Delirium is a syndrome of acute brain dysfunction occurring due to a complex interplay between disease-related factors, predisposing risk factors, and environmental factors. It manifests with acute and fluctuating alterations in awareness, attention, and cognition (1). Delirium has significant impact on patient outcomes and is associated with a longer duration of mechanical ventilation, longer ICU and hospital stays, increased healthcare costs and increased mortality (1–3). In fact, among critically ill children, delirium has been found to be a stronger predictor of mortality than the Pediatric Index of Mortality-3 score (2). While delirium has been well studied in adults, pediatric delirium is less well understood (2). Prior to 2009, most of the literature on delirium in critically ill children comprised case reports and case series that used inconsistent terminology and unvalidated diagnostic criteria (4). Since then, the development of several validated bedside screening tools has led a rapid expansion in delirium research (5–8).

Delirium has been found to be common in PICUs, with the prevalence ranging between 15.9% and 44.0% in general PICUs and at much higher rates of 49.0–67.0% in surgical or cardiac PICUs (1,9). Most studies report that delirium tends to develop early in the PICU stay, lasting for a median of 2 days (1,4,10). Additionally, some studies found that children who screened positive for delirium had longer PICU stays compared to children without (9,11). Approximately 27.0% of children develop recurrent delirium, characterized by multiple discrete episodes, with normal mental status for at least 24 hours in between episodes (1). There are three subtypes of delirium: 1) hypoactive, the most common (46.4–55.2%); 2) mixed type (19.2–45.2%); and 3) hyperactive type (5.0–20.7%) (1,2). The key implication of these subtypes is that without routine delirium screening, a significant proportion of critically ill children with delirium may be missed. This begs the question of whether delirium screening should be standard of care in all PICUs around the world. And if so, then the next logical question would be whether we, as practitioners in the PICU, can modify the risk and prevent delirium from developing in our sickest children. A systematic review and meta-analysis published in this issue of Pediatric Critical Care Medicine lay the foundations for the answers to these two pressing questions.

Ista et al (12), a team comprised of well-established and prominent leaders in the field of pediatric delirium, present the findings of an important meta-analysis on delirium in the PICU, reporting risk factors for developing delirium during pediatric critical illness. By including 24 studies and more than 10,000 pediatric patients in their review, the authors identified seven risk factors associated with greater odds of developing delirium. Of these, only one, the presence of developmental delay, was nonmodifiable. The remaining six risk factors were modifiable and these included (in descending order according to the magnitude of the strength of their association with the odds of developing delirium): need for mechanical ventilation, use of physical restraints, use of benzodiazepines, vasoactive medications, opiates, or steroids (12).

The publication of this meta-analysis is timely, given the increasing recognition of the prevalence of delirium in critically ill children and its associated morbidity and mortality, which is reflected in the growth of delirium research over the last decade (13). If the introduction of routine delirium screening in all PICUs (or in any at-risk child outside the PICU) is the first step, identification of risk factors is the logical next step to facilitating a paradigm shift in the management of the critically ill child and limiting exposure to these risk factors. This is especially important given the paucity of pediatric data demonstrating the efficacy of nonpharmacologic and pharmacologic interventions for delirium (2,13). While these results do not establish causality, they represent the most current robust data to guide practitioners in tailoring interventions to reduce delirium. Regardless, studies of delirium in adults have demonstrated that routine screening and nonpharmacologic interventions to reduce harm have been successful in decreasing delirium rates (2,13).

One major strength of this systematic review is its extensive literature search across multiple databases, including studies from 1990 to 2022, with no language restrictions imposed. This ensured that all relevant literature on risk factors associated with developing delirium in critically ill children were included. One of the key findings of the meta-analysis performed together with this review is that six of the seven identified risk factors were modifiable (i.e., mechanical ventilation, physical restraints, benzodiazepines, vasoactive medications, opiates, or steroids). From a practical standpoint, it may be challenging to limit exposure to certain risk factors at the bedside (e.g., limiting the use of vasoactive medications in a hemodynamically unstable patient or limiting the use of steroids in a patient with a disease for which steroids are strongly indicated and proven to be beneficial). Indeed, practitioners must exercise clinical judgment to weigh the advantages and disadvantages of withholding exposure to these risk factors according to each individual patient’s clinical context. Alternatively, when these deliriogenic drugs may not be avoided, practitioners may consider limiting their use in terms of dosage or duration. This is a pressing clinical research question—future studies are urgently required to reassess the safety and efficacy of select medications, balanced against the risk of precipitating delirium. Thus, we propose that investigators consider including delirium as an outcome when investigating safety and efficacy of such interventions. While developmental delay is a nonmodifiable risk factor, its presence may still be actionable, and it may prompt more frequent delirium screening or influence alterations in management strategies to reduce exposure to risk factors for delirium in a stricter fashion.

The meta-analysis reported several unexpected results. Of these, perhaps the most unexpected is that an age of less than 2 years was not associated with greater odds of developing delirium. Notably, 12 of the 24 included studies demonstrated an independent association between age and delirium, with nine of these 12 studies reporting that children under 2 years old had a greater prevalence of delirium. The predisposition of the elderly and young children, especially in those with dementia or developmental delay, to developing delirium in the face of a physiological stressor has often been compared, with the proposed mechanism thought to be their abnormal or immature brains having poorer reserve and thus being more prone to developing delirium (14). The extremes of age and risk of delirium have also been linked to hypotheses about cholinergic deficiency and the use of anti-cholinergic drugs (15). Thus, it is uncertain why the association between an age of less than 2 years or the use of anti-cholinergic drugs and the development of delirium did not reach statistical significance in the current meta-analysis. Another unexpected finding included the significant association between the use of opiates or steroids and the greater odds of developing delirium. This is not consistent with data in adult studies. As alluded to by the authors, these results may be due to confounders which they were unable to study. These contradictory findings to our current understanding should be corroborated in subsequent large-scale studies. In addition, there are a number of other previously identified risk factors for delirium that were not included in this meta-analysis: presence of significant organ dysfunction (e.g., congenital heart disease, liver failure, neurological disease), the extent of systemic inflammation, the extent of malnutrition and the use of blood products (16,17). Hence, there may be a need for serial updates of this systematic review and meta-analysis as future studies are published.

In conclusion, this systematic review and meta-analysis is an important next step in improving our understanding of delirium in critically ill children. Coming back to our two pressing questions at hand; we strongly propose that the time has come to consider elevating the “status” of delirium to become our next routinely monitored vital sign, at least within the critical care population. The challenge for all of us is how we incorporate delirium screening as routine care in the PICUs we work in. Further studies to refine our screening process, delirium severity stratification and diagnostic tools for delirium are still needed. Ista et al (12) have provided some preliminary direction for us to search for the answer to the second question. The identification of risk factors associated with delirium will assist critical care practitioners to alter their management strategies to prevent and treat delirium. However, there remain many unanswered questions in this area. Future delirium research should delineate the prognostic impact of the various subtypes of delirium. There is also a need to assess the efficacy and safety of nonpharmacologic and pharmacologic interventions for the prevention and management of delirium in the PICU. Finally, there is a need to determine the long-term impact of delirium on cognitive, social, and psychological functions in PICU survivors and their families.

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