Signa Vitae. 2023; 19(5): 38-46. doi: 10.22514/sv.2023.007
Review

Procedural sedation and analgesia in the pediatric intensive care unit

Ivana Budic1,2,*,, Vesna Marjanovic1,2, Ivona Djordjevic2,3, Marija Stevic4,5, Dragoljub Zivanovic2,3, Dusica Simic4,5

1Clinic for Anesthesiology and Intensive Care, University Clinical Centre Nis, 18000 Nis, Serbia

2Medical Faculty, University of Nis, 18000 Nis, Serbia

3Clinic for Children’s Surgery, University Clinical Centre Nis, 18000 Nis, Serbia

4University Children’s Hospital, 11000 Belgrade, Serbia

5Medical Faculty, University of Belgrade, 11000 Belgrade, Serbia

*Corresponding Author(s):md.ivanabudic@gmail.com (Ivana Budic)

History Submitted: 28 June 2022 | Accepted: 30 August 2022 | Published: 08 September 2023
Copyright:  ©2023  The Author(s). Published by MRE Press.
This is an open access article under the CC BY 4.0 license (https://creativecommons.org/licenses/by/4.0/).

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Abstract

Children frequently experience more painful, stressful, and traumatic medical procedures and treatments in the pediatric intensive care unit (PICU) than when they are hospitalized in general wards. An essential part of care in the PICU is providing critically ill children with appropriate sedation and analgesia. Finding the perfect combination of adequate analgesia and sufficient sedation in a patient group with a wide range of ages, sizes, and developmental stages can be challenging. Administration of sedatives and analgesics to critically ill patients may be challenging and complicated by unpredictable pharmacokinetics (PK) and pharmacodynamics (PD). It is important to keep in mind that optimal agents for procedural sedation and analgesia (PSA) differ from those used for long-term sedation in the PICU. In addition to pharmacological measures, different non-pharmacological methods can be applied and have been shown to be effective for pain relief in children. Efforts are being made to improve PSA management with the use of national surveys, recommendations and guidelines.

Keywords:Procedural sedationProcedural analgesiaNeonateChildIntensive care unit
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Cite this article

Ivana Budic, Vesna Marjanovic, Ivona Djordjevic, Marija Stevic, Dragoljub Zivanovic, Dusica Simic. Procedural sedation and analgesia in the pediatric intensive care unit. Signa Vitae. 2023; 19(5): 38-46. doi: 10.22514/sv.2023.007

1. Introduction

Due to the nature of the pediatric intensive care unit (PICU), children frequently undergo more painful and stressful medical procedures and traumatic treatments than children who are hospitalized in general wards [1]. As opposed to adults, most children are unable to comprehend the necessity of medical intervention and often refuse to comply with medical professionals. Furthermore, children require invasive testing, monitoring, and challenging, frightful medical procedures in the PICU, requiring the administration of analgesics and sedatives [2]. Even in the PICU, pediatric patients have historically, for a long time, been restrained physically during procedures [3]. Because untreated pain frequently has both short- and long-term physiological, physical, and psychological consequences for children, it is practically necessary to relieve fear and procedural pain in children [4].

Procedural sedation and analgesia (PSA) are defined as the administration of amnestic, anxiolytic, or analgesic agents, which facilitates the completion of painful procedures, ensures the immobility and safety of the patient, and prevents the child from remembering or feeling the interventions [5, 6]. PSA practices need to be based on valid, high-fidelity research [7]. Finding the perfect combination of adequate analgesia and sufficient sedation in a patient group with a wide range of ages, sizes, and developmental stages can be challenging [2]. The added difficulties of critical illness in the pediatric population, such as evolving pathophysiology, impaired organ function, and changed pharmacodynamics and pharmacokinetics, must be considered [8].

Undersedation induces physical and psychological distress, may lead to adverse events such as unplanned extubation and unintended removal of catheters, and may also have long-term consequences. On the other hand, excessive sedation puts the child at risk of prolonged respiratory support, an extended stay in the intensive care unit, the development of tolerance to opioids and benzodiazepines, as well as an elevated possibility of withdrawal syndrome [9]. Interventions to reduce pain cannot be “one size fits all” due to the variability of this patient population. It is necessary to have a better grasp of the different types of pain and how they are identified and managed in PICUs [10]. Studies already conducted on PICUs have mostly used data gathered from adult intensive care unit (ICU) patients and have failed to take into account the heterogeneity of pediatric patients or the physiological, anatomical, and biological differences between children and adults [11].

With a focus on the issues that arise most frequently, the objective of this mini-review is to present the most recent and pertinent research that covers significant elements of procedural sedation and analgesia in the PICU.

2. Methods

The electronic search for this mini-review included three databases, PubMed, EMBASE, and Google Scholar, and used search terms: “procedural sedation”, “procedural analgesia”, “pediatric”, “neonate”, “infant”, “child”, “intensive care”. Articles containing full texts and studies involving newborns and children met the inclusion criteria. Articles that were not in English or that fell under the category of “gray literature” were excluded. A manual search among the cited references from the publications that were found in the initial round of searching led to the discovery of additional references. Seventy-one papers that were confirmed to be eligible for the study were found after the search was restricted to works published between 2010 and 2022. Due to a lack of available literature, papers published prior to 2010 were included for some issues.

3. Pharmacological aspects of PSA in PICU

3.1 Pharmacokinetics/pharmacodynamics

Very few studies have evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) properties of analgesic and sedative drugs in critically ill patients. Also, it is important to keep in mind that optimal agents for PSA differ from those used for long-term sedation in the PICU [6]. Despite the aforementioned, administration of sedatives and analgesics to critically ill patients may be challenging and complicated by unpredictable PK and PD due to internal factors (impaired organ function, drug interactions, altered protein binding, and fluctuating volumes of distribution) as well as external factors that can change the PK and PD of drugs (renal replacement therapy, extra-corporeal membrane oxygenation, therapeutic hypothermia) [2, 12]. The lowest dose of a drug with the highest therapeutic index for the procedure should be administered [7]. It should be emphasized that the PK and PD profiles of sedatives and analgesics in the PICU context have become even more complicated as a result of recent improvements in neonatal resuscitation and a significant decrease in mortality [2].

The PK of drugs in infants and children is strongly influenced by developmental changes in absorption, distribution, metabolism, and elimination. Children undergo many PK alterations as they grow and mature; drug distribution changes, hepatic enzymatic capacity matures, and renal function develops. P-glycoprotein expression is a cell membrane efflux transport protein crucial for the passage of opioids over the blood-brain barrier. The P-glycoprotein levels in the brain reach adult levels by the age of 3 to 6 months [13]. In comparison to adults and children, neonates and infants have higher fentanyl clearance and volume of distribution (Vd), which is likely due to increased hepatic blood flow and/or different protein binding [14]. The biotransformation capacities of all the phase I and II hepatic enzymes mature at different rates. For example, cytochrome P450 3A4 (CYP3A4) is responsible for primarily metabolizing midazolam. Because of the immature CYP3A4 enzyme activity in an infant, a decreased clearance of midazolam would be expected. As a result, the dosing regimen for adults cannot be simply or linearly extrapolated to children, especially in neonates and infants [15]. Polymorphisms of genes that participate in sedatives and analgesics metabolism promote the individual variability of drug response [16] and could contribute to the ontogenic alterations in drug disposition, drug response, and clinical application.

In everyday clinical practice it is noticed that the severity of the critical illness itself may have a significant impact on analgesia and sedation. For example, the underlying illness of a critically ill child (e.g., sepsis) will influence the response to the administered drug to be different compared to a healthy child [17].

3.2 Pharmacological agents

The choice of drug and the route of administration used during PSA in the PICU should consider the criteria related to the type of procedure that the patient will undergo, as well as the criteria related to the baseline state and comorbidities. Benzodiazepines and opioids are traditionally used for PSA in the PICU, α-2 agonists and intravenous anesthetics are used as adjuncts in the therapeutic arsenal.

Benzodiazepines are hypnotic sedative agents. They bind to postsynaptic gamma-aminobutyric acid (GABA) receptors and increase the permeability to chlorine ions, leading to hyperpolarization and stabilization of the neuronal membrane. Benzodiazepines have hepatic metabolism and renal excretion and exhibit pharmacological effects such as sedation, hypnosis, anxiety reduction, amnesia, muscle relaxation, and anticonvulsant effects [18]. Concerns about benzodiazepines have recently emerged. Drugs acting on the γ-aminobutyric acid (GABA) receptor might promote a neurotoxic effect, especially in patients younger than 3 years [19, 20]. Additionally, it has been found that benzodiazepines directly and dose-dependently contribute to the emergence of delirium in critically ill children [21, 22, 23].

Opioids modulate the cortical perception of pain. At equianalgesic doses, all of the µ-opioid receptor agonists have similar pharmacodynamic effects that include analgesia, respiratory depression, sedation, nausea and vomiting, pruritus, constipation, miosis, tolerance, and physical dependence. Elimination half-life is prolonged in neonates due to reduced hepatic activity and blood flow [24]. Fentanyl is the most commonly used analgesic for procedures and pain control in the PICU.

In contrast to opioids and benzodiazepines, α-2 agonists like clonidine and dexmedetomidine induce relatively minimal respiratory depression [6]. Dexmedetomidine (DEX), an α-2 agonist with characteristics resembling those of clonidine, has just lately become a procedural sedation alternative. While still providing anxiolysis, dexmedetomidine enables children to cooperate during procedures and keeps their respiratory drive. A highly selective agonist of the α-2 adrenergic receptor, DEX has a better pharmacokinetic profile than clonidine [6].

Propofol, a diisopropyphenol anesthetic and a GABA receptor agonist, is useful for procedural sedation in the PICU, because of its quick onset (30 sec), high potency, constant production of the required sedative effect, and brief duration of action (4–10 min) [2]. Propofol has several cardiovascular effects, with hypotension being the most significant.

Ketamine is an N-methyl-D-aspartate (NMDA) antagonist that has been available since the mid-20th century. It makes sense that ketamine is a useful opioid adjuvant because NMDA receptors have been proven to play a significant role in the development of central sensitization [25]. When administered intravenously, ketamine has a quick onset of 30 to 60 seconds; effective procedural sedation conditions are attained in 1 minute and last for up to 15 minutes.

Etomidate is a carboxylated imidazole ring-containing intravenous anesthetic agent used as an ultra-fast acting (onset 30–60 sec) sedative-hypnotic agent that binds to GABA receptors in the central nervous system (duration of action 5–15 min). As etomidate possesses limited analgesic properties, it should be coadministered with an analgesic drug [18].

The recommended doses of pharmacological agents used for PSA in the PICU are presented in Table 1. The key to success and safety is to titrate drugs based on the patient’s response and the onset time of the drug(s) administered [27].

Table 1.The recommended doses of pharmacological agents used for PSA in the PICU [6, 18, 26, 27].
Drug classRouteDosagePharmacodynamic propertiesIndications and special considerationsAdverse effects
Onset of actionDuration of action
Benzodiazepines
Midazolam
IV0.1–0.2 mg/kg1–3 min30–60 minMinimal sedationAccumulation in hepatic/renal failure
IM0.1–0.3 mg/kg5–10 minFast actingParadoxical CNS stimulatory effect
PO0.4–0.5 mg/kg10–30 min
IN0.2–0.4 mg/kg5–10 min
PR0.3–0.5 mg/kg10–30 min
Diazepam
IV0.04–0.3 mg/kg1–3 min25–60 minPoor choice for PSA due to long half-lifePain, phlebitis after IV administration
PO0.25–0.3 mg/kg30–60 min2–3 hAccumulation in hepatic/renal failure
PR0.25–0.5 mg/kg7–15 min2–3 h
Lorazepam
IV0.02–0.1 mg/kg1–5 min3–4 hPoor choice for PSAPropylene glycol toxicity
IM0.05 mg/kg10–20 min3–6 hMetabolism independent of liver and kidney functionCould cause acidosis seizures and renal failure
PO0.05 mg/kg30–60 min3–6 h
Alpha-2 agonists
Clonidine
IV1–2 µg/kg10 min3–7 hAnxiolysisBradycardia
IN3–4 µg/kg>30 minSlow onsetRebound hypertension
PO2–4 µg/kg90–120 minMinimal effect on respiratory function
Dexmedetomidine
IV1 µg/kg over 10 min5–10 min1–3 hSedation (moderate and deep), small analgesic effectBradycardia
0.2–0.7 µg/kg/h
(continuous infusion)
IN2–3 µg/kg10–30 min1–1.5 hMinimal effect on respiratory functionHypotension
PO2–3 µg/kg25–35 min1–2 hArrhythmia
Barbiturate
Thiopental
IV4–6 mg/kg20–40 sec5–15 minProfound sedation Decreases intracranial pressureSignificant hypotension in hypovolemic patients Respiratory depression Apnea
Other
Propofol
IV1–2 mg/kg (bolus) 6–10 mg/kg/h (continuous infusion)30 sec4–10 minSedation (moderate or deep) Fast-acting, short half-lifeInjection pain Cardiovascular depressant Could cause propofol infusion syndrome (PRIS)
Esketamine
IV0.5–2 mg/kg (bolus)30–60 sec5–15 minDissociative sedation (moderate or deep)Nausea, salivation
0.25–1.0 mg/kg repetition
IM2–4 mg/kg5–6 min40–50 minAnalgesia No effect on respiratory driveRaise intracranial pressure
IN2–4 mg/kg4–6 min30–70 minMay be combined with midazolam (“ketazolam”) or propofol (“ketofol”)Hypertension
Etomidate
IV0.2–0.3 mg/kg30–60 sec5–15 minFast and short sedationInjection pain Myoclonus Transient adrenal suppression
Opioids
Fentanyl
IV1–2 µg/kg1–2 min30–60minAnalgesiaBradycardia
IN1–2 µg/kg2–3 min30–60 minRapid onset Procedures with moderate to severe painApnea Chest wall rigidity
Alfentanil
IV5–10 µg/kg1–2 min30–60 minAnalgesiaBradycardia
IN10 µg/kg1–2 min30–60 minRapid onset Procedures with moderate to severe painApnea
Remifentanil
IV1–3 µg/kg<1 min5–10 minAnalgesiaBradycardia
0.1–0.3 µg/kg/minRapid onsetApnea
(continuous infusion)Procedures with moderate to severe pain
Morphine
IV0.05–0.2 mg/kg 10–40 µg/kg/h20 min60–90 minAnalgesia Procedures with moderate to severe painHistamine release Vasodilation Hypotension Nausea
PSA, procedural sedation and analgesia; CNS, central nervous system; IV, intravenous; IM, intramuscular; PO, oral route; IN, intranasal; PR, per rectum.

Combinations of different drugs can also be used to provide procedural sedation in the PICU. A combination of ketamine and propofol (“ketofol”) allows a smaller dose of each one, thus potentially improving the quality, safety, and duration of recovery time [28]. With few side effects, procedural sedation in the PICU using ketamine and midazolam is considered generally safe [29].

Naloxone and flumazenil boluses are used for reversal of unwanted opioid- and benzodiazepine-induced respiratory depression and oversedation.

The use of potent inhalational anesthetics for sedation in the PICU environment is still relatively new. An alternative to current protocols of intravenous sedation for patients requiring intensive care is the Anesthetic Conserving Device, also known as “AnaConDa®” (ACD, Hudson RCI, Upplands Väsby, Sweden). It is a modified heat-moisture exchanger that may allow a streamlined method of administering inhalational anesthetic agents in the ICU setting [30]. One of the first to report the use of the AnaConDa device as an adjunct to extubation in a pediatric burn patient was Jung et al. [31] in 2008.

Most sedatives and analgesics in the PICU are administered intravenously. Enteral administration may lead to sub-optimal analgesia and sedation due to a slower onset or a prolonged and unpredictable duration [32]. In addition, in many children, especially in surgical intensive care units, enteral intake is stopped. Intranasal (IN) drug administration has become an alternative way to less invasive and quick delivery of drugs, mainly in pediatric emergency departments when intravenous access is not yet established. The dose of IN midazolam used in the different studies ranged between 0.2 mg/kg and 0.4 mg/kg or 0.5 mg/kg [33, 34]. Fentanyl is generally administered IN at a dose of 1.5–2 µg/kg [35]. Dexmedetomidine is administered at a dose of 2–4 µg/kg [36]. A wide dose range of IN ketamine is used in children (3–9 mg/kg) [37], compared to 2–4 mg/kg in neonates [38]. Drug administration via the IN route may be distressing to some children.

4. Non-pharmacological measures

The high safety profile of non-pharmacological measures is one of their main benefits. Most crucially, even though the benefits are modest, all non-pharmacological approaches have a very favorable benefit-to-risk ratio because the risk is extremely low. The main advantages of non-pharmacological therapies include simplicity of use, apparent safety, viability, and simplicity of learning, all of which would permit the universal application of any of these interventions [39].

Non-pharmacological measures could be divided into five main groups (Table 2).

Table 2.Non-pharmacological measures for procedural sedation and analgesia [23, 39, 40, 41, 42].
Non-pharmacological measuresMethods and techniques
Environmental control
Skin-to-skin contact
Swaddling
Facilitated tucking
Lighting optimization
Minimization of noise
Concentrating the procedures on daytime
Feeding methods
Non-nutritive sucking
Sucrose/glucose solutions
Cognitive techniques
Distraction techniques
Active distraction
Video games, virtual reality goggles
Passive distraction
Audiovisual (music and cartoons)
Acupressure
Massage
Complementary techniques
Toy therapy
Physical methods
Comfort position
Heat/cold therapy

Bucsea et al. [40] indentified proximal and distal nonpharmacological interventions in newborns. By giving soothing tactile stimuli prior to, during, and/or after the painful procedure, proximal approaches to pain management help newborns to reduce discomfort and achieve baseline states.

For the most common painful procedures in newborns, a lot of research supports the analgesic efficacy of sweet solutions [43, 44], non-nutritive sucking [45], breastfeeding [46], and skin-to-skin contact [47, 48]. The use of either approach alone has been demonstrated to be less effective than combinations (e.g., music therapy and sucrose). For many neonates receiving invasive or non-invasive ventilation in the ICU, breastfeeding may be impossible.

In order to reduce the neonate’s pain response and pain-related suffering, distal pain management therapies involve altering the environment of the newborn [40]. Sedatives and analgesics can be reduced by optimizing the sleep-wake cycle with simple non-pharmacological interventions such as exposing them to sunlight during the day and reducing noise at night [6].

The use of non-pharmacologic pain therapy varies among PICUs and may be underreported or underutilized [41].

5. Discussion

Pain relief is a basic human right at any age. Children have historically received inadequate care for discomfort and invasive treatments. Many medical professionals held the opinion that children do not remember or feel pain to the same degree as adults. Due to the intrinsic difficulty in identifying pain in newborns and the widespread misconception that neonates lack the required physiological pathways for pain transmission, this age group has historically received less attention. Early neonatal exposure to untreated pain has been associated with a variety of deleterious short- and long-term effects, including the emergence of pain hypersensitivity, negative psychological symptomology, and altered neurodevelopment [49]. Researchers also found that intensive care units are the most common places where term and preterm newborns are exposed to uncontrolled and repetitive pain [50]. These exposures may affect the infants’ perception of pain in later infancy and negatively impact their neurodevelopmental outcomes in terms of cognition [51], motor function [52], and brain development [53, 54].

It is already common knowledge that infants hospitalized to critical care units (ICU) endure a number of painful treatments during their stay. A newborn may require up to 14 attempts to successfully insert an intravenous cannula, according to the Epidemiology of Procedural Pain in Neonates (EPIPPAIN 1) study, which collected data in 2005–2006 [50]. According to available literature, the most frequently performed and most painful procedures in the PICU are listed in Table 3.

Table 3.Most frequently performed and most painful procedures in PICU [12, 55, 56, 57].
Most frequently performedMost painful
Endotracheal suctioningChest tube removal
Oral/nasal suctioningWound drain removal
Finger prick/heel prickArterial line insertion
Peripheral IV cannula insertion/removalLumbar puncture
Nasogastric tube insertionPeripheral IV cannula insertion
Adhesive removalUrinary catheter insertion
Wound dressingSuctioning
Arterial line insertionFinger prick/heel prick
Nasal flow cannula placementPeripheral blood draw
Urinary catheter insertionSubcutaneous injection
IV, intravenous.

Courtois et al. [58] reported that neonates admitted to ICUs typically required 3.8 venipunctures over the course of an 8-day stay. Furthermore, one-quarter of neonates required more than five venipunctures, 76 percent of venipunctures required preprocedural specific analgesia, with wide variations in center practices, and only 61.7 percent of venipunctures were successful on the first attempt. According to their findings, 38.3 percent of venipunctures required more than one try, with 20% requiring three or more. A mean of 7.5–17.3 painful procedures per patient per day in the neonatal intensive care unit (NICU) setting were reported in a systematic review of 18 papers by Cruz et al. [59]. In an attempt to provide an in-depth analysis of the prevalence of painful and stressful procedures in the PICU, Barslaag et al. [12] conducted a prospective observational cohort study that included 229 patients, accounting for 955 patient days. Based on their research, the median number of painful and stressful procedures per patient per day was 11. The most prevalent procedure (45%) was endotracheal suctioning, which was followed by oral and nasal suctioning. The most painful procedures were rated as arterial and lumbar punctures, peripheral IV cannula insertion, and venipuncture. Mechanically ventilated patients underwent significantly more painful procedures than non-ventilated patients. They found that procedural analgesia or sedation was often not used during these most painful procedures.

Indeed, very little is known about international sedation and analgesia practices at the bedside. Efforts are being made to improve analgesia and sedation management with the use of recommendations [23], national surveys, and guidelines [60, 61, 62, 63, 64, 65, 66], but in practice, many guidelines are based on experts’ consensus, experience, local protocols, or even personal preferences. Even more, studies show gaps between health professionals’ knowledge and practice for the management of pain [50]. A secondary analysis of the EPIPPAIN 1 study found that the use of specific analgesics for painful procedures in ICUs was more frequent during the daytime than at night. Moreover, a sharp decrease in the use of analgesics from morning to afternoon, followed by a gentle decline thereafter, was described, which can be considered an indicator of poor quality care that needs to be overcome [67]. Despite the distribution of national guidelines, Lago et al. [68] discovered a generally common but incredibly varied use of procedural sedation and analgesia in Italian NICUs. In a level III NICU in India, pharmacological agents were used in 33.48 percent of the procedures, according to a study by Kothari et al. [56]. This suggests poor pain management practices and emphasizes the urgent need for education of NICU nurses, residents, fellows, and attendings. Almost two-thirds of the time, no pharmaceutical pain relief methods were used, and when administered, the pharmaceutical agents were rarely intended for pain relief.

There are global initiatives that are trying to overcome this problem. By giving special recognition to institutions that meet the requirements, the ChildKind program aims to raise the standard of pediatric pain management in hospitals. It serves as an alternative to other models that could be more punitive in nature and frequently have less success in altering the institution’s established culture [69].

It is important to keep in mind the numerous challenges associated with applying procedural sedation and analgesia, even in the PICU. Apnea, hypotension, laryngospasm, bradycardia, clinically evident pulmonary aspiration, total airway obstruction, lifelong neurological impairment, or even death, are examples of significant adverse events [4]. Green et al. [70] concluded that aspiration during procedural sedation appeared rare and idiosyncratic. Children treated with midazolam, propofol, and morphine were more likely to experience high levels of post-traumatic stress syndrome (PTSS) within one month of being released from the PICU [1].

Due to the fact that many sedatives given to children are used off-label or unlicensed and have not completed the strict testing requirements to be approved for pediatric usage, children represent an at-risk population [12, 71].

Limitations of the published studies should also be taken into account, as there is a risk of bias by under-reporting of painful and stressful procedures in the PICU. Baarslag et al. [12] pointed out that the painfulness of a procedure can vary within and between patients and that caregiver perceptions of pain may also affect pain management (e.g., topical anesthesia is frequently used before peripheral IV cannula insertion but is rarely ever used before heel or finger sticks). On the other hand, it is possible that the caregivers, knowing that they are participating in the study, slightly modify their practices that result in greater attention to pain management [58].

6. Conclusion

Due to the fact that children often experience physiological, physical, as well as psychological effects from untreated pain, adequate procedural sedation and analgesia are morally necessary during painful and stressful procedures in the ICUs. A rational choice for a particular agent should be based on the desired effects of the drug, its pharmacokinetic properties, and its side-effects. Different non-pharmacological methods can be applied and have been shown to be effective for pain relief in children.

It would be wise to take steps to cut down on the number of painful and stressful procedures in the PICU. One of the measures would be re-evaluating the indications that should be supported by current evidence. Another way is to improve technical skills to reduce the number of attempts for certain procedures that require multiple attempts.

Availability of data and materials

The data are contained within this article.

Author contributions

IB, VM and MS—designed the research study; IB and VM—performed the research; ID, MS and DZ—analyzed the data; IB and MS—wrote the manuscript; DS—supervised and reviewed. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Acknowledgment

Not applicable.

Funding

This study is funded by Ministry of Education, Science, and Technological Development of the Republic of Serbia (Grant No: 451-03-68/2022-14/200113).

Conflict of interest

The authors declare no conflict of interest.

References

Long D, Gibbons K, Le Brocque R, Schults JA, Kenardy J, Dow B. Midazolam exposure in the paediatric intensive care unit predicts acute post-traumatic stress symptoms in children. Australian Critical Care. 2022; 35: 408–414.

[Google Scholar]

Egbuta C, Mason KP. Current state of analgesia and sedation in the pediatric intensive care unit. Journal of Clinical Medicine. 2021; 10: 1847.

[Google Scholar]

Homma Y, Norii T, Kanazawa T, Hoshino A, Arino S, Takase H, et al. A mini‐review of procedural sedation and analgesia in the emergency department. Acute Medicine & Surgery. 2020; 7: e574.

[Google Scholar]

Aslam SL, Haque A, Jamil MT, Ariff M, Nasir S. Safety and Efficacy of Procedural Sedation and Analgesia in Pediatric Oncology Patients. Cureus. 2020; 12: e7442.

[Google Scholar]

Chawla N, Boateng A, Deshpande R. Procedural sedation in the ICU and emergency department. Current opinion in anesthesiology. 2017; 30: 507–512.

[Google Scholar]

Barnes S, Yaster M, Kudchadkar SR. Pediatric sedation management. Pediatrics in Review. 2016; 37: 203–212.

[Google Scholar]

Fagin A, Palmieri TL. Considerations for pediatric burn sedation and analgesia. Burns & Trauma. 2017; 5: 28.

[Google Scholar]

Thakkar N, Salerno S, Hornik CP, Gonzalez D. Clinical pharmacology studies in critically ill children. Pharmaceutical Research. 2017; 34: 7–24.

[Google Scholar]

Koizumi T, Kurosawa H. Survey of analgesia and sedation in pediatric intensive care units in Japan. Pediatrics International. 2020; 62: 535–541.

[Google Scholar]

LaFond CM, Hanrahan KS, Pierce NL, Perkhounkova Y, Laures EL, McCarthy AM. Pain in the pediatric intensive care unit: how and what are we doing? American Journal of Critical Care. 2019; 28: 265–273.

[Google Scholar]

Tabacco B, Tacconi C, Amigoni A. Survey on monitoring analgesia and sedation in the Italian pediatric intensive care units. Minerva Anestesiologica. 2017; 83: 1010–1016.

[Google Scholar]

Baarslag MA, Allegaert K, Knibbe CAJ, van Dijk M, Tibboel D. Pharmacological sedation management in the paediatric intensive care unit. Journal of Pharmacy and Pharmacology. 2017; 69: 498–513.

[Google Scholar]

Lam J, Baello S, Iqbal M, Kelly LE, Shannon PT, Chitayat D, et al. The ontogeny of P-glycoprotein in the developing human blood–brain barrier: implication for opioid toxicity in neonates. Pediatric Research. 2015; 78: 417–421.

[Google Scholar]

Ziesenitz VC, Vaughns JD, Koch G, Mikus G, van den Anker JN. Pharmacokinetics of fentanyl and its derivatives in children: a comprehensive review. Clinical Pharmacokinetics. 2018; 57: 125–149.

[Google Scholar]

Lu H, Rosenbaum S. Developmental pharmacokinetics in pediatric populations. The Journal of Pediatric Pharmacology and Therapeutics. 2014; 19: 262–276.

[Google Scholar]

MacKenzie M, Hall R. Pharmacogenomics and pharmacogenetics for the intensive care unit: a narrative review. Canadian Journal of Anesthesia. 2017; 64: 45–64.

[Google Scholar]

Vet NJ, Kleiber N, Ista E, de Hoog M, de Wildt SN. Sedation in critically ill children with respiratory failure. Frontiers in Pediatrics. 2016; 4: 89.

[Google Scholar]

Ramalho CE, Bretas PMC, Schvartsman C, Reis AG. Sedation and analgesia for procedures in the pediatric emergency room. Jornal De Pediatria. 2017; 93: 2–18.

[Google Scholar]

Andropoulos DB, Greene MF. Anesthesia and developing brains—implications of the FDA warning. New England Journal of Medicine. 2017; 376: 905–907.

[Google Scholar]

Zuppa AF, Curley MAQ. Sedation analgesia and neuromuscular blockade in pediatric critical care: overview and current landscape. Pediatric clinics of North America. 2017; 64: 1103–1116.

[Google Scholar]

Mody K, Kaur S, Mauer EA, Gerber LM, Greenwald BM, Silver G, et al. Benzodiazepines and development of delirium in critically ill children: estimating the causal effect. Critical Care Medicine. 2018; 46: 1486–1491.

[Google Scholar]

Smith HAB, Gangopadhyay M, Goben CM, Jacobowski NL, Chestnut MH, Thompson JL, et al. Delirium and benzodiazepines associated with prolonged ICU stay in critically ill infants and young children. Critical Care Medicine. 2017; 45: 1427–1435.

[Google Scholar]

Amigoni A, Conti G, Conio A, Corno M, Fazio PC, Ferrero F, et al. Recommendations for analgesia and sedation in critically ill children admitted to intensive care unit. Journal of Anesthesia, Analgesia and Critical Care. 2022; 2: 9.

[Google Scholar]

Zalieckas J, Weldon C. Sedation and analgesia in the ICU. Seminars in Pediatric Surgery. 2015; 24: 37–46.

[Google Scholar]

Kaye A, Urman R, Rappaport Y, Siddaiah H, Cornett E, Belani K, et al. Multimodal analgesia as an essential part of enhanced recovery protocols in the ambulatory settings. Journal of Anaesthesiology Clinical Pharmacology. 2019; 35: 40.

[Google Scholar]

Nasr VG, DiNardo JA. Sedation and analgesia in pediatric cardiac critical care. Pediatric Critical Care Medicine. 2016; 17: S225–S231.

[Google Scholar]

Zielinska M, Bartkowska-Sniatkowska A, Becke K, Höhne C, Najafi N, Schaffrath E, et al. Safe pediatric procedural sedation and analgesia by anesthesiologists for elective procedures: a clinical practice statement from the European Society for Paediatric Anaesthesiology. Pediatric Anesthesia. 2019; 29: 583–590.

[Google Scholar]

Foo TY, Mohd Noor N, Yazid MB, Fauzi MH, Abdull Wahab SF, Ahmad MZ. Ketamine-propofol (Ketofol) for procedural sedation and analgesia in children: a systematic review and meta-analysis. BMC Emergency Medicine. 2020; 20: 81.

[Google Scholar]

Hazwani TR, Alem HA. Procedural moderate sedation with ketamine in pediatric critical care unit. Avicenna Journal of Medicine. 2017; 07: 7–11.

[Google Scholar]

Karnjus I, Mekis D, Krizmaric M. Inhalation sedation with the ’Anaesthetic Conserving Device’ for patients in intensive care units: a literature review. Signa Vitae. 2016; 11: 1–24.

[Google Scholar]

Jung C, Granados M, Marsol P, Murat I, Gall O. Use of sevoflurane sedation by the AnaConDa® device as an adjunct to extubation in a pediatric burn patient. Burns. 2008; 34: 136–138.

[Google Scholar]

Mudd S. Intranasal fentanyl for pain management in children: a systematic review of the literature. Journal of Pediatric Health Care. 2011; 25: 316–22.

[Google Scholar]

Lane RD, Schunk JE. Atomized intranasal midazolam use for minor procedures in the pediatric emergency department. Pediatric Emergency Care. 2008; 24: 300–303.

[Google Scholar]

Conway A, Rolley J, Sutherland JR. Midazolam for sedation before procedures. The Cochrane Database of Systematic Reviews. 2016; 2016: CD009491.

[Google Scholar]

Pansini V, Curatola A, Gatto A, Lazzareschi I, Ruggiero A, Chiaretti A. Intranasal drugs for analgesia and sedation in children admitted to pediatric emergency department: a narrative review. Annals of Translational Medicine. 2021; 9: 189–189.

[Google Scholar]

Poonai N, Spohn J, Vandermeer B, Ali S, Bhatt M, Hendrikx S, et al. Intranasal dexmedetomidine for procedural distress in children: a systematic review. Pediatrics. 2020; 145: e20191623.

[Google Scholar]

Poonai N, Canton K, Ali S, Hendrikx S, Shah A, Miller M, et al. Intranasal ketamine for procedural sedation and analgesia in children: a systematic review. PLoS One. 2017; 12: e0173253.

[Google Scholar]

Milési C, Baleine J, Mura T, Benito-Castro F, Ferragu F, Thiriez G, et al. Nasal midazolam vs. ketamine for neonatal intubation in the delivery room: a randomised trial. Archives of Disease in Childhood-Fetal and Neonatal Edition. 2018; 103: F221–F226.

[Google Scholar]

Mangat AK, Oei JL, Chen K, Quah-Smith I, Schmölzer GM. A review of non-pharmacological treatments for pain management in newborn infants. Children. 2018; 5: 130.

[Google Scholar]

Bucsea O, Pillai Riddell R. Non-pharmacological pain management in the neonatal intensive care unit: managing neonatal pain without drugs. Seminars in Fetal and Neonatal Medicine. 2019; 24: 101017.

[Google Scholar]

Bohr NL, Ely E, Hanrahan KS, McCarthy AM, LaFond CM. Predicting who receives nonpharmacologic pain interventions in the pediatric intensive care unit. Pain Management Nursing. 2022; 23: 267–272.

[Google Scholar]

Riddell RP, Racine N, Turcotte K, Uman LS, Horton R, Osmun LD, et al. Nonpharmacological management of procedural pain in infants and young children: an abridged cochrane review. Pain Research and Management. 2011; 16: 321–330.

[Google Scholar]

Bueno M, Yamada J, Harrison D, Khan S, Ohlsson A, Adams-Webber T, et al. A systematic review and meta-analyses of nonsucrose sweet solutions for pain relief in neonates. Pain Research and Management. 2013; 18: 153–161.

[Google Scholar]

Stevens B, Yamada J, Ohlsson A, Haliburton S, Shorkey A. Sucrose for analgesia in newborn infants undergoing painful procedures. The Cochrane Database of Systematic Reviews. 2016; 7: CD001069.

[Google Scholar]

Vu-Ngoc H, Uyen NCM, Thinh OP, Don LD, Danh NVT, Truc NTT, et al. Analgesic effect of non-nutritive sucking in term neonates: a randomized controlled trial. Pediatrics & Neonatology. 2020; 61: 106–113.

[Google Scholar]

Shah PS, Herbozo C, Aliwalas LL, Shah VS. Breastfeeding or breast milk for procedural pain in neonates. The Cochrane Database of Systematic Reviews. 2012; 12: CD004950.

[Google Scholar]

Akcan E, Yiğit R, Atici A. The effect of kangaroo care on pain in premature infants during invasive procedures. The Turkish Journal of Pediatrics. 2009; 51: 14–18.

[Google Scholar]

Johnston C, Campbell-Yeo M, Fernandes A, Inglis D, Streiner D, Zee R. Skin-to-skin care for procedural pain in neonates. The Cochrane Database of Systematic Reviews. 2014; 23: CD008435.

[Google Scholar]

Avila-Alvarez A, Carbajal R, Courtois E, Pertega-Diaz S, Muñiz-Garcia J, Anand KJS. Sedation and analgesia practices among Spanish neonatal intensive care units. An Pediatr. 2015; 83: 75–84.

[Google Scholar]

Carbajal R. Epidemiology and treatment of painful procedures in neonates in intensive care units. JAMA. 2008; 300: 60.

[Google Scholar]

Vinall J, Miller SP, Bjornson BH, Fitzpatrick KPV, Poskitt KJ, Brant R, et al. Invasive procedures in preterm children: brain and cognitive development at school age. Pediatrics. 2014; 133: 412–421.

[Google Scholar]

Grunau RE, Whitfield MF, Petrie-Thomas J, Synnes AR, Cepeda IL, Keidar A, et al. Neonatal pain, parenting stress and interaction, in relation to cognitive and motor development at 8 and 18 months in preterm infants. Pain. 2009; 143: 138–146.

[Google Scholar]

Anand KJ, Palmer FB, Papanicolaou AC. Repetitive neonatal pain and neurocognitive abilities in ex-preterm children. Pain. 2013; 154: 1899–1901.

[Google Scholar]

Zwicker JG, Grunau RE, Adams E, Chau V, Brant R, Poskitt KJ, et al. Score for neonatal acute physiology-II and neonatal pain predict corticospinal tract development in premature newborns. Pediatric Neurology. 2013; 48:123–129.e1.

[Google Scholar]

Puntillo KA, Max A, Timsit J, Vignoud L, Chanques G, Robleda G, et al. Determinants of procedural pain intensity in the intensive care unit. The Europain® study. American Journal of Respiratory and Critical Care Medicine. 2014; 189: 39–47.

[Google Scholar]

Kothari SY, Dongara AR, Nimbalkar SM, Phatak AG, Nimbalkar AS. Missed opportunities for sedation and pain management at a level III neonatal intensive care unit, India. Frontiers in Pediatrics. 2016; 4: 7.

[Google Scholar]

Assefa E, Dinkiye M, Geleta T, Tantu T, Wondwosen M, Zewdu D. The practice of procedural pain assessment and management in neonatal intensive care unit in Ethiopia: cross-sectional study. Health Science Reports. 2022; 5: e533.

[Google Scholar]

Courtois E, Cimerman P, Dubuche V, Goiset M, Orfèvre C, Lagarde A, et al. The burden of venipuncture pain in neonatal intensive care units: EPIPPAIN 2, a prospective observational study. International Journal of Nursing Studies. 2016; 57: 48–59.

[Google Scholar]

Cruz MD, Fernandes AM, Oliveira CR. Epidemiology of painful procedures performed in neonates: a systematic review of observational studies. European Journal of Pain. 2016; 20: 489–498.

[Google Scholar]

Debillon T, Bureau V, Savagner C, Zupan-Simunek V, Carbajal R. Pain management in French neonatal intensive care units. Acta Paediatrica. 2002; 91: 822–826.

[Google Scholar]

McKechnie L, Levene M. Procedural pain guidelines for the newborn in the United Kingdom. Journal of Perinatology. 2008; 28: 107–111.

[Google Scholar]

Harrison D, Loughnan P, Johnston L. Pain assessment and procedural pain management practices in neonatal units in Australia. Journal of Paediatrics and Child Health. 2006; 42: 6–9.

[Google Scholar]

Lago P, Guadagni A, Merazzi D, Ancora G, Bellieni CV, Cavazza A. Pain management in the neonatal intensive care unit: a national survey in Italy. Pediatric Anesthesia. 2005; 15: 925–931.

[Google Scholar]

Gharavi B, Schott C, Nelle M, Reiter G, Linderkamp O. Pain management and the effect of guidelines in neonatal units in Austria, Germany and Switzerland. Pediatrics International. 2007; 49: 652–658.

[Google Scholar]

Mehler K, Oberthuer A, Haertel C, Herting E, Roth B, Goepel W. Use of analgesic and sedative drugs in VLBW infants in German NICUs from 2003–2010. European Journal of Pediatrics. 2013; 172: 1633–1639.

[Google Scholar]

Eriksson M, Gradin M. Pain management in Swedish neonatal units—a national survey. Acta Paediatrica. 2008; 97: 870–874.

[Google Scholar]

Guedj R, Danan C, Daoud P, Zupan V, Renolleau S, Zana E, et al. Does neonatal pain management in intensive care units differ between night and day? An observational study. BMJ Open. 2014; 4: e004086.

[Google Scholar]

Lago P, Frigo AC, Baraldi E, Pozzato R, Courtois E, Rambaud J, et al. Sedation and analgesia practices at Italian neonatal intensive care units: results from the EUROPAIN study. Italian Journal of Pediatrics. 2017; 43: 26.

[Google Scholar]

Schechter NL, Finley GA, Bright NS, Laycock M, Forgeron P. ChildKind: a global initiative to reduce pain in children. Pediatric Pain Letter. 2010; 12: 26–30.

[Google Scholar]

Green SM, Mason KP, Krauss BS. Pulmonary aspiration during procedural sedation: a comprehensive systematic review. British Journal of Anaesthesia. 2017; 118: 344–354.

[Google Scholar]

Mason KP. Challenges in paediatric procedural sedation: political, economic, and clinical aspects. British Journal of Anaesthesia. 2014; 11: ii48–62.

[Google Scholar]