Delirium

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28 Delirium

Michelle Goldsmith, Paulina Ortiz-Rubio, Sandra Staveski, Melanie Chan, Richard J. Shaw

When a man lacks mental balance in pneumonia he is said to be delirious. When he lacks mental balance without the pneumonia, he is pronounced insane by all smart doctors.

—Martin Henry Fischer

Pediatric delirium is an under-recognized and often reversible complication of critical illness that is considered a medical emergency demanding immediate management.¹ New research on the clinical presentation of pediatric delirium and age-appropriate assessment tools for prompt identification have highlighted some of the differences between the adult and pediatric populations.²^–⁶ In the context of palliative care, delirium is one of many crises, including pain, anxiety, and dyspnea, which require a thorough and collaboratively developed plan of care.⁷

In the adult palliative care setting, delirium has been carefully studied and identified as a sign of impending death.^8,⁹ Among adult patients who are terminally ill, delirium is the most common neuropsychiatric disorder with a prevalence estimated as high as 85%.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 patients nearing the end of life and that improved methods of diagnosis and management are warranted for this highly distressing and often reversible condition. Therefore, in all critically ill patients of every age, mental status should be carefully evaluated in addition to conventional monitoring of pulse, temperature, respiratory rate, blood pressure, and pain.¹²

The study of delirium is at the confluence of a number of 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,¹³ 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 care.¹⁴

The aim of this chapter is to provide an overview of pediatric delirium and its clinical relevance in the palliative care setting. An additional goal includes underscoring the interdisciplinary nature of delirium. Any clinician or caregiver, including respiratory therapist, nurse, doctor, pharmacist, and parent, has the opportunity to screen patients for delirium. Delirium has 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 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.¹⁵ 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, phenomenology, 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 Manual¹⁶ 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 (Box 28-1). Delirium has been associated with rates of morbidity and mortality that surpass those of all other psychiatric diagnoses.¹⁷ Across clinical disciplines and countries, there are many ambiguities in the terminology used to describe delirium.¹⁸ Such terms as acute brain failure, encephalopathy, acute confusional state, and intensive care unit (ICU) psychosis have been widely employed, and the critical care literature has now conformed 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.¹⁹ The need for shared terminology reflects the challenges clinicians face in diagnosing delirium across clinical settings and age groups.

BOX 28-1 DSM-IV-TR Diagnostic Criteria for Delirium

Adapted from the American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th edition revised, (DSM-IV-TR).Washington, DC, American Psychiatric Press, 2000.

Disturbance of consciousness

• Reduced clarity in awareness of the environment, that is a reduced ability to focus, sustain, or shift attention

Change in cognition

• Memory deficit, disorientation, language disturbance, or development of a perceptual disturbance not better accounted for by a pre-existing cognitive disorder

Temporal character

• Develops over a short period, usually hours to days, and fluctuates during the course of the day

Etiology

• There is evidence from the history, physical examination, or laboratory findings of a general medical condition, including possible substance intoxication or substance withdrawal, that is deemed etiologically related to the disturbance

Clinical presentation

Although the clinical presentation of delirium in children and adolescents is considered to be 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 varied 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 contrast⁶ 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 Some⁴ have suggested that delusions and hallucinations may not be core symptoms of pediatric delirium. Alternatively, a study of pediatric patients emerging from anesthesia reported that younger children had higher rates of hallucinations and other perceptual disturbances, compared with older children.²⁰ 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.²¹ The variance in observed clinical features is wide and may result from the fluctuating nature of the illness, the subjective nature of clinical assessment, lack of age-appropriate screening tools, and the various causes of delirium.

Subtypes of Delirium

Three motoric subtypes of delirium–hypoactive, hyperactive, and mixed–have been well described in the adult literature.²² Delirium is also categorized on the basis of symptom severity, with terms such as pre-delirium, sub-syndromal, veiled, and full-blown used to designate differences in presentation.²³ These additional terms reflect growing 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 (Table 28-1).

TABLE 28-1 Characteristics of Delirium Subtypes

The term hyperactive refers to patients who present with symptoms of confusion, psychosis, disorientation, agitation, hypervigilance, hyperalertness, 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.

Anna was a 14-year-old previously healthy girl who presented with the sudden onset of dizziness, shortness of breath, lethargy, and chest pain. Chest x-ray showed signs of cardiomegaly which prompted cardiology consultation. Following a cardiology workup, including an echocardiogram, Anna was diagnosed with idiopathic dilated cardiomyopathy, and hospitalized in the ICU. By hospital day 4, Anna’s cardiac function had declined rapidly, and she was placed on the cardiac transplant waiting list. Despite intensive pharmacologic treatment, her worsening cardiac status necessitated Anna being placed on a ventricular assist device. Anna’s course was further complicated by a small cerebral vascular accident on hospital day 17. The night following her stroke, Anna was unable to sleep and became acutely agitated, and needed soft physical restraints to prevent her from pulling out her lines and catheters. She was clearly confused and disoriented, and unable to reason with the medical staff. By the following morning, Anna said she was hearing the voice of her deceased grandfather, and believed that he had visited her the previous night. She also reported seeing blood coming out of the faucet in her room, and the feeling of spiders walking over her face.

Anna received a psychiatric consultation and was diagnosed as having a hyperactive delirium with a score of 22/32 on the Delirium Rating Scale-Revised-98 (DRS-R-98). Recommendations were made for treatment with intravenous (IV) haloperidol 0.5 mg q6h, pending review of her ECG. Although Anna’s ECG showed evidence of a prolonged QTc interval (410 mseconds), it was considered safe to prescribe the haloperidol with close cardiac monitoring. This was very helpful in reducing her level of agitation, and re-establishing her normal sleep-wake cycle. By hospital day 20, Anna’s symptoms of delirium had resolved and her DRS-R-98 score was 5/32. The following day, an organ became available, and Anna underwent cardiac transplant surgery.

By contrast, patients with hypoactive or silent delirium present with somnolence, decreased activity, slow or decreased speech, psychomotor slowing, withdrawal, apathy, and confusion. These patients may also be perceived as calm and somnolent by the medical and nursing staff. Patients with this latter presentation who demand less care are less likely to be diagnosed with delirium, or may be misdiagnosed with depression.

In these cases, parental opinion comparing current presentation and baseline functioning can be very useful. Often it is a parent’s observation, such as this is not my child that alerts clinicians to assess mental status more carefully and frequently.

Adapted from Karnik NS, Joshi SV, Paterno C, Shaw R: Subtypes of pediatric delirium: a treatment algorithm. Psychosomatics. 2007;48:254. Copyright 2007 American Psychiatric Publishing, Inc. Used with permission.

Barry was a 16-year-old male with a history of acute lymphoblastic leukemia with central nervous system involvement. Although he initially responded well to chemotherapy, his treatment was complicated by both herpes simplex virus as well as hemorrhagic stroke requiring intensive rehabilitation. Although Barry made a good recovery, residual damage to his frontal lobes was evident on MRI scan. After 3 years in remission, Barry relapsed and was restarted on a re-induction regimen of methotrexate, vincristine, daunorubicin, and asparaginase. After his second dose of chemotherapy, Barry developed fever and signs of neutropenia, and was admitted for intravenous antibiotics. By hospital day 3, although Barry’s fever had resolved and his white blood count was recovering, he was noted to be increasingly withdrawn, spending much of the day in silence, avoiding eye contact, and appearing internally distracted. He started to refuse food, was sleeping excessively during the day, and became almost mute. On hospital day 5, Barry was referred for psychiatric consultation due to concerns about possible depression related to his relapse. Barry was quite uncommunicative during the assessment and either unable or unwilling to cooperate with simple tests of attention and cognition. However, he did appear quite profoundly impaired even with respect to simple questions about orientation and memory. Due to concerns about a possible hypoactive delirium, recommendations were made for a comprehensive medical workup, including an MRI scan, as well as a trial of treatment with risperidone at a dose of 0.5 mg bid. By the following day, although still slowed motorally, Barry had made a quite remarkable improvement. He was more talkative, expressive, and able to answer questions. He was noted to have difficulty with several items on his mental status examination, in particular questions about his level of orientation, tests of attention and memory, and pen and paper tests of his visual-spatial abilities. He also endorsed vague but strongly held beliefs that “men in black were outside his room, waiting for him to die.” His score on the DRS-R-98 was 18/32, and he was thought to meet criteria for hypoactive delirium. Barry was continued on risperidone for a further 5 days. His medical workup was unremarkable, and no etiology was ever established to explain his symptoms. His psychotic symptoms resolved quite rapidly, and by hospital day 9, he was fully oriented, with a score of 3/32 on the DRS-R-98. One week after discharge Barry was titrated down to risperidone 0.5 mg qhs, and after 5 days it was discontinued. Both he and his mother reported that his mood and affect remained appropriate, and he did not exhibit any further evidence of symptoms of delirium.

Mixed delirium describes patients who fluctuate between hyperactive and hypoactive states.^22,²⁵ These critically ill patients present with an array of symptoms, in the context of possible pain, anxiety, and nausea, making it difficult to recognize delirium and identify the cause.

Jackie is a 9-year-old girl with a glioblastoma who, during hospitalization for chemotherapy, developed pressured speech, periods of confusion, and occasional disorientation.

She was noticed to be sleeping as little as 4 hours a night. Her level of activity was also increased, and nursing staff reported that she would spend significant periods of time cleaning and ordering items in her hospital room. She expressed less interested in toys and games, or participating in care. She had a score of 18/32 on the DRS-98, and was diagnosed with acute delirium. Jackie was initially treated with risperidone 0.5 mg qhs. She seemed to improve on this regimen, with better sleep and less pressured activity, but continued to have episodes of increased confusion, disorientation, apathy and talking to herself during the day. Her risperidone dose was increased to 0.5 mg bid, with the addition of zolpidem 5 mg for insomnia. She showed improvement on this regimen and gradually returned to her baseline over several days, at which time she had a score of 4/32 on the DRS-R-98.

Prevalence and Epidemiology

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.¹⁷ One of the largest retrospective pediatric studies on delirium,³ reported a 9% prevalence of delirium in a sample of 1027 patients referred for psychiatric consultation (Table 28-2). Another study⁵ reported a lower prevalence of 4.6% in a pediatric sample of 877 critical care patients.

TABLE 28-2 Studies Examining Clinical Aspects of Pediatric Delirium

Among pediatric patients, age as a risk factor for delirium is not well known. The study of 1027 patients ³ 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 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 to 18 years), but these data were not analyzed for statistical significance. Conversely, another study²⁶ 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% to 88% have been reported in adult oncology patients.^11,²⁷ More specifically, according to a review⁸ hypoactive delirium, which is easily overlooked, has been reported as high as 40% to 78% in adult palliative care patients.^11,^28,²⁹

Attempts to quantify the prevalence of delirium by subtype among adults have resulted in a range of findings. For example, a study ³⁰ 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%.^22,³¹ On the other hand, the high number of cases in the cohort³⁰ of 375 elderly diagnosed with hypoactive delirium suggests that careful screening may accurately identify more subtle presentations of delirium. The only comparison⁴ of the prevalence of hyperactive and hypoactive states in adults to children found 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%.

In adult palliative care literature, the rates of hypoactive delirium are as high as 86%, mean prevalence 48% in one meta-analysis, while rates of hyperactive delirium vary between 13% to 46% of patients.^29,³² Figures for the prevalence of delirium by subtype in the pediatric palliative care setting are not known.

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 non-motoric features of delirium,³³ etiology and pathophysiology,³⁴ ease of detection and assessment, response to treatment,²⁴ and outcome.³⁵ Notably, clinician observations of patient psychomotor disturbance were less reliable when compared with data from electronic motion detectors.³⁶ 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 (see Table 28-2).

Etiology

Causes and risk factors for delirium are often multifaceted and include vascular, infectious, neoplastic, degenerative, organ failure, toxic, deficiencies including vitamin, congenital, central nervous system pathologic, traumatic, endocrinological, metabolic, dehydration, heavy metal, and anoxic phenomena.¹⁷ 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.

Tristan, a 16-year-old boy with chronic myelogenous leukemia (CML), was scheduled to receive a blood transfusion. He was pretreated with IV diphenhydramine to prevent allergic reactions. He had previously received three doses of diphenhydramine in the prior 36-hour period for itching and insomnia. After transfusion, he complained of blurry vision, appeared flushed and became agitated. He also reported that there were cameras in his room and snakes coming out of his arm. On examination, he had dilated pupils, dry mucous membranes, and flushed skin. He was assessed as having classic signs of an anticholinergic delirium related to his treatment with diphenhydramine.

In the palliative care setting, delirium often results from aggressive 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, neurological disorders, infections, 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 care³⁷; however, in the palliative care setting where the goal of care is to decrease pain and suffering, this approach is often modified.

Pathogenesis

Delirium is a neuropsychiatric disorder involving global en-cephalopathy dysfunction caused by multiple impaired neural pathways and physiologic compromises. The neurotransmitters that have been implicated in the pathophysiology of delirium include acetylcholine, dopamine, glutamine, gamma aminobutyric acid (GABA), and serotonin.³⁴ Dopamine is thought to modulate 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 are effective in treating delirium.³⁸ 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 medications such as benzodiazepines and propofol, which directly affect GABA receptors, are frequently used and have been found to contribute to the development of delirium in the ICU setting.³⁹ Likewise, acetylcholine deficiency is associated with delirium and the use of anticholinergic drugs has been found to precipitate and worsen symptoms of delirium.⁴⁰ These neurotransmitter perturbations are thought to cause neuronal membrane hyperpolarization, thus spreading neuronal depression, which is seen on EEG as a diffuse slowing.⁴¹

Other insults to cerebral functioning such as inflammation, hypoxia, metabolic encephalopathies, and drugs or toxins, are implicated in 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.⁴² 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.⁴³ There are reports of chemokine elevations in patients with delirium, and one study found IL-6 increase in children with influenza that developed delirium.⁴⁴ 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.^38,⁴⁵

Assessment

The diagnosis of delirium is primarily made on clinical examination, which should always include an interview with parents and primary caregivers. There should also be 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 the clinicians who have the most frequent clinical contact with patients.⁴⁶ Although not generally standard of care, EEG findings may offer diagnostic support of delirium and perhaps subtype.⁴¹ 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.

To supplement and help guide the direct clinical evaluation, there are a number of structured assessments and rating scales to diagnose and track symptoms related to delirium (Table 28-3). These tools include assessment for cognitive impairment, such as Mini Mental Status Exam⁴⁷; screening for delirium using DSM-IV-TR diagnostic criterias including the Confusion Assessment Measure^48,⁴⁹; and delirium-specific numeric scales to rate severity, that is, Delirium Rating Scale-Revised-98 (DRS-R-98).⁵⁰ 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 the serial assessment of delirium, and has been used and validated for pediatric patients.⁵¹ The Pediatric Anesthesia Emergence Delirium Scale (PAEDS) is a measure designed to rate post-surgical 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. 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.^52,⁵³ Unlike the DRS-R-98, the p-CAM is designed to diagnose delirium rather than to rate symptom severity. The Pediatric Index of Mortality (PIM)⁵⁴ and the Pediatric Risk of Mortality (PRISM II)⁵⁵ are scales used in the pediatric intensive care setting to predict outcome. Using PIM and PRISM, one study⁵⁶ found the positive predictive value was low mostly due to few identified cases of delirium, 40 out of 877 patients, the negative predictive value was very high at 99%, suggesting that these scales can be used to rule out non-occurrence of delirium.⁵⁶ A 2009 study suggested an algorithm for diagnosing and managing pediatric delirium using the RASS and PAEDS.²³ As the authors point out, further research is required to validate any proposed methods. Likewise, the overview (see Fig. 28-1, p. 262) included in this chapter highlights important aspects of identifying and treating pediatric delirium. Further research will be needed to establish best evidenced-based practices (see Table 28-3).

TABLE 28-3 Scales to Assess Pediatric Delirium

Fig. 28–1 Algorithm for education, assessment, and treatment of delirium.

Treatment

An interdisciplinary approach for the clinical management of delirium combines the identification of risk factors, patient and family education, environmental modification, treatment of underlying etiologies, and use of appropriate medications. In the setting of comfort care, the management of delirium is further complicated by the goal of providing relief from suffering while avoiding medication-induced delirium when treating pain and other discomforts. For example, patients with terminal illness often receive, or are withdrawn from, high doses of opiates and benzodiazepines, which may cause delirium. Another challenge in the pediatric population is differentiating between agitation, delirium, fear, anxiety, and pain. Few age-appropriate validated assessments tools are available that easily make the distinction in young patients.^57,⁵⁸ Parents often are the best indicators of the nature and intensity of their child’s distress. Parent opinion regarding symptoms of discomfort should be sought by clinical staff. The interdisciplinary treatment team, the patient, and the family should create repeated opportunities to discuss goals of care regarding treatment and comfort. When illness cure is no longer the goal, symptomatic control remains the sole aim; refractory symptoms of discomfort may necessitate deeper or palliative sedation.⁸

The first step in the management of delirium should be to treat the underlying cause. In the palliative population this approach requires prudence and collaboration. More simple, less invasive interventions may include restoring electrolyte imbalances, ensuring adequate hydration and oxygenation, judicious tapering of medications, controlling pain, and treating infections.¹ Clinicians should conduct a diagnostic workup taking into account the treatment goals of the specific patient and weighing such factors as distress related to invasive procedures as well as the potential efficacy of the intervention.³⁷ In an effort to minimize suffering, it should be noted that in one prospective adult study⁵⁹ the cause of delirium was identified in less than 50% of terminally ill patients. Advanced care planning involving the family, and the patient when age appropriate, is essential in managing palliative care crises such as delirium. Anticipating delirium, which can occur in 85% of adult palliative care patients,¹⁰ should be an essential step in end-of-life treatment planning. Children as young as 10 years old have demonstrated the ability to express preferences regarding end-of-life treatment, an understanding of possible consequences to their decisions, and the capacity to weigh complex issues.⁶⁰ Education about delirium before onset is an opportunity for pediatric patients and their families to participate in care, especially those with chronic illness, and thereby minimize distress and promote a sense of agency.

Prevention

Awareness of the major risk factors for delirium is critical for prevention and early recognition. Although current research focuses on risk factors in adults, there is overlap with the pediatric population. Risk factors can be divided into three categories: predisposing, precipitating, and environmental factors (Table 28-4).

TABLE 28-4 Risk Factors for Delirium

Predisposing factors	Precipitating factors	Environmental factors
Age Genetic predisposition Neurological disease Psychiatric illness Visual impairment Hearing impairment Surgery

Electrolyte imbalance

Medication withdrawal

Reduced social interactions

Pain

Use of IV lines

Physical restraints

Delirium prevention involves clinical staff and family education, recognition of high-risk populations, correction of underlying illness, appropriate medication management, and environmental interventions. Education of family members can be an investment in comprehensive clinical care. Education of medical staff, both physicians and nurses, is also important because they have control over such issues as rate of medication tapering and maintenance of an appropriate environment. High-risk populations, such as post-surgical patients, those being weaned from intubation and those with underlying neurological and psychiatric conditions, should be closely monitored. Environmental interventions include orientation to date and time, social interactions and activities during the day, sleep hygiene at night, such as light and noise reduction, relaxation including calming music, massage and reassurance, and avoidance of immobility with ambulation or bedside exercises.

Medications, which are often major contributors to the development of delirium, should be chosen with care and with appropriate evaluation of possible unwanted drug-drug interactions. In the palliative care setting, careful attention to the dosing and scheduling of sedatives, analgesics, anticholinergics, including some low-potency antipsychotics, corticosteroids, and anticonvulsants, is essential in reducing the incidence of delirium. In particular, tapering medications should be carefully managed because withdrawal from drugs such as opioids and benzodiazepines can trigger or worsen symptoms of delirium. Pain should also be frequently assessed and appropriately managed. In the palliative care setting, avoiding medications that may exacerbate delirium is often the first and only step taken to treat delirium, particularly when it is not possible to treat the primary immediate cause, such as cancer.⁶¹

Nonpharmacologic treatment

Nonpharmacologic treatment of delirium should focus on correction of underlying causes, reorientation, and patient safety. Interventions such as restoring electrolyte imbalances, ensuring adequate hydration and oxygenation, improving bowel and bladder function, slow taper of medications, controlling pain, and treating infections have been shown to improve the rate of delirium recovery.^1,⁶²

Environmental modifications are also beneficial. An effort should be made to orient the patient using calendars, clocks, and familiar objects such as toys and pictures.⁵ There should be a clear distinction between night and day to help restore disturbances in the sleep-wake cycle. Some options include the minimization of noise and light at night, organizing vital sign checks, procedures, and medications at a time that does not interrupt sleep, and massage and music for relaxation. During the day, social interactions that are soothing and familiar should be encouraged. Every effort should be made to minimize the use of catheters, intravenous lines, and other items that limit physical mobility. Family, visitors, and clinical staff should attempt to speak in short simple sentences, avoiding confrontation and provide reassurance whenever possible. Patients should ideally be placed in a single-patient room with either one-on-one nursing or a family member present. This direct observation is important to ensure patients do not harm themselves or others. If the patient is highly agitated, physical restraints may be necessary to prevent dislodgement of lines or catheters. However, physical restraints have been reported as an independent risk factor for delirium and should be used only with careful monitoring and a clear, time-limited plan.⁶² The appropriate use of the nonpharmacologic measures should include a thoughtful and supportive discussion with family members (Table 28-5).

TABLE 28-5 Nonpharmacologic Management Guideline for Pediatrics

Intervention type	Potential activities
Sensory and environmental modification	Favorite or soothing music Gentle touch and massage Minimize immobilizing lines, catheters, and restraints Minimize noise Calming and clear speech Lighting Familiar objects in the room and with patient when leaving the room

Caregiver measures

Proper body alignment

• Assist with passive range of motion

• Avoid immobility

Time and place re-orientation

• Boards to communicate with pictures or words

• Clocks

• Photos

• Daily schedules to promote sleep-wake cycles

Sleep protocols

Play favorite movies and/or shows

Parental participation in care

Parental and significant other presence

Parents holding child in bed or chair

Scheduling medications and treatments to accommodate child’s routine and minimize intrusion

Pharmacologic interventions

While a diagnostic workup of potential causes is being conducted, pharmacologic interventions may still be required to manage symptoms in patients with delirium (Table 28-6). Antipsychotic and sedative agents can be used to diminish levels of agitation, correct disturbances in the sleep-cycle, and minimize perceptual disturbances. Haloperidol, second-generation antipsychotics, and benzodiazepines have all been used in the treatment of delirium with varying degrees of success. The side effect profile of each agent should be considered and individualized to each patient. Moreover, treatments should always be accompanied by adequate pain management and monitoring of potential medication withdrawal reactions.

TABLE 28-6 Pharmacologic Management Guidelines for Pediatrics

Haloperidol, one of the first-generation antipsychotics, is the most frequently used pharmacologic treatment of delirium.⁶³ Although not approved by the Federal Drug Administration (FDA) for treatment of delirium, reasons for its use include considerations of efficacy, cost, and intravenous route of administration. Intravenous use results in more reliable absorption, decreased incidence of extrapyramidal reactions, and minimal effects on blood pressure, respiration, and heart rate.^64,⁶⁵ The intravenous dose is twice as potent as oral administration. This high-potency agent is preferred to low-potency antipsychotics because of the decreased likelihood of hypotensive and anticholinergic effects, and has been found to be safe and effective in managing cases of pediatric delirium.⁶⁶ In the palliative care population, subcutaneous and intramuscular injection are also convenient options. The primary mechanism of haloperidol’s action is inhibition of dopaminergic pathways that may be overstimulated in states of hyperactive delirium, thus helping restore normal thought patterns and sensorium. The cautious use of haloperidol is recommended in patients with hypoactive delirium, who may already have dopaminergic suppression and consequently its use may exacerbate symptoms of delirium.³⁹ A double-blinded, randomized control trial compared haloperidol, chlorpromazine, and lorazepam for the treatment of delirium reports both haloperidol and chlorpromazine as effective in improving symptoms of delirium and cognitive function, while lorazepam was not only ineffective but also worsened symptoms in some patients.

All antipsychotics have side effects and patients must be closely monitored. Serious adverse reactions requiring im- mediate medical attention include malignant hyperthermia. Also, extrapyramidal movement disorders including laryngeal spasm, hypotension, and glucose and lipid dysregulation; anticholinergic effects, such as constipation, urinary retention, and dry mouth; and cardiac effects such as QTc prolongation and torsades de pointes, need to be monitored. Electrocardiogram monitoring is strongly recommended for those on intravenous haloperidol. Significant complications such as dystonia, hypotension, and hyperpyrexia in more than 20% of pediatric burn patients treated with haloperidol were reported.⁶⁸

Second-generation antipsychotics, such as risperidone, olanzapine, and quetiapine, is another option for the treatment of delirium. Most second-generation antipsychotics act on both dopaminergic and serotonergic receptors. Their side effect profile is commonly reported as more favorable than that of the first-generation antipsychotics. Although there have been few efficacy studies directly comparing the second-generation antipsychotic agents and haloperidol, there may be some benefits in terms of the second-generation antipsychotic side effect profile.^62,⁶⁹ A review on the topic concluded that second-generation antipsychotics are effective in treating delirium and have fewer side effects compared with high-dose haloperidol. In addition, in the case of hypoactive delirium, second-generation antipsychotics may be indicated because their mechanisms of action extend beyond dopamine blockade and affect other pathways likely implicated in the pathophysiology of delirium.²⁴ Disadvantages of second-generation antipsychotic agents include the lack of an intravenous formulation. Although most of these agents must be given orally, some, such as risperidone and olanzapine, have intramuscular and sublingual formulations (see Table 28-6).

Like haloperidol, second-generation antipsychotics also carry an FDA warning of increased risk of death, mostly cardiovascular related, in elderly patients. Controlled studies for delirium in the pediatric population, comparing both classes of antipsychotics for efficacy and safety, have yet to be undertaken. Of note, all of the antipsychotics are employed off-label when used to treat delirium. The second-generation antipsychotics have been tested in children with approval for other indications. For example, risperidone has been approved for use in children ages 5 to 16 for management of aggressive behavior related to autism. Olanzapine is indicated for the treatment of schizophrenia and manic or mixed episodes of bipolar disorder in 13- to 17-year-olds. These medications can be safely used at low doses in young children with appropriate monitoring when treating delirium.⁷⁰

Benzodiazepines, such as lorazepam and diazepam, are GABA agonists that treat distress related to anxiety and sleep-wake cycle disturbance in delirious patients. They have amnesic properties and consequently can worsen cognitive impairment. There are also reports of paradoxical effects, such as aggression, violence, and irritability in pediatric patients.⁷¹ In general, there appears to be some consensus that benzodiazepines should not be used as first-line agents in the treatment of pediatric delirium. In addition, a longer duration of benzodiazepines and opiate use in critically ill children was associated with increased reports of delusional memory, which is associated with greater risk for post-traumatic stress disorder.⁷² In some cases when a benzodiazepine is required, lorazepam combined with haloperidol for severe agitation in older adolescent and adult patients has been beneficial.⁶²

Figure 28-1 describes an algorithm that depicts the key factors and decision points salient to education, assessment, and treatment of delirium in the pediatric palliative care setting. Although this algorithm is not an evidenced-based protocol, it does suggest a paradigm for understanding delirium and its management.

Palliative care, as an interdisciplinary field, lends itself to the management of delirium with its fluctuating course and multiple causes. All members of the care team should play a role in the education, prevention, detection, and treatment of delirium. Roles can be divided into educator, detector, screener, and treater. Anyone with patient contact should be warned about the potential for delirium and become an educator. For example, the evening shift nurse can educate the mother about delirium. The mother then teaches the sibling, who will be with the patient during the day about the possibility of confusion, agitation, and other associated signs. The ultimate goal is to educate the patient and all caregivers about the phenomenon of delirium for the purpose of preventing and identifying signs and symptoms if they occur. Anyone with patient contact should be trained as a detector. This includes primary and consulting physicians, nurses, social workers, psychologists, chaplains, dieticians, and therapists (respiratory, physical, occupational, and child-life specialists).

A smaller subset of the care team, which manages daily patient care responsibilities, will be systematic screeners and treaters. If delirium is suspected as a result of systematic screening, and the primary team has evaluated for poly-pharmacy intoxication or withdrawal, and has made the appropriate intervention without improvement, a pediatric psychiatry consult should be requested. At that time, further information from detectors and screeners should be collected to develop a longitudinal picture of the patient’s mental status. Once delirium is diagnosed, every member of the care team should be instructed in the appropriate nonpharmacologic interventions. Screeners and treaters, that is, nurses and doctors, will administer pharmacologic treatment and track progress. This team approach also suits the goals of comfort care for monitoring pain, anxiety, and nausea.

Sequelae of Delirium

The psychological and cognitive impact of delirium on patients, families, and caregivers of critically ill adults at the end of life has been well explored and reviewed.⁸ Delirium is related to longer hospital stay, higher rates of morbidity and mortality, and negative outcome post recovery.^73,⁷⁴ Post-traumatic stress disorder (PTSD) in adults following the experience of delirium has also been reported.^75,^76,⁷⁷

Post-traumatic stress disorder

The recognition of post-traumatic stress disorder in medically ill patients, including those receiving treatment in ICUs, is now well recognized. These symptoms include flashbacks, nightmares, avoidance of reminders, anger, and hypervigilance.¹⁶ More recently, there have also been a number of studies examining the relationship between PTSD and the experience of delirium. This is particularly relevant because there is evidence that a great number of patients with mild to moderate delirium (43% of those with hypoactive delirium and 66 % of patients with hyperactive features), recall their experience.⁷⁵ This vignette describes the traumatic experience of delirium and its impact.

Cassie, a 14-year-old girl with a history of asthma, was admitted for treatment of acute respiratory distress syndrome. After initial continuous nebulized albuterol treatments, she went into respiratory failure and was intubated and transferred to the ICU. She remained on the ventilator for 3 days before being extubated. Although Cassie improved medically, she became increasingly anxious, particularly when approached by nursing staff. She also had increased difficulty sleeping at night. At one point, she became combative, and hit her nurse while she was attempting to administer an IV medication with a syringe.

Cassie received a psychiatry consultation, and was noted to be confused and disoriented during her evaluation. Careful questioning elicited the history that Cassie believed that her nurse was attempting to kill her by injecting poison into her IV line. She also reported being afraid to fall asleep at night, believing that someone might come into her room at night to turn off her oxygen supply. Cassie was diagnosed with acute delirium and started on risperidone 0.5 mg bid. She made a rapid recovery, and was soon transferred to a general pediatric unit, and then home.

Cassie was seen in follow-up a month after her discharge. A psychiatric consultation was requested again after her mother reported that Cassie was still having difficulties sleeping at night and had missed 13 of her last 17 regular school days. Cassie reported persistent distressing dreams as well as intrusive memories of her hospitalization, prompted by events such as watching television episodes of “ER“ or visiting the hospital. She described conscious efforts to avoid things that reminded her of her experience. She tried to be outside as much as possible because being indoors gave her a boxed-in feeling that reminded her of the ICU. She was also reluctant to take her asthma medications, and stated that she worried that they might be contaminated, even though she knew this to be impossible. In addition, she described a feeling of a foreshortened future and fear that she was likely to die at an early age because of asthma. Cassie was assessed as having symptoms of post-traumatic stress disorder related to the traumatic medical experience during her inpatient hospitalization. Her symptoms persisted despite vigorous attempts by her parents to reassure her, and were clearly interfering with her ability to function at school. She was referred to the local university child psychiatry clinic for further evaluation and treatment.

Adult and pediatric studies have explored the association between delirium and PTSD in intensive care patients and have found that those with delusional memories have increased risk of developing PTSD symptoms compared with those with factual memories.^72,⁷⁸ Because alterations in memory and perception are common presentations of delirium, children with delirium may be at greater risk of developing PTSD. Such sequelae should not be taken lightly because it can cause significant social impairment and can negatively impact academic performance.⁷⁹

If pediatric patients experience delirium, when they recover it is appropriate to ask what they remember. Some children do not recall the experience or report positive associations.⁷² The specifics of delusions should not be over-interpreted (e.g., intravenous lines being perceived as snakes) rather, themes of fear, anxiety, loss, and mortality can be considered and explored. Further psychological support is recommended both for patient and the family if delirium has been distressing whether for themselves or for anyone else, including caregivers and staff.

Impact on caregivers

Delirium affects not only patients but also family members and medical staff. Mean distress levels regarding delirium on a 4.0 scale were highest among spouses (3.75), nurses (3.09), and then patients (3.02).⁷⁷ For families, hyperactive delirium and severe physical debilitation were the strongest predictors of distress in contrast to nurses who rated the severity of the delirium and perceptual disturbances more highly.⁷⁷ Interviews conducted of bereaved family members who witnessed delirium revealed they were often troubled by feelings of guilt and helplessness, struggled with making proxy decisions, and worried about the burden of care.⁸⁰ Families often equate signs of delirium with pain or discomfort, going crazy, and death anxiety.⁸⁰ In addition, family members of patients with delirium reported both concerns about inadequate medical care as well as a desire for more information about the condition.⁸¹

These accounts by families likely reflect the challenge that medical staff face when caring for patients with delirium. Nurses commonly reported stress from increased workload, safety concerns for themselves and their patients, and difficulty finding a balance between connecting with the patient and being on guard.⁸² Long-term consequences for caregivers are yet to be fully investigated. Similarly, parents who have children hospitalized in intensive care are at increased risk of developing PTSD.⁸³ All caregivers, including parents, siblings, nurses, doctors, other clinicians, social workers, and clergy are at risk of psychological sequelae from traumatic experiences with critically ill patients.