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

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