Introduction

Delirium is an established neuropsychiatric syndrome that is increasingly recognized in infants [1,2,3,4]. Among infants admitted to the neonatal intensive care unit (NICU), it is estimated that about 22% suffer from delirium [5]. Risk factors for delirium include young age, developmental delay, invasive ventilation, severe illness, surgery, and exposure to neuro-sedative drugs. The frequency of these risk factors makes the NICU a high-risk environment for developing delirium [6,7,8,9,10].

Recognition of this condition is critical as delirium is associated with higher mortality in children [11]. Delirium is also associated with significant morbidity, including longer time on mechanical ventilation, longer hospitalizations and ICU length of stay, and higher hospitalization costs [10,11,12]. Recognition of delirium in the NICU is challenging as there are no NICU-specific diagnostic tools available yet. Instead, recognition is based on clinical suspicion and knowledge of current practices in pediatric and neonatal ICUs.

Delirium management is based on addressing the underlying etiology, risk factor mitigation, supportive care, and pharmacologic strategies [6, 13]. There are currently no FDA-approved medications to treat delirium. However, when non-pharmacologic management has been optimized, medications including antipsychotics have been used in children [6, 14,15,16]. Knowledge of the safety and efficacy of antipsychotics is currently limited.

There is little information about delirium in the NICU. Much of what is currently known is extrapolated from pediatric literature. It is prudent for the NICU clinician to learn about its identification, prevention, and treatment due to diagnostic and treatment challenges that are unique to the NICU population. The goal of this review is to summarize current knowledge, enhance recognition of delirium in infants, and to discuss potential future directions to guide the care of infants at risk for delirium.

For the purposes of this review, “infant” will be used to define patients admitted to the NICU and will include preterm, term, and term-corrected patients.

Definition

The Diagnostic and Statistical Manual of Mental Disorders V defines delirium as an “acute disturbance of consciousness, consisting of disturbance in attention, cognition changes, short time in course, and fluctuating symptoms as a physiologic consequence of a medical condition, medication, or intoxication” [17]. This definition does not reference pediatrics and there are no qualifiers for infants. The same principles apply to children but are complicated by rapid developmental changes in early childhood [1, 3, 13, 18]. Appreciation of this condition relies on the clinician having a baseline level of suspicion for delirium in order to include it in the differential diagnosis.

Pathogenesis

The pathogenesis of delirium is not fully understood though there are several pathways thought to contribute to delirium, including (but not limited to) neuroinflammatory, oxidative stress, and neurotransmitter hypotheses (Fig. 1) [1, 8, 13, 19]. These pathways are intricate and attempt to describe the drivers for cerebral dysfunction in delirium. There may be overlap between hypothesized pathways rather than each being independent and mutually exclusive [19].

Fig. 1: Hypothesis of pathogenesis of delirium.
figure 1

Several of the etiologies described may play a role in development of delirium, including the neuroinflammatory hypothesis, oxidative stress hypothesis, and neurotransmitter hypothesis. These are not mutually exclusive as delirium may represent a complex network of pathways that may overlap [19].

The neuroinflammatory hypothesis involves inflammatory stimuli that lead to a cascade of events affecting cellular function through neuronal and synaptic dysfunction. This produces functional changes that manifest as neurologic cognitive, behavioral, or emotional disturbances [20, 21]. In the oxidative stress hypothesis, insufficient oxygenation from oxidative stress or antioxidant deficiencies manifest as cerebral dysfunction, including delirium [19]. The neurotransmitter hypothesis suggests that delirium occurs from changes in neurotransmitter function, availability, or balance. This includes key neurotransmitters such as acetylcholine, serotonin, dopamine, glutamate, GABA, and others that may be implicated in these processes [19, 21, 22]. All of these mechanisms are plausible in the NICU population given the unique physiology of infants: an evolving blood brain barrier, susceptibility to inflammatory conditions, vulnerability to oxygen toxicity, and a developing nervous system.

Epidemiology and risk factors

Due to limited NICU-specific reports, the current understanding of delirium in the NICU is extrapolated from older children. It is estimated that about 20–40% of children experience delirium in pediatric ICUs; prevalence was estimated to be approximately 22% in a single NICU study [5, 10, 23]. Ranges in reported prevalence may be attributable to variations in screening practices, prevention measures, age range included, comorbidities, and medical complexity present.

Prevalence increases with mechanical ventilation, age < 2 years old, if course involves post-operative care, or if length of stay is greater than 48 h [24,25,26,27]. Higher risk of delirium is seen in children with developmental delay [9, 24, 27]. Co-morbidities that increase risk of delirium include congenital heart disease, respiratory failure, major surgery and systemic inflammation [6, 8, 9, 19, 25]. Familiarity of risk factors is essential for proper recognition and management of delirium (Table 1). Risk factors are considered as modifiable versus non-modifiable. The distinction between what is modifiable and non-modifiable is imperfect: for example, while ventilation is mandatory for life-sustaining measures, it may become modifiable as the medical course improves. Identification of risk factors facilitates recognition of this condition and allows the medical team to capitalize on aspects that may indeed be modifiable. Modifiable risk factors have a role in both prevention and treatment of delirium and include environmental triggers, dysregulated sleep, immobility/restraint devices, and medication exposure (e.g., opioids, benzodiazepines) [6]. It is plausible that the risk factors identified in older children can be applied to the NICU population as some epidemiology studies included infants in their cohorts. Prematurity has not been identified as a risk factor for delirium yet, however, with both younger age ( < 2 years) and developmental delay being risk factors, prematurity may also be implicated.

Table 1 Risk factors associated with delirium. Identification of modifiable and non-modifiable risk factors can assist the clinician identifying how to optimize care. As the medical course evolves, the clinician should be vigilant in recognizing what can be modified.

Presentation

The three subtypes of delirium include hyperactive, hypoactive, and mixed types (Table 2) [1, 8, 19]. The subtypes are not clearly defined in children nor infants but may be useful in describing the range of potential symptoms. Hypoactive delirium may be the most prevalent form in pediatrics, but because of its less disruptive clinical presentation, hypoactive delirium may go underrecognized [11, 28]. Hyperactive delirium may be more overt with refractory agitation, or mimic difficult sedation [3, 29].

Table 2 Delirium Subtypes. Three types of delirium include hyperactive, hypoactive, and mixed subtypes.

Special considerations are warranted for the identification of delirium in infants [28]. For example, comorbid conditions coexist in the NICU that may have overlap in symptomology, including medication withdrawal, medication over-use, or baseline state dysregulation [8, 13, 30]. The NICU population also includes patients with diverse stages of development, with evolving displays of mental status, sensory processing, and response to stimuli [1, 13]. Detecting delirium requires experience with a typical infant examination to detect deviance from the expected state [27, 31].

Screening and diagnosis

No screening nor diagnostic tools have been specifically validated in a NICU population. However, two tools that are used in the pediatric population included infants in their validation. Two tools will be discussed here, the Preschool Confusion Assessment Method for the ICU (PsCAM-ICU), and the Cornell Assessment of Pediatric Delirium (CAPD) [26, 27]. Other pediatric tools, such as the Vanderbilt Assessment for Delirium in Infants and Children, are intended for use by pediatric psychiatrists, and will not be discussed in this review [32].

Preschool confusion assessment method for the ICU (PsCAM-ICU) [26]

The PsCAM-ICU tool was developed by an interdisciplinary team with critical care, neurodevelopmental, child and adolescent psychiatry, and anesthesiology input based on the Pediatric Confusion Assessment Method. The tool evaluates (1) fluctuation or acute change from baseline mental status, (2) inattention, (3) altered level of consciousness, and (4) presence of disorganized thinking. The PsCAM-ICU tool was validated in 300 children by comparing it with delirium assessments conducted by a standard reference team of child and adolescent psychiatrists. The results showed a prevalence of 44%, specificity of 91%, sensitivity of 75%, negative predictive value of 86%, and positive predictive value of 84%.

This tool included infants as young as 11 months of age and included developmental considerations. There is one report of it studied in a PICU setting with infants < 6 months old [33]. Caution must be exercised applying this tool the NICU because its initial development did not include younger infants, did not specify different gestational ages, and is not validated for use in the NICU. However, this tool could serve as a foundation for investigation for developing future validated tools.

Cornell assessment of pediatric delirium (CAPD) [27]

The CAPD is an observational tool developed for use at the bedside to identify delirium in the pediatric ICU. The tool evaluates (1) eye contact, (2) purposeful actions, (3) awareness of surroundings, (4) communication, (5) restlessness, (6) inconsolability, (7) activity level in awake states, and (8) timing/response to interactions. This tool acknowledges the difficulty in assessing infants and includes “anchor points” for reference that characterize what “normal” evaluation represents. Of the 111 patient validation cohort, 7 were less than 1 month of age, 37 were ages 0 to 24 months, 22 had developmental delay, and 22 had prematurity [5, 27]. The overall prevalence was reported as 20.6% of the study population. A CAPD score of 9 or greater had sensitivity of 94.1% and specificity of 79.2% and was assessed for interrater reliability [27].

This tool is able to be performed serially at the bedside and the developmental “anchor points” may be more inclusive of developmental diversity [31]. It has been applied in children with developmental disabilities [34]. While it has been studied in the NICU in a pilot study with term and term- corrected infants, it is not validated in the NICU setting, and there is not enough information for its widespread application in the NICU [5].

Both tools attempt to identify core symptoms of delirium including altered consciousness, attention, and other mental status criteria. Despite the different approaches of these tools, they both provide an assessment of current mental status and are valuable to be tracked over time. Challenges to developing tools for use in the NICU are the various ages of infants, degrees of prematurity, and developmental stages. Diagnosis of delirium is a clinical diagnosis; the clinician is required to understand the expected mental status based on age and development and must be able to recognize deviation from that. Involvement of pediatric subspecialists (e.g., Pediatric Psychiatry) may be indicated if further diagnostic considerations are warranted [32].

Nonpharmacologic and supportive management

The mainstay approach to management of delirium is to focus on prevention, treat underlying reversible causes, and mitigate risk factors. This requires a working knowledge of the risk factors for delirium and a multifaceted approach compiled in Table 3 [1, 7, 8, 11, 35,36,37]. A nonpharmacologic, multifaceted, bundled approach is used in adult ICUs involving minimizing sedation, optimizing sleep, reducing immobility, and encouraging family involvement; this has demonstrated reduction in delirium [38, 39]. Adult literature has also found that involvement of occupational and physical therapists, respiratory therapists, pharmacists, and nurses in a multidisciplinary approach is beneficial [40,41,42,43].

Table 3 Management Strategies for Delirium. While not an all-inclusive list of modifiable risk factors to address, many strategies can be implemented in the medical care plan to minimize contribution to delirium.

Evidence-based strategies for preventing and reducing delirium specific to the NICU setting are lacking. However, strategies from pediatric and adult care are likely readily adaptable to the NICU because of how NICU care is structured. For example, a multidisciplinary approach may be able to reduce prevalence of delirium [23, 44]. Further, nursing may be well suited for serial delirium scoring or for sedation evaluation [27, 45]. Neurodevelopmentally appropriate care is typically a priority in the NICU. This includes optimization of the patient’s environment, including modulating excessive or invasive light or sound exposure, gentle caregiver-infant interactions, and minimizing external stressors for each individual infant [46,47,48,49]. Family involvement is also a cornerstone of NICU practice that could be adapted to optimize delirium management [50]. The NICU setting is well-equipped to adopt a holistic approach to delirium. A proposed comprehensive, multidisciplinary team may help facilitate this process (Fig. 2). The multidisciplinary approach can be adapted beyond this diagram depending on access at different institutions, including developmental therapists, child life specialists, acute pain teams, palliative care teams, or other subspecialists.

Fig. 2: Multidisciplinary approach to delirium.
figure 2

Many members of the medical team may be able to contribute to delirium management to promote multidisciplinary care.

Pharmacologic considerations

There are no drugs that are FDA-approved for treatment of delirium in any age group. In adult and pediatric literature, antipsychotics have been described for treatment of delirium. However, more recent reports have challenged the use of antipsychotics for prevention and treatment of delirium in adults as they do not seem to impact the incidence, severity, or duration of delirium [41, 51,52,53]. Antipsychotics have potentially serious side-effects (e.g., dystonia, arrythmias, sedation) that must be weighed against the potential benefits of treating delirium.

While there are reports of using antipsychotics in pediatric delirium, robust literature about dosing, efficacy, and side effect profiles is lacking [4, 16, 54,55,56,57]. This is particularly true for infants where literature is largely confined to case reports and series describing antipsychotic use [2, 3, 58]. Typical antipsychotics, such as haloperidol, and atypical antipsychotics, such as risperidone, quetiapine, and olanzapine, have been described in pediatrics including infants. Notably, haloperidol has been used in infants as young as 3 months old and quetiapine has been used in infants as young as 4 weeks corrected gestational age to 2 months old [3, 54, 56]. In pediatrics, the side effects of antipsychotics, including extrapyramidal symptoms, sedation, weight gain, and metabolic effects occur more frequently than in adults [59, 60]. QTc interval prolongation is also a known risk of antipsychotics. The side effect profile differs between antipsychotics, largely based on their various neuroreceptor binding profiles [59]. For example, typical antipsychotics and atypical antipsychotics with greater dopamine receptor affinity (like risperidone) have a greater risk for extrapyramidal symptoms. Antipsychotics with more anticholinergic properties are more sedating. The atypical antipsychotics, olanzapine in particular, have a greater risk for metabolic effects [60, 61]. Literature regarding the safety profile of antipsychotics use specific to an ICU setting remains extremely limited, with case series of patients on quetiapine suggesting safety [54]. Providers should utilize knowledge of side effect profile when selecting an antipsychotic medication and should consider cardiac, metabolic, and abnormal movement motoring when utilizing antipsychotics [16]. Judicious use of antipsychotics may be considered for short-term application for delirium refractory to supportive care and medication optimization. They may facilitate removal of other deliriogenic medications, after which antipsychotics could also be considered for removal. Overall, efficacy and safety in infants are not established and more information is needed on determining the role of antipsychotic use in the NICU.

Apart from antipsychotics, other adjunctive medications may have a role in mitigating delirium. For example, alpha-receptor agonizts such as dexmedetomidine or clonidine, have been shown to facilitate decreased opioid or benzodiazepine use [62]. Alpha-receptor agonizts may also facilitate post-operative extubation, contributing to risk factor mitigation to minimize risk for delirium. This in turn may permit weaning of medications that are known contributors to delirium risk. Similarly, melatonin which functions in sleep maintenance and circadian rhythm regulation, can optimize sleep patterns to potentially reduce delirium risk. Experimental trials examining melatonin use in infants are scarce and a direct relationship between sleep and delirium has not been adequately evaluated in pediatrics [63, 64]. Melatonin may be considered as an adjunct therapy when trying to optimize sleep regulation and could be an area of future study. Lastly, gabapentin, a gamma-aminobutyric acid analog, has had increasing utilization in the NICU [65]. It has not been studied in the setting of delirium in the PICU nor NICU.

Benzodiazepines and opioids, which are commonly used in ICU settings, should not be considered as treatment for delirium because they are known risk factors for delirium [11, 14, 66,67,68,69,70]. Receipt of opioids or benzodiazepines increases the odds of pediatric delirium [70]. It is up to the clinician to determine adequate pain control; caution must be used in balancing necessary sedation and pain control with the risk of delirium [67, 69]. Recognition of medications that are associated with higher odds of pediatric delirium, including benzodiazepines, opioids, steroids, and vasoactive drugs is warranted to develop individualized treatment plans to reduce pharmacologic risk as able [70].

Pharmacologic treatment should not take precedence over non-pharmacologic supportive care and medical management optimization. Nonetheless, for instances where the clinician concludes that pharmacologic treatment is warranted (specifically, severe hyperactive delirium that does not respond to non-pharmacologic interventions), there are important principles to inform care decisions. Pharmacokinetics differ in the neonatal and infant period and they may be at heightened risk for adverse drug effects [16]. Efficacy studies are inherently difficult to interpret because of the need to distinguish the contribution of supportive care, treatment of the underlying case, versus pharmacologic treatment. Drug safety profiles must be weighed against the risk of untreated delirium, and safety profiles must consider the potential long term effects of early exposure to psychoactive medications.

Outcomes and neurodevelopment

In adult literature, delirium is associated with increased morbidity and mortality including increased time on mechanical ventilation, increased length of ICU and hospital stay, increased hospitalization cost, and increased likelihood for readmission within 1 year of hospital discharge [10,11,12, 71]. In pediatrics, there is conflicting information on whether delirium is associated with higher mortality [10, 11]. Pediatric delirium is also associated with significant morbidity, including decline in cognitive function from ICU admission to discharge, longer time on mechanical ventilation, longer hospitalizations and ICU length of stay, and higher hospitalization costs [10,11,12, 72]. Pediatric delirium may also be associated with reduced health-related quality of life after discharge [73].

Outcomes for NICU delirium are not yet known. Infants may be vulnerable to adverse effects of delirium because of critical brain development and maturation in early life. Patients in the NICU are at highly vulnerable states in development; the threat of untreated delirium, pain and sedation, and pharmacologic adverse effects, should be considered against the stakes involved in neurodevelopment. There is an urgent need to understand how delirium affects infants at a crucial time in brain development [74].

Limitations and future directions

There is insufficient primary literature on neonatal delirium and more information is desperately needed. This review is limited by evidence selection bias from the limited data on this topic and extrapolation from other disciplines. Understanding of neonatal delirium is still in its early stages and it is imperative that future research focus on the infant patient, with special regard to their complex medical needs, fragile neurodevelopment, and unquantified risk of potential harm from delirium.

We propose several items as research priorities to further advance knowledge in this field. First, a validated tool that is specific to neonates and the NICU setting is needed. Ideally, this tool would identify neonatal delirium in the context of development and other conditions such as drug withdrawal, pain, or sedation. Next, NICU related risk factors should be identified not only to enhance recognition of delirium, but to also to identify the infants at highest risk with the most severe risk factor profile. Once delirium is successfully diagnosed, safe and impactful interventions should be established to reduce delirium burden. This would include research into both supportive care and pharmacologic strategies with consideration of neonatal pharmacokinetics and drug safety. Lastly, the long term neurodevelopmental impact of delirium at such a young age should be quantified so that infants may receive developmental therapy intervention if needed.

Conclusions

Delirium is increasingly recognized in infants in the NICU. There are various pediatric screening tools used to identify delirium in infants and older children, but more work is needed to validate these tools in the NICU setting. Management should incorporate a team approach, focus on minimizing modifiable risk factors, maximizing robust supportive care, and optimizing non-pharmacologic treatment. Pharmacologic agents may be considered for refractory hyperactive delirium but are not yet well studied in this population. Long term outcomes of delirium in the NICU are not established but there may be a high risk of neurodevelopmental effects from delirium. There is an urgent need for more NICU delirium research to improve care for infants at a neuro-vulnerable state in their lives.