Background

Until the early 1990s, critically ill children were routinely treated without sedatives or analgesics [1, 2]. The studies conducted during this time period confirmed that sedation and analgesia in postoperative settings and pediatric intensive care units (PICUs) were essential for patient care and for reducing morbidity and mortality [1, 3]. Most PICUs currently use opioids and/or sedatives (e.g., benzodiazepines, dexmedetomidine, and propofol) for sedation and analgesia to reduce pain, stress, and anxiety in critically ill children, particularly those on mechanical ventilation or postoperative care [1].

While recent guidelines advocate lowering sedation and analgesia because numerous patients who are administered high doses of opioids and benzodiazepines via continuous intravenous infusion for prolonged periods develop cognitive morbidities [4,5,6,7,8,9]. Protracted benzodiazepine and opioid therapy frequently result in tolerance, which manifests as diminished pharmacological effects. Furthermore, withdrawal symptoms are associated with tolerance upon discontinuation [5].

Iatrogenic withdrawal syndrome (IWS) definition

IWS is a clinical reaction or phenomenon that occurs when opioid sedatives or benzodiazepines are discontinued after a long period of use. Typically, signs appear between 8 and 48 h after discontinuation, including autonomic dysregulation, gastrointestinal problems, central nervous system arousal, and motor abnormalities that can occur with the abrupt cessation or rapid tapering of the doses of these medications. [6,7,8,9,10]. Mixed IWS occurs in 7.5%–100% of pediatric patients receiving both opioids and benzodiazepines, with no mention of sequential withdrawal [4, 11, 12].

IWS is a syndrome that has been observed in many pediatric patients receiving opioids and/or sedatives for a long duration. The withdrawal was first described in adult opioid addiction literature and in neonates born to opioid-addicted mothers. However, it was first observed in pediatric patients in the 1990s [1, 13,14,15]. Arnold et al. were the first to describe this entity in neonates, noting that it could occur in infants as well [14].

Furthermore, Tobias et al. reported a protocol for preventing and treating opioid withdrawal [13].

IWS manifestations

Typically, patients who have been exposed to opioids for a long period of time suddenly develop IWS. However, it can occur within three days at high cumulative doses if drug is discontinued abruptly. According to several studies, IWS affects 35%– 64% of PICU patients [5, 8, 16]. According to an American Academy of Pediatrics clinical report, 50 to 100% of patients exposed to seven days of fentanyl therapy or a fentanyl threshold of 2 mg/kg are likely to develop withdrawal syndrome [5, 17]. IWS causes physiologic stressors such as fever, respiratory distress, tachycardia, hypertension, and feeding difficulties, as well as neurologic sequelae such as agitation, hallucinations, and seizures, which lead to prolonged hospitalization, PICU, and mechanical ventilation duration [5, 8,9,10, 18]. When reporting IWS manifestations (or any other medical condition), considering the specific age group and any potential differences in symptoms or manifestations from other age groups is important.

In pediatric patients, owing to the differences in physiology and medication use, IWS manifestations may differ from those in adults and the elderly. Therefore, a detailed description of the manifestations and any potential differences in relation to age and medication use is crucial.

For example, in pediatric patients, IWS may present as agitation, irritability, and restlessness, which could be challenging to recognize in younger children. Furthermore, medication use in pediatrics may differ from that in adults, and certain medications may be associated with an increased risk of IWS in this population.

In this vulnerable population, healthcare providers can improve their ability to recognize and manage this condition by providing a detailed description of IWS manifestations in pediatric patients and any potential differences related to age and medication use.

IWS prevalence

The reported prevalence of IWS ranges widely from 5 to 87% [12, 19], with a large prospective multicenter study in the United States involving over 1,000 patients finding a prevalence of 47% [19, 20]. For a long time, delirium has been recognized in adult ICU patients, but healthcare professionals (HCPs) haven’t recognized pediatric delirium existence before the early 2000s [21,22,23], after which several assessment tools for infants and children were validated [24,25,26]. The pediatric delirium prevalence is estimated to be 34%, ranging from 17 to 66% which depends on the studied subgroup [27]. The symptoms of pediatric delirium and IWS might overlap significantly regarding pain and sedation, [28, 29]. Dokken et al. reported that 95% of the patients had IWS based on.

Peak Withdrawal Assessment Tool Version 1 (WAT-1) scores 3 or more [30], with thiopental and propofol being the most frequently used drugs as rescue medications to treat IWS. Similar studies have found that the prevalence of IWS ranges between 47 and 77% [16, 20, 31]. Franck et al. found an IWS rate of 77% [31]. An observational multicentric study done by Amigoni et al. in 2017 observed withdrawal syndrome in 64% of PICU patients (n 1⁄4 113) who received sedation and analgesia for at least five days [5, 16]. The variation in prevalence could be attributed to a lack of universal clinical practice guidelines for preventing IWS in critically ill patients, unclear IWS signs and symptoms, and differences in medications, treatment duration, and assessment tools [5].

IWS risk factors

Investigating potential risk factors for IWS development enables healthcare providers to identify patients at risk. The incidence and influencing factors for the development of withdrawal symptoms after prolonged use of benzodiazepines or opioids in children have been extensively reported [5, 8, 32, 33]. The main risk factors associated with IWS include young age, typically less than six months, preexisting cognitive weakness, higher illness severity, cumulative dose of opioid or benzodiazepine administered, duration of treatment with these analgesics or sedatives, regular exposure for 72 h or longer, duration of extracorporeal membrane oxygenation, higher nursing workload, and lack of a sedative weaning protocol [4, 5, 10].

IWS assessment tools

In the 1990s, HCPs recognized that pain assessment in hospitalized.

Children is important, which led to several observational pain assessment tools development [34], either for use for chronic pain and after major surgery, or for acute procedural pain, like prick pain. In PICU settings, 40%–65% of children cannot self-report because of mechanical ventilation and also for their young age (below the age of four) [34,35,36]. Considering the prevalence of noncommunicative kids and the requirement of quality care, it is essential that HCPs use a variety of measurement instruments to assess pain, sedation, delirium, and iatrogenic withdrawal and manage these conditions effectively [19, 37], as well as to individualize treatment and plan appropriate multimodal interventions. HCPs have access to a variety of pain and sedation assessment instruments [34, 38], and also for assessing iatrogenic withdrawal and delirium recently, [28, 34]. A recent study of 168 PICUs done in 18 countries reported that there is a wide variation in the measurement instrument use in practice regarding these four conditions [39]. Indeed, it was reported by some studies that HCPs fight to choose the appropriate assessment instrument for these four conditions [40, 41]. This could be due to the overlap of similar behavioral cue items in measurement instruments across these four conditions, or to the abundance of measurement instruments available [29, 32].

Self-report tools are the gold standard for children aged 4 and up who can communicate [38, 42]. The use of self-report tools is often not feasible in PICUs, where two-thirds of the children are under the age of four or are sedated. Therefore, after assessing pain, PICU staff members often need to assess the children’s level of sedation.

Because symptoms of distress and pain (such as hyper alertness and body movements) overlap, studies have validated some tools for both conditions. For instance, Neonatal Pain, Agitation, and Sedation Scale [43] and the COMFORT Behavior Scale. [44, 45] have both been validated for different types of pain and levels of undersedation. In addition, the COMFORT Behavior Scale also detects adequate and over sedation.

According to a 2013 systematic review, approximately 11% of PICU patients suffered from undersedation [46]. Because children admitted to a PICU often receive benzodiazepines and/or opioids, they are at risk of IWS, especially if they have been taking these drugs for more than five days. The most widely used tools for assessing IWS risk are the WAT-1 [9, 31] and the Sophia Observation withdrawal Symptoms scale (SOS) [47, 48]. The WAT-1 is an 11-item scale, with scores of 3 or higher on a scale of 0 to 12 indicating withdrawal. It was shown to have high sensitivity and specificity, as well as similar psychometric characteristics [9, 31, 49]. In addition, it has greater diagnostic accuracy, with higher areas under the receiver operating characteristic curve [9, 31, 49, 50]. Furthermore, according to Franck et al., WAT-1 is more effective in detecting opioid withdrawal symptoms than benzodiazepine withdrawal symptoms [31].

In clinical practice, four different instruments may be required to determine why a child is uncomfortable in order to decide on the first line of treatment [19]. HCPs may be unable to use four instruments on a regular basis due to time constraints, as well as a shortage of ICU nurses in most European countries, including an unknown number of nurses leaving their profession as a result of the coronavirus disease 2019 pandemic [51, 52]. Nonetheless, the European Society of Pediatric and Neonatal Intensive Care recommended that “validated assessment tools for pain, undersedation, withdrawal syndrome, and delirium be integrated into pain treatment protocols” [32].

To fill this gap, a Delphi study was conducted among experts working in PICUs around the world to determine which cues should be included in a new holistic instrument known as the mosaic checklist. The name refers to the phenomenon in which a collection of different mosaic pieces, in this case the various adverse conditions, generates an overall picture that tells more than the individual elements. In this way, nurses can efficiently choose which condition—pain, undersedation, delirium, or IWS —is most likely to be present in an ill child and should be treated first [19].

A trend to introduce sedation protocols to avoid pediatric delirium, oversedation, or IWS in the PICU community is reported. A guideline which was published by the Society of Critical Care Medicine in 2022 addresses the need for routine monitoring of pain, agitation, withdrawal, and pediatric delirium using validated tools [53], since the introduction of sedation protocols may affect not only the level of sedation but also the risk of IWS and pediatric delirium [54, 55].

IWS management and practice

Inadequate pain and sedation management in critically ill children can result in unnecessary suffering and agitation, as well as delirium and iatrogenic withdrawal [34]. Thus, it is important to address these four interconnected conditions concurrently. Although managing pain and sedation for pediatric patients is a balancing act for HCPs in order to provide optimal comfort while avoiding delirium and iatrogenic withdrawal, management recommendations for these four interrelated conditions are conflicting. Some clinical practice guidelines (CPGs) for managing pain and sedation are available, while a few CPGs are available for managing delirium and iatrogenic withdrawal in PICUs. CPGs are developed through synthesizing research in order to help the evidence-to-practice gap to be bridged. Their implementation is advantageous for standardizing care practices and improving patient safety and outcomes [56]. In PICUs, there are few CPGs for managing these four conditions, with only two for pain [57, 58] and one for sedation, and delirium [59]. Harris et al. [32] recommend using validated IWS assessment tools that have been tested and demonstrated in children for reliability, validity, and clinical utility. The WAT-1, SOS, and the Opioid-Benzodiazepine Withdrawal Scale (OBWS) have all been validated. Yet, their items do not adapt to the various pediatric ages.

There are a few recommendations on which drugs should be used for sedation and analgesia in critically ill pediatric patients. In clinical practice, the most commonly used pharmacological agents in PICUs are opioids and benzodiazepines, with fentanyl being the most used analgesic, then paracetamol followed by metamizole, and midazolam being the most used sedative, followed by lorazepam, ketamine, and propofol [60, 61].

Several reviews recommended drugs such as clonidine, dexmedetomidine, or methadone to reduce IWS severity in pediatric patients, but no conclusive data is available in the literature [12, 62,63,64]. Given the limited evidence, it is assumed that adjuvant drugs should be used with caution.

In adult ICU settings, methadone has been successfully employed to facilitate narcotic weaning, reducing the duration of opioid infusion [65], and the length of exposure to mechanical ventilation in specific populations [66, 67]. Accordingly, switching to a long-acting opioid such as methadone is a widely accepted approach for narcotic weaning in pediatric patients [68]. In a recent large study, 30% of pediatric patients receiving usual-care sedation management for acute respiratory failure received methadone [69]. This approach is supported by pharmacologic data. Methadone pharmacokinetics in pediatrics and neonates are similar to those in adults, and its excellent oral bioavailability and long half-life allow for very stable serum levels with intermittent dosing [70], including simple once-daily oral regimens. Therefore, it can be used to reduce or prevent IWS, with few side effects. Siddappa et al. [71] converted an intravenous fentanyl dose into equipotent methadone doses, which were then completely administered. This method has been suggested and used by numerous researchers [13, 72, 73]. However, when changing the administration route, it is essential to consider fentanyl’s capacity (100 times greater than methadone) as well as methadone’s average half-life and bioavailability (75%–100% and 75%–80%, respectively) [13]. Although a minimum initial dose of methadone was used by Lugo et al. [74], it was increased depending on the requirement. It is argued that even when the capacity and average half-life of both drugs are considered, the resulting equivalent dose is higher than the dose required to prevent IWS, thus prolonging dependence and opiate withdrawal time [74]. There is some disagreement about the best initial dose to prevent IWS. Siddappa et al. [71] recommended 2.4 times the fentanyl dose every six hours, whereas Lugo et al. [74] recommended a dose of 0.1 mg/kg every six hours. However, Johnson et al. [63] advocated for more frequent administration intervals ranging from 3.8 to 62 h.

Accordingly, it seems to be more effective to apply smaller intervals between doses to achieve therapeutic levels in a more precocious method.

Weber et al. [75] conducted the only study that investigated phenobarbital in combination with clonidine for IWS treatment. The subject’s choreiform movements stopped, and stress and fever subsided two days after phenobarbital administration. This treatment reduced the need for additional doses of sedatives and analgesics, allowing withdrawal in less than a week with no adverse effects.

Finkel et al. [76] conducted a descriptive study using dexmedetomidine to facilitate opiate withdrawal in two hospitalized children in a PICU with denervated hearts due to cardiac transplantation [76]. Initial doses of dexmedetomidine for adults were recommended, and additional dexmedetomidine doses were administered if withdrawal symptoms appeared [76]. Non-pediatric doses were used because of a lack of research on the dexmedetomidine use in children having transplanted hearts. The findings partially agree with Tobias’s descriptive study, in which dexmedetomidine effectively controlled IWS manifestations without causing hemodynamic disturbances [77].

In a systematic review, Ávila-Alzate et al. revealed the effectiveness of clonidine in alleviating withdrawal symptoms from sedoanalgesia. Ladrieri et al. [78] used clonidine transdermally, while Cho et al. [79] and Weber et al. [76] used it enterally, achieving similar effects and even facilitating opioid analgesic withdrawal, though trembling could not be eliminated. In addition, Weber et al. [76] reported that clonidine did not have the expected prophylactic effect and that the IWS was activated.

Transdermal clonidine is slightly more effective than enteral clonidine due to several factors. First, low tissue infusion in critically ill patients’ leads to organ atrophy and decreased gastrointestinal motility, resulting in decreased gastrointestinal absorption of medicines [80]. Second, clonidine has significant protective value after sedative withdrawal for IWS in the first 24 h, particularly in children with respiratory failure [78].

Finally, several studies have reported that transdermal clonidine is safer because it delivers constant doses, reducing peak doses and adverse reactions [77,78,79,80,81].

Regardless of the drug used to treat IWS, all studies confirmed the importance of administering an adequate dosage, as inadequate or excessive doses increase the IWS risk. In addition, the treatment plan must be strictly followed in order to avoid developing another IWS situation [1, 4, 5, 18, 19, 32].

In terms of IWS, the European Society of Pediatric and Neonatal Intensive Care recommended HCPs consider the potential risk of opioid and/or benzodiazepine IWS five days after continuous administration of these drugs and use standardized IWS assessment instruments with proven clinical utility, validity, and reliability, such as WAT-1 or SOS, in infants and children [32].

Conclusion

IWS in critically ill children is difficult to diagnose and manage, with numerous confounders and limited research. More research is required to determine an accurate and reliable prevalence of IWS among pediatric patients, identify the benefits and drawbacks of existing assessment tools and treatments, and develop more effective assessment tools and treatments. IWS in PICU is summarized in Fig. 1.

Fig. 1
figure 1

Iatrogenic withdrawal syndrome in PICU

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