20 Pediatric Delirium in the Palliative Care Setting

Paula Tran, Jeffrey Moss, Eunice Koh, Katherine Ort, Richard J. Shaw, and Michelle Goldsmith

Introduction

Pediatric delirium, an often underrecognized and reversible complication of illness, is a clinical emergency demanding immediate management.¹ New research on the clinical presentation of pediatric delirium and age-appropriate assessment tools for prompt identification highlight some of the phenomenological differences between adults and children.^2,3,4,5,6 In the context of palliative care, delirium requires an immediate response and a collaboratively developed plan of care similar to that for pain, anxiety, nausea, and dyspnea.⁷ In the adult palliative care setting, delirium has been carefully studied and identified commonly in the elderly, medically ill, and toward the end of life.^8,9 Delirium is the most common neuropsychiatric disorder, with prevalence estimated as high as 85% among those who are terminally ill.¹⁰ In a palliative care setting, researchers¹¹ identified 42% of the patients with a diagnosis of delirium at the time of hospital admission and an additional 45% who developed delirium during their hospital stay. These data suggest that delirium occurs in the majority of adult patients nearing the end of life and that improved methods of diagnosis and management are warranted for this highly distressing and often reversible condition.

Between children and adults, much overlap exists in the presentation of delirium such as waxing and waning sensorium and disorientation; however, several pertinent symptoms emerge in our younger patients which distinguish them from adults. Changes in affect with increased irritability, inconsolability, decreased eye contact with close care givers, and the loss of previously achieved developmental milestones should raise suspicion that a child is experiencing delirium.^12,13 Frequently parents will say things such as “this is not my child,” or “I don’t know how to help her.” While hallucinations and delusions remain a sine qua non in established criteria for adult delirium, the absence of psychotic features among children does not rule out the phenomenon. Therefore, in all critically ill patients of every age, mental status, and relatability to loved ones should be carefully evaluated in addition to the conventional monitoring of pulse, temperature, respiratory rate, blood pressure, and pain.¹⁴

The study of delirium is at the confluence of several clinical disciplines including anesthesiology, critical care medicine, pediatrics, geriatrics, oncology, pain medicine, palliative medicine, neurology, psychiatry, psychology, nursing, pharmacy, and bioethics. Across these domains, there has been a recent groundswell of interest in delirium,¹⁵ and specifically pediatric delirium, after a long period of neglect between 1980 and 2003.^2,3 Advances in medical care that prolong life place critically ill patients at greater risk for delirium. In addition, awareness of potential cognitive and psychological sequelae of delirium has led to efforts directed at early recognition and treatment. Goals of palliative and general clinical care target delirium as a symptom that necessitates immediate attention.¹⁶

This chapter offers an overview of pediatric delirium, its clinical relevance, and its emotional impact in seriously ill children, families, and clinical providers. An additional goal includes underscoring the interdisciplinary nature of delirium. Any clinician or caregiver, including respiratory therapist, nurse, doctor, intensive care unit (ICU) pharmacist, and parent, can screen patients for delirium. Delirium stems from many causes, occurs in both simple and complex clinical situations, and should be suspected in all circumstances when mental status is altered. One long-term study involving adult inpatients has shown that nurse-directed delirium prevention and management programs involving multidisciplinary education and collaboration have led to a decrease in delirium and clinician workload.¹⁷ Every member of the treatment team serves as a resource in the prevention, recognition, and management of delirium.

Topics addressed in this chapter include definitions, clinical presentation, prevalence and epidemiology, etiology and risk factors, pathogenesis, assessment, and treatment. Finally, there is a review of the relationship between delirium and posttraumatic stress symptoms, including its effects on caregivers.

Definition

According to the Diagnostic and Statistical Manual (DSM),¹⁸ the core features of delirium include a disturbance of consciousness, change in cognition, and perceptual disturbance that develops over a short period, usually hours to days, and fluctuates over time (see Box 20.1). Delirium has been associated with rates of morbidity and mortality that surpass those of all other psychiatric diagnoses.¹⁹ Across clinical disciplines and countries, many ambiguities prevail in the terminology used to describe delirium.²⁰ Such terms as “acute brain failure,” “encephalopathy,” “acute confusional state,” and “ICU psychosis” have been widely employed, and the critical care literature now conforms to the recommendations of the American Psychiatric Association and other experts that the term “delirium” be used uniformly to describe this syndrome of brain dysfunction.²¹ The need for shared terminology reflects the challenges clinicians face in diagnosing delirium across clinical settings and age groups.

Although the clinical presentation of delirium in children and adolescents is similar to that of adults, there are observed differences in the type and frequency of symptoms across various age groups.^4,5,6 Clinician-observed features of pediatric delirium vary across several studies. Pediatric patients are described as having more frequent fluctuation in symptoms, greater affective lability, impaired attention, and disturbances in their sleep–wake cycle.⁴ By contrast,⁶ a study described pediatric patients as having lower rates of sleep disturbance, fewer cognitive deficits, and lower levels of symptom fluctuation.

With regard to psychotic symptoms, authors have described both lower and higher prevalence of perceptual disturbances and delusions among children compared to adults.^4,6 Some have suggested that delusions and hallucinations may not be core symptoms of pediatric delirium.⁴ Alternatively, a study of pediatric patients emerging from anesthesia reported that younger children had higher rates of hallucinations and other perceptual disturbances when compared with older children.²² These differences may reflect variations in brain function across the age span, developmental immaturity in children, functional decline in old age, and differences in the expression of distress during hospitalization.²³ The variance in observed clinical features is wide and may result from the fluctuating nature of the illness, the subjective nature of clinical assessment, limitations of age-appropriate screening tools, and the various causes of delirium.

Subtypes

The adult literature well-describes three motoric subtypes of delirium: hypoactive, hyperactive, and mixed.²⁴ Delirium is also categorized on the basis of symptom severity, with terms such as “pre-delirium,” “subsyndromal,” “veiled,” and “full-blown,” all of which designate differences in presentation.²⁵ These additional terms reflect increasing research into the phenomenology of delirium. Although few studies have focused on categorizing delirium temporally or by severity, the practical finding from this work is that delirium may be detectable earlier in its course with vigilant screening. In this chapter, a discussion of motoric subtypes is reviewed with vignettes.

The term “hyperactive” refers to patients who present with symptoms of confusion, psychosis, disorientation, agitation, hypervigilance, hyper-alertness, fast or loud speech, combativeness, and behavioral problems such as pulling out catheters and lines. These patients quickly come to the attention of the medical staff and are less likely to be overlooked.

Mixed delirium describes patients who fluctuate between hyperactive and hypoactive states.^23,27 These critically ill patients present with an array of symptoms in the context of possible pain, anxiety, and nausea, thus making it difficult to recognize delirium and identify the cause.

Prevalence and Epidemiology

One of the largest retrospective pediatric studies on delirium³ reported a 9% prevalence of delirium in a sample of 1,027 patients referred for psychiatric consultation. Another study⁵ reported a lower prevalence of 4.6% in a pediatric sample of 877 critical care patients. By comparison, among adult studies, delirium has been reported in 15% to 18% of patients on acute medical and surgical wards, with higher rates in specific populations.¹⁹

Regarding age, a study of 1,027 patients³ identified 84 patients with delirium ages 6 months to 18 years, and there was no significant difference in mean and median age based on the cause of delirium. The study did not assess whether age itself was a risk factor for delirium. According to the study⁵ that presented data stratified by age, the greatest incidence of delirium occurred among the oldest children (15–18 years), but these data were not analyzed for statistical significance. Conversely, another study²⁸ found a negative correlation between age and delirium among post-anesthesia patients suffering with emergence delirium.

Although studies to assess the prevalence of delirium in children receiving end-of-life care have not yet been undertaken, data from adult studies suggest potentially much higher rates in this population. For example, immediately before death, delirium rates of 68–88% have been reported in adult oncology patients.^11,29 More specifically, according to a review,⁸ hypoactive delirium, which is easily overlooked, has been reported as being as high as 40–78% in adult palliative care patients.^11,30,31

Attempts to quantify the prevalence of delirium by subtype among adults have resulted in a range of findings. For example, a study³² reported hypoactive delirium (43.5%) occurring considerably more often than “purely” hyperactive delirium (1.6%), and mixed delirium was the most frequently observed subtype (54.1%). The low number of cases with hyperactive delirium in this cohort is unusual when compared with other studies that report rates of hyperactive delirium ranging from 15% to 80%.^24,33 On the other hand, the high number of cases in the cohort³² of 375 elderly diagnosed with hypoactive delirium suggests that careful screening may accurately identify more subtle presentations of delirium. The only comparison⁴ of prevalence of delirium subtype between adults to children found that, across three adult studies, there was an average of 59% hypoactive delirium, similar to a pediatric prevalence of 69%. Agitation was noted in the adult studies at a combined rate of 44%, which was significantly lower than the pediatric rate of hyperactive delirium of 68%.

Figures for the prevalence of delirium by subtype in the pediatric palliative care setting are not known. In adult palliative care literature, the rates of hypoactive delirium are as high as 86%, with a mean prevalence 48% in one meta-analysis, while rates of hyperactive delirium vary between 13% and 46% of patients.^31,34

Despite the varied estimates on prevalence, numerous studies suggest that the motoric subtypes of delirium differ beyond the degree of psychomotor activity. Studies show variation between hypoactive, hyperactive, and mixed delirium with regard to other nonmotoric features of delirium,³⁵ etiology and pathophysiology,³⁶ ease of detection and assessment, response to treatment,²⁶ and outcome.³⁷ Notably, clinician observations of patient psychomotor disturbance were less reliable when compared with data from electronic motion detectors.³⁸ Because recognition of delirium continues to be challenging and machine-assisted assessment is helpful, there is the potential that future technological innovations may enhance clinician assessment. For example, similar to the use of heart monitors in the ICU, motion detection may be used to help alert clinicians to the presence of delirium among high-risk groups.

Etiology and Risk Factors

Causes and risk factors for delirium are often multifaceted and include vascular, infectious, neoplastic, degenerative, organ failure, toxic, deficiencies including vitamin, congenital, CNS pathologic, traumatic, endocrinological, metabolic, dehydration, heavy metal, and anoxic phenomena.¹⁹ Medication-related etiologies, as a result of toxic effects or withdrawal reactions, are also common. As with adults, certain classes of medications, such as steroids, opiates, benzodiazepines, and anticholinergic agents, are frequent precipitants.

At end of life, delirium often results from intensive treatment of pain and suffering, which can lead to drug-induced change in mental status.⁹ A study of 40 critically ill children⁵ found that the most frequent causes of delirium in decreasing order included a change in analgosedative medication, infections, and neurological and respiratory disorders. Often there were multiple causes for delirium. Infection was twice as often the precipitating factor compared with drug induced-delirium in one report.⁴ A thorough diagnostic workup to identify the cause is the standard of care³⁹; however, in the palliative care setting where the goal of care is to decrease pain and suffering, this approach is often modified

Pathogenesis

Delirium as a neuropsychiatric disorder involves global encephalopathic dysfunction caused by multiple impaired neural pathways and physiologic compromises. The neurotransmitters implicated in the pathophysiology of delirium include acetylcholine, dopamine, glutamine, gamma-aminobutyric acid (GABA), and serotonin.³⁶ Dopamine modulates mood and cognitive function, and in excess can lead to psychotic disorders. Similarly, acute alterations in dopamine levels may contribute to the characteristic symptoms of delirium. Antipsychotic medications that inhibit the dopamine pathway effectively treat delirium.⁴⁰ Alteration of GABA, an inhibitory neurotransmitter, may also cause changes in cerebral functioning, possibly by affecting sleep patterns. In the critical and palliative care setting, benzodiazepines and propofol, which directly affect GABA receptors, are frequently administered, and contribute to the development of delirium.⁴¹ Likewise, the use of anticholinergic drugs precipitate and worsen symptoms of delirium.⁴² These neurotransmitter perturbations are thought to cause neuronal membrane hyperpolarization, thus spreading neuronal depression, which is seen on electroencephalogram (EEG) as a diffuse slowing.⁴³

Other insults to cerebral functioning such as inflammation, hypoxia, metabolic encephalopathies, and drugs or toxins, compound the development of delirium. Inflammation, caused by infection, surgery, or other tissue injury, heightens blood–brain barrier permeability leading to translocation of inflammatory mediators, such as cytokines and chemokines, into the CNS, causing encephalopathy dysfunction.⁴⁴ Cytokines such as interleukin (IL)-1, IL-2, interferon (IFN), and tumor necrosis factor (TNF) can affect neuronal pathways by inhibiting acetylcholine, leading to agitation, perceptual disturbances, seizures, and delirium.⁴⁵ There are reports of chemokine elevations in patients with delirium, and one study found IL-6 increases in children with influenza who developed delirium.⁴⁶ Inability to meet oxygen needs, either because of increased demand or decreased delivery, contributes to development of delirium because of disruption of ionic gradients, neurotransmitter homeostasis, and neurotoxic byproduct elimination. The compromise of oxygen metabolism can be due to hypoglycemia, hyper- or hypothermia, and vitamin or amino acid deficiencies. Impaired oxygen metabolism leads to reduced neurotransmitter synthesis, causing a deregulation of sleep–wake cycle, behavior, and mood, and psychomotor activity, all of which are clinical manifestations of delirium.^40,47

Assessment

The diagnosis of pediatric delirium is primarily made on clinical examination, which should always include an interview with parents and primary caregivers. Suspicion of delirium also necessitates a review of the medical chart, including laboratory and imaging test results. Nursing staff and parents’ observations are particularly important to evaluate fluctuations in levels of consciousness and sleep disturbance. The Nursing Staff Delirium Screening Scale (NDSS) provides a quick and consistent measure for those clinicians who have the most frequent clinical contact with patients.⁴⁸ Although not generally standard of care, EEG findings may offer diagnostic support of delirium and perhaps subtype.⁴³ Additionally, family members serve as a valuable clinical resource regarding the patient’s state of arousal, activity, and orientation, especially in the pediatric population. In palliative care, the education of patients and family members in recognizing signs of delirium can aid in assessment and early intervention, minimize distress to the patient and family, and support clinical decision-making in end-of-life care.

Structured Delirium Assessment Instruments

To supplement and help guide the direct clinical evaluation, there are several structured assessments and rating scales to diagnose and track symptoms related to delirium. These tools include assessment for cognitive impairment, such as Mini Mental Status Exam⁴⁹; screening for delirium using DSM-IV-TR diagnostic criteria including the Confusion Assessment Measure^50,51; and delirium-specific numeric scales to rate severity, including the Delirium Rating Scale-Revised-98 (DRS-R-98).⁵⁰

Delirium Rating Scale-Revised-98

The DRS-R-98 is widely used to assess delirium in adults using a 16-item scale with items that include disturbances of cognition, perception, thought, language, sleep, affect, and psychomotor function. Items are rated based on direct observation, data from the medical record, and accounts from caregivers. The DRS-R-98 has been proved reliable for both the diagnosis and serial assessment of delirium and has been used and validated for pediatric patients. The scale was validated for children based on retrospective chart review identifying 84 individuals ages 6 months to 19 years. All of these highly medically compromised patients experienced lengthy hospital stays with an average hospitalization of 43 days.^52,53

Pediatric Anesthesia Emergence Delirium Scale

The Pediatric Anesthesia Emergence Delirium Scale (PAEDS) is a measure designed to rate postsurgical emergence delirium and has been validated for use in children.²⁶ Unlike other scales, the PAEDS is a clinician report of observed behaviors and responses to stimuli, which differentiate it from the DRS-R-98.

Pediatric Confusion Assessment Measure

The Pediatric Confusion Assessment Measure (p-CAM) is a two-part assessment tool that screens for overall cognitive impairment using the Richmond Agitation Sedation Scale (RASS) and then distinguishes delirium from other causes of cognitive impairment.^54,55 Unlike the DRS-R-98, the p-CAM is designed to diagnose delirium rather than to rate symptom severity. The Pre-School Confusion Assessment Method (ps-CAM) is designed to assess for delirium in critically ill infants and preschool-aged children.⁵⁶

Cornell Assessment of Pediatric Delirium

The Cornell Assessment of Pediatric Delirium (CAP-D) is a screening tool adapted from the PAED to improve identification of hypoactive and hyperactive delirium by using a behavioral scale. It has been validated for use in children of all ages and provides developmental anchor points to help guide clinicians’ assessment of CAP-D symptoms based on a developmental understanding of the presentation of delirium.⁵⁷

Pediatric Index of Mortality and Pediatric Risk of Mortality

The Pediatric Index of Mortality (PIM)⁵⁸ and the Pediatric Risk of Mortality (PRISM II)⁵⁹ are scales used in the pediatric intensive care setting to predict outcome. Using PIM and PRISM, one study⁶⁰ found the positive predictive value was low mostly due to few identified cases of delirium (40 out of 877 patients), but the negative predictive value was very high at 99%, suggesting that these scales can be used to rule out nonoccurrence of delirium.⁶⁰ A 2009 study suggested an algorithm for diagnosing and managing pediatric delirium using the RASS and PAEDS.²⁵ As the authors point out, further research is required to validate any proposed methods. Likewise, the overview (see Figure 20.1) included in this chapter highlights important aspects of identifying and treating pediatric delirium. Further research will be needed to establish best evidenced-based practices.

Catatonia

Delirium always includes a change in mental status and may be accompanied by other alterations in sensorium such as catatonia. Distinguishing these clinical phenomena remains difficult, even among adults, as each syndrome can present with both agitated and negativistic features. Careful and repeated assessment by experienced clinicians remains necessary because treatment approaches for each entity are quite different. Like delirium, catatonia can present with changes in behavior, motor activity, affect, and responsiveness to the surrounding environment. Catatonia though may also include autonomic instability, fever, and leukocytosis, and it possesses less of a waxing and waning quality. Both diagnoses may be related to underlying medical conditions. However, neuroleptic medications, the first-line pharmacologic treatment for delirium, can worsen catatonia; benzodiazepines, helpful for catatonia, can exacerbate delirium.

The DSM-5 defines catatonia as the presence of at least 3 of the following 12 symptoms: catalepsy, waxy flexibility, stupor, agitation, mutism, negativism, posturing, mannerisms, stereotypies, grimacing, echolalia, and echopraxia.¹⁸ The Bush Francis Catatonia Rating Scale (BFCRS) is a clinical tool that captures these symptoms as well as their severity. Although the DSM-5 characterizes catatonia related to a medical cause as being diagnostically possible only in the absence of a delirium diagnosis, studies have shown that the two conditions can coexist. In one study of more than 200 adult hospital patients diagnosed with delirium, 12.7–30.2% also met criteria for catatonia.⁶¹ In another prospective study involving more than 130 adult intensive care patients, delirium and catatonia were both present in 31% of the cohort.⁶²

Catatonia has been studied in pediatric patients, including in those with neurodevelopmental disorders such as autism.⁶³ Identifying and addressing catatonia in pediatric cases resembles the process in adult medical care.⁶⁴ Experts in the diagnosis and treatment of catatonia have argued that the condition is often underrecognized⁶⁵ and have reasoned for routine screening in the pediatric population. Esseveld and colleagues have proposed that catatonia be considered in critically ill pediatric patients exhibiting changes in behavior or affect.⁶⁶ Differentiation of delirium from catatonia prevents healthcare teams from proceeding down the wrong treatment path and delaying appropriate medical intervention.

Structured Assessments

Despite the availability of validated tools to rapidly and accurately detect delirium, few ICUs, worldwide, are routinely evaluating patients for delirium using a validated screening tool.^{67,68,69,70,71,72} In an international online survey of PICUs, 71% of respondents reported they did not practice delirium screening, and only 2% reported screening every patient at least once per 12-hour shift.^73,74

Although there is no evidence that the use of a structured assessment tool results in improved outcomes,⁷⁵ the use of such tools has been shown to lead to an understanding of risk factors, associated morbidities, and strategies to prevent and treat delirium in adults.^{76,77,78,79,80,81,82} In adults, without the use of a structured screening tool, delirium goes undetected in up to 60–75% of patients.^75,83,84

In 2013, the Society of Critical Care Medicine’s clinical practice guidelines for the management of pain, agitation, and delirium (PAD) in adult patients in the ICU recommended routine monitoring of delirium.⁷⁷ The 2018 guidelines updated and expanded the 2013 PAD guidelines with the addition of immobility and sleep disruption (PADIS) and issued a good practice statement that critically ill adults should be regularly assessed for delirium using a valid tool because early detection may lead to prompt identification of cause, guide treatment, and determine effectiveness of treatment.⁸⁵

Treatment

Prevention and Nonpharmacologic Interventions

The recognition and treatment of delirium in the hospital setting requires a team effort. This includes observational input from and implementation of treatment recommendations by nursing staff and caretakers at the bedside. Ancillary staff involved with the delirious patient’s care, including physical therapists, occupational therapists, and art therapists, also play important roles in communicating clinical information to the rest of the hospital team as they may observe changes in a patient’s behaviors and alertness when parents, nursing staff, and physicians are not in the room. Thus, it is important that psychoeducation on the prevention, identification, and treatment of delirium be provided to all those involved in the patient’s care. Silver and colleagues have outlined a clinical pathway with suggestions regarding delirium prevention measures.⁸⁶

Risk Factors for Delirium

Knowledge of the risk factors for delirium allows for their mitigation, when possible. The risk factors for pediatric delirium are like those seen in adult delirium and can be categorized as (1) predisposing, (2) precipitating, and (3) environmental (see Table 20.2). A documented predisposing risk factor for pediatric delirium is younger age, described as younger than 5 years old in one prospective study involving almost 100 critically ill patients ranging from infant age to 21 years old⁸⁷ and identified as less than 2 years of age in a separate multisite study involving 25 critical care centers throughout the world.⁸⁸ Though predisposing risk factors are often unchangeable, many precipitating and environmental risk factors are either reversible or reducible. For example, an electrolyte imbalance caused by an acute illness would be considered a precipitating risk factor that can be corrected. Likewise, a precipitating infection can be treated. Loud noise and limited social interactions are examples of environmental risk factors that may be addressed in a timely fashion. The use of physical restraints, known to independently increase risk of delirium fourfold,⁸⁸ is another environmental risk factor that can be directly modified.

Prevention

Especially in high-risk populations where multiple risk factors for developing delirium are present, close observation, monitoring, and optimization of the patient’s surroundings by the entire treatment team is critical to minimize the risk of developing delirium. Promotion of the sleep–wake cycle, constant reorientation with calendars and clocks, providing reassurance with familiar objects from home, keeping a calm environment by minimizing bright lights and loud activity, adequate treatment of pain, and encouraging mobility are additional recommended environmental interventions. Nighttime interruptions can be reduced by clustering clinical care and administration of scheduled medications at the same time.

Given the potential of medications to cause and/or worsen delirium, checking medication lists for drug-drug interactions, minimizing use of known deliriogenic medications such as anticholinergics,^89,90 benzodiazepines,^91,92 corticosteroids,⁹³ and sedating medications,⁹⁴ as well as ensuring appropriate tapering of medications such as opiates and benzodiazepines to prevent withdrawal symptoms, are all critical steps to minimize delirium risk. Management guidelines for pediatric delirium that do not involve introducing an antipsychotic medication are provided in Table 20.3.

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