012 to January 2020 for systematic reviews and from January 2015 to January 2020 for primary studies. Searches were restricted to studies published in English. Search strategies were conducted in consultation with the taskforce in order to review literature based on the actionable and descriptive questions. A core search pertaining to critically ill children was created with separate searches layered on each topic (e.g., delirium, neuromuscular blockade, sedation). Controlled vocabulary was incorporated (e.g., “ICUs, Pediatric,” “Critical Illness,” “Ventilators,” “Mechanical”) along with keywords (e.g., “PICU,” “critically ill,” “intubation”) in addition to a sensitive pediatric filter to identify records specific to this population. All study types (primary reports and systematic reviews) were included within the searches. A detailed search strategy including terms is available in 8 Appendix 1 (SDC Section I‚ ). Relevant studies were also identified from reference sections of identified studies, review articles, and systematic reviews as well as taskforce members’ individual recollections if they were not identified in the literature searches. Studies published after the concluding date of the literature search were considered for inclusion if they were deemed to be of sufficient significance to either alter the strength of evidence or provide a recommendation for an otherwise unanswered question due to insufficient or contradictory evidence. https://links.lww.com/PCC/B920 Literature Review
The taskforce literature review incorporated the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology (
). The GRADE approach included determination of the following domains: risk of bias, precision, consistency, directness of the evidence, risk of publication bias, presence of a dose-effect relationship, magnitude of effect, and assessment of the effect of plausible residual confounding or bias. Primary and secondary reviewers were assigned literature for each PICO question. The primary reviewer performed the initial literature review which began with title/abstract screening to identify full-text manuscripts to be reviewed. From the list of full-text manuscripts, the primary reviewer then created data spreadsheets consisting of extracted study data, assignment of GRADE ratings, and additional discussion points. These spreadsheets were reviewed and confirmed by a secondary reviewer after which both reviewers together developed recommendations to present to their specific subgroup for discussion and consideration. If conflicts or differences of opinion occurred, further discussion ensued at the taskforce level. If resolution was unable to be achieved, final arbitration was performed by the cochairs and methodologist when appropriate. Subgroups reviewed recommendations and rationales with quality of evidence descriptions including “high-level evidence” (i.e., randomized controlled trial [RCT] or large prospective cohort study/further research “unlikely” to change confidence estimate of effect), “moderate-level evidence” (i.e., prospective cohort studies/further research “likely” to have some impact on confidence estimate), “low-level evidence” (i.e., retrospective cohort studies/future research “very likely” to have important impact on confidence estimate), and “very low-level evidence” (i.e., case reports/estimate of effect is uncertain). Clinical care proposals were denoted as “strong” using “we recommend” or “conditional” with “we suggest.” When evidence quality was “very-low” or “absent” yet consensus by the taskforce was that a clinical practice was beneficial and had no or very low risk, statements were presented as “good practice.” No recommendations were made based exclusively on adult or NICU literature, although relevant themes identified from these resources were referenced when appropriate. Topics/questions for which available data were inadequate to make recommendations were identified and explicitly noted as areas for future research. 9–12 Recommendations/Voting Procedures
The full taskforce reviewed all subgroup PICO questions, recommendations, and rationales. Suggested amendments and dissenting opinions were sent back to the pertinent subgroup for consideration. Following revision, if required, voting on the final recommendations by the full taskforce proceeded using Survey Monkey (
). Individuals who had an overt or potential conflict of interest abstained from relevant votes. Per SCCM standard operating procedure (SOP) voting policies and procedures, recommendation acceptance required both of 1) greater than 70% participation by the taskforce and 2) approval by greater than 80% of voters. All dissenting votes were required to be accompanied by a rationale for the dissent. No recommendations were excluded from the guideline due to dissent or disagreement by a majority of the taskforce. http://www.surveymonkey.com RESULTS
This guideline includes 44 recommendations (14 strong and 30 conditional) and five good practice statements (
Table 1). Figure 1 summarizes the findings of this guideline and provides a graphic representation of the interplay between the seven main domains of care addressed. Information addressing descriptive questions is presented in the preambles for each major domain below. Additional detail may also be found in the SDC ( ), referenced by clicking on the relevant inserted hyperlinks. https://links.lww.com/PCC/B920 Analgesia
The majority of critically ill pediatric patients experience pain during their PICU course (
). Risk factors for experiencing pain in children are varied. Patient-specific factors include developmental and cognitive stage, communication capabilities, mental status, and underlying comorbidities/organ dysfunction, whereas PICU-specific factors include the presence of MV, need for invasive procedures and devices, medication exposures, sleep disruption, and mobility status ( 13–15 ). Analgesia is provided to relieve pain, control agitation, prevent accidental removal of devices (i.e., endotracheal tubes [ETTs], thoracostomy tubes, and intravascular devices), improve patient-ventilator synchrony, optimize hemodynamics, decrease oxygen consumption, and modulate the stress response. Providing adequate analgesia is important as persistent pain has adverse physiologic and psychologic consequences including immunosuppression, delayed wound healing, impaired sleep, hyperalgesia ( 16–20 ) as well as feelings of helplessness, parental separation, and posttraumatic stress disorder ( 21–26 18 , 27 , ). 28
Accurate assessment of pediatric pain is critical, but significant barriers to this exist including patient-related factors such as developmental variation, premorbid neurocognitive delay, or illness-related neurobehavioral sequelae (
). Caregivers may lack training or time to perform assessments, possess intrinsic bias, have inadequate analgesic availability, or lack understanding of the adverse effects (AEs) of both pain and analgesic agents ( 29 22 , ). Management of pain in critically ill children involves primarily the use of opioids, either alone or in combination with nonopioid agents ( 29–32 33 , ) ( 34 SDC Tables 1 and 2, ). Nonpharmacologic therapies complement pharmacologic interventions by decreasing environmental stressors, facilitating relaxation and distraction, and facilitating sleep ( https://links.lww.com/PCC/B920 35 , ). The reader is referred to 36 SDC Section B ( ) for more detailed discussion of pain assessment tools, analgesic choices and pharmacology, and nonpharmacologic adjuncts. https://links.lww.com/PCC/B920 Assessment of Pain.
Question: What pain assessment tools should be used in critically ill pediatric patients? (
SDC Section B1, ). https://links.lww.com/PCC/B920
1) Self-report scales:
a) “We suggest” that, in critically ill pediatric patients 6 years old and older who are capable of communicating, pain assessment via self-report be routinely performed using the Visual Analog Scale (VAS), Numeric Rating Scale, Oucher Scale, or Wong-Baker Faces pain scale (
conditional, low-level evidence). 2) Behavioral/Observational scales:
a) “We recommend” the use of either the Faces, Legs, Activity, Cry, and Consolability (FLACC) or COMFORT-Behavior (COMFORT-B) scales for assessing pain in noncommunicative critically ill pediatric patients (
strong, moderate-level evidence). b) “We recommend” the use of observational pain assessment tools rather than vital signs alone for assessment of postoperative pain in critically ill pediatric patients (
strong, moderate-level evidence). c) “We suggest” the use of observational pain assessment tools rather than vital signs alone for assessment of procedure-related pain in critically ill pediatric patients (
conditional, low-level evidence) in critically ill pediatric patients.
Rationale: Pain assessment tools can be divided into self-report and observational rating scales. In children able to express themselves, self-report represents the “gold standard” for pain assessment (
20 , 22 , ). The most commonly used pediatric self-report tools are the VAS ( 34–39 ), Numerical Rating Scale ( 40 ), Oucher scale ( 41 ), and the Wong Baker Faces pain scale ( 42 ) (SDC Table 1, 43 ). Although all of these tools have been broadly validated in pediatric populations as young as 3 years old, self-report tools are felt to be most reliable in patients who are at least 6 years old ( https://links.lww.com/PCC/B920 17 , 19 , 22 , 37–39 , ). 44
Observational pain scoring systems incorporate behavioral ± physiologic variables to assess pain in patients unable to self-report pain (
). The FLACC, COMFORT, and COMFORT-B scales have been the most widely applied observational tools in critically ill children (SDC Table 2, 45–48 ) ( https://links.lww.com/PCC/B920 30 , 37 , 38 , 49 , ). The FLACC score evaluates five behavioral components and is highly valid and reliable in assessing postoperative pain in critically ill children ( 50 51 , ). The revised FLACC was developed and validated for use in nonverbal and cognitively impaired children ( 52 ). The COMFORT score was initially developed and validated to assess general distress in critically ill pediatric patients but has additionally been shown valid for differentiating pain from other sources of distress ( 53 54 , ). The modified COMFORT-B scale removed the vital sign elements of the COMFORT scale due to concerns regarding their reliability for the assessment of pain and distress during critical illness ( 55 55 , ). 56
Although consensus regarding the optimum method of assessing pain in nonverbal children remains elusive, investigators increasingly advocate for scoring systems incorporating a combination of behavioral and physiologic variables (
27 , 28 , 48 , 57 , ). No pain or sedation tools have been validated for use in critically ill pediatric patients receiving neuromuscular blocking agents (NMBAs). Consequently, despite reliability limitations, changes in vital signs in these patients may indicate acute pain and should be addressed ( 58 59 , ). 60 Pharmacologic Management of Pain.
Question: What class of analgesic is superior for treating pain in critically ill pediatric patients? (
SDC Section B2, ) https://links.lww.com/PCC/B920
Answer: “We recommend” that IV opioids be used as the primary analgesic for treating moderate to severe pain in critically ill pediatric patients (
strong, moderate-level evidence).
Rationale: Opioids remain the mainstay of therapy for management of acute surgical and medical pain in the critically ill pediatric patient, including pain associated with MV (
33 , ) ( 34 SDC Table 3, ). There are no studies comparing analgesic classes across the spectrum of pediatric critical illness. However, multiple practice survey and intra-analgesic class comparative studies do describe IV opioids as the primary analgesic class used across the spectrum of critically ill pediatric patients ( https://links.lww.com/PCC/B920 3 , 5 , 33 , 61 , ). A variety of IV opioids have been used in this setting including fentanyl, morphine, hydromorphone, and remifentanil ( 62 ). Due to lack of active metabolites, fentanyl may be preferred in the setting of renal dysfunction. Morphine and hydromorphone should be used cautiously in patients with renal dysfunction as active metabolites may accumulate and prolong duration of effects ( 63–69 70 , ). 71
Question: Should nonopioid analgesic medications be added to opioid-based regimens to improve postoperative pain control?
1) “We recommend” the addition of an adjunct nonsteroidal anti-inflammatory drug (NSAID) (IV or oral) to “improve early postoperative analgesia” in critically ill pediatric patients (
strong, moderate-level evidence). 2) “We suggest” the addition of an adjunct NSAID agent to “decrease opioid requirements” in the immediate postoperative period in critically ill pediatric patients (IV or oral) (
conditional, low-level evidence). 3) “We suggest” the addition of adjunct acetaminophen (IV or oral) to “improve early postoperative analgesia” in critically ill pediatric patients (
conditional, low-level evidence). 4) “We suggest” the addition of adjunct acetaminophen (IV or oral) to “decrease opioid requirements” in the immediate postoperative period in critically ill pediatric patients (
conditional, low-level evidence).
Rationale: Nonopioid adjuncts such as NSAIDs and acetaminophen are commonly used to provide analgesia in critically ill children (
SDC Table 4, ). Multiple studies including systematic reviews have observed that the use of adjunct NSAIDs (primarily ibuprofen and ketorolac) in postoperative cardiac ( https://links.lww.com/PCC/B920 ) and noncardiac surgical PICU patients ( 72 73 , ) is associated with improved pain scores and decrease in opioid requirements ( 74 SDC Table 5, ). However, their use has not been associated with reductions in opioid-related AEs ( https://links.lww.com/PCC/B920 ). Short-term NSAID use was not associated with increased postoperative bleeding, significant changes in renal function, or development of gastritis ( 72–76 77 , ). No trials were found evaluating the use of NSAIDs for adjunct analgesia in nonsurgical PICU patients. 78
In critically ill pediatric patients following major noncardiac abdominal or thoracic surgery (
) and idiopathic scoliosis repair ( 79 ), addition of IV acetaminophen was associated with reduced morphine use (SDC Table 5, 80 ). Two systematic reviews evaluated the impact of adjunct oral or IV acetaminophen on opioid requirements in nonICU patients, and 16 of 26 studies found an opioid sparing effect of acetaminophen, regardless of administration route ( https://links.lww.com/PCC/B920 77 , ). Adjunct acetaminophen at least preserves and in some studies improves pain scores ( 78 77 , ). Reductions in opioid-related AEs have not been observed with the addition of acetaminophen ( 78 ). 79 Nonpharmacologic Management of Pain.
Question: Does the use of music therapy decrease postoperative pain in critically ill pediatric patients? (
SDC Section B3, ). https://links.lww.com/PCC/B920
Answer: “We recommend” that music therapy be offered to augment analgesia for critically ill postoperative pediatric patients (
strong, moderate-level evidence).
Rationale: Benefits of music therapy include reductions in pain, anxiety, medication requirements, and inflammatory markers in addition to improvements in sleep quality and ability to mobilize (
16 , ). Following general surgical procedures, music therapy is associated with decreased postoperative pain, anxiety and distress, and decreased opioid requirements ( 81–86 35 , ). In critically ill neonates, music therapy is also associated with decreased pain during heel prick procedures ( 87 88 , ). Prerecorded music played to pediatric cardiac surgical patients perioperatively was associated with reduced surgical stress response, decreased agitation in the immediate postextubation period, and improved pain scores with lower analgesic requirements compared with controls not exposed to music ( 89 ). A systematic review of music therapy via prerecorded music in postoperative patients, including critically ill children, reported significant reductions in pain scores, anxiety scores, and opioid use in the immediate postoperative period ( 90 35 , ). 87
Question: Does the addition of nonnutritive sucking augment analgesia during procedures in critically ill pediatric patients?
Answer: “We recommend” that nonnutritive sucking with oral sucrose be offered to neonates and infants (< 12 mo old) prior to performing invasive procedures (
strong, high-level evidence).
Rationale: Nonnutritive sucking with oral sucrose and expressed breast milk have been well studied in the NICU population (
83 , 86 , ). The use of oral sucrose has had the biggest effect in some studies, but combinations of all nonnutritive suck techniques with swaddling have shown additive effects on pain reduction during heel stick procedures with no AEs reported among infants ( 91–98 ). The use of oral sucrose solution alone is beneficial during painful procedures without evidence of blunting of the analgesic response with repeated use ( 99–101 102 , ). Compared with no pretreatment, the use of sublingual sucrose was prospectively associated with blunting of the discomfort associated with orogastric tube insertion ( 103 ). Since a systematic review of sweet tasting solutions in older children (1–16 yr) reported conflicting evidence in the preschool aged population and no benefit in the school aged population on pain scores, this recommendation is limited to the infant (< 12 mo old) population ( 104 ). 105 Sedation
The majority of patients requiring MV will receive analgesia and/or sedation to reduce anxiety, maintain ventilator-patient synchrony, and facilitate necessary care procedures (
). Finding a balance between over- and undersedation is paramount. Undersedation may lead to inadvertent device removal ( 106–108 109 , ), or increased anxiety which may lead to residual psychologic and behavioral sequelae post PICU discharge ( 110 106 , ). Oversedation is associated with prolonged MV, increased risk of inadvertent tracheal extubation failure ( 111 6 , ), delirium ( 112 ), prolonged PICU length of stay (LOS) ( 113 ), and the development of tolerance and iatrogenic withdrawal ( 106 ). The ideal depth of sedation has significant intra- and interpatient variability based on the disease process being treated, stage of disease evolution, invasiveness of therapy required, and developmental abilities to cooperate with treatments and therapies. Multiple sedative options including benzodiazepines, alpha 114–116 2-agonists, propofol, and ketamine are available to the pediatric critical provider. Although specific recommendations regarding these agents are found below, the reader is also referred to the SDC, Section C ( ) for additional discussion, especially about agents for which evidence was inadequate to make recommendations. https://links.lww.com/PCC/B920 Assessment of Sedation.
Question: What sedation assessment scales are valid for assessing depth of sedation in critically ill pediatric patients? (
SDC Section C1, ). https://links.lww.com/PCC/B920
1) “We recommend” the use the Comfort-B Scale or the State Behavioral Scale (SBS) to assess level of sedation in mechanically ventilated pediatric patients (
strong, moderate-level evidence). 2) “We suggest” the use of the Richmond Agitation-Sedation Scale (RASS) to assess level of sedation in mechanically ventilated pediatric patients (
conditional, low-level evidence).
Rationale: The Comfort-B Scale (
56 , 117 , ) and the SBS ( 118 119 , ) have both been validated in several PICU settings to assess the level of sedation in mechanically ventilated pediatric patients. Both scales reliably differentiate adequate from over- or undersedation in patients not receiving NMBAs. Their psychometric validity has been supported in a meta-analysis of 13 sedation scales ( 120 ). Although the RASS has only been validated in a single trial, it is extensively used in pediatric critical care as it forms the basis for determining the appropriateness of delirium screening with the pediatric Confusion Assessment Method for the ICU (pCAM-ICU) and Cornell Assessment of Pediatric Delirium (CAPD) delirium screening tools ( 121 ). Characteristics of each sedation assessment scale are described in detail in 122 SDC Table 6 ( ). https://links.lww.com/PCC/B920 Protocolized Sedation.
Question: Should critically ill pediatric patients requiring MV routinely be assigned a target depth of sedation? (
SDC Section C2, ). https://links.lww.com/PCC/B920
Answer: “We suggest” that all pediatric patients requiring MV be assigned a target depth of sedation using a validated sedation assessment tool at least once daily (
conditional, low-level evidence).
Rationale: Two studies assessing the impact of goal-directed sedation concluded that targeting a sedation score may minimize time the patient is agitated (
123 , ). Although a larger multicenter RCT found no difference in rates of inadequate sedation or analgesia, the intervention group in this study was exposed to interventions beyond just targeting sedation depth ( 124 ). 69
Question: Is protocolized sedation superior to nonprotocolized sedation in critically ill pediatric patients?
Answer: “We suggest” the use of protocolized sedation in all critically ill pediatric patients requiring sedation and/or analgesia during MV (
conditional, low-level evidence).
Rationale: Ten studies (1 RCT and 9 before-and-after retrospective reviews) evaluated the impact of protocolized sedation/analgesia on various outcomes including length of MV, PICU LOS, exposure to benzodiazepines and opioids, development of iatrogenic withdrawal syndrome (IWS), and other adverse events (
SDC Table 7, ) ( https://links.lww.com/PCC/B920 69 , ). In the only RCT, outcomes were compared between PICUs randomized to provide protocolized care (targeted sedation score, arousal assessment, extubation readiness testing, sedation adjustment every 8 hr, sedation weaning, and prescribed sedative/analgesic agent choice and titration) versus units providing nonprotocolized care ( 123–131 ). Although there were no between-group differences in inadequate analgesia or sedation, duration of MV, PICU LOS, opioid or benzodiazepine exposure, or IWS, post hoc analysis revealed a higher percentage of study days in which patients were awake and calm while intubated in the intervention group. Several before-and-after studies also reported associated improvements in one or more of these outcomes, particularly benzodiazepine exposure, with no studies reporting worse outcomes with protocolization. 69 Daily Sedation Interruptions or Drug Holidays.
Question: Should routine daily sedation interruption (DSI) be implemented in critically ill pediatric patients requiring MV and receiving continuous sedative infusions? (
SDC Section C3, ) https://links.lww.com/PCC/B920
Answer: The addition of DSI to sedation protocolization is “not suggested” due to lack of improvement in outcomes (
conditional, low-level evidence).
Rationale: A small single-center RCT reported reductions in sedative infusion rates, duration of MV, and PICU LOS with DSI but is limited in that there were multiple exclusions to DSI, and many eligible patients were excluded due to safety concerns (
). A larger multicenter RCT found that protocolized sedation with DSI compared with protocolized sedation alone was not associated with improvements in outcomes, whereas mortality was actually increased in the DSI arm ( 132 ). Additionally, one third of patients failed a safety screen preceding the conduct of a DSI which may have biased safety results. A large multicenter RCT comparing outcomes in mechanically ventilated patients receiving either protocolized or nonprotocolized sedation included DSI in the protocolized arm when sedation was deeper than the predefined sedation score ( 133 ). Since only 4% of patients required DSI for over sedation, DSI may not be necessary when goal-directed sedation is already being used. There is insufficient literature to enable comment on the role of DSI in patients who are not receiving protocolized sedation ( 69 SDC Table 8, ). https://links.lww.com/PCC/B920 Periextubation Strategies.
Question: Are there interventions that are associated with or decrease the risk of unintended device removal in mechanically ventilated pediatric patients? (
SDC Section C4, ) https://links.lww.com/PCC/B920
Answer: During the periextubation period when sedation is typically lightened, “we suggest” the following bundle strategies to decrease risk of inadvertent device removal (
conditional, low-level evidence):
1) Assign a target depth of sedation at increasing frequency to adapt to changes in patient clinical status and communicate strategies to reach titration goal.
2) Consider a sedation weaning protocol.
3) Consider unit standard for the securement of ETTs and safety plan.
4) Restrict nursing workload to facilitate frequent patient monitoring, decrease sedation requirements, and risk of self-harm.
Rationale: Studies addressing level of sedation and impact on risks of unplanned events or unintended device removal in mechanically ventilated pediatric patients are heterogeneous in design (
SDC Table 9, ). Institution of DSI or targeted sedation protocols in two separate RCTs demonstrated similar device-related adverse event rates in each group ( https://links.lww.com/PCC/B920 69 , 133 , ). In six quality improvement studies, rates of unintended device removal consistently decreased after implementation of bundle components (standardized ETT securement, standardized ETT suctioning, identification of high risk patients, targeted sedation assessments, sedation standardization and/or protocolization, and sedation weaning protocol during ventilator weaning) ( 134 ). 135–140 Pharmacologic provision of sedation.
Multiple sedative options including benzodiazepines, alpha
2-agonists, propofol, and ketamine are available to the pediatric critical provider ( SDC Section C5, ). Although specific recommendations regarding these agents are found below, the reader is also referred to the SDC, Section III ( https://links.lww.com/PCC/B920 ) for additional discussion, especially about agents for which evidence was inadequate to make recommendations. A summary of the relevant pharmacology of these agents is found in https://links.lww.com/PCC/B920 SDC Section C5, Table 10 ( ). https://links.lww.com/PCC/B920
Question: What is the preferred sedative class for sedation of critically ill mechanically ventilated pediatric patients?
Answer: “We suggest” the use of alpha
2-agonists as the primary sedative class in critically ill pediatric patients requiring MV ( conditional, low-level evidence).
Rationale: Five RCTs found that sedation efficacy with an alpha
2-agonist was similar to sedation with a benzodiazepine ( ). Several small RCTs have demonstrated that sedation with alpha 141–146 2-agonists versus midazolam in mechanically ventilated PICU patients was associated with a reduction in opioid requirements following congenital cardiac surgery, scoliosis surgery, burn injury, and in general PICU patients ( 141 , 144 , 145 , ). One study of clonidine use in neonates also demonstrated a reduction in opioid administration ( 147 ). One prospective cohort ( 144 ) and two RCTs ( 148 146 , ) further reported significant reductions in opioid and benzodiazepine exposure with the addition of scheduled enteral clonidine. Although mean heart rates were lower in alpha 149 2-agonist–treated patients ( 141 , ), bradycardia or hypotension requiring intervention was not increased compared with benzodiazepine sedation. Caution is advised when using alpha 145 2-agonists administered as continuous infusions in patients with underlying bradycardia or in patients concurrently receiving heart rate lowering medications ( SDC Table 11, ). Benzodiazepine use has been independently associated with an increased incidence of delirium development ( https://links.lww.com/PCC/B920 ) (please see 150–152 Delirium section for further discussion).
Question: Should an alpha
2-agonist when compared with a benzodiazepine be used for sedation in mechanically ventilated pediatric patients after cardiac surgery?
1) “We recommend” that dexmedetomidine be considered as a primary agent for sedation in critically ill pediatric postoperative cardiac surgical patients with expected early extubation (
strong, moderate-level evidence). 2) “We suggest” the use of dexmedetomidine for sedation in critically ill pediatric postoperative cardiac surgical patients to decrease the risk of tachyarrhythmias (
conditional, low-level evidence).
Rationale: Several studies including two systematic reviews (
153 , ), and two RCTs ( 154 143 , ), compared postcardiac surgical outcomes in pediatric patients receiving sedation with dexmedetomidine versus other regimens, primarily benzodiazepines with or without opioids. Two studies reported reduced duration of MV with dexmedetomidine sedation ( 155 153 , ), and one showed no difference ( 155 ). Both systematic reviews reported aggregate reductions in ICU LOS and tachyarrhythmias, including junctional ectopic tachycardia. No increases in clinically relevant adverse hemodynamic effects were reported. Three retrospective studies reported reduced midazolam use with dexmedetomidine sedation ( 143 147 , 156 , ) and three similar studies reported reduced opioid use ( 157 147 , 156 , ). One retrospective study reported that dexmedetomidine use was associated with reduced odds of developing acute kidney injury following cardiac surgery ( 158 ) ( 159 SDC Table 12, ). https://links.lww.com/PCC/B920 Propofol.
Question: Is propofol sedation safe in mechanically ventilated children and what is its role?
1) “We suggest” that continuous propofol sedation at doses less than 4 mg/kg/hr (67 µg/kg/min) and administered for less than 48 hours may be a safe sedation alternative to minimize the risk of propofol-related infusion syndrome (PRIS) development (
conditional, low-level evidence). 2) Short term (< 48 hr) continuous propofol sedation may be a useful adjunct during the periextubation period to facilitate weaning of other analgosedative agents prior to extubation (
Rationale: Initially described in 1992, PRIS continues to concern pediatric critical care practitioners (
). Although PRIS developed in 84% of a small cohort receiving propofol at doses exceeding both 4 mg/kg/hr (67 µg/kg/min) and a 48 hour duration ( 160 ), in five larger prospective observational series, no cases were reported when high doses (4 mg/kg/hr) and long durations (48 hr) were avoided ( 161 160 , ). Suggested monitoring/screening for PRIS during continuous propofol sedation includes continuous electrocardiogram (ECG) and intermittent measurement of lactic acid, triglycerides, creatine kinase, serum creatinine, and liver function studies ( 162–165 ). Several small studies have reported successful early extubation using propofol sedation in children following cardiac surgical procedures ( 166 ), patients at high risk for extubation failure ( 163 ), or burn injury patients ( 167 ) ( 168 SDC Table 13, ). https://links.lww.com/PCC/B920 Ketamine.
Question: What is the role of ketamine in the sedation of critically ill pediatric patients?”
Answer: “We suggest” consideration of adjunct sedation with ketamine in patients who are not otherwise at their predefined target sedation depth (
conditional, low-level evidence).
Rationale: Ketamine appears to be a safe and effective alternative in patients who are not adequately sedated with other agents (alpha
2-agonists, benzodiazepines, opioids, barbiturates, or propofol for example) or as part of a drug rotation strategy ( 169 , ). Although ketamine use has been largely avoided in patients with traumatic brain injury (TBI) due to reports of increases in cerebrospinal fluid pressure ( 170 ), a more recent prospective trial in 30 mechanically ventilated children with TBI reported that intracranial pressure (ICP) decreased when adjunct ketamine was used for premedication prior to ETT suctioning as well as when administered for refractory intracranial hypertension, during which a small increase in cerebral perfusion pressure also resulted ( 171–173 ). Premedication with ketamine may be considered in 1) critically ill children with raised ICP prior to performing noxious or potentially distressing procedures and 2) in critically ill children with raised ICP refractory to other medical management including deep sedation and analgesia. 174 Neuromuscular Blockade
Historically, NMBAs have been used for the optimization of patient-ventilator synchrony, reduction of oxygen consumption, and prevention of unintended extubation or device removal (
). More recently, the reliance on NMBAs has declined due to concern regarding associated complications such as residual neuropathy or weakness, and the increasingly recognized benefits of lighter sedation strategies, when appropriate, for neurocognitive recovery ( 163 ). However, disease states/conditions that necessitate neuromuscular blockade remain. Relevant pharmacology and dosing of different NMBAs is found in 164 SDC Section D1, Table 14 ( ), including considerations and/or cautions in the setting of renal and/or hepatic dysfunction/failure. Potentiation or antagonism of neuromuscular blockade can also occur in the setting of concomitant drug therapy or certain medical disease states or conditions ( https://links.lww.com/PCC/B920 SDC Table 15, ) ( https://links.lww.com/PCC/B920 ). The reader is additionally referred to 175–177 SDC Sections D2-D4, ( ) for discussion of important NMBA-related questions for which specific recommendations were unable to be made. https://links.lww.com/PCC/B920 NMB Monitoring.
Question: How should depth of neuromuscular blockade be monitored in critically ill pediatric patients receiving continuous NMBA infusions?
1) “We suggest” that train-of-four (TOF) monitoring be used in concert with clinical assessment to determine depth of neuromuscular blockade (
conditional, low-level evidence). 2) “We suggest” using the lowest dose of NMBA required to achieve desired clinical effects and manage undesired breakthrough movement (
conditional, low-level of evidence).
Rationale: The most commonly described method to assess the level of neuromuscular blockade in critically ill patients receiving NMBAs is by peripheral nerve stimulation or TOF monitoring. One to three twitches typically indicates adequate neuromuscular blockade (
). Surveys have reported that TOF monitoring along with clinical assessment is used in 63–84% of critically ill patients receiving NMBAs ( 178 179 , ), whereas a small percentage of patients are assessed using only TOF ( 180 ). Although studies in adults have reported lower cumulative NMBA exposure, titration is guided by TOF use rather than clinical variables alone ( 181 ), corroborating data do not exist in PICU patients. However, since studies do a positive correlation between duration of exposure or cumulative NMBA dose and prolonged recovery time ( 182 ), it appears prudent to use the lowest continuous infusion dose and closely monitor blockade depth. TOF reliability may be adversely affected by a number of patient factors including diaphoresis, extremes of skin temperature, peripheral edema, and young age (i.e., use of large electrodes may directly initiate muscle twitch rather than nerve stimulation) ( 178 178 , ). Benefits of intermittent NMBA discontinuation to assess the level of sedation/analgesia, facilitate neurologic examination, and reduce the total NMBA drug exposure have been reported and may be valuable, especially when TOF use is unavailable ( 183 178 , 184 , ). 185
Question: Should measures of brain activity (raw or processed electroencephalogram) be used rather than validated clinical scoring tools to assess depth of sedation in critically ill pediatric patients receiving NMBAs?
Answer: Electroencephalogram-based monitoring may be a useful adjunct for assessment of sedation depth in critically ill pediatric patients receiving NMBAs (
Rationale: Assessment of sedation depth during NMBAs use is especially challenging. Formal measurement of brain activity has been proposed as an adjunct modality to complement clinical assessment or be used when clinical assessments are not available. Three electroencephalogram-based monitors have been evaluated in critically ill children including the bispectral index (BIS) (
), the SNAP II monitor ( 186 187 , ), and the amplified electroencephalogram (aEEG), although aEEG has been almost exclusively used to predict outcomes following neonatal hypoxemic ischemic injury ( 188 ). BIS monitoring has been the most widely evaluated tool in critically ill children ( 189–191 ). The only reported correlations between BIS and clinical sedation scores have been with the COMFORT scale, in which BIS was found to better discriminate under—from adequate versus over—from adequate sedation ( 186 ). Due to significant interpatient variability at similar sedation depths, BIS monitoring is better suited for trending sedation depth rather than targeting a specific score ( 192–194 195 , ). Limitations of BIS monitoring include sensitivity to some psychoactive agents (ketamine) ( 196 ) and physiologic alterations (hypothermia, hypoglycemia, or cerebral ischemia) leading to erroneous measurements ( 197–199 ). The SNAP II monitor has been inadequately studied to date in the PICU environment. 200–202 Sedation and Analgesia During NMBA Management.
Question: What is the necessary sedation and analgesia management of pediatric patients requiring NMBAs?
Answer: “We suggest” that sedation and analgesia should be adequate to prevent awareness prior to and throughout NMBA use (
conditional, low-level evidence).
Rationale: Adequacy of analgesia and sedation cannot be assessed clinically during NMBA use. Historically, variables such as changes in vital signs, diaphoresis, and lacrimation were relied upon to suggest agitation or pain, although these lack specificity compared with objective patient assessment (
56 , ). The “fifth National Audit Project of the Royal College of Anesthetists and the Association of Anesthetists of Great Britain and Ireland” reported that the occurrence rate of accidental awareness during general anesthesia in children is one in 135 by direct questioning and one in 51,500 when determined by spontaneous reporting, with the majority of spontaneously reported cases involving unrelieved pain ( 203 ). The “Pediatric Acute Lung Injury Consensus Conference” stated that patients with pediatric acute respiratory distress syndrome should receive minimal yet effective targeted sedation and that NMBAs should be used only when sedation alone is inadequate to achieve effective MV ( 204 ). To date, no pediatric studies have specifically addressed optimal sedation and analgesia in the setting of NMBA use. Despite this, the standard of practice for sedation and analgesia provision during NMBAs administration should be to avoid the potential of awareness. The use of NMBAs in a “bolus only” manner or scheduled discontinuation of continuous infusions, if clinically appropriate, permits both assessment of the adequacy of analgesia and sedation and the need for ongoing paralysis. 205 NMBA AEs and Complications.
Question: Should passive eyelid closure and lubrication versus other eye protection measures be used to prevent corneal abrasions in critically ill children receiving NMBAs? (
SDC Section D5, ). https://links.lww.com/PCC/B920
Answer: “We recommend” routine use of passive eyelid closure and eye lubrication for the prevention of corneal abrasions in critically ill pediatric patients receiving NMBAs (
strong, moderate-level evidence).
Rationale: NMBAs inhibit skeletal muscle contraction including muscles associated with eye closure and the blink reflex. As a result, significant eye drying, corneal ulceration, infection, and/or loss of visual acuity may occur (
). The reported occurrence rate of corneal abrasions in critically ill patients is 8–60%, although pediatric data are less robust ( 206 ). Standard protective interventions include passive eyelid closure, eye taping, and ophthalmic lubricating ointment. Only one study has specifically evaluated the use of an intervention beyond this to prevent corneal abrasions in children. In a multicenter, RCT of 237 children receiving NMBAs for greater than 36 hours, addition of a moisture chamber to standard care with routine eye lid closure and lubricating ointment did not decrease the occurrence rate of corneal abrasions ( 206–210 ). The investigators concluded that the use of routine eye closure and ophthalmic lubricating ointment was as effective as a moisture chamber with eye lubrication. As corneal abrasions in children receiving NMBAs may develop quickly (within 48 hr), vigilant use of eye lubrication and passive eyelid closure should be a priority. 206 ICU Delirium
Delirium is a syndrome of acute brain dysfunction that is characterized by the core features of inattention and unawareness, with possible secondary changes in cognition. Delirium often manifests with a fluctuating course of severity and occurs as a direct physiologic consequence of a medical or surgical condition. The associated acute neurocognitive disturbances will be an alteration from an established or evolving baseline neurocognitive disorder (
). Pathophysiologically, aberrant neurotransmission from an imbalance of stimulatory versus inhibitory neurotransmitter and receptor actions leads to the observed presenting symptoms and behaviors ( 211 ). Delirium is categorized based on psychomotor symptoms including hypoactivity, hyperactivity, or a mixture of the two. 212–214
Delirium is categorized based on psychomotor symptoms. Patients with hypoactive delirium may appear apathetic, withdrawn from the environment, or with depressed levels of arousal (
215 , ), and rarely provoke concern despite being more likely to have poorer outcomes ( 216 215 , 217 , ). Patients with hyperactive delirium suffer from agitation, emotional lability, or disruptive behavior, although this is the least common form of ICU delirium ( 218 219 , ). Patients who demonstrate hyperactive and hypoactive behaviors are categorized as having a mixed subtype of delirium. 220
Delirium is highly prevalent (reported rates up to 80%) across the spectrum of disease states in the PICU and its development should be considered a possibility in all critically ill pediatric patients (
113 , 152 , ). Multiple studies have determined key risk factors for ICU delirium in pediatric patients. “Predisposing risk factors” for delirium include younger age, neurodevelopmental delay, poor nutritional status, and cyanotic heart disease. “Precipitating risk factors” include benzodiazepine exposure, coma and deep sedation, requirement for invasive MV, and prolonged cardiopulmonary bypass time ( 221–236 113 , 151 , 152 , 221 , 222 , 226 , 234 , ) ( 237–239 SDC Section E1, Table 16, ). Delirium in critically ill pediatric patients is associated with increases in hospital and PICU LOS, duration of MV, hospital costs, and in-hospital mortality ( https://links.lww.com/PCC/B920 113 , 151 , 221 , 222 , 224 , 234 , ). 237–240 Delirium Monitoring.
Question: Which delirium screening tools have the best validity and reliability in critically ill pediatric patients? (
SDC Section E2, ). https://links.lww.com/PCC/B920
Answer: “We recommend” use of the preschool and pCAM-ICU (ps/pCAM-ICU) or the CAPD as the most valid and reliable delirium monitoring tools in critically ill pediatric patients (
strong, high-level evidence).
Rationale: Of five pediatric-specific delirium screening tools available, three are relevant to PICU patients (
SDC Section E2b, ). The ps/pCAM-ICU are considered “point-in-time” assessments, using both observation and interactive components ( https://links.lww.com/PCC/B920 ), and maintaining the basic foundation of its highly valid and reliable precursor, the adult Confusion Assessment Method for the ICU. The pCAM-ICU was originally validated in a prospective cohort of general medical/surgical PICU patients over 5 years old and performed with a high sensitivity (83%) and specificity (99%) compared with psychiatry assessment, and high interrater reliability (kappa of 0.96) ( 241 ). The preschool CAM-ICU psCAM-ICU is an adaptation of the pCAM-ICU for purposes of meeting the language and cognitive deficits in children developmentally less than 5 years old. The psCAM-ICU was initially validated in a large prospective cohort of medical/surgical PICU patients less than 5 years old and demonstrated good sensitivity (75%) and high specificity (91%) compared with psychiatry assessment and good interrater reliability (kappa of 0.79) ( 225 ). The psCAM-ICU was subsequently validated in infants less than 6 months old and again performed with a high sensitivity (95%) and specificity (81%) ( 226 ). ( 242 SDC Table 17, ). The Cornell Assessment for Pediatric Delirium (CAPD) is an observational delirium instrument, adapted from the Pediatric Anesthesia Emergence Delirium scale, designed to improve the ability to detect all delirium subtypes ( https://links.lww.com/PCC/B920 223 , ) ( 227 SDC Table 18, ). In a mixed medical-surgical PICU population, the CAPD performed well, sensitivity (94%) and specificity (79%), compared with psychiatry assessment. Reliability or consistency of scoring between nurse assessors was high with a kappa of 0.94 ( https://links.lww.com/PCC/B920 ), although this was lower in a recent follow-up nurse assessor reliability study (kappa of 0.6) particularly in patients less than 2 years old ( 214 ). 243
Question: Should critically ill pediatric patients undergo routine delirium screening?
Answer: “We recommend” routine screening for ICU delirium using a validated tool in critically ill pediatric patients upon admission through ICU discharge or transfer (
strong, high-level evidence).
Rationale: The care of critically ill pediatric patients is complicated and requires the collaboration and effectiveness of an interdisciplinary team. Routine monitoring in the ICU incorporates multiple organ/system surveillance supporting the acute management of ongoing organ dysfunction. Therefore, the recommendation for the implementation of routine monitoring for acute brain dysfunction considers the availability of valid and efficient bedside tools and the ability to identify and modify risk factors by which an opportunity is created to reduce prevalence, morbidity, and mortality associated with delirium. With the availability of validated screening tools (see above), delirium monitoring in the PICU is feasible (
152 , 224–227 , 229 , ). We now recognize that ICU delirium is highly prevalent among critically ill children, with predominance of the hypoactive subtype which is most easily missed without routine screening. The goal of delirium monitoring is ultimately to implement patient care strategies to diminish its occurrence rate and effect on clinical outcomes such as mortality and further understand the role of acute brain dysfunction on the quality of life for pediatric survivors of critical illness. 242 Delirium Prevention and Management in the PICU.
Nonpharmacologic management of delirium
Question: Among critically ill pediatric patients, what “nonpharmacologic” strategies reduce the incidence and/or decrease duration or severity of delirium? (
SDC Section E3, ). https://links.lww.com/PCC/B920
1) Given low patient risk, and possible patient benefit to reduce the occurrence rate and/or decrease duration or severity of delirium, “we suggest” the following “nonpharmacologic strategies”: optimization of sleep hygiene, use of interdisciplinary rounds, family engagement on rounds, and family involvement with direct patient care (
conditional, low-level evidence). 2) “We suggest” performing EM, when feasible, to reduce the development of delirium (
conditional, low-level evidence) although data are insufficient to make a recommendation regarding the impact of this intervention on the duration or severity of delirium.
Rationale: Environmental impact on the prevention of delirium has yet to be studied in a robust manner in children. Despite the limited data, implementation of environmental modifications such as maintaining day/night cycles with the use of artificial light and sunlight during the day and healthy sleep conditions at night (minimizing noise, light, and stimulation) may impact the occurrence rate and severity of delirium in children (
). Interactive approaches such as cognitive stimulation and physical activity during the day may increase orientation during the day and quality sleep at night. Family presence and involvement, familiar care team members, and comforting objects from home can also help reassure and reorient patients. Studies in critically ill adults have shown decreased occurrence rate and duration of delirium with implementation of EM. A single-center prospective study indirectly supports potential effectiveness of this approach in children. Over a 22-month period, phased implementation of protocolized sedation followed by EM was associated with a near 40% reduction in delirium rates ( 244–246 ). Mitigation of delirium is often achieved by resolution of the underlying critical illness or other contributing medical conditions. Therefore, the initial steps in delirium management should focus on identification and treatment of these underlying etiologies ( 224 231 , 239 , 240 , ). Differential diagnoses should be considered using a model such as Bring oxygen, Remove/Reduce deliriogenic drugs, patient Atmosphere, Immobilization, New organ dysfunction, Metabolic disturbances, Awake, Pain, Sedation ( 247–249 SDC Table 19, ) ( https://links.lww.com/PCC/B920 ). 247 Pharmacologic management of delirium
Question: What “pharmacologic” sedation strategies reduce the incidence and/or decrease the duration or severity of delirium in critically ill pediatric patients?
1) “We recommend” minimizing benzodiazepine-based sedation when feasible in critically ill pediatric patients to decrease occurrence rate and/or duration or severity of delirium (
strong, moderate-level evidence). 2) “We suggest” strategies to minimize overall sedation exposure whenever feasible to reduce coma and the occurrence rate and/or severity of delirium in critically ill pediatric patients (
conditional, low-level evidence).
Rationale: Severe and multiple organ dysfunction or requirement of prolonged sedation for MV complicates the management and successful resolution of delirium. Due to relative nonspecificity of delirium symptoms (e.g., anxiety, agitation, or combativeness), differentiation of delirium from other causes may be challenging, and inappropriately treating delirium symptoms with sedation, for example, further exacerbates symptoms. Benzodiazepine exposure is an independent risk factor for delirium (
). Therefore, the avoidance and/or decreased use of benzodiazepine sedation is important for delirium prevention and management. In a small single-center RCT, delirium rates were significantly lower in dexmedetomidine compared with midazolam-sedated patients following scoliosis surgery ( 150–152 125 , ). Other cohort studies have demonstrated improvement of delirium severity or resolution with decreasing or discontinuation of benzodiazepines ( 141 ). Deep sedation states have also been associated with delirium ( 150–152 ). RCTs in healthy pediatric patients have reported decreased emergence delirium after general anesthesia with the use of dexmedetomidine ( 113 ) and melatonin ( 250 ), but no such studies have been completed in the PICU setting. Reducing benzodiazepine exposure by addition of or transition to dexmedetomidine sedation has decreased occurrence rate of delirium in several adult RCTs ( 251 ). 252–256
Question: Does the use of haloperidol or atypical antipsychotics reduce the occurrence rate and/or decrease the duration or severity of delirium in critically ill pediatric patients?
1) “We do not suggest” routine use of haloperidol or atypical antipsychotics for the prevention of or decrease in duration of delirium in critically ill pediatric patients (
conditional, low-level evidence). 2) “We suggest” that in critically ill pediatric patients with refractory delirium, haloperidol or atypical antipsychotics be considered for the management of severe delirium manifestations with consideration of possible adverse drug effects (
conditional, moderate-level evidence). 3) “We recommend” a baseline ECG followed by routine electrolyte and QTc interval monitoring for patients receiving haloperidol or atypical antipsychotics (
strong, moderate-level evidence).
Rationale: Antipsychotics have been used to manage delirium manifestations in the adult and pediatric populations. However, a recent multicenter RCT in adults found no reduction in delirium duration with use of haloperidol or an atypical antipsychotic (ziprasidone) (
). Although pediatric efficacy data are lacking, in refractory or severe delirium, use of atypical antipsychotics may improve delirium symptoms and facilitate weaning of sedation and MV ( 257 258 , ). The global or long-term effects of this strategy are not known. Consequently, routine use of antipsychotics to prevent delirium in critically ill pediatric patients is not suggested although their use may be carefully considered for symptom control in patients with refractory and/or severe delirium. The management of delirium with any antipsychotic is not approved for use in pediatric patients in the United States by the Food and Drug Administration. As antipsychotics do not “treat” the cause(s) of delirium, vigilance to identify and modify exacerbating factors remains key. Due to the cardiac side effects, patients treated with haloperidol or atypical antipsychotics should have electrolyte and ECG monitoring at regular intervals. Management of severe delirium exacerbations should be limited to the smallest effective dose to decrease risk of side effects and occur in concert with low risk nonpharmacologic treatments preferably prior to initiating pharmacologic therapy ( 259 SDC Table 20, ) ( https://links.lww.com/PCC/B920 244 , 245 , ). Collaboration with child and adolescent psychiatry may be beneficial when available to provide guidance on pharmacologic management and ongoing care once transferred out of the PICU. 260–262 Iatrogenic Withdrawal Syndrome
IWS is a clinical syndrome that manifests after a drug is either stopped, rapidly weaned, or chemically reversed after prolonged exposure (
116 , 263 , ) and is generally correlated with the development of drug tolerance ( 264 SDC Sections F and G, ). IWS symptoms can often be nonspecific, frequently representing autonomic activation and/or dysfunction (tachypnea, tachycardia, hyperpyrexia, and diaphoresis) ( https://links.lww.com/PCC/B920 116 , ), gastrointestinal dysfunction (vomiting and diarrhea), and/or CNS alterations (agitation, jitteriness, seizures, hallucinations, delirium) ( 265 ). The onset of IWS symptoms may be delayed following weaning or discontinuation of drugs with active drug metabolites (e.g., morphine, diazepam, midazolam), or in the setting of renal and/or hepatic dysfunction ( 266–269 ). IWS prevalence following administration of opioid and/or benzodiazepines in PICU patients has been reported to be as high as 87% ( 265 61 , 263 , 264 , 267 , ). Delineation of the epidemiology of IWS from specific drug classes remains challenging due to the frequent concomitant use of drug classes and variability in weaning strategies. Risk factors for the development of IWS from opioids and/or benzodiazepines include duration and cumulative dose, use of multiple opioids and sedatives, age less than 6 years (particularly < 6 mo), pre-existing cognitive impairment, and critical illness involving the CNS ( 269–272 263 , 264 , 266 , 269 , 270 , ). Although substantial variability in cumulative opioid and benzodiazepine dose exposure has been reported to correlate with IWS development, more recent reports of lower doses suggest that liberal thresholds for IWS screening would be prudent ( 272 268 , ). Choice of opioid has not been found to significantly impact the risk of IWS, whereas three or more classes of analgesics and/or sedatives have been independently associated with an increased risk of IWS ( 270 ) ( 268 SDC Table 21, ). Although a formal description of IWS to alpha https://links.lww.com/PCC/B920 2-agonists has yet to be published, a common constellation of symptoms including rebound tachycardia or hypertension, agitation/irritability, sleeplessness, tremors, hypertonicity, emesis, and diarrhea has been described frequently and suggests that IWS to alpha 2 agonists occurs and is also quite prevalent (27–83%) ( ). 273–278 Monitoring for IWS.
Question: How should critically ill pediatric patients be monitored for IWS from opioids and/or benzodiazepines?
1) “We recommend” use of either the Withdrawal Assessment Tool-1 (WAT-1) or Sophia Observation Scale (SOS) for the assessment of IWS due to opioid or benzodiazepine withdrawal in critically ill pediatric patients (
strong, moderate-level evidence). 2) “We suggest” routine IWS screening after a shorter duration (3–5 d) when higher opioid or benzodiazepine doses are used (
conditional, moderate-level evidence).
Rationale: Although clinical symptoms alone may produce suspicion of IWS development, the use of validated screening tools allows for consistency and standardization of diagnosis. Until relatively recently, the only validated tools available to PICU practitioners were those based on neonatal opioid withdrawal such as Finnegan’s Neonatal Abstinence Score (
114 , 115 , 264 , 269 , ). The WAT-1 ( 279–281 ) and the SOS ( 282 ) have been validated for the diagnosis of opioid and benzodiazepine-based IWS in PICU populations ( 283 ). The WAT-1 uses a 12-point numerical scale and is recommended to be scored at intervals of 12 hours or less. Scores greater than or equal to 3 are consistent with the presence of IWS but cannot differentiate between opioid and benzodiazepine withdrawal ( 284 263 , ). The WAT-1 is highly sensitive and specific for IWS from both benzodiazepines and opioids with good inter-rater reliability. It cannot, however, differentiate between opioid and benzodiazepine withdrawal ( 271 ). The SOS has been validated in a single-center study ( 271 ). Similar to the WAT-1, sensitivity and specificity are good, as is concurrent validity ( 283 ). It is comprised of a 15-item scale incorporating changes in heart rate and respiratory rate in addition to signs of autonomic dysfunction, CNS irritability, and gastrointestinal dysfunction ( 267 272 , ). Scores of greater than or equal to 4 are consistent with IWS. Similar to the WAT-1, sensitivity and specificity are good, as is concurrent validity. Due to the additional incorporation of movement disturbances and the presence of hallucinations, the SOS may be more sensitive in screening for benzodiazepine withdrawal although the significance of these differences has not been adequately evaluated. 283
Question: How should critically ill pediatric patients be monitored for IWS from alpha
Answer: Until a validated screening tool is developed, monitoring for IWS from alpha
2-agonists should be performed using a combination of associated symptoms (unexplained hypertension or tachycardia) with adjunct use of a validated benzodiazepine or opioid screening tool ( good practice).
2-agonist–based sedation regimens are being increasingly used in the PICU setting for care of critically ill pediatric patients. Currently available IWS screening tools including the WAT-1, SOS, and Opioid Benzodiazepine Withdrawal Score are inadequate for assessing alpha 2-agonist withdrawal as they do not include several symptoms that appear to be unique to alpha 2-agonist withdrawal, especially otherwise unexplained hypertension and tachycardia ( 264 , 266 , 274–276 , ) ( 278 SDC Table 22, ). As opioids and benzodiazepines may also be administered concurrently with alpha https://links.lww.com/PCC/B920 2-agonists, overlap of IWS symptoms across all three agent classes may make identification of the agent(s) responsible for IWS development challenging, prevent correct diagnosis, and, thus, prompt initiation of appropriate mitigation strategies. Common to IWS from all agents, the relative nonspecificity of symptoms may also prevent identification of pain, nonwithdrawal based agitation, and delirium, which may further delay appropriately directed interventions ( 6 , ). 115 IWS Prevention and Management.
Question: What are the optimal strategies for management of opioid and benzodiazepine IWS in critically ill pediatric patients?
1) “We suggest” that opioid related IWS be treated with opioid replacement therapy to attenuate symptoms, irrespective of preceding dose and/or duration or opioid exposure (
conditional, low-level evidence). 2) Benzodiazepine-related IWS should be treated with benzodiazepine replacement therapy to attenuate symptoms, irrespective of preceding dose and/or duration of benzodiazepine exposure (
Rationale: As IWS is a receptor-based phenomenon, management should include reinstitution of an agent (opioid or benzodiazepine) that has the same receptor activity. The preponderance of studies evaluating opioid replacement therapy for IWS have been performed using methadone, likely due to its high enteral bioavailability and long half-life which allows for less frequent dosing (
285 , ). In two RCTs, high dose methadone and a longer taper period tended to be more effective in decreasing the development of IWS ( 286 287 , ). Two systematic reviews support methadone safety and efficacy for IWS prevention during opioid weaning and management if symptoms develop ( 288 285 , ). As IWS symptoms develop or recur in up to one third of patients using a methadone taper, IWS screening during methadone weaning remains important ( 289 290 , ). Data describing use of other enteral opioids (morphine, oxycodone) are limited, and no comparisons of different enteral agents have been performed, precluding the recommendation of a specific agent. In patients not tolerating enteral intake, IV agents may be used. 291
Fewer data exist regarding treatment of benzodiazepine related IWS. Two retrospective studies reported symptom mitigation with use of gradual taper and/or conversion from IV to longer-acting enteral benzodiazepines (
114 , ). Although most studies discussing enteral benzodiazepines for IWS prevention/management use lorazepam due to its longer duration of action, efficacy studies comparing enteral benzodiazepines have not been performed. Limited data from two small prospective series suggest that addition of alpha 292 2-agonist agents may also mitigate the development of opioid and/or benzodiazepine IWS ( 143 , ) ( 293 SDC Section G3, ). https://links.lww.com/PCC/B920
Question: What are the optimal strategies for management of alpha
2-agonist IWS in critically ill pediatric patients?
2-agonist–related IWS should be treated with IV and/or or enteral alpha 2-agonist replacement therapy to attenuate symptoms, irrespective of preceding dose and/or duration of alpha 2-agonist exposure ( good practice).
Rationale: As with IWS associated with other agents, alpha
2-agonist–associated IWS is ideally managed with replacement of an IV or enteral alpha 2-agonist. However, data regarding the optimal weaning and/or replacement strategies remain limited. Limited data suggest reduced IWS symptoms, specifically otherwise unexplained tachycardia and hypertension, with adjunct use of enteral clonidine prior to dexmedetomidine infusion weaning and/or discontinuation ( 156 , 294 , ). Based on an international survey of practices related to dexmedetomidine use and withdrawal management, the above practice appears to be common as 81% of respondents reported clonidine initiation in conjunction with a regimented dexmedetomidine wean to prevent withdrawal. However, reported dosing of clonidine in these protocols was variable, and the rate of dexmedetomidine wean was not provided. The survey was also not designed to evaluate the impact of this practice on breakthrough IWS symptoms, leaving this an area requiring further study ( 295 ). 273
Question: Should protocolized analgesic/sedative versus nonprotocolized analgesic/sedative weaning be used to reduce the duration of agent tapering and prevent or reduce IWS development in critically ill pediatric patients?
Answer: “We suggest” use of a standardized protocol for sedation/analgesia weaning to decrease duration of sedation taper and attenuate emergence of IWS (
conditional, low-level evidence).
Rationale: Whereas protocolized sedation typically encompasses titration of agents to meet sedation targets during MV, IWS most often occurs during ventilator weaning or following extubation, when sedatives are being weaned. Six studies were found more specifically addressing protocolization of opioid and benzodiazepine weaning (IV and/or enteral agents) and their impact on weaning process duration, cumulative drug exposure, and development of IWS symptoms (
SDC Table 23, ). All five studies evaluating duration of sedative wean reported more rapid weaning with protocolization ( https://links.lww.com/PCC/B920 124 , ) as well as a decrease ( 296–299 124 , ) or no difference ( 297 298 , ) in the occurrence rate of IWS development. Two studies reported similar ( 299 ) or reduced IWS rates ( 300 ) with protocolized versus nonprotocolized weaning with more protocolized patients being totally weaned off sedatives prior to hospital discharge. 299 Optimizing Environment
The PICU environment may negatively influence patients during management and recovery from critical illness. There may be significant benefit in practicing patient and family-centered care, improving sleep hygiene, and fostering a culture of EM and exercise in the PICU. Although data are limited on the effects of environmental optimization, the risks of implementing such changes are often low with potentially beneficial effects for patients and families. Supporting an environment of parental and caregiver engagement with patient care likely benefits patients directly and can decrease parental stress and anxiety levels. Indeed, the American Academy of Pediatrics and the ACCM recommend a focus on patient and family-centered care, taking into account patient or family needs, values, and preferences when making clinical decisions, keeping families well-informed, and actively involving them in patient care (
Environment also directly impacts patient sleep quality and quantity. Sleep deprivation is a significant stressor reported by survivors of critical illness (
302 , ) and has been linked to increased metabolic requirements ( 303 ), altered adrenocortical axis function ( 304 ), altered immune competence ( 305 306 , ), increased pain perception ( 307 308 , ), and development of delirium in adults ( 309 ) and possibly children ( 310 ). ICU factors disrupting sleep include patient-related factors such as presence of invasive devices, need for MV, immobility, medication effects, and inadequately controlled pain, as well as environmental factors such as ambient noise and light levels as well as the performance of frequent caregiver assessments ( 311 21 , 23 , 312 , ). Few pediatric studies have assessed environmental interventions effects on sleep and patient outcomes, but simple interventions may positively impact patients ( 313 SDC Section H, ). https://links.lww.com/PCC/B920
Last, the PICU environment routinely leads to a culture of immobility. Prolonged immobility has been shown to increase the risk of comorbidities such as ICU-acquired weakness, delirium, and iatrogenic sedative and analgesic drug withdrawal (
). Adult ICU evidence suggests that EM activities can reduce the complications of immobility and comorbidities, and preliminary data suggest positive benefits in critically ill children ( 314 ). Recent observational studies have found the implementation of an EM program to be feasible and safe in critically ill children with the use of standardized guidelines and collaboration of an interdisciplinary team to train PICU personnel and provide essential resources ( 315–317 ). Despite this, a recent survey of 161 international PICUs reported infrequent presence of mobility protocols (26% of participating PICUs), whereas a point prevalence study of 31 European PICUs found that only 39% of patients received any mobilization procedures on the days of observation ( 316–321 322 , ). 323 Family Presence.
Question: Does parent or caregiver presence during procedure performance improve outcomes in critically ill pediatric patients?
Answer: “We suggest” facilitation of parental or caregiver presence in the PICU during routine care and interventional procedures to 1) provide comfort to the child, 2) decrease parental levels of stress and anxiety, and 3) increase level of satisfaction of care (
conditional, low-level evidence).
Rationale: PICU specific studies show parents/caregivers have a decreased level of anxiety and stress when involved in family-centered care, they are more satisfied with the care their child is receiving, and when allowed to be present for procedures or resuscitations, it has helped with the parental or caregiver’s coping while maintaining both quality care and patient safety (
). In a PICU study assessing the utility of a daily parental comforting protocol, most parents (70%) and all nurses in the intervention group reported that they felt the intervention had positive patient impact ( 324–331 ). Although concerns have been raised about the impact of parent or caregiver presence during procedures, a study on family presence during tracheal intubation reported no adverse impact on first attempt success, adverse events, or team stress level ( 332 ) ( 333 SDC Section H1, ). https://links.lww.com/PCC/B920 Sleep Hygiene.
Question: Do environmental interventions to decrease excessive noise positively impact sleep hygiene and comfort in critically ill pediatric patients?
1) “We suggest” that PICU teams make environmental and/or behavioral changes to reduce excessive noise and therefore improve sleep hygiene and comfort, in critically ill pediatric patients (
conditional, low-level evidence). 2) “We suggest” offering patients the use of noise reducing devices such as ear plugs or headphones to reduce the impact of nonmodifiable ambient noise (
conditional, low-level evidence).
Rationale: Excessive noise is a ubiquitous problem in the ICU setting. Five studies were found evaluating the impact of a noise reduction strategy in the ICU (
311 , ). Two studies evaluating the use of a light trigger during both daytime and nighttime hours to remind PICU ( 334–337 ) or NICU ( 338 ) staff when ambient noise levels became excessive demonstrated minor (1–3 dB) reductions in average noise levels but no increase in time spent below recommended noise thresholds. NICU studies aimed to reduce anytime ambient noise via staff education similarly have resulted in minimal or no impact ( 339 340 , ). A single study in a PICU setting demonstrated significant noise reductions, particularly during evening/nighttime hours, following implementation of a comprehensive delirium bundle, although the bundle components deemed most impactful on noise reduction were not described ( 341 303 , ). In neonates, earmuff use for noise reduction was associated with increased quiet sleep time and/or less variability in motor responses ( 311 337 , ) ( 342–344 SDC Section H2, ). https://links.lww.com/PCC/B920 Early Mobility.
Question: Does the use of an EM protocol impact clinical outcomes in critically ill pediatric patients?
Answer: “We suggest” performing EM to minimize the effects of immobility in critically ill pediatric patients (
conditional, low-level evidence).
Rationale: In a three-step quality improvement project, implementation of PICU bundle including delirium screening, protocolized sedation, and an EM protocol was associated with a significant reduction in delirium (
). In a pre- and postcohort study in 75 pediatric liver transplant patients, implementation of an EM protocol was associated with earlier mobility to walk greater than 50 yards and reduced hospital LOS ( 224 ). An earlier analysis of 57 postprotocol liver transplantation patients also reported more rapid development of functional mobility but no improvement in length of intubation, PICU stay, and hospital LOS ( 316 ). A small RCT, mostly focusing on feasibility and safety, found no statistical differences in hospital or ICU lengths of stay, outpatient physical, occupational, or speech therapy prescription, placement of new technological devices at hospital discharge, or in quality of life and functional scores at 6 months post discharge with a PICU EM protocol ( 317 ). Although not statistically significant, less children in the EM protocol group were admitted to an inpatient rehabilitation facility following their hospital stay. 345
Question: What factors promote success of EM among critically ill pediatric patients?
Answer: “We suggest” the use of a standardized EM protocol that outlines readiness criteria, contraindications, developmentally appropriate mobility activities and goals, and safety thresholds guided by the multidisciplinary team and family decision-making (
conditional, low-level evidence).
Rationale: Strategies to promote the success of a PICU EM program are primarily based on observational studies (
224 , 321 , ). The implementation of an EM program in these single-center PICUs demonstrated a significant increase in early rehabilitation consults and frequency of EM in critically ill children without increased adverse events. These studies all describe the use of a standardized multicomponent EM protocol that included multidisciplinary daily screening for appropriateness, progressive levels of mobility activities, and variables to monitor for safety and tolerance of the activity ( 346–348 SDC Section H3, ). https://links.lww.com/PCC/B920 SUMMARY
The current guidelines represent a comprehensive list of practical clinical recommendations for the assessment, prevention, and management of comfort in critically ill pediatric patients. In the development of these guidelines, the multidisciplinary taskforce of pediatric critical care providers sought to ask and provide guidance regarding questions that they felt were relevant to pediatric critical care providers globally and irrespective of preconceptions regarding the quantity or quality of data they felt might be present for questions of interest. Although the above recommendations represent guidance for only questions which the taskforce found adequate evidence to address, many unanswered questions remain, and further discussion of them is found in the provided SDC (
). As stated in the https://links.lww.com/PCC/B920 Methods section, the guidelines above encompass seven distinct but intertwined domains relevant to comfort of the critically ill pediatric patient. However, the authors would also like to note that several key themes may also be identified within these domains. In multiple domains, including pain, agitation, IWS, and delirium, patient assessment must precede intervention. We intend that these guidelines stress the use of validated tools for making these assessments within each domain, and advocate for their development if validated tools are not yet available. Related to comfort management, these guidelines encourage an enhanced use of protocolized sedation and analgesia provision, both during the acute phase of critical illness and during the resolution phases when de-escalations are occurring. We have also attempted to highlight the value of adjunctive/synergistic therapies as well as the importance of nonpharmacologic interventions for enhancing patient comfort and comprehensive care provision, especially given the minimal risks associated with nonpharmacologic interventions and the associated potential benefits of decreasing the need for medications.
These guidelines do have several important limitations which should be mentioned. A significant limitation is the lack of available literature discussing many of the questions taskforce wished to address. Consequently, there are many important questions for which recommendation(s) were unable to be provided and represent opportunities for additional research (see
Future Directions section below). Although the majority of recommendations made are meant to apply to all critically ill pediatric patients, the taskforce understands that not all critically ill pediatric populations are the same, and although we endeavored to qualify where recommendations may not be relevant for certain populations, we may not foresee all possible nuances for where certain recommendations may not be relevant, either due to patient needs or local resource availability. In retrospect, as some of the questions these guidelines sought to address apply directly to patients and their families, we did not solicit advice from patients and/or the families of critically ill children. We would suggest that this be a consideration made when the time comes for these guidelines to be updated. In similar fashion, we did not solicit input from other ancillary members of the critical care team for questions which might be directly relevant to them, including physical and occupational therapists for EM-related issues and bedside registered nurses (RNs) (although all advanced practice RN members on the taskforce had bedside experience and brought this to the discussion as well). FUTURE DIRECTIONS
One of the limitations of these guidelines discussed above is the lack of available literature to enable the taskforce to create recommendations for other important clinical questions facing all pediatric critical care practitioners. Consequently, we felt it was appropriate to outline these issues intentionally in the hopes that this listing will both stimulate new research and serve as a guide to subsequent updates of these guidelines.
outlines questions that the taskforce found insufficient evidence with which to create either specific recommendations or good practice statements. Table 2 outlines topics for which recommendations may have been created but within which were still areas the taskforce felt additional study would be of value. Table 3
Table 2. -
Unanswered Questions Requiring Further Evaluation
1) What opioid provides a therapeutic advantage for critically ill pediatric patients?
2) Do low-dose opioid antagonists alleviate opioid-induced adverse effects or have opioid-sparing effects?
3) Does the adjunct use of neuraxial or regional analgesia in critically ill pediatric patients shorten the duration of MV or ICU LOS?
4) Does the addition of acupuncture impact outcomes including a decrease in postoperative or procedural pain, decrease in duration of MV, or reduction in PICU LOS?
5) Does the direct application of heat or cold aid in pain management for critically ill pediatric patients?
1) How does body mass index impact dosing of NMBA, and what is the role of dosing based on actual body weight vs ideal body weight in the morbidly obese pediatric patient?
2) Does the use of neuromuscular blockade improve clinical outcomes in critically ill pediatric patients suffering from decreased oxygen delivery?
3) Does the use of NMBAs improve outcomes in critically ill pediatric patients with pediatric acute respiratory distress syndrome or severe status asthmaticus?
4) Does the use of neuromuscular blockade improve survival or clinical outcomes for critically ill pediatric patients with acute brain injury or increased intracranial pressure?
5) Does rotation of NMBAs and/or class reduce the development of tolerance?
6) Does the use of routine “drug holidays” reduce prolonged neuromuscular blockade or other NMBA-associated complications in critically ill pediatric patients?
7) In critically ill children receiving NMBA, how are caloric goals altered and what modalities are best to meet these goals?
8) Does use of NMBAs increase the risk of ventilator-associated events?
9) Does concurrent use of corticosteroids affect the risk of myopathy/neuropathy/weakness in pediatric patients receiving NMBAs?
10) In critically ill pediatric patients with myasthenia gravis, how should NMBAs be dosed and clinical effect monitored?
Tolerance/iatrogenic withdrawal syndrome
1) What is the prevalence of, and risk factors for, the development of tolerance to opioids, benzodiazepines, or alpha
2-agonists in critically ill pediatric patients?
2) Does goal-directed (targeted) sedation reduce sedation tolerance among critically ill pediatric patients receiving MV?
3) Does the addition of adjunct enteral alpha
2-agonists reduce requirements for other sedative or opioid agents in critically ill pediatric patients?
4) What is the prevalence of IWS following exposure to opioids and/or benzodiazepines in critically ill pediatric patients?
5) What is the prevalence of IWS following exposure to alpha
2-agonists in critically ill pediatric patients?
6) What are the risk factors for development of IWS to opioids and/or benzodiazepines in critically ill pediatric patients?
7) What are the risk factors for development of IWS to alpha
8) Should protocolized analgesic/sedative vs nonprotocolized analgesic/sedative weaning be used to reduce the duration of agent tapering and prevent or reduce IWS development in critically ill pediatric patients?
9) Does use of an “analgesia with sedative” compared with “single-class” sedation strategy decrease IWS development and associated outcomes in critically ill pediatric patients?
10) Are alpha
2-agonists effective in preventing or treating symptoms in critically ill pediatric patients with opioid and/or benzodiazepine-related IWS?
11) In patients with IWS from prolonged alpha
2-agonist sedation, what is the optimal replacement strategy for reducing development of or treating alpha 2-agonist related IWS?
Optimizing PICU environment
1) Should a parent or caregiver be present during interventional procedures in critically ill infants and children?
2) Do environmental interventions to improve day-night cycling positively impact sleep hygiene in critically ill pediatric patients?
3) Is early mobility safe and feasible in critically ill pediatric patients?
4) What factors promote success of EM among critically ill pediatric patients?
IWS = iatrogenic withdrawal syndrome, LOS = length of stay, MV = mechanical ventilation, NMBA = neuromuscular blocking agent.
Table 3. -
Topics Requiring Further Investigation
1) Specific study of current or new pain scoring tools in critically ill pediatric patients and specific populations such as neonates, developmentally delayed, nonverbal patients.
2) The impact of other non-opioid adjuncts including gabapentanoids, subanesthetic doses of ketamine on analgesic quality, opioid requirements, and opioid-related adverse effects.
1) Identification of the components of protocolized sedation that may impact outcomes in mechanically ventilated pediatric patients.
2) Evaluation of educational strategies which may optimize outcomes (tolerance and withdrawal, drug exposure, delirium development, etc) associated with implementation of protocolized sedation programs.
3) Dosing strategies for the safe and expanded use of propofol as a sedation choice in the PICU with considerations for the avoidance of propofol-related infusion syndrome.
4) Strategies for propofol use during the periextubation period.
5) The effects of propofol vs other agents, including barbiturates, in the setting of traumatic brain injury and intracranial hypertension.
6) The safety, efficacy, and outcomes including resource utilization of enteral vs IV sedative infusions during the acute phase of illness.
7) Scenarios under which daily sedation interruption trials may be safe and appropriate.
1) The role and/or utility of brain activity-based monitors to assess sedation depth.
2) Methods with which to better assess indicators of unintended awareness during neuromuscular blocking agent use.
1) The valid and reliable assessment of delirium in infants less than 6 mo old, including those with a history of prematurity.
2) Ongoing assessment of risk factors for ICU-delirium with a focus on infants less than 6 mo old and patients with primary or secondary neurologic injury.
3) The impact of sedation strategy on delirium occurrence rate and duration including protocolization and sedation choice (dexmedetomidine, ketamine, barbiturates).
4) The impact of opioid choice on delirium occurrence rate or severity.
5) Further studies evaluating dexmedetomidine-based sedation and delirium in critically ill children are warranted.
6) The impact of the ICU environment (sleep, early mobility, dedicated family care) on delirium development, severity, and duration.
7) The relationship between delirium and long-term outcomes such as cognitive or executive dysfunction, psychologic recovery, and posttraumatic symptoms.
8) The role of antipsychotic use for either prevention or management of ICU delirium.
9) The role of pharmacologic agents to promote sleep quality and how this impacts delirium.
10) Determine possible biomarkers for the diagnosis or prognostication of ICU delirium.
11) Determine whether use of brain activity monitors correlate with delirium presence or severity.
12) Determine whether bundled care practices such as the ABCDEF bundle impact ICU delirium and long-term outcomes.
Tolerance/iatrogenic withdrawal syndrome
1) Development of an operational definition of tolerance.
2) The impact of sedative choice (agent and route) on tolerance development including opioids, benzodiazepines, barbiturates, propofol, and ketamine.
3) Validate a bedside tool for the screening of alpha
2-agonist associated withdrawal.
4) The impact of targeted sedation protocols on the development of IWS and related outcomes.
5) The impact of analgosedation strategies (combination sedatives, analgesics vs sedatives alone, analgesics alone, continuous vs intermittent) on the development of IWS and related outcomes.
6) Best practice for conversion from IV to enteral sedation/analgesia.
7) The impact of early transition to long-acting enteral analgesics and/or sedatives for the prevention of IWS.
Optimizing PICU environment
1) The impact of active parent provision of routine patient care on perceived pain and anxiety, key short-term outcomes (duration of MV and LOS), and long-term cognitive and psychologic outcomes.
2) Describe risks associated with parental involvement and best practice for communication and empowerment.
3) The impact of child life/expressive therapies on environmental comfort in critically ill children.
4) The impact of improved sleep hygiene on outcomes (delirium, length of MV, sedation/opioid exposure, LOS, neurocognitive recovery).
5) Determine objective and efficient monitors of sleep in the PICU.
6) Describe best practices for a successful EM program in the PICU.
7) Determine the impact of EM on outcomes (delirium, duration of MV, sedation/opioid exposure, LOS, neurocognitive recovery, functional recovery).
EM = early mobility, LOS = length of stay, MV = mechanical ventilation.
The American College of Critical Care Medicine, which honors individuals for their achievements and contributions to multidisciplinary critical care medicine, is the consultative body of the Society of Critical Care Medicine (SCCM) that possesses recognized expertise in the practice of critical care. The College supports development of new and revised guidelines and clinical practice parameters for the critical care practitioner. Librarian services, systematic review, and analysis for these guidelines were provided contractually through the Guidelines in Intensive Care, Development, and Evaluation (Guide Group), McMaster University, Canada. Methodologists served as expert panel members specializing in this area. We gratefully appreciate the efforts of Michel Atlas, Master of Library and Information Science (MLIS) (University of Louisville), Nancy Aldrich MLIS (Advent Health, Orlando, FL), and Rebecca Skidmore (Independent Information Specialist, Ottawa, ON) for their invaluable assistance in performing the extensive literature searches required to develop these Guidelines. We would like to thank Zackary Schoonover (Middle Tennessee State University) for creation and formatting of literature tables. We also would like to acknowledge SCCM Staff, particularly Julie Higham, BA, Guidelines Manager, for her contributions toward the development of the guidelines.
1. Barr J, Fraser GL, Puntillo K, et al.; American College of Critical Care Medicine: Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 2013; 41:263–306
2. Devlin JW, Skrobik Y, Gélinas C, et al.: Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med 2018; 46:e825–e873
3. Twite MD, Rashid A, Zuk J, et al.: Sedation, analgesia, and neuromuscular blockade in the pediatric intensive care unit: Survey of fellowship training programs. Pediatr Crit Care Med 2004; 5:521–532
4. Long D, Horn D, Keogh S: A survey of sedation assessment and management in Australian and New Zealand paediatric intensive care patients requiring prolonged mechanical ventilation. Aust Crit Care 2005; 18:152–157
5. Jenkins IA, Playfor SD, Bevan C, et al.: Current United Kingdom sedation practice in pediatric intensive care. Paediatr Anaesth 2007; 17:675–683
6. Harris J, Ramelet AS, van Dijk M, et al.: Clinical recommendations for pain, sedation, withdrawal and delirium assessment in critically ill infants and children: an ESPNIC position statement for healthcare professionals. Intensive Care Med 2016; 42:972–986
7. Playfor S, Jenkins I, Boyles C, et al.; United Kingdom Paediatric Intensive Care Society Sedation; Analgesia and Neuromuscular Blockade Working Group: Consensus guidelines on sedation and analgesia in critically ill children. Intensive Care Med 2006; 32:1125–1136
8. Heneghan C: Bmj evidence-based medicine in 2018. BMJ Evid-Based Med 2019; 24:43–44
9. Guyatt G, Gutterman D, Baumann MH, et al.: Grading strength of recommendations and quality of evidence in clinical guidelines: Report from an American College of Chest Physicians Task Force. Chest 2006; 129:174–181
10. Guyatt GH, Oxman AD, Kunz R, et al.: Going from evidence to recommendations. BMJ 2008; 336:1049–1051
11. Guyatt GH, Oxman AD, Kunz R, et al.; GRADE Working Group: What is “quality of evidence” and why is it important to clinicians? BMJ 2008; 336:995–998
12. Guyatt GH, Oxman AD, Vist GE, et al.: Grade: An emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008; 336:924–926
13. Kozlowski LJ, Kost-Byerly S, Colantuoni E, et al.: Pain prevalence, intensity, assessment and management in a hospitalized pediatric population. Pain Manag Nurs 2014; 15:22–35
14. Groenewald CB, Rabbitts JA, Schroeder DR, et al.: Prevalence of moderate-severe pain in hospitalized children. Paediatr Anaesth 2012; 22:661–668
15. Cummings EA, Reid GJ, Finley AG, et al.: Prevalence and source of pain in pediatric inpatients. Pain 1996; 68:25–31
16. Aranda JV, Carlo W, Hummel P, et al.: Analgesia and sedation during mechanical ventilation in neonates. Clin Ther 2005; 27:877–899
17. Cignacco E, Hamers JP, van Lingen RA, et al.: Pain relief in ventilated preterms during endotracheal suctioning: A randomized controlled trial. Swiss Med Wkly 2008; 138:635–645
18. Kortesluoma RL, Nikkonen M, Serlo W: “You just have to make the pain go away”–children’s experiences of pain management. Pain Manag Nurs 2008; 9:143–9, 149.e1
19. Sönmez Düzkaya D, Kuğuoğlu S: Assessment of pain during endotracheal suction in the pediatric intensive care unit. Pain Manag Nurs 2015; 16:11–19
20. Baarslag MA, Jhingoer S, Ista E, et al.: How often do we perform painful and stressful procedures in the paediatric intensive care unit? A prospective observational study. Aust Crit Care 2019; 32:4–10
21. Aitken LM, Elliott R, Mitchell M, et al.: Sleep assessment by patients and nurses in the intensive care: An exploratory descriptive study. Aust Crit Care 2017; 30:59–66
22. American Academy of Pediatrics. Committee on Psychosocial Aspects of Child and Family Health; Task Force on Pain in Infants, Children, and Adolescents: The assessment and management of acute pain in infants, children, and adolescents. Pediatrics 2001; 108:793–797
23. Armour AD, Khoury JC, Kagan RJ, et al.: Clinical assessment of sleep among pediatric burn patients does not correlate with polysomnography. J Burn Care Res 2011; 32:529–534
24. Hermann C, Hohmeister J, Demirakça S, et al.: Long-term alteration of pain sensitivity in school-aged children with early pain experiences. Pain 2006; 125:278–285
25. Ismail A: The challenges of providing effective pain management for children in the pediatric intensive care unit. Pain Manag Nurs 2016; 17:372–383
26. Nimmo WS, Duthie DJ: Pain relief after surgery. Anaesth Intensive Care 1987; 15:68–71
27. Jones SM, Fiser DH, Livingston RL: Behavioral changes in pediatric intensive care units. Am J Dis Child 1992; 146:375–379
28. Melnyk BM, Alpert-Gillis L, Feinstein NF, et al.: Creating opportunities for parent empowerment: Program effects on the mental health/coping outcomes of critically ill young children and their mothers. Pediatrics 2004; 113:e597–e607
29. Czarnecki ML, Simon K, Thompson JJ, et al.: Barriers to pediatric pain management: A nursing perspective. Pain Manag Nurs 2011; 12:154–162
30. LaFond CM, Van Hulle Vincent C, Oosterhouse K, et al.: Nurses’ beliefs regarding pain in critically ill children: A mixed-methods study. J Pediatr Nurs 2016; 31:691–700
31. Twycross A: Achieving consensus about pain content for child branch curricula. J Adv Nurs 2001; 34:51–60
32. Van Hulle Vincent C: Nurses’ knowledge, attitudes, and practices: Regarding children’s pain. MCN Am J Matern Child Nurs 2005; 30:177–183
33. Kudchadkar SR, Yaster M, Punjabi NM: Sedation, sleep promotion, and delirium screening practices in the care of mechanically ventilated children: a wake-up call for the pediatric critical care community. Crit Care Med 2014; 42:1592–1600
34. Ismail A, Forgeron P, Polomeno V, et al.: Pain management interventions in the paediatric intensive care unit: A scoping review. Intensive Crit Care Nurs 2019; 54:96–105
35. van der Heijden MJ, Oliai Araghi S, van Dijk M, et al.: The effects of perioperative music interventions in pediatric surgery: A systematic review and meta-analysis of randomized controlled trials. PLoS One 2015; 10:e0133608
36. Hoffman HG, Rodriguez RA, Gonzalez M, et al.: Immersive virtual reality as an adjunctive non-opioid analgesic for pre-dominantly Latin American children with large severe burn wounds during burn wound cleaning in the intensive care unit: A pilot study. Front Hum Neurosci 2019; 13:262
37. Beltramini A, Milojevic K, Pateron D: Pain assessment in newborns, infants, and children. Pediatr Ann 2017; 46:e387–e395
38. Huguet A, Stinson JN, McGrath PJ: Measurement of self-reported pain intensity in children and adolescents. J Psychosom Res 2010; 68:329–336
39. Stinson JN, Kavanagh T, Yamada J, et al.: Systematic review of the psychometric properties, interpretability and feasibility of self-report pain intensity measures for use in clinical trials in children and adolescents. Pain 2006; 125:143–157
40. McGrath PA, Seifert CE, Speechley KN, et al.: A new analogue scale for assessing children’s pain: An initial validation study. Pain 1996; 64:435–443
41. Szyfelbein SK, Osgood PF, Carr DB: The assessment of pain and plasma beta-endorphin immunoactivity in burned children. Pain 1985; 22:173–182
42. Beyer JE, Aradine CR: Content validity of an instrument to measure young children’s perceptions of the intensity of their pain. J Pediatr Nurs 1986; 1:386–395
43. Bieri D, Reeve RA, Champion DG, et al.: The faces pain scale for the self-assessment of the severity of pain experienced by children: Development, initial validation, and preliminary investigation for ratio scale properties. Pain 1990; 41:139–150
44. Rotondi AJ, Chelluri L, Sirio C, et al.: Patients’ recollections of stressful experiences while receiving prolonged mechanical ventilation in an intensive care unit. Crit Care Med 2002; 30:746–752
45. Franck LS, Ridout D, Howard R, et al.: A comparison of pain measures in newborn infants after cardiac surgery. Pain 2011; 152:1758–1765
46. Dantas LV, Dantas TS, Santana Filho VJ, et al.: Pain assessment during blood collection from sedated and mechanically ventilated children. Rev Bras Ter Intensiva 2016; 28:49–54
47. Välitalo PAJ, van Dijk M, Krekels EHJ, et al.: Pain and distress caused by endotracheal suctioning in neonates is better quantified by behavioural than physiological items: A comparison based on item response theory modelling. Pain 2016; 157:1611–1617
48. Büttner W, Finke W: Analysis of behavioural and physiological parameters for the assessment of postoperative analgesic demand in newborns, infants and young children: A comprehensive report on seven consecutive studies. Paediatr Anaesth 2000; 10:303–318
49. Dorfman TL, Sumamo Schellenberg E, Rempel GR, et al.: An evaluation of instruments for scoring physiological and behavioral cues of pain, non-pain related distress, and adequacy of analgesia and sedation in pediatric mechanically ventilated patients: A systematic review. Int J Nurs Stud 2014; 51:654–676
50. Ahlers SJ, van Gulik L, van der Veen AM, et al.: Comparison of different pain scoring systems in critically ill patients in a general ICU. Crit Care 2008; 12:R15
51. Manworren RC, Hynan LS: Clinical validation of FLACC: Preverbal patient pain scale. Pediatr Nurs 2003; 29:140–146
52. Voepel-Lewis T, Zanotti J, Dammeyer JA, et al.: Reliability and validity of the face, legs, activity, cry, consolability behavioral tool in assessing acute pain in critically ill patients. Am J Crit Care 2010; 19:55–61; quiz 62
53. Malviya S, Voepel-Lewis T, Burke C, et al.: The revised FLACC observational pain tool: Improved reliability and validity for pain assessment in children with cognitive impairment. Paediatr Anaesth 2006; 16:258–265
54. Ambuel B, Hamlett KW, Marx CM, et al.: Assessing distress in pediatric intensive care environments: The COMFORT scale. J Pediatr Psychol 1992; 17:95–109
55. van Dijk M, de Boer JB, Koot HM, et al.: The reliability and validity of the COMFORT scale as a postoperative pain instrument in 0 to 3-year-old infants. Pain 2000; 84:367–377
56. Ista E, van Dijk M, Tibboel D, et al.: Assessment of sedation levels in pediatric intensive care patients can be improved by using the COMFORT “behavior” scale. Pediatr Crit Care Med 2005; 6:58–63
57. Boerner KE, Birnie KA, Caes L, et al.: Sex differences in experimental pain among healthy children: A systematic review and meta-analysis. Pain 2014; 155:983–993
58. Puntillo KA, White C, Morris AB, et al.: Patients’ perceptions and responses to procedural pain: Results from Thunder Project II. Am J Crit Care 2001; 10:238–251
59. Smith HA, Berutti T, Brink E, et al.: Pediatric critical care perceptions on analgesia, sedation, and delirium. Semin Respir Crit Care Med 2013; 34:244–261
60. Johnson PN: Pain and sedation.
: Advanced Pediatric Therapeutics. Eiland LTT, (Ed). First Edition. Memphis, TN, Pediatric Pharmacy Advocacy Group, 2015, pp 433
61. Garcia Guerra G, Joffe AR, Cave D, et al.; Sedation Withdrawal and Analgesia Team, and the Canadian Critical Care Trials Group: Survey of sedation and analgesia practice among Canadian pediatric critical care physicians. Pediatr Crit Care Med 2016; 17:823–830
62. Playfor SD, Thomas DA, Choonara I: Sedation and neuromuscular blockade in paediatric intensive care: A review of current practice in the UK. Paediatr Anaesth 2003; 13:147–151
63. Welzing L, Oberthuer A, Junghaenel S, et al.: Remifentanil/midazolam versus fentanyl/midazolam for analgesia and sedation of mechanically ventilated neonates and young infants: A randomized controlled trial. Intensive Care Med 2012; 38:1017–1024
64. Reiter PD, Ng J, Dobyns EL: Continuous hydromorphone for pain and sedation in mechanically ventilated infants and children. J Opioid Manag 2012; 8:99–104
65. Akinci SB, Kanbak M, Guler A, et al.: Remifentanil versus fentanyl for short-term analgesia-based sedation in mechanically ventilated postoperative children. Paediatr Anaesth 2005; 15:870–878
66. Chiaretti A, Pietrini D: Safety and efficacy of remifentanil infusion in craniosynostosis repair in infants. Pediatr Neurosurg 2002; 36:55–56
67. Alencar AJ, Sanudo A, Sampaio VM, et al.: Efficacy of tramadol versus fentanyl for postoperative analgesia in neonates. Arch Dis Child Fetal Neonatal Ed 2012; 97:F24–F29
68. Hungerford JL, O’Brien N, Moore-Clingenpeel M, et al.: Remifentanil for sedation of children with traumatic brain injury. J Intensive Care Med 2019; 34:557–562
69. Curley MA, Wypij D, Watson RS, et al.: Protocolized sedation vs usual care in pediatric patients mechanically ventilated for acute respiratory failure: A randomized clinical trial. JAMA 2015; 313:379–389
70. Smith MT, Watt JA, Cramond T: Morphine-3-glucuronide–A potent antagonist of morphine analgesia. Life Sci 1990; 47:579–585
71. Pasternak GW, Bodnar RJ, Clark JA, et al.: Morphine-6-glucuronide, a potent mu agonist. Life Sci 1987; 41:2845–2849
72. Inoue M, Caldarone CA, Frndova H, et al.: Safety and efficacy of ketorolac in children after cardiac surgery. Intensive Care Med 2009; 35:1584–1592
73. Sutters KA, Shaw BA, Gerardi JA, et al.: Comparison of morphine patient-controlled analgesia with and without ketorolac for postoperative analgesia in pediatric orthopedic surgery. Am J Orthop (Belle Mead NJ) 1999; 28:351–358
74. Munro HM, Walton SR, Malviya S, et al.: Low-dose ketorolac improves analgesia and reduces morphine requirements following posterior spinal fusion in adolescents. Can J Anaesth 2002; 49:461–466
75. Nour C, Ratsiu J, Singh N, et al.: Analgesic effectiveness of acetaminophen for primary cleft palate repair in young children: A randomized placebo controlled trial. Paediatr Anaesth 2014; 24:574–581
76. Dawkins TN, Barclay CA, Gardiner RL, et al.: Safety of intravenous use of ketorolac in infants following cardiothoracic surgery. Cardiol Young 2009; 19:105–108
77. Wong I, St John-Green C, Walker SM: Opioid-sparing effects of perioperative paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs) in children. Paediatr Anaesth 2013; 23:475–495
78. Zhu A, Benzon HA, Anderson TA: Evidence for the efficacy of systemic opioid-sparing analgesics in pediatric surgical populations: A systematic review. Anesth Analg 2017; 125:1569–1587
79. Ceelie I, de Wildt SN, van Dijk M, et al.: Effect of intravenous paracetamol on postoperative morphine requirements in neonates and infants undergoing major noncardiac surgery: A randomized controlled trial. JAMA 2013; 309:149–154
80. Olbrecht VA, Ding L, Spruance K, et al.: Intravenous acetaminophen reduces length of stay via mediation of postoperative opioid consumption after posterior spinal fusion in a pediatric cohort. Clin J Pain 2018; 34:593–599
81. Drahota A, Ward D, Mackenzie H, et al.: Sensory environment on health-related outcomes of hospital patients. Cochrane Database Syst Rev 2012; 2021:CD005315
82. Alay B, Esenay FI: The clinical effect of classical music and lullaby on term babies in neonatal intensive care unit: A randomised controlled trial. J Pak Med Assoc 2019; 69:459–463
83. Mahmud S, Shah SA, Khattak SZ: Neonatal pain and preventive strategies: An experience in a tertiary care unit. J Ayub Med Coll Abbottabad 2017; 29:42–44
84. O’Toole A, Francis K, Pugsley L: Does music positively impact preterm infant outcomes? Adv Neonatal Care 2017; 17:192–202
85. Ranger A, Helmert E, Bott TS, et al.: Physiological and emotional effects of pentatonic live music played for preterm neonates and their mothers in the Newborn Intensive Care Unit: A randomized controlled trial. Complement Ther Med 2018; 41:240–246
86. Tekgündüz KŞ, Polat S, Gürol A, et al.: Oral glucose and listening to lullaby to decrease pain in preterm infants supported with NCPAP: A randomized controlled trial. Pain Manag Nurs 2019; 20:54–61
87. Nilsson S, Kokinsky E, Nilsson U, et al.: School-aged children’s experiences of postoperative music medicine on pain, distress, and anxiety. Paediatr Anaesth 2009; 19:1184–1190
88. Bergomi P, Chieppi M, Maini A, et al.: Nonpharmacological techniques to reduce pain in preterm infants who receive heel-lance procedure: A randomized controlled trial. Res Theory Nurs Pract 2014; 28:335–348
89. Butt ML, Kisilevsky BS: Music modulates behaviour of premature infants following heel lance. Can J Nurs Res 2000; 31:17–39
90. Abd-Elshafy SK, Khalaf GS, Abo-Kerisha MZ, et al.: Not all sounds have negative effects on children undergoing cardiac surgery. J Cardiothorac Vasc Anesth 2015; 29:1277–1284
91. Disher T, Cameron C, Mitra S, et al.: Pain-relieving interventions for retinopathy of prematurity: A meta-analysis. Pediatrics 2018; 142:e20180401
92. Kristoffersen L, Malahleha M, Duze Z, et al.: Randomised controlled trial showed that neonates received better pain relief from a higher dose of sucrose during venepuncture. Acta Paediatr 2018; 107:2071–2078
93. Liu Y, Huang X, Luo B, et al.: Effects of combined oral sucrose and nonnutritive sucking (nns) on procedural pain of NICU newborns, 2001 to 2016: A prisma-compliant systematic review and meta-analysis. Medicine (Baltimore) 2017; 96:e6108
94. Matar EM, Arabiat DH, Foster MJ: Oral glucose efficacy on neonate’s pain responses at the NICU: A quasi experimental trial of two clinical procedures. Appl Nurs Res 2016; 32:36–40
95. Sethi A, Sankar MJ, Kulkarni S, et al.: Low dose fentanyl infusion versus 24% oral sucrose for pain management during laser treatment for retinopathy of prematurity-an open label randomized clinical trial. Eur J Pediatr 2020; 179:285–292
96. Stevens B, Yamada J, Campbell-Yeo M, et al.: The minimally effective dose of sucrose for procedural pain relief in neonates: A randomized controlled trial. BMC Pediatr 2018; 18:85
97. Turan O, Akkoyun I, Ince DA, et al.: Effect of breast milk and sucrose on pain and perfusion index during examination for retinopathy of prematurity. J Matern Fetal Neonatal Med 2021; 34:1138–1142
98. Valeri BO, Gaspardo CM, Martinez FE, et al.: Effectiveness of sucrose used routinely for pain relief and neonatal clinical risk in preterm infants: A nonrandomized study. Clin J Pain 2018; 34:713–722
99. Liaw JJ, Yang L, Lee CM, et al.: Effects of combined use of non-nutritive sucking, oral sucrose, and facilitated tucking on infant behavioural states across heel-stick procedures: A prospective, randomised controlled trial. Int J Nurs Stud 2013; 50:883–894
100. Peng HF, Yin T, Yang L, et al.: Non-nutritive sucking, oral breast milk, and facilitated tucking relieve preterm infant pain during heel-stick procedures: A prospective, randomized controlled trial. Int J Nurs Stud 2018; 77:162–170
101. Leng HY, Zheng XL, Zhang XH, et al.: Combined non-pharmacological interventions for newborn pain relief in two degrees of pain procedures: A randomized clinical trial. Eur J Pain 2016; 20:989–997
102. Stevens B, Yamada J, Beyene J, et al.: Consistent management of repeated procedural pain with sucrose in preterm neonates: Is it effective and safe for repeated use over time? Clin J Pain 2005; 21:543–548
103. Meesters N, Simons S, van Rosmalen J, et al.: Waiting 2 minutes after sucrose administration-unnecessary? Arch Dis Child Fetal Neonatal Ed 2017; 102:F167–F169
104. Pandey M, Datta V, Rehan HS: Role of sucrose in reducing painful response to orogastric tube insertion in preterm neonates. Indian J Pediatr 2013; 80:476–482
105. Harrison D, Yamada J, Adams-Webber T, et al.: Sweet tasting solutions for reduction of needle-related procedural pain in children aged one to 16 years. Cochrane Database Syst Rev 2015; 2015:CD008408
106. Vet NJ, Ista E, de Wildt SN, et al.: Optimal sedation in pediatric intensive care patients: A systematic review. Intensive Care Med 2013; 39:1524–1534
107. Hartman ME, McCrory DC, Schulman SR: Efficacy of sedation regimens to facilitate mechanical ventilation in the pediatric intensive care unit: A systematic review. Pediatr Crit Care Med 2009; 10:246–255
108. Nasr VG, DiNardo JA: Sedation and analgesia in pediatric cardiac critical care. Pediatr Crit Care Med 2016; 17:S225–S231
109. Fitzgerald RK, Davis AT, Hanson SJ; National Association of Children’s Hospitals and Related Institution PICU Focus Group Investigators: Multicenter analysis of the factors associated with unplanned extubation in the PICU. Pediatr Crit Care Med 2015; 16:e217–e223
110. Lucas da Silva PS, Fonseca MCM: Incidence and risk factors for cardiovascular collapse after unplanned extubations in the pediatric ICU. Respir Care 2017; 62:896–903
111. Colville G, Kerry S, Pierce C: Children’s factual and delusional memories of intensive care. Am J Respir Crit Care Med 2008; 177:976–982
112. Randolph AG, Wypij D, Venkataraman ST, et al.; Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network: Effect of mechanical ventilator weaning protocols on respiratory outcomes in infants and children: A randomized controlled trial. JAMA 2002; 288:2561–2568
113. Traube C, Silver G, Gerber LM, et al.: Delirium and mortality in critically ill children: Epidemiology and outcomes of pediatric delirium. Crit Care Med 2017; 45:891–898
114. Fonsmark L, Rasmussen YH, Carl P: Occurrence of withdrawal in critically ill sedated children. Crit Care Med 1999; 27:196–199
115. Ista E, van Dijk M, Gamel C, et al.: Withdrawal symptoms in children after long-term administration of sedatives and/or analgesics: A literature review. “Assessment remains troublesome”. Intensive Care Med 2007; 33:1396–1406
116. Anand KJ, Willson DF, Berger J, et al.; Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network: Tolerance and withdrawal from prolonged opioid use in critically ill children. Pediatrics 2010; 125:e1208–e1225
117. Johansson M, Kokinsky E: The COMFORT behavioural scale and the modified FLACC scale in paediatric intensive care. Nurs Crit Care 2009; 14:122–130
118. Boerlage AA, Ista E, Duivenvoorden HJ, et al.: The COMFORT behaviour scale detects clinically meaningful effects of analgesic and sedative treatment. Eur J Pain 2015; 19:473–479
119. Curley MA, Harris SK, Fraser KA, et al.: State behavioral scale: A sedation assessment instrument for infants and young children supported on mechanical ventilation. Pediatr Crit Care Med 2006; 7:107–114
120. Lebet R, Hayakawa J, Chamblee TB, et al.: Maintaining interrater agreement of core assessment instruments in a multisite randomized controlled clinical trial: The randomized evaluation of sedation titration for respiratory failure (RESTORE) trial. Nurs Res 2017; 66:323–329
121. Ge X, Zhang T, Zhou L: Psychometric analysis of subjective sedation scales used for critically ill paediatric patients. Nurs Crit Care 2018; 23:30–41
122. Kerson AG, DeMaria R, Mauer E, et al.: Validity of the Richmond Agitation-Sedation Scale (RASS) in critically ill children. J Intensive Care 2016; 4:65
123. Dreyfus L, Javouhey E, Denis A, et al.: Implementation and evaluation of a paediatric nurse-driven sedation protocol in a paediatric intensive care unit. Ann Intensive Care 2017; 7:36
124. Jin HS, Yum MS, Kim SL, et al.: The efficacy of the COMFORT scale in assessing optimal sedation in critically ill children requiring mechanical ventilation. J Korean Med Sci 2007; 22:693–697
125. Deeter KH, King MA, Ridling D, et al.: Successful implementation of a pediatric sedation protocol for mechanically ventilated patients. Crit Care Med 2011; 39:683–688
126. Gaillard-Le Roux B, Liet JM, Bourgoin P, et al.: Implementation of a nurse-driven sedation protocol in a PICU decreases daily doses of midazolam. Pediatr Crit Care Med 2017; 18:e9–e17
127. Kongkiattikul L, Dagenais M, Ruo N, et al.: The impact of a quality improvement project to standardize pain, agitation, and withdrawal assessments on the use of morphine and midazolam in the pediatric intensive care unit. Paediatr Anaesth 2019; 29:322–330
128. Larson GE, McKeever S: Nurse titrated analgesia and sedation in intensive care increases the frequency of comfort assessment and reduces midazolam use in paediatric patients following cardiac surgery. Aust Crit Care 2018; 31:31–36
129. Neunhoeffer F, Kumpf M, Renk H, et al.: Nurse-driven pediatric analgesia and sedation protocol reduces withdrawal symptoms in critically ill medical pediatric patients. Paediatr Anaesth 2015; 25:786–794
130. Neunhoeffer F, Seitz G, Schmidt A, et al.: Analgesia and sedation protocol for mechanically ventilated postsurgical children reduces benzodiazepines and withdrawal symptoms-but not in all patients. Eur J Pediatr Surg 2017; 27:255–262
131. Saelim K, Chavananon S, Ruangnapa K, et al.: Effectiveness of protocolized sedation utilizing the COMFORT-B scale in mechanically ventilated children in a pediatric intensive care unit. J Pediatr Intensive Care 2019; 8:156–163
132. Verlaat CW, Heesen GP, Vet NJ, et al.: Randomized controlled trial of daily interruption of sedatives in critically ill children. Paediatr Anaesth 2014; 24:151–156
133. Vet NJ, de Wildt SN, Verlaat CW, et al.: A randomized controlled trial of daily sedation interruption in critically ill children. Intensive Care Med 2016; 42:233–244
134. Gupta K, Gupta VK, Jayashree M, et al.: Randomized controlled trial of interrupted versus continuous sedative infusions in ventilated children. Pediatr Crit Care Med 2012; 13:131–135
135. da Silva PS, de Aguiar VE, Neto HM, et al.: Unplanned extubation in a paediatric intensive care unit: Impact of a quality improvement programme. Anaesthesia 2008; 63:1209–1216
136. Kaufman J, Rannie M, Kahn MG, et al.: An interdisciplinary initiative to reduce unplanned extubations in pediatric critical care units. Pediatrics 2012; 129:e1594–e1600
137. Popernack ML, Thomas NJ, Lucking SE: Decreasing unplanned extubations: Utilization of the Penn State Children’s Hospital sedation algorithm. Pediatr Crit Care Med 2004; 5:58–62
138. Rachman BR, Watson R, Woods N, et al.: Reducing unplanned extubations in a pediatric intensive care unit: A systematic approach. Int J Pediatr 2009; 2009:820495
139. Sadowski R, Dechert RE, Bandy KP, et al.: Continuous quality improvement: Reducing unplanned extubations in a pediatric intensive care unit. Pediatrics 2004; 114:628–632
140. Tripathi S, Nunez DJ, Katyal C, et al.: Plan to have no unplanned: A collaborative, hospital-based quality-improvement project to reduce the rate of unplanned extubations in the pediatric ICU. Respir Care 2015; 60:1105–1112
141. Aydogan MS, Korkmaz MF, Ozgül U, et al.: Pain, fentanyl consumption, and delirium in adolescents after scoliosis surgery: Dexmedetomidine vs midazolam. Paediatr Anaesth 2013; 23:446–452
142. Fagin A, Palmieri T, Greenhalgh D, et al.: A comparison of dexmedetomidine and midazolam for sedation in severe pediatric burn injury. J Burn Care Res 2012; 33:759–763
143. Garisto C, Ricci Z, Tofani L, et al.: Use of low-dose dexmedetomidine in combination with opioids and midazolam in pediatric cardiac surgical patients: Randomized controlled trial. Minerva Anestesiol 2018; 84:1053–1062
144. Hünseler C, Balling G, Röhlig C, et al.; Clonidine Study Group: Continuous infusion of clonidine in ventilated newborns and infants: A randomized controlled trial. Pediatr Crit Care Med 2014; 15:511–522
145. Tobias JD, Berkenbosch JW: Sedation during mechanical ventilation in infants and children: Dexmedetomidine versus midazolam. South Med J 2004; 97:451–455
146. Wolf A, McKay A, Spowart C, et al.: Prospective multicentre randomised, double-blind, equivalence study comparing clonidine and midazolam as intravenous sedative agents in critically ill children: The SLEEPS (safety profile, efficacy and equivalence in paediatric intensive care sedation) study. Health Technol Assess 2014; 18:1–212
147. Jiang L, Ding S, Yan H, et al.: A retrospective comparison of dexmedetomidine versus midazolam for pediatric patients with congenital heart disease requiring postoperative sedation. Pediatr Cardiol 2015; 36:993–999
148. Arenas-López S, Riphagen S, Tibby SM, et al.: Use of oral clonidine for sedation in ventilated paediatric intensive care patients. Intensive Care Med 2004; 30:1625–1629
149. Salarian S, Khosravi R, Khanbabaei G, et al.: Impact of oral clonidine on duration of opioid and benzodiazepine use in mechanically ventilated children: A randomized, double-blind, placebo-controlled study. Iran J Pharm Res 2019; 18:2157–2162
150. Mody K, Kaur S, Mauer EA, et al.: Benzodiazepines and development of delirium in critically ill children: Estimating the causal effect. Crit Care Med 2018; 46:1486–1491
151. Smith HAB, Gangopadhyay M, Goben CM, et al.: Delirium and benzodiazepines associated with prolonged ICU stay in critically ill infants and young children. Crit Care Med 2017; 45:1427–1435
152. Traube C, Silver G, Reeder RW, et al.: Delirium in critically ill children: An international point prevalence study. Crit Care Med 2017; 45:584–590
153. Ghimire LV, Chou FS: Efficacy of prophylactic dexmedetomidine in preventing postoperative junctional ectopic tachycardia in pediatric cardiac surgery patients: A systematic review and meta-analysis. Paediatr Anaesth 2018; 28:597–606
154. Li X, Zhang C, Dai D, et al.: Efficacy of dexmedetomidine in prevention of junctional ectopic tachycardia and acute kidney injury after pediatric cardiac surgery: A meta-analysis. Congenit Heart Dis 2018; 13:799–807
155. Prasad SR, Simha PP, Jagadeesh AM: Comparative study between dexmedetomidine and fentanyl for sedation during mechanical ventilation in post-operative paediatric cardiac surgical patients. Indian J Anaesth 2012; 56:547–552
156. Gupta P, Whiteside W, Sabati A, et al.: Safety and efficacy of prolonged dexmedetomidine use in critically ill children with heart disease. Pediatr Crit Care Med 2012; 13:660–666
157. Hasegawa T, Oshima Y, Maruo A, et al.: Dexmedetomidine in combination with midazolam after pediatric cardiac surgery. Asian Cardiovasc Thorac Ann 2015; 23:802–808
158. Su X, Meng ZT, Wu XH, et al.: Dexmedetomidine for prevention of delirium in elderly patients after non-cardiac surgery: A randomised, double-blind, placebo-controlled trial. Lancet 2016; 388:1893–1902
159. Kwiatkowski DM, Axelrod DM, Sutherland SM, et al.: Dexmedetomidine is associated with lower incidence of acute kidney injury after congenital heart surgery. Pediatr Crit Care Med 2016; 17:128–134
160. Bray RJ: Propofol infusion syndrome in children. Paediatr Anaesth 1998; 8:491–499
161. Parke TJ, Stevens JE, Rice AS, et al.: Metabolic acidosis and fatal myocardial failure after propofol infusion in children: Five case reports. BMJ 1992; 305:613–616
162. Rigby-Jones AE, Nolan JA, Priston MJ, et al.: Pharmacokinetics of propofol infusions in critically ill neonates, infants, and children in an intensive care unit. Anesthesiology 2002; 97:1393–1400
163. Cray SH, Holtby HM, Kartha VM, et al.: Early tracheal extubation after paediatric cardiac surgery: The use of propofol to supplement low-dose opioid anaesthesia. Paediatr Anaesth 2001; 11:465–471
164. Martin PH, Murthy BV, Petros AJ: Metabolic, biochemical and haemodynamic effects of infusion of propofol for long-term sedation of children undergoing intensive care. Br J Anaesth 1997; 79:276–279
165. Svensson ML, Lindberg L: The use of propofol sedation in a paediatric intensive care unit. Nurs Crit Care 2012; 17:198–203
166. Timpe EM, Eichner SF, Phelps SJ: Propofol-related infusion syndrome in critically ill pediatric patients: coincidence, association, or causation? J Pediatr Pharmacol Ther 2006; 11:17–42
167. Teng SN, Kaufman J, Czaja AS, et al.: Propofol as a bridge to extubation for high-risk children with congenital cardiac disease. Cardiol Young 2011; 21:46–51
168. Sheridan RL, Keaney T, Stoddard F, et al.: Short-term propofol infusion as an adjunct to extubation in burned children. J Burn Care Rehabil 2003; 24:356–360
169. Neunhoeffer F, Hanser A, Esslinger M, et al.: Ketamine infusion as a counter measure for opioid tolerance in mechanically ventilated children: A pilot study. Paediatr Drugs 2017; 19:259–265
170. Heiberger AL, Ngorsuraches S, Olgun G, et al.: Safety and utility of continuous ketamine infusion for sedation in mechanically ventilated pediatric patients. J Pediatr Pharmacol Ther 2018; 23:447–454
171. Kaul HL, Bhaskaran K, Saxena N, et al.: Alterations in intracranial pressure following ketamine anesthesia in hydrocephalic children. Indian J Pediatr 1984; 51:25–28
172. Wyte SR, Shapiro HM, Turner P, et al.: Ketamine-induced intracranial hypertension. Anesthesiology 1972; 36:174–176
173. Crumrine RS, Nulsen FE, Weiss MH: Alterations in ventricular fluid pressure during ketamine anesthesia in hydrocephalic children. Anesthesiology 1975; 42:758–761
174. Bar-Joseph G, Guilburd Y, Tamir A, et al.: Effectiveness of ketamine in decreasing intracranial pressure in children with intracranial hypertension. J Neurosurg Pediatr 2009; 4:40–46
175. Tobias JD: The use of neuromuscular-blocking agents in children. Pediatr Ann 1997; 26:482–489
176. Jacobi J, Farrington EA: Supportive care of the critically ill patient. In: Pharmacology Self-Assessment Program, Critical Care, Module 2. Carter BL, Lake KD, Raebel MA, et al (Eds). Kansas City, MO American College of Clinical Pharmacy, 1998, pp 129–159
177. Jurado L, Allison TA, Bulbis B, et al.: Neuromuscular blocking agents. In: Casebook in Clinical Pharmacokinetics and Drug Dosing. Cohen H (Ed). New York, McGraw-Hill Publishing, 2015
178. Johnson PN, Miller J, Gormley AK: Continuous-infusion neuromuscular blocking agents in critically ill neonates and children. Pharmacotherapy 2011; 31:609–620
179. Foster JG, Kish SK, Keenan CH: A national survey of critical care nurses’ practices related to administration of neuromuscular blocking agents. Am J Crit Care 2001; 10:139–145
180. Rhoney DH, Murry KR: National survey on the use of sedatives and neuromuscular blocking agents in the pediatric intensive care unit. Pediatr Crit Care Med 2002; 3:129–133
181. Martin LD, Bratton SL, Quint P, et al.: Prospective documentation of sedative, analgesic, and neuromuscular blocking agent use in infants and children in the intensive care unit: A multicenter perspective. Pediatr Crit Care Med 2001; 2:205–210
182. Frankel H, Jeng J, Tilly E, et al.: The impact of implementation of neuromuscular blockade monitoring standards in a surgical intensive care unit. Am Surg 1996; 62:503–506
183. Mueller SW, Winn R, Macht M, et al.: Neuromuscular blockade resistance during therapeutic hypothermia. Ann Pharmacother 2011; 45:e15
184. Playfor S, Jenkins I, Boyles C, et al.; United Kingdom Paediatric Intensive Care Society Sedation, Analgesia and Neuromuscular Blockade Working Group: Consensus guidelines for sustained neuromuscular blockade in critically ill children. Paediatr Anaesth 2007; 17:881–887
185. Zuppa AF, Curley MAQ: Sedation analgesia and neuromuscular blockade in pediatric critical care: Overview and current landscape. Pediatr Clin North Am 2017; 64:1103–1116
186. Johansen JW, Sebel PS: Development and clinical application of electroencephalographic bispectrum monitoring. Anesthesiology 2000; 93:1336–1344
187. Nievas IF, Spentzas T, Bogue CW: SNAP II index: An alternative to the COMFORT scale in assessing the level of sedation in mechanically ventilated pediatric patients. J Intensive Care Med 2014; 29:225–228
188. Thompson C, Shabanova V, Giuliano JS Jr: The SNAP index does not correlate with the state behavioral scale in intubated and sedated children. Paediatr Anaesth 2013; 23:1174–1179
189. Klebermass K, Olischar M, Waldhoer T, et al.: Amplitude-integrated EEG pattern predicts further outcome in preterm infants. Pediatr Res 2011; 70:102–108
190. Benavente-Fernández I, Lubián-López SP, Jiménez-Gómez G, et al.: Low-voltage pattern and absence of sleep-wake cycles are associated with severe hemorrhage and death in very preterm infants. Eur J Pediatr 2015; 174:85–90
191. Shellhaas RA, Kushwaha JS, Plegue MA, et al.: An evaluation of cerebral and systemic predictors of 18-month outcomes for neonates with hypoxic ischemic encephalopathy. J Child Neurol 2015; 30:1526–1531
192. Triltsch AE, Nestmann G, Orawa H, et al.: Bispectral index versus COMFORT score to determine the level of sedation in paediatric intensive care unit patients: A prospective study. Crit Care 2005; 9:R9–17
193. Twite MD, Zuk J, Gralla J, et al.: Correlation of the bispectral index monitor with the COMFORT scale in the pediatric intensive care unit. Pediatr Crit Care Med 2005; 6:648–53; quiz 654
194. Courtman SP, Wardurgh A, Petros AJ: Comparison of the bispectral index monitor with the Comfort score in assessing level of sedation of critically ill children. Intensive Care Med 2003; 29:2239–2246
195. Berkenbosch JW, Fichter CR, Tobias JD: The correlation of the bispectral index monitor with clinical sedation scores during mechanical ventilation in the pediatric intensive care unit. Anesth Analg 2002; 94:506–511; table of contents
196. Crain N, Slonim A, Pollack MM: Assessing sedation in the pediatric intensive care unit by using BIS and the COMFORT scale. Pediatr Crit Care Med 2002; 3:11–14
197. Grindstaff RJ, Tobias JD: Applications of bispectral index monitoring in the pediatric intensive care unit. J Intensive Care Med 2004; 19:111–116
198. Amigoni A, Mozzo E, Brugnaro L, et al.: Assessing sedation in a pediatric intensive care unit using comfort behavioural scale and bispectral index: These tools are different. Minerva Anestesiol 2012; 78:322–329
199. Aneja R, Heard AM, Fletcher JE, et al.: Sedation monitoring of children by the bispectral index in the pediatric intensive care unit. Pediatr Crit Care Med 2003; 4:60–64
200. Vivien B, Langeron O, Riou B: Increase in bispectral index (BIS) while correcting a severe hypoglycemia. Anesth Analg 2002; 95:1824–1825
201. Mychaskiw G, Heath BJ, Eichhorn JH: Falsely elevated bispectral index during deep hypothermic circulatory arrest. Br J Anaesth 2000; 85:798–800
202. Azim N, Wang CY: The use of bispectral index during a cardiopulmonary arrest: A potential predictor of cerebral perfusion. Anaesthesia 2004; 59:610–612
203. van Dijk M, Peters JW, van Deventer P, et al.: The COMFORT behavior scale: A tool for assessing pain and sedation in infants. Am J Nurs 2005; 105:33–36
204. Sury MR: Accidental awareness during anesthesia in children. Paediatr Anaesth 2016; 26:468–474
205. Valentine SL, Nadkarni VM, Curley MA; Pediatric Acute Lung Injury Consensus Conference Group: Nonpulmonary treatments for pediatric acute respiratory distress syndrome: Proceedings from the Pediatric Acute Lung Injury Consensus Conference. Pediatr Crit Care Med 2015; 16:S73–S85
206. Sorce LR, Hamilton SM, Gauvreau K, et al.: Preventing corneal abrasions in critically ill children receiving neuromuscular blockade: A randomized, controlled trial. Pediatr Crit Care Med 2009; 10:171–175
207. Lenart SB, Garrity JA: Eye care for patients receiving neuromuscular blocking agents or propofol during mechanical ventilation. Am J Crit Care 2000; 9:188–191
208. Imanaka H, Taenaka N, Nakamura J, et al.: Ocular surface disorders in the critically ill. Anesth Analg 1997; 85:343–346
209. Hernandez EV, Mannis MJ: Superficial keratopathy in intensive care unit patients. Am J Ophthalmol 1997; 124:212–216
210. Cortese D, Capp L, McKinley S: Moisture chamber versus lubrication for the prevention of corneal epithelial breakdown. Am J Crit Care 1995; 4:425–428
211. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders. Fifth Edition. Washington, DC, American Psychiatric Association, 2013
212. Flacker JM, Lipsitz LA: Neural mechanisms of delirium: Current hypotheses and evolving concepts. J Gerontol A Biol Sci Med Sci 1999; 54:B239–B246
213. Gunther ML, Morandi A, Krauskopf E, et al.; VISIONS Investigation, VISualizing Icu SurvivOrs Neuroradiological Sequelae: The association between brain volumes, delirium duration, and cognitive outcomes in intensive care unit survivors: The VISIONS cohort magnetic resonance imaging study. Crit Care Med 2012; 40:2022–2032
214. Karnik NS, Joshi SV, Paterno C, et al.: Subtypes of pediatric delirium: A treatment algorithm. Psychosomatics 2007; 48:253–257
215. Meagher DJ, Trzepacz PT: Motoric subtypes of delirium. Semin Clin Neuropsychiatry 2000; 5:75–85
216. Peterson JF, Pun BT, Dittus RS, et al.: Delirium and its motoric subtypes: A study of 614 critically ill patients. J Am Geriatr Soc 2006; 54:479–484
217. Siddiqi N, Harrison JK, Clegg A, et al.: Interventions for preventing delirium in hospitalised non-ICU patients. Cochrane Database Syst Rev 2016; 3:CD005563
218. Siddiqi N, House AO, Holmes JD: Occurrence and outcome of delirium in medical in-patients: A systematic literature review. Age Ageing 2006; 35:350–364
219. Grover S, Sharma A, Aggarwal M, et al.: Comparison of symptoms of delirium across various motoric subtypes. Psychiatry Clin Neurosci 2014; 68:283–291
220. Pandharipande P, Cotton BA, Shintani A, et al.: Motoric subtypes of delirium in mechanically ventilated surgical and trauma intensive care unit patients. Intensive Care Med 2007; 33:1726–1731
221. Alvarez RV, Palmer C, Czaja AS, et al.: Delirium is a common and early finding in patients in the pediatric cardiac intensive care unit. J Pediatr 2018; 195:206–212
222. Meyburg J, Dill ML, Traube C, et al.: Patterns of postoperative delirium in children. Pediatr Crit Care Med 2017; 18:128–133
223. Silver G, Traube C, Kearney J, et al.: Detecting pediatric delirium: development of a rapid observational assessment tool. Intensive Care Med 2012; 38:1025–1031
224. Simone S, Edwards S, Lardieri A, et al.: Implementation of an ICU bundle: An interprofessional quality improvement project to ehance delirium management and monitor delirium prevalence in a single PICU. Pediatr Crit Care Med 2017; 18:531–540
225. Smith HA, Boyd J, Fuchs DC, et al.: Diagnosing delirium in critically ill children: Validity and reliability of the pediatric confusion assessment method for the intensive care unit. Crit Care Med 2011; 39:150–157
226. Smith HA, Gangopadhyay M, Goben CM, et al.: The preschool confusion assessment method for the ICU: Valid and reliable delirium monitoring for critically ill infants and children. Crit Care Med 2016; 44:592–600
227. Traube C, Silver G, Kearney J, et al.: Cornell assessment of pediatric delirium: A valid, rapid, observational tool for screening delirium in the PICU. Crit Care Med 2014; 42:656–663
228. Cano Londoño EM, Mejía Gil IC, Uribe Hernández K, et al.: Delirium during the first evaluation of children aged five to 14 years admitted to a paediatric critical care unit. Intensive Crit Care Nurs 2018; 45:37–43
229. de Castro REV, Prata-Barbosa A, de Magalhães-Barbosa MC, et al.: Validity and reliability of the Brazilian Portuguese version of the pediatric confusion assessment method for the ICU. Pediatr Crit Care Med 2020; 21:e39–e46
230. Grover S, Kate N, Malhotra S, et al.: Symptom profile of delirium in children and adolescent–Does it differ from adults and elderly? Gen Hosp Psychiatry 2012; 34:626–632
231. Ista E, van Beusekom B, van Rosmalen J, et al.: Validation of the SOS-PD scale for assessment of pediatric delirium: A multicenter study. Crit Care 2018; 22:309
232. Luetz A, Gensel D, Müller J, et al.: Validity of different delirium assessment tools for critically ill children: Covariates matter. Crit Care Med 2016; 44:2060–2069
233. Matsuishi Y, Hoshino H, Shimojo N, et al.: Verifying the Japanese version of the preschool confusion assessment method for the ICU (psCAM-ICU). Acute Med Surg 2019; 6:287–293
234. Patel AK, Biagas KV, Clarke EC, et al.: Delirium in children after cardiac bypass surgery. Pediatr Crit Care Med 2017; 18:165–171
235. Schieveld JN, Leroy PL, van Os J, et al.: Pediatric delirium in critical illness: Phenomenology, clinical correlates and treatment response in 40 cases in the pediatric intensive care unit. Intensive Care Med 2007; 33:1033–1040
236. Rodríguez-Rubio M, Álvarez-Rojas E, de la Oliva P: The diagnosis of delirium in pediatric intensive care: A burdensome yet essential task. Med Intensiva (Engl Ed) 2020; 44:128
237. Dervan LA, Di Gennaro JL, Farris RWD, et al.: Delirium in a tertiary PICU: Risk factors and outcomes. Pediatr Crit Care Med 2020; 21:21–32
238. Silver G, Traube C, Gerber LM, et al.: Pediatric delirium and associated risk factors: A single-center prospective observational study. Pediatr Crit Care Med 2015; 16:303–309
239. Traube C, Ariagno S, Thau F, et al.: Delirium in hospitalized children with cancer: Incidence and associated risk factors. J Pediatr 2017; 191:212–217
240. Smeets IA, Tan EY, Vossen HG, et al.: Prolonged stay at the paediatric intensive care unit associated with paediatric delirium. Eur Child Adolesc Psychiatry 2010; 19:389–393
241. Paterson RS, Kenardy JA, De Young AC, et al.: Delirium in the critically ill child: Assessment and sequelae. Dev Neuropsychol 2017; 42:387–403
242. Canter MO, Tanguturi YC, Ellen Wilson J, et al.: Prospective validation of the preschool confusion assessment method for the ICU to screen for delirium in infants less than 6 months old. Crit Care Med 2021; 49:e902–e909
243. Valdivia HR, Carlin KE: Determining interrater reliability of the Cornell assessment of pediatric delirium screening tool among PICU nurses. Pediatr Crit Care Med 2019; 20:e216–e220
244. Silver GH, Kearney JA, Kutko MC, et al.: Infant delirium in pediatric critical care settings. Am J Psychiatry 2010; 167:1172–1177
245. Van Tuijl SG, Van Cauteren YJ, Pikhard T, et al.: Management of pediatric delirium in critical illness: A practical update. Minerva Anestesiol 2015; 81:333–341
246. Practice guideline for the treatment of patients with delirium. American Psychiatric Association. Am J Psychiatry 1999; 156:1–20
247. Smith HA, Brink E, Fuchs DC, et al.: Pediatric delirium: Monitoring and management in the pediatric intensive care unit. Pediatr Clin North Am 2013; 60:741–760
248. Patel AK, Bell MJ, Traube C: Delirium in pediatric critical care. Pediatr Clin North Am 2017; 64:1117–1132
249. Traube C, Silver G: Identify delirium, then investigate for underlying etiology. Pediatr Crit Care Med 2018; 19:86–87
250. Shukry M, Clyde MC, Kalarickal PL, et al.: Does dexmedetomidine prevent emergence delirium in children after sevoflurane-based general anesthesia? Paediatr Anaesth 2005; 15:1098–1104
251. Kain ZN, MacLaren JE, Herrmann L, et al.: Preoperative melatonin and its effects on induction and emergence in children undergoing anesthesia and surgery. Anesthesiology 2009; 111:44–49
252. Pandharipande PP, Pun BT, Herr DL, et al.: Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: The MENDS randomized controlled trial. JAMA 2007; 298:2644–2653
253. Maldonado JR, Wysong A, van der Starre PJ, et al.: Dexmedetomidine and the reduction of postoperative delirium after cardiac surgery. Psychosomatics 2009; 50:206–217
254. Riker RR, Shehabi Y, Bokesch PM, et al.; SEDCOM (Safety and Efficacy of Dexmedetomidine Compared with Midazolam) Study Group: Dexmedetomidine vs midazolam for sedation of critically ill patients: A randomized trial. JAMA 2009; 301:489–499
255. Su F, Hammer GB: Dexmedetomidine: Pediatric pharmacology, clinical uses and safety. Expert Opin Drug Saf 2011; 10:55–66
256. Reade MC, Eastwood GM, Bellomo R, et al.; DahLIA Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group: Effect of dexmedetomidine added to standard care on ventilator-free time in patients with agitated delirium: A randomized clinical trial. JAMA 2016; 315:1460–1468
257. Girard TD, Exline MC, Carson SS, et al.; MIND-USA Investigators: Haloperidol and ziprasidone for treatment of delirium in critical illness. N Engl J Med 2018; 379:2506–2516
258. Joyce C, Witcher R, Herrup E, et al.: Evaluation of the safety of quetiapine in treating delirium in critically ill children: A retrospective review. J Child Adolesc Psychopharmacol 2015; 25:666–670
259. Capino AC, Miller JL, Johnson PN: Clonidine for sedation and analgesia and withdrawal in critically ill infants and children. Pharmacotherapy 2016; 36:1290–1299
260. Schieveld JN, Leentjens AF: Delirium in severely ill young children in the pediatric intensive care unit (PICU). J Am Acad Child Adolesc Psychiatry 2005; 44:392–4; discussion 395
261. Trzepacz PT: Delirium. Advances in diagnosis, pathophysiology, and treatment. Psychiatr Clin North Am 1996; 19:429–448
262. Turkel SB, Hanft A: The pharmacologic management of delirium in children and adolescents. Paediatr Drugs 2014; 16:267–274
263. Franck LS, Harris SK, Soetenga DJ, et al.: The withdrawal assessment tool-1 (WAT-1): An assessment instrument for monitoring opioid and benzodiazepine withdrawal symptoms in pediatric patients. Pediatr Crit Care Med 2008; 9:573–580
264. Best KM, Boullata JI, Curley MA: Risk factors associated with iatrogenic opioid and benzodiazepine withdrawal in critically ill pediatric patients: A systematic review and conceptual model. Pediatr Crit Care Med 2015; 16:175–183
265. Oschman A, McCabe T, Kuhn RJ: Dexmedetomidine for opioid and benzodiazepine withdrawal in pediatric patients. Am J Health Syst Pharm 2011; 68:1233–1238
266. Fernández-Carrión F, Gaboli M, González-Celador R, et al.: Withdrawal syndrome in the pediatric intensive care unit. Incidence and risk factors. Med Intensiva 2013; 37:67–74
267. Ista E, de Hoog M, Tibboel D, et al.: Psychometric evaluation of the Sophia observation withdrawal symptoms scale in critically ill children. Pediatr Crit Care Med 2013; 14:761–769
268. Best KM, Wypij D, Asaro LA, et al.; Randomized Evaluation of Sedation Titration For Respiratory Failure Study Investigators: Patient, process, and system predictors of iatrogenic withdrawal syndrome in critically ill children. Crit Care Med 2017; 45:e7–e15
269. Katz R, Kelly HW, Hsi A: Prospective study on the occurrence of withdrawal in critically ill children who receive fentanyl by continuous infusion. Crit Care Med 1994; 22:763–767
270. Amigoni A, Mondardini MC, Vittadello I, et al.; Network of Paediatric Intensive Care Unit Study Group (TIPNet): Withdrawal assessment tool-1 monitoring in PICU: A multicenter study on iatrogenic withdrawal syndrome. Pediatr Crit Care Med 2017; 18:e86–e91
271. Franck LS, Naughton I, Winter I: Opioid and benzodiazepine withdrawal symptoms in paediatric intensive care patients. Intensive Crit Care Nurs 2004; 20:344–351
272. Ista E, van Dijk M, Gamel C, et al.: Withdrawal symptoms in critically ill children after long-term administration of sedatives and/or analgesics: A first evaluation. Crit Care Med 2008; 36:2427–2432
273. Thompson RZ, Gardner BM, Autry EB, et al.: Survey of the current use of dexmedetomidine and management of withdrawal symptoms in critically ill children. J Pediatr Pharmacol Ther 2019; 24:16–21
274. Banasch HL, Dersch-Mills DA, Boulter LL, et al.: Dexmedetomidine use in a pediatric intensive care unit: A retrospective cohort study. Ann Pharmacother 2018; 52:133–139
275. Burbano NH, Otero AV, Berry DE, et al.: Discontinuation of prolonged infusions of dexmedetomidine in critically ill children with heart disease. Intensive Care Med 2012; 38:300–307
276. Carney L, Kendrick J, Carr R: Safety and effectiveness of dexmedetomidine in the pediatric intensive care unit (SAD-PICU). Can J Hosp Pharm 2013; 66:21–27
277. Haenecour AS, Seto W, Urbain CM, et al.: Prolonged dexmedetomidine infusion and drug withdrawal in critically ill children. J Pediatr Pharmacol Ther 2017; 22:453–460
278. Whalen LD, Di Gennaro JL, Irby GA, et al.: Long-term dexmedetomidine use and safety profile among critically ill children and neonates. Pediatr Crit Care Med 2014; 15:706–714
279. Hughes J, Gill A, Leach HJ, et al.: A prospective study of the adverse effects of midazolam on withdrawal in critically ill children. Acta Paediatr 1994; 83:1194–1199
280. Kaltenbach K, Finnegan LP: Neonatal abstinence syndrome, pharmacotherapy and developmental outcome. Neurobehav Toxicol Teratol 1986; 8:353–355
281. Finnegan LP, Connaughton JF Jr, Kron RE, et al.: Neonatal abstinence syndrome: Assessment and management. Addict Dis 1975; 2:141–158
282. Franck LS, Scoppettuolo LA, Wypij D, et al.: Validity and generalizability of the Withdrawal Assessment Tool-1 (WAT-1) for monitoring iatrogenic withdrawal syndrome in pediatric patients. Pain 2012; 153:142–148
283. Ista E, van Dijk M, de Hoog M, et al.: Construction of the Sophia observation withdrawal symptoms-scale (SOS) for critically ill children. Intensive Care Med 2009; 35:1075–1081
284. Chiu AW, Contreras S, Mehta S, et al.: Iatrogenic opioid withdrawal in critically ill patients: A review of assessment tools and management. Ann Pharmacother 2017; 51:1099–1111
285. Bichaff P, Setani KT, Motta EHG, et al.: Opioid tapering and weaning protocols in pediatric critical care units: A systematic review. Rev Assoc Med Bras (1992) 2018; 64:909–915
286. Meyer MM, Berens RJ: Efficacy of an enteral 10-day methadone wean to prevent opioid withdrawal in fentanyl-tolerant pediatric intensive care unit patients. Pediatr Crit Care Med 2001; 2:329–333
287. Bowens CD, Thompson JA, Thompson MT, et al.: A trial of methadone tapering schedules in pediatric intensive care unit patients exposed to prolonged sedative infusions. Pediatr Crit Care Med 2011; 12:504–511
288. Berens RJ, Meyer MT, Mikhailov TA, et al.: A prospective evaluation of opioid weaning in opioid-dependent pediatric critical care patients. Anesth Analg 2006; 102:1045–1050
289. Dervan LA, Yaghmai B, Watson RS, et al.: The use of methadone to facilitate opioid weaning in pediatric critical care patients: A systematic review of the literature and meta-analysis. Paediatr Anaesth 2017; 27:228–239
290. Siddappa R, Fletcher JE, Heard AM, et al.: Methadone dosage for prevention of opioid withdrawal in children. Paediatr Anaesth 2003; 13:805–810
291. Lugo RA, MacLaren R, Cash J, et al.: Enteral methadone to expedite fentanyl discontinuation and prevent opioid abstinence syndrome in the PICU. Pharmacotherapy 2001; 21:1566–1573
292. van der Vossen AC, van Nuland M, Ista EG, et al.: Oral lorazepam can be substituted for intravenous midazolam when weaning paediatric intensive care patients off sedation. Acta Paediatr 2018; 107:1594–1600
293. Deutsch ES, Nadkarni VM: Clonidine prophylaxis for narcotic and sedative withdrawal syndrome following laryngotracheal reconstruction. Arch Otolaryngol Head Neck Surg 1996; 122:1234–1238
294. Lee MM, Caylor K, Gockenbach N: Evaluating the transition from dexmedetomidine to clonidine for the prevention of withdrawal in critically ill pediatric patients. J Pediatr Pharmacol Ther 2020; 25:104–110
295. Lardieri AB, Fusco NM, Simone S, et al.: Effects of clonidine on withdrawal from long-term dexmedetomidine in the pediatric patient. J Pediatr Pharmacol Ther 2015; 20:45–53
296. Abdouni R, Reyburn-Orne T, Youssef TH, et al.: Impact of a standardized treatment guideline for pediatric iatrogenic opioid dependence: A quality improvement initiative. J Pediatr Pharmacol Ther 2016; 21:54–65
297. Amirnovin R, Sanchez-Pinto LN, Okuhara C, et al.: Implementation of a risk-stratified opioid and benzodiazepine weaning protocol in a pediatric cardiac ICU. Pediatr Crit Care Med 2018; 19:1024–1032
298. Sanchez-Pinto LN, Nelson LP, Lieu P, et al.: Implementation of a risk-stratified opioid weaning protocol in a pediatric intensive care unit. J Crit Care 2018; 43:214–219
299. Vipond JM, Heiberger AL, Thompson PA, et al.: Shortened taper duration after implementation of a standardized protocol for iatrogenic benzodiazepine and opioid withdrawal in pediatric patients: Results of a cohort study. Pediatr Qual Saf 2018; 3:e079
300. Solodiuk JC, Greco CD, O’Donnell KA, et al.: Effect of a sedation weaning protocol on safety and medication use among hospitalized children post critical illness. J Pediatr Nurs 2019; 49:18–23
301. Davidson JE, Aslakson RA, Long AC, et al.: Guidelines for family-centered care in the neonatal, pediatric, and adult ICU. Crit Care Med 2017; 45:103–128
302. Playfor S, Thomas D, Choonara I: Recollection of children following intensive care. Arch Dis Child 2000; 83:445–448
303. Chahraoui K, Laurent A, Bioy A, et al.: Psychological experience of patients 3 months after a stay in the intensive care unit: A descriptive and qualitative study. J Crit Care 2015; 30:599–605
304. Bonnet MH, Berry RB, Arand DL: Metabolism during normal, fragmented, and recovery sleep. J Appl Physiol (1985) 1991; 71:1112–1118
305. Akerstedt T, Palmblad J, de la Torre B, et al.: Adrenocortical and gonadal steroids during sleep deprivation. Sleep 1980; 3:23–30
306. Palmblad J, Cantell K, Strander H, et al.: Stressor exposure and immunological response in man: Interferon-producing capacity and phagocytosis. J Psychosom Res 1976; 20:193–199
307. Palmblad J, Petrini B, Wasserman J, et al.: Lymphocyte and granulocyte reactions during sleep deprivation. Psychosom Med 1979; 41:273–278
308. Christensen J, Noel M, Mychasiuk R: Neurobiological mechanisms underlying the sleep-pain relationship in adolescence: A review. Neurosci Biobehav Rev 2019; 96:401–413
309. Roehrs T, Hyde M, Blaisdell B, et al.: Sleep loss and REM sleep loss are hyperalgesic. Sleep 2006; 29:145–151
310. Patel J, Baldwin J, Bunting P, et al.: The effect of a multicomponent multidisciplinary bundle of interventions on sleep and delirium in medical and surgical intensive care patients. Anaesthesia 2014; 69:540–549
311. Corser NC: Sleep of 1- and 2-year-old children in intensive care. Issues Compr Pediatr Nurs 1996; 19:17–31
312. Al-Samsam RH, Cullen P: Sleep and adverse environmental factors in sedated mechanically ventilated pediatric intensive care patients. Pediatr Crit Care Med 2005; 6:562–567
313. Cureton-Lane RA, Fontaine DK: Sleep in the pediatric ICU: An empirical investigation. Am J Crit Care 1997; 6:56–63
314. Kukreti V, Shamim M, Khilnani P: Intensive care unit acquired weakness in children: Critical illness polyneuropathy and myopathy. Indian J Crit Care Med 2014; 18:95–101
315. Choong K, Foster G, Fraser DD, et al.; Canadian Critical Care Trials Group: Acute rehabilitation practices in critically ill children: A multicenter study. Pediatr Crit Care Med 2014; 15:e270–e279
316. Tsuboi N, Hiratsuka M, Kaneko S, et al.: Benefits of early mobilization after pediatric liver transplantation. Pediatr Crit Care Med 2019; 20:e91–e97
317. Tsuboi N, Nozaki H, Ishida Y, et al.: Early mobilization after pediatric liver transplantation. J Pediatr Intensive Care 2017; 6:199–205
318. Choong K, Awladthani S, Khawaji A, et al.; Canadian Critical Care Trials Group: Early exercise in critically ill youth and children, a preliminary evaluation: The wEECYCLE Pilot Trial. Pediatr Crit Care Med 2017; 18:e546–e554
319. Choong K, Chacon MDP, Walker RG, et al.: In-bed mobilization in critically ill children: A safety and feasibility trial. J Pediatr Intensive Care 2015; 4:225–234
320. Choong K, Fraser D, Al-Harbi S, et al.: Functional recovery in critically ill children, the “WeeCover” multicenter study. Pediatr Crit Care Med 2018; 19:145–154
321. Wieczorek B, Ascenzi J, Kim Y, et al.: PICU Up!: Impact of a quality improvement intervention to promote early mobilization in critically ill children. Pediatr Crit Care Med 2016; 17:e559–e566
322. Ista E, Redivo J, Kananur P, et al.: ABCDEF Bundle Practices for Critically Ill Children: An International Survey of 161 PICUs in 18 Countries. Crit Care Med 2022; 50:114-125
323. Ista E, Scholefield BR, Manning JC, et al.; EU PARK-PICU Collaborators: Mobilization practices in critically ill children: A European point prevalence study (EU PARK-PICU). Crit Care 2020; 24:368
324. Bauchner H, Vinci R, Bak S, et al.: Parents and procedures: A randomized controlled trial. Pediatrics 1996; 98:861–867
325. Béranger A, Pierron C, de Saint Blanquat L, et al.: Communication, information, and roles of parents in the pediatric intensive care unit: A review article. Arch Pediatr 2017; 24:265–272
326. Davidson JE: Family-centered care: Meeting the needs of patients’ families and helping families adapt to critical illness. Crit Care Nurse 2009; 29:28–34; quiz 35
327. Maxton FJ: Parental presence during resuscitation in the PICU: The parents’ experience. Sharing and surviving the resuscitation: A phenomenological study. J Clin Nurs 2008; 17:3168–3176
328. McAlvin SS, Carew-Lyons A: Family presence during resuscitation and invasive procedures in pediatric critical care: A systematic review. Am J Crit Care 2014; 23:477–84; quiz 485
329. Piira T, Sugiura T, Champion GD, et al.: The role of parental presence in the context of children’s medical procedures: A systematic review. Child Care Health Dev 2005; 31:233–243
330. Smith AB, Hefley GC, Anand KJ: Parent bed spaces in the PICU: Effect on parental stress. Pediatr Nurs 2007; 33:215–221
331. Çakmak E, Karaçam Z: The correlation between mothers’ participation in infant care in the NICU and their anxiety and problem-solving skill levels in caregiving. J Matern Fetal Neonatal Med 2018; 31:21–31
332. Rennick JE, Stremler R, Horwood L, et al.: A pilot randomized controlled trial of an intervention to promote psychological well-being in critically ill children: Soothing through touch, reading, and music. Pediatr Crit Care Med 2018; 19:e358–e366
333. Sanders RC Jr, Nett ST, Davis KF, et al.; National Emergency Airway Registry for Children NEAR4KIDS Investigators; Pediatric Acute Lung Injury and Sepsis Investigators Network: Family presence during pediatric tracheal intubations. JAMA Pediatr 2016; 170:e154627
334. Bailey E, Timmons S: Noise levels in PICU: An evaluative study. Paediatr Nurs 2005; 17:22–26
335. Kramer B, Joshi P, Heard C: Noise pollution levels in the pediatric intensive care unit. J Crit Care 2016; 36:111–115
336. Milette IH, Carnevale FA: I’m trying to heal…noise levels in a pediatric intensive care unit. Dynamics 2003; 14:14–21
337. Zahr LK, de Traversay J: Premature infant responses to noise reduction by earmuffs: Effects on behavioral and physiologic measures. J Perinatol 1995; 15:448–455
338. Jousselme C, Vialet R, Jouve E, et al.: Efficacy and mode of action of a noise-sensor light alarm to decrease noise in the pediatric intensive care unit: A prospective, randomized study. Pediatr Crit Care Med 2011; 12:e69–e72
339. Wang D, Aubertin C, Barrowman N, et al.: Reduction of noise in the neonatal intensive care unit using sound-activated noise meters. Arch Dis Child Fetal Neonatal Ed 2014; 99:F515–F516
340. Elander G, Hellström G: Reduction of noise levels in intensive care units for infants: Evaluation of an intervention program. Heart Lung 1995; 24:376–379
341. Liu WF; NIC/Q 2005 Physical Environment Exploratory Group: The impact of a noise reduction quality improvement project upon sound levels in the open-unit-design neonatal intensive care unit. J Perinatol 2010; 30:489–496
342. Khalesi N, Khosravi N, Ranjbar A, et al.: The effectiveness of earmuffs on the physiologic and behavioral stability in preterm infants. Int J Pediatr Otorhinolaryngol 2017; 98:43–47
343. Duran R, Ciftdemir NA, Ozbek UV, et al.: The effects of noise reduction by earmuffs on the physiologic and behavioral responses in very low birth weight preterm infants. Int J Pediatr Otorhinolaryngol 2012; 76:1490–1493
344. Abdeyazdan Z, Ghasemi S, Marofi M, et al.: Motor responses and weight gaining in neonates through use of two methods of earmuff and receiving silence in NICU. ScientificWorldJournal 2014; 2014:864780
345. Fink EL, Beers SR, Houtrow AJ, et al.; PICU-Rehabilitation Study Group: Early protocolized versus usual care rehabilitation for pediatric neurocritical care patients: A randomized controlled trial. Pediatr Crit Care Med 2019; 20:540–550
346. Betters KA, Hebbar KB, Farthing D, et al.: Development and implementation of an early mobility program for mechanically ventilated pediatric patients. J Crit Care 2017; 41:303–308
347. Colwell BRL, Williams CN, Kelly SP, et al.: Mobilization therapy in the pediatric intensive care unit: A multidisciplinary quality improvement initiative. Am J Crit Care 2018; 27:194–203
348. Hanna ES, Zhao S, Shannon CN, et al.: Changes in provider perceptions regarding early mobility in the PICU. Pediatr Crit Care Med 2020; 21:e30–e38