By: Brooke Jacobson and Kyle Roof, PharmD Candidates 2021; UMKC School of Pharmacy
Mentor: Ekeni Livingston, PharmD, BCPPS; Children’s Mercy Kansas City
Managing patients in the pediatric intensive care unit (PICU) has evolved immensely over the years. While striving to successfully treat the patient’s underlying conditions, providers have often encountered consequences from their own interventions. The goals of caring for critically ill patients not only entails preventing mortality but also avoiding complications associated with prolonged stays in the PICU.1 Delirium is a common consequence addressed in the adult intensive care unit (ICU) population. Conversely, delirium in the pediatric population is often not addressed and rarely studied. The Diagnostic and Statistical Manual of Mental Disorders: Fifth Edition (DSM-5) characterizes delirium as an acute onset of fluctuating disturbances of consciousness, attention, cognition, and perception.2 According to multiple studies, delirium is associated with higher rates of increased hospital length of stay, long-term cognitive impairment, increased time on mechanical ventilation and mortality.1,3
Multiple proposed mechanisms exist to explain the manifestation of delirium in critically ill patients. The first mechanism is the predisposition of patient-related factors (e.g. age, genetics, underlying diseases) and the second is precipitating factors.1 Some examples of precipitating factors can include medications, metabolic dysfunction, progression of disease, and the stressful environment that is associated with a PICU stay.4 Prolonged use of sedatives and analgesics are often the predominant medications that contribute to delirium in the PICU. There are a few processes thought to contribute to delirium in the pediatric population.
The first process proposes an alteration in the blood-brain barrier’s (BBB) permeability secondary to a high prevalence of systemic inflammation.1,4 This leads to an increased production of cytokines and the transport of cytokines across the BBB resulting in ischemia and the destruction of neurons.1,4 The second hypothesis suggests an alteration of neurotransmitter regulation. Decreased levels of acetylcholine and increased levels of dopamine are likely the main contribution to delirium, however, the dysregulation of norepinephrine, serotonin, melatonin, gamma amino-butyric acid (GABA), histamine, and glutamate are also thought to play a role in the process.1,4 The last proposed hypothesis suggests a production of reactive oxygen species as a result of hypoxia and increased cerebral metabolism.1,4 Multiple studies have demonstrated that hypoxia in the intraoperative setting is associated with a reduction in cognitive function.1 The above proposed hypotheses give insight as to how delirium manifests in the pediatric population and can help determine possible treatment options.
Presentation and Screening
There are three main subtypes used to classify delirium in the PICU based on the patient’s presenting behaviors.5 Patients can be classified as hypoactive, hyperactive, or mixed-type delirium depending on the presence or absence of dopamine.5 Hypoactive delirium, the most common form, results from a significant deficiency of dopamine and is demonstrated in patients through a depressed level of consciousness and withdrawal from their environment.5 Unfortunately, hypoactive delirium rarely raises concern within the medical team and patients are often incorrectly categorized as non-delirious. Hyperactive delirium results from an excess of dopamine and triggers agitation, restlessness, emotional instability, and psychosis.5 Mixed-type delirium consists of the fluctuation between hypoactive and hyperactive states.5
Several tools have been created to assess delirium in PICU patients. One of the earlier tools created was the Pediatric Confusion Assessment Method for the Intensive Care Unit (pCAM-ICU). This tool assesses the clinical features of altered mental status, inattention, altered level of consciousness, and disorganized thinking.6 There are multiple limitations associated with the pCAM-ICU including but not limited to: requirement of patient cooperation, extensive nurse training, limitations in patients with developmental delay, and restricted use to children greater than 5-years-old.7 Another tool designed for the assessment of pediatric delirium is the Pediatric Anesthesia Emergence Delirium (PAED) screen.7 This screening tool only detects the hyperactive subtype of delirium which entails obvious limitations. Lastly, the Cornell Assessment of Pediatric Delirium (CAPD) screening tool is an adaptation of PAED. CAPD is a more ideal screening tool due to its additional components that allow detection of all three subtypes of delirium.6,7 Table 1 demonstrates the CAPD screening tool. Elements 7 and 8 allow the detection of both hypoactive and mixed-type delirium. Using this tool, a collective score of 9 or above indicates detection of delirium. Table 2 is included below to characterize the normal behavior of a developing child in the PICU environment.7
Risk factors for developing pediatric delirium include younger age, male gender, preexisting cognitive impairment, development delay, previous delirium, positive family history of delirium, and preexisting emotional and behavioral problems.4 While these factors are not adjustable, there are other non-pharmacological interventions that can help prevent and treat pediatric delirium. Environmental factors such as physical restraints, high noise levels, poor lighting, frequent staff changes, and disease entities may exacerbate delirium and are often associated with high mortality risk.4 Environmental interventions may be sufficient to manage pediatric delirium without the use of medications. These strategies include repeated reorientation by family or familiar nurse, calendars and clocks, pictures of family, familiar toys from home, maintaining bright light during the day and dimming light at night, keeping a regular routine, and minimizing noise levels.4 These strategies help decrease confusion and fear and ultimately decrease the risk and prevalence of delirium.
Delirium is most often related to the use of pain and sedation medications. This can include benzodiazepines, opioids, propofol, barbiturates, and ketamine.6 Utilization of these medications is often necessary as they are crucial for the comfort and care of the patient. However, reducing the dose of these medications whenever possible and using pain and sedation scoring tools [e.g. Faces, Legs, Activity, Cry and Consolidation (FLACC) tool and Richmond Agitation Sedation Scale (RASS)] to obtain an appropriate pain and sedation level is imperative.7 Daily sedation interruption or a “sedation holiday,” is an important element of PICU management. These interruptions not only reduce opioid and sedative exposure, but also orients the patient to time and place which can reduce delirium and delirium-associated complications.
The disruption of the sleep-wake cycle and alterations of sleep stages are prevalent in delirium.6 Benzodiazepines affect both the slow-wave and non-REM sleep.6 This might explain the mechanism by which this drug class causes delirium. Although an effective sedative class, multiple studies render benzodiazepines a high-risk medication for delirium and should carry limited use in critically ill patients and avoided in patients experiencing delirium. Because the circadian rhythm appears to be disrupted with high sedation and in the presence of delirium,4 this introduces a theory that melatonin may be reduced in critically ill patients.6 Kain et al,8 a randomized placebo-controlled double-blind trial, is a small study (n=140) that compared midazolam with melatonin for pre-operative anxiety (primary outcome), compliance with induction, emergence behavior, and parental anxiety (secondary outcomes). The study compared melatonin 0.05 mg/kg, 0.2 mg/kg, 0.4 mg/kg (max 20mg), and midazolam 0.5 mg/kg. Although midazolam demonstrated greater reduction in preoperative anxiety (p < 0.001), patients who received melatonin at higher doses demonstrated less emergence delirium than those who received midazolam (p < 0.05). It should be noted that this study only assessed short-term use of melatonin for emergence delirium. However, there might be a role for melatonin in the prevention of delirium in the PICU, but further studies are needed to make this claim.
The alpha-2 adrenergic agonists, dexmedetomidine and clonidine, are useful anxiolytic and sedative agents utilized in the pediatric population.6 These agents carry minimal risk for respiratory depression and have a decreased amnestic effects reducing the risk for delirium.6 Although dexmedetomidine is the only agent of the two that are approved for pediatric sedation, they are both widely used.6 Dexmedetomidine decreases the need for benzodiazepines, blunts the sympathetic stress response and catecholamine release, and may reduce the need for other sedatives.4 However, prolonged use of these agents can cause significant hemodynamic instability. Dexmedetomidine can be transitioned to clonidine for a continued, long-term alpha-2 agonist effect.4
Important aspects for the management of delirium are identifying the underlying cause and treating patients early. Delirium is typically multifactorial, and it is important to resolve the underlying cause while also avoiding agents that may worsen delirium. Most often, delirium will improve with management of the underlying illness, minimizing triggers, and optimizing the patient’s environment.1 However, if delirium persists, pharmacologic therapies should be used. As previously mentioned, one hypothesized delirium mechanism suggests that excessive dopamine and deficiency of acetylcholine contributes to delirium.9 As a result, antipsychotics, specifically atypical antipsychotics, are most often used for treatment. They relieve agitation, perceptual disturbance, sleep-wake cycle abnormalities, and behavioral abnormalities. In comparison with the earlier generations of antipsychotics, atypical antipsychotics have less extrapyramidal side effects and drug interactions.9 Antipsychotic therapy is used off-label as they are not approved by the Food and Drug Administration for treatment of delirium in adults or children.9
In a recent retrospective matched cohort study, the University of Maryland Children’s Hospital compared the use of antipsychotics versus no pharmacological interventions for the treatment of delirium in critically ill children.9 The most common antipsychotic drugs that were used were haloperidol, risperidone, and quetiapine. This study demonstrated that patients treated with antipsychotics had more delirium days (6 vs. 3, p=0.022), longer mechanical ventilation days (14 vs. 7, p=0.017), and longer PICU stay (34 vs. 16 days, p=0.029). However, although no significant differences were found, more patients requiring pharmacological treatment for delirium had previously been medicated with benzodiazepines (2 vs. 12), opioids (3 vs. 13), and dexmedetomidine (2 vs. 13) than with the untreated group.9 It is also important to note that the sample size for the study was 15 patients, and only 8 of 15 patients were treated on day 2 of diagnosed delirium.
Haloperidol, although a first generation antipsychotic, is frequently used in the adult population to treat hyperactive delirium in the ICU.5 Haloperidol is a dopamine antagonist that exerts its action in the brain to reduce hallucinations, anxiety, sedation, and restore attention.5 It has few anticholinergic and hypotensive side effects and is less sedating than other agents. However, due to its significant extrapyramidal and cardiac adverse effects it has been generally replaced by atypical antipsychotics with similar efficacy.6 Haloperidol is an option for patients with hyperactive delirium and/or requiring intravenous (IV) medication administration.9
Atypical antipsychotics such as risperidone, olanzapine, ziprasidone, and quetiapine are the most commonly used atypical antipsychotics in critically ill patients with delirium.5 This class of medication not only blocks dopamine, but also significantly blocks serotonin, norepinephrine, and acetylcholine.5 Due to the activity on additional receptors, they are generally more sedating and may cause tachycardia, hypotension, lower seizure threshold, and weight gain. Tukel SB, et al,10 compared the effectiveness and safety of olanzapine, risperidone, and quetiapine in pediatric patients with delirium. This was a retrospective descriptive study of 110 patients that concluded the following: the final Delirium Rating Scale-Revised-98 scores in pharmacologically treated patients were significantly lower than the original scores at diagnosis (p<0.001).10 The authors concluded that higher doses were needed when delirium was drug-induced. No significant adverse effects occurred.10 Although this study had many limitations, it is important to note that there were no differences between the effectiveness of antipsychotics, and no significant side effects were discovered in the study. Because side effects are still a concern, it is suggested to use antipsychotics for the shortest duration and smallest dose necessary in order to avoid unwanted side effects.10 Information about each medication is indicated in Table 3.
Delirium can cause severe and irreversible cognitive impairments if not appropriately addressed and managed. Although there is limited literature available, it is a rising area of concern due to its increasing incidence and poor outcomes. The morbidity of delirium may manifest as post-traumatic stress, depression, anxiety, and permanent changes in cognitive function.6 Despite high prevalence rates and concern for delirium, hesitation remains to embrace pharmacological therapy due to uncertainty of clinical diagnosis and lack of clear treatment options within available literature. This provides a clear need for additional studies for the treatment of delirium in critically ill pediatric patients.