Delirium is an acute cerebral condition complicating outcome in critically ill children. According to Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) by the American Psychiatric Association, delirium presents 5 key features: a disturb of consciousness and “awareness”, acute onset (hours to days) with a fluctuating course during the day, presence of other cognitive deficit (memory, language, visive-spatial, perceptive), criteria 1 and 3 are not dependent on pre-existing neurocognitive deficits or on a severe awareness deficit (like coma), evidence (history, physical examination, laboratory tests) that delirium is a consequence of a clinical condition, a substance intoxication, weaning from drugs, toxin or multifactorial factors. [80, 81, 21]
The physiopathology of delirium is complex. Three mechanisms seem to be particularly involved: neuroinflammation, modification of neurological mediators due to drugs administration, oxidative stress due to a clinical condition. The final result is a modification of neurological transmission with integration/processing of sensory inputs and motorial response.
In critically ill children three factors contribute to delirium development: clinical condition, pharmacological treatments, environmental factors. [83, 84]
Three subtypes of pediatric delirium exist: hyperactive delirium (characterized by agitation, restlessness, hypervigilance, combative behaviour), hypoactive delirium (characterized by lethargy, deficit of attention, decreased response to stimulus), mixed delirium (characterized by hyperactive and hypoactive aspects). Hypoactive delirium is the most frequent subtype. It is correlated with a worse outcome. In a longitudinal study on pediatric delirium, hypoactive and mixed delirium were the most frequent subtypes (46,4% and 45,2% respectively) whereas hyperactive one was present in only 8,4% of patients. Children with delirium often show a modification of psychomotor activity, with delay in response to a stimulus or continuous agitation; moreover, emotional lability, inconsolable status, excessive quietude are present.
Frequently, the onset of pediatric delirium is during the first three days of ICU admission. [85, 82, 86, 87] Recent studies reported delirium in more than 20% of ICU admission. In a multicentric paper on 25 PICUs, the general prevalence of delirium was 25%, 53% in ventilated children. The highest prevalence was reported in critically ill children affected by inflammatory/infective diseases. [88]
Finally, it must be considered that the presence of delirium increases costs of PICU admission, independently from duration of PICU admission, patient’s severity and age.[89]
The presence of delirium promotes complications in pediatric critically ill patients. A prospective study showed a strong and independent association between pediatric delirium and mortality. [85] A previous study reported that pediatric delirium increases duration of ventilation and length of ICU stay. [90] Nowadays, no evidence exists on the presence of long-term cognitive disorders in children with a diagnosis of delirium during ICU admission. However, literature is scarce and the impact on caregivers has not been studied. [91]
IS IT IMPORTANT TO WORK ON RISK FACTORS FOR PEDIATRIC DELIRIUM IN ICU?
Non -modifiable risk factors for the development of pediatric delirium are: pre-scholar age, mechanical ventilation, cognitive deficit, congenital cardiopathy, hepatic insufficiency, the severity on admission, treatment with vasopressors or with antiepileptic drugs, ICU stay longer than 5 days. [92, 85, 89, 93, 86, 87] At present, other potential factors (burns, transfusions) need to be confirmed.
Modifiable factors for the development of pediatric delirium are: treatment with benzodiazepines (it increases from 2.5 up to 5 times the risk of developing delirium, with dose-dependent effect), use of restraint and patient’s immobilization, presence of noise, presence of light, modification of sleep- awake rhythm, absence of parents during ICU stay, treatment with anticholinergic drugs. [85, 23, 82, 87, 22] For this reason, preventive bundles for delirium are proposed with to reduce its incidence in critically ill children. (Figure 2) However, their implementation may be hindered by structural problems or lack of resources.
RECOMMENDATION 8:
We recommend working on modifiable risk factors, particularly reducing the use of benzodiazepines.
Strength of recommendation: Strong
WHICH IS THE BEST STRATEGY TO USE IN PEDIATRIC DELIRIUM?
The pivot of strategy is represented by the identification and treatment of risk factors. Moreover, modifiable factors need to be considered and minimized. [43, 95]
Great attention should be paid to create a familiar and comfortable environment, with light and noise reduction. Strategies to prevent delirium are usually displayed in “bundles”. [96, 97] If a patient presents delirium despite the preventive strategies, bundles application should be maximized.
Pharmacologic treatment follows adult therapies, due to the paucity and low quality of literature in pediatric age. Antipsychotic drugs, off-label for indication and, sometimes, age, in children may be used in selected cases. An electrocardiogram needs to be checked before treatment, particularly QT interval. A multidisciplinary approach is suggested, involving a neurologist or neuropsychiatrist.
These drugs are contraindicated if other molecules prolonging QT are administered to the patient or if patient suffers of severe cardiopathy or heart block. Finally, electrolytes should be regularly assessed. [98]
According to a recent study, haloperidol reported adverse events even if the dosage was correct and blood level was below the therapeutic range, due to the occupation of dopaminergic receptor D2. [99] Olanzapine, risperidone e quetiapine has been used in pediatric delirium with good efficacy in low-quality studies (retrospective ones, case series). [100, 101, 102]
Promising but anecdotal studies suggest a role of dexmedetomidine in the treatment of pediatric delirium. [103]
RECOMMENDATION 9:
We suggest basing the treatment of pediatric delirium on maximizing preventive bundles. Antipsychotic drugs may be used with careful consideration of contraindications.
Strength of recommendation: Moderate
WHICH IS THE ADEQUATE MONITORING OF DELIRIUM IN PEDIATRIC PATIENTS ADMITTED TO ICU?
At present, only a third of PICUs adopt tools to monitor delirium [104], despite validated scales exist. In 2011, following the Confusion Assessment Method for Intensive Care Unit (CAM-ICU) for adults, the Pediatric Confusion Assessment Method for the Intensive Care Unit (pCAM-ICU) was developed to monitor delirium in children older than 5 years. [105] In 2014, the Cornell Assessment of Pediatric Delirium (CAPD) was validated, including one year later “anchor points” to make the diagnosis of delirium in younger age and in children with developmental delay. [106,107] To be applicable in the same groups of patients, in 2016 the Preschool Confusion Assessment Method for the ICU (psCAM-ICU), was developed. [108]
In 2018 the Sophia Observation Symptoms-Pediatric Delirium (SOS-PD) scale was derived from the Sophia Observation withdrawal Symptoms scale (SOS); to monitor with a single tool both withdrawal syndrome and, thanks to the inclusion of items related to the cognitive and behavioural status, delirium. This scale may be applied in children older than 3 months. [109]
All tools for the diagnosis of delirium include signs and symptoms of WS. Therefore, despite literature reported the presence of WS and delirium in the pediatric population, the overlap of signs and symptoms makes it difficult to distinguish between the two entities. [110]
ESPNIC recommends adopting CAPD to monitor pediatric delirium and to educate health professionals working in PICU to identify it.[4]
RECOMMENDATION 10:
We recommend regular monitoring delirium in critically ill children every day of the ICU stay, using validated tools.
Strength of recommendation: Strong