Procedural sedation for children outside of the operating room is a common practice in emergency departments, outpatient clinics, radiology suites, and dental offices for painful and anxiety-provoking procedures. However, there is emerging evidence that so-called "delayed maladaptive behaviors" (disordered sleep, anxiety, and aggression) affect nearly a quarter of children for up to 2 weeks following sedation. This can lead to poor school attendance, reduced extracurricular involvement, disruptions to caregivers' employment obligations, and poor patient satisfaction. As this phenomenon has only recently been identified, very little is known about what factors predispose children to delayed maladaptive behaviors, however, small studies suggest younger age and pre-procedural anxiety may be involved. The aim of our study is to characterize risk factors for delayed maladaptive behavior in a large multicentre study involving emergency departments, dental offices, and hospital sedation services. Understanding these risk factors may help healthcare workers prevent delayed maladaptive behaviors and provide patients with anticipatory guidance, akin to post-operative recovery instructions.

There is emerging evidence that maladaptive behaviors, including significant negative behavioral changes, can occur in children following procedural sedation. These include disordered sleep, anxiety, and aggression)1,2 and affect up to 24% of children following inhalational anesthetics3 and intravenous sedatives such as ketamine.1 Moreover, these appear to be more pronounced in children <4 years4 and can persist for up to 2 weeks post-sedation. Unfortunately, only two trials have reported delayed maladaptive behaviors.1,2 Data on immediate and delayed AEs are urgently needed for safe clinical decision-making and anticipatory guidance surrounding ED anxiolytics. In a prospective cohort study of children undergoing emergency department procedural sedation with intravenous ketamine, 22% exhibited significant negative behavioral changes 1-2 weeks after discharge, as measured by the Post-Hospitalization Behavior Questionnaire. High pre-procedure anxiety have been identified as independent predictors of these maladaptive behaviors.5 Additionally, irritability, hyperactivity, and hallucinations during recovery have been reported and are associated with lower parental satisfaction.6

RESEARCH QUESTION What are the risk factors for delayed maladaptive behaviors in children and adolescents 1-17 years undergoing procedural sedation or anxiolysis?

OBJECTIVES i) Characterize the risk factors associated with delayed maladaptive behaviors in children undergoing procedural sedation or anxiolysis in the ED and dental clinics.

ii) Determine the proportion of children with delayed maladaptive behaviors following procedural sedation or anxiolysis.

iii) Determine the degree to which delayed maladaptive behaviors are associated with post-sedation pain.

HYPOTHESES i) An increased risk of delayed maladaptive behaviors (> 3 in negative behaviors score from pre-sedation to 3-days post-sedation) will be associated with younger age, greater pre-sedation anxiety (Modified Yale Pre-Operative Anxiety Scale score > 40), greater pre-sedation pain (Parent's Post-Operative Pain Measure - Short Form), sedative drug combinations, and baseline temperament (Integrative Childhood Temperament Screener - age < 8 years) and Integrative Late Childhood Temperament Inventory - age > 8 years). This hypothesis is based on previous associations identified in children receiving inhalational anesthetics.7-9 ii) The proportion of children with delayed maladaptive behaviors will be > 20% based on prior literature.5,10 iii) Delayed maladaptive behaviors will be associated with greater post-sedation pain.

BACKGROUND Procedural sedation in children outside of the operating room (OR) is routinely performed for orthopedic reductions, laceration repairs, diagnostic imaging, and other painful or anxiety-provoking procedures.[3-6] Data from the Pediatric Sedation Research Consortium identified 432,842 outpatient pediatric procedural sedation encounters over an 11-year period, reflecting widespread use in settings such as emergency departments (EDs), radiology suites, and dedicated sedation units.14,15 Most sedations are performed in children under 10 years of age.[3-4] Ketamine is the most commonly used agent,16 but other common sedatives include propofol, nitrous oxide, and dexmedetomidine.15,17 Children also receive anxiolysis (nitrous oxide; midazolam) for procedural distress. Typically, these agents do not sedative children but may be associated with delayed maladaptive behaviors.

Although procedural sedation outside the OR is widely regarded as safe,18-20 there is emerging evidence that delayed maladaptive behaviors, manifesting as disordered sleep, separation anxiety, and aggression towards authority2,5 can affect up to a third of children.5,10,21 Delayed maladaptive behaviors have been described following general anesthesia in the perioperative setting,7,8 where they can persist for up to a month post-anesthesia.8 Moreover, they appear to be more pronounced in children under 4 years of age.7 However, only two studies have characterized delayed maladaptive behaviors following procedural sedation outside the OR.2,5 A prospective single-center study of 97 children undergoing ED procedural sedation with intravenous ketamine found that 22% of children exhibited significant negative behavioral changes up to 2 weeks after discharge with high pre-procedural anxiety identified as a risk factor.5 Another study of 60 children found that 20% exhibited delayed maladaptive behaviors that persisted for one week following ED discharge.10

Although there are similarities between the ED and perioperative setting, there are some important differences. Unlike the OR, procedural sedation in the ED is largely unscheduled, and with a relatively short time period from decision to performance of the procedure. This together with the time constraints of busy EDs often precludes the ability of healthcare workers to enact measures to reduce pre-procedural anxiety and provide anticipatory guidance to families. In addition, procedural sedation in the ED is often performed to facilitate low morbidity procedures with an anticipated short recovery time. In contrast to surgical procedures in the OR, children are often expected to resume normal activities shortly after an ED visit. Thus, the frequency, severity, and functional impact of delayed maladaptive behaviors on children and their caregivers may be significantly greater.

RATIONALE AND SIGNIFICANCE Procedural sedation and anxiolysis is frequently performed in children and preliminary evidence suggests delayed maladaptive behaviors are common. These behaviors may reduce school attendance and participation in extracurricular activities and compromise caregivers' abilities to fulfill employment responsibilities. Characterizing the risk factors for delayed maladaptive is essential to extending the care of children and supporting their caregivers following ED discharge. The Canadian Paediatric Society (CPS) strongly recommends managing distress during medical procedures, but lacks guidance for pre-sedation pain and anxiety,22 which may contribute to delayed maladaptive behaviors. Our study will fill this unmet need and identify modifiable risk factors such as pain and pre-procedural anxiety that can be addressed through interventions by certified child life specialists (CCLSs) and bedside nurses. Currently, measures to reduce anxiety and pain-related procedural distress in children are inconsistently used.23,24 Our findings will also inform more comprehensive amendments to existing pain and anxiety management recommendations set by the CPS.22

Characterizing risk factors for delayed maladaptive behaviors in children undergoing procedural sedation or anxiolysis is highly innovative because current research has focused primarily on immediate adverse events and neurodevelopmental outcomes, leaving a significant gap in understanding the behavioral sequelae of procedural sedation outside the OR.6,20,25,26 Recent large-scale studies have identified risk factors for acute adverse events and prolonged recovery, such as higher body weight, prior sedation history, and specific sedative agents, but have not systematically addressed delayed maladaptive behavioral changes.17,20 The American Academy of Pediatrics highlighted the need for further work to determine the magnitude and causation of behavioral and executive function deficits in children with repeated sedation exposures, especially those with developmental disabilities.27 Our work will fill this unmet need. Moreover, parental dissatisfaction and negative recovery experiences are associated with behavioral symptoms that persist into the post-sedation period, yet these outcomes remain poorly characterized in the literature.6 By prospectively identifying modifiable and non-modifiable risk factors for delayed maladaptive behaviors, this study will address critical knowledge gaps and inform safer, more personalized sedation practices for children and adolescents.

EXPECTED OUTCOMES Overall, the study is expected to provide actionable data on modifiable and non-modifiable risk factors for maladaptive behavioral outcomes with the overarching aim of informing safer and more personalized sedation practices in children. In the short-term, we expect to characterize risk factors that increase the risk for delayed maladaptive behaviors in children and adolescents undergoing procedural sedation or anxiolysis, identify the prevalence of maladaptive behaviors, and identify links with post-sedation pain. In the long-term, we expect to use this knowledge to implement practice change through i) education of certified child life specialist and nurses on the importance of measures to reduce pre-procedural anxiety such as providing age-appropriate anticipatory guidance, distraction, and caregiver involvement; ii) education of physicians on the importance of screening for at-risk patients and choosing sedative or anxiolytic and doses that are associated with a lower risk of maladaptive behaviors; iii) standardizing pre-procedural analgesia through nurse-initiated medical directives for common indications such as orthopedic manipulation, laceration repair, and dental procedures. We will evaluate the impact of the study's findings using a quality improvement (QI) framework.

Inclusion Criteria:

• Children and adolescents 1-17 years undergoing procedural sedation or anxiolysis with any agent for any indication in the ED and dental clinics

Exclusion Criteria:

• Patients where the primary caregiver lacks English or French (if applicable to site) comprehension in the absence of a native language interpreter
• Lack a smartphone able to receive SMS text messages
• Caregiver and/or patient are not available for all of the planned follow-up dates
• Previously enrolled in the study

Children and adolescents 1-17 years undergoing procedural sedation or anxiolysis with any agent for any indication in the ED and dental clinics

This was not specified in the ethics application.