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Delirium in Palliative CarePublished on Physicians Practice (http://www.physicianspractice.com)

Delirium in Palliative CareReview Article [1] | October 01, 2004By Miriam M. Friedlander, MD [2] and William S. Breitbart, MD [3]

Delirium is highly prevalent in cancer patients with advanced disease. Frequently a preterminalevent, the condition is a sign of significant physiologic disturbance, typically involving multiplemedical etiologies including infection, organ failure, adverse medication effects, and in raresituations, paraneoplastic syndromes. Unfortunately, delirium is frequently underrecognized ormisdiagnosed and, therefore, inappropriately treated or untreated in terminally ill patients. Theclinical features of delirium are numerous and encompass a variety of neuropsychiatric symptomscommon to other psychiatric disorders. Three clinical subtypes of delirium, based on arousaldisturbance and psychomotor behavior, have been described: hyperactive, hypoactive, and mixed.The differential diagnosis for delirium includes depression, mania, psychosis, and dementia.Numerous instruments have been developed to aid the clinician in rapidly screening for the disorder.Standard management requires an investigation of the etiologies, correction of the contributingfactors, and management of symptoms. Symptomatic and supportive therapies, including numerouspharmacologic approaches, are important, but several aspects of the use of neuroleptics and otheragents in the management of delirium in the dying patient remain controversial.

ABSTRACT: Delirium is highly prevalent in cancer patients with advanced disease.Frequently a preterminal event, the condition is a sign of significant physiologicdisturbance, typically involving multiple medical etiologies including infection, organfailure, adverse medication effects, and in rare situations, paraneoplastic syndromes.Unfortunately, delirium is frequently underrecognized or misdiagnosed and, therefore,inappropriately treated or untreated in terminally ill patients. The clinical features ofdelirium are numerous and encompass a variety of neuropsychiatric symptoms commonto other psychiatric disorders. Three clinical subtypes of delirium, based on arousaldisturbance and psychomotor behavior, have been described: hyperactive, hypoactive,and mixed. The differential diagnosis for delirium includes depression, mania, psychosis,and dementia. Numerous instruments have been developed to aid the clinician in rapidlyscreening for the disorder. Standard management requires an investigation of theetiologies, correction of the contributing factors, and management of symptoms.Symptomatic and supportive therapies, including numerous pharmacologic approaches,are important, but several aspects of the use of neuroleptics and other agents in themanagement of delirium in the dying patient remain controversial.

Delirium is the most common and serious neuropsychiatric complication in cancer patients withadvanced illness and has enormous relevance to symptom control and palliative care. The conditionis highly prevalent in cancer patients with advanced disease, particularly in the last weeks of life,with prevalence rates ranging from 25% to 85%.[1-8] Indeed, delirium is one of the most commonmental disorders encountered in general hospital practice. An estimated 33% of hospitalizedmedically ill patients have serious cognitive impairments.[9]In a study of 334 hospitalized cancer patients evaluated by psychiatric consultation, 25% werediagnosed with delirium. In a smaller sampling of 13 terminal cancer patients, 85% were diagnosedwith delirium.[6] Pereira and coworkers identified the prevalence of cognitive impairment in cancerinpatients to be 44%, with the prevalence rising to 62.1% prior to death.[10] Delirium has beendescribed in up to 51% of postoperative patients.[11,12]With increased numbers of elderly patients who are particularly susceptible, the incidence ofdelirium is rising.[11] Studies of elderly patients admitted to medical wards estimate that 30% to50% of patients age 70 years or older demonstrate symptoms of delirium at some point during theirhospitalization.[13-17] Elderly patients who develop delirium during a hospitalization have anestimated 22% to 76% chance of dying during that admission.[18]

Delirium in the Terminally Ill

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In the terminally ill, delirium is associated with increased morbidity, which causes distress inpatients, family members, and staff.[2,19,20] In a recent study of terminally ill cancer patients,Breitbart and colleagues[19] discovered that 54% of patients recalled their delirium experience afterresolution of their delirium. Factors predicting diminished recollection of the delirium experienceincluded severe short-term memory impairment, severe delirium, and the presence of intenseperceptual disturbances.In the same study, distress related to the episode of delirium was rated by patients, spouses orcaregivers, and nurses.[19] Distress was rated as severe by all three groups, with the spouse orcaregiver group experiencing the most distress. A significant predictor of heightened spouse distresswas a low Karnofsky performance status for the patient, indicating debilitation. The most significantfactor predicting distress for patients was the presence of delusions. Patients with hypoactivedelirium were as distressed as patients with hyperactive delirium (see Subtypes of Delirium, below).Delirium severity and intensity of perceptual disturbances also enhanced nurses' distress. In thelater stages of illness, delirium interferes dramatically with the recognition and control of otherphysical and psychological symptoms such as pain.[21-23]A recent retrospective study of 284 hospice patients sought to identify factors that contribute to theimpairment of communication capacity in terminally ill cancer patients.[24] The study demonstratedthat communication capacity was frequently impaired in terminally ill cancer patients, and thedegree of impairment significantly associated with higher doses of opioids. Patients who did notrequire high doses of opioids were able to retain complex and simple communication capacity longerthan those who required high doses of opioids prior to death. Delirium was found in 20% of patientsin this study, which emphasized the importance of further investigations to explore new strategiesfor maintaining communication capacity in this population.Frequently a preterminal event, delirium is a sign of significant physiologic disturbance, typicallyinvolving multiple medical etiologies including infection, organ failure, adverse medication effects,and in rare situations, paraneoplastic syndromes.[8,25-28] Lawlor and colleagues[29] recentlyreported on their experience in the management of delirium in advanced cancer patients admitted toa palliative care unit. While only 42% of patients had delirium upon admission, "terminal" deliriumwas seen in 88% of patients at the time of death.Unfortunately, delirium is frequently underrecognized or misdiagnosed, and thereforeinappropriately treated or untreated in terminally ill patients. Impediments to progress in therecognition and treatment of delirium include confusion regarding terminology as well as lack ofconsistency in utilizing diagnostic classification systems. In addition, the signs and symptoms ofdelirium are diverse and frequently mistaken for other psychiatric disorders. Practitioners need todiagnose delirium accurately, undertake appropriate assessment of etiologies, and familiarizethemselves with the benefits and risks of pharmacologic and nonpharmacologic interventionscurrently available to manage delirium in the terminally ill.

Assessment

The clinical features of delirium are numerous and encompass a variety of neuropsychiatricsymptoms common to other psychiatric disorders, including depression, dementia, andpsychosis.[30] Clinical features of delirium include prodromal symptoms (restlessness, anxiety, sleepdisturbance, and irritability); rapidly fluctuating course; reduced attention (easily distractible);altered arousal; increased or decreased psychomotor activity; disturbance of the sleep-wake cycle;affective symptoms (emotional lability, sadness, anger, or euphoria); altered perceptions(misperceptions, illusions, poorly formed delusions, and hallucinations); disorganized thinking andincoherent speech; disorientation as to time, place, or person; and memory impairment (difficultyregistering new material).Neurologic abnormalities may be present during delirium, including cortical abnormalities(dysgraphia, constructional apraxia, dysnomic aphasia); motor abnormalities (tremor, asterixis,myoclonus, and reflex or tone changes); and electroencephalogram (EEG) abnormalities (typicallyglobal slowing). The protean nature of delirium, with its profound variability and fluctuation in clinicalcourse, makes the condition more difficult to diagnose accurately and treat effectively. TABLE 1

DSM-IV Criteria for Delirium Due to a General Medical Condition of 14

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Table 1 lists the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV),criteria for delirium.[31] The essential defining features of delirium, based on DSM-IV criteria, haveshifted from an extensive list of typical symptoms and abnormalities to a focus on the two essentialconcepts of disordered attention (arousal) and cognitive disturbance. The definition continues torecognize the importance of acute onset, fluctuating course, and organic etiology. Associatedphenomena including altered psychomotor activity and behavior, perceptual disturbances, anddelusions are not essential for the diagnosis of delirium.Delirium is now conceptualized primarily as "a disorder of arousal and cognition,"[32] in contrast todementia, which is a disorder of cognition without an arousal disturbance. Disorder of the arousalsystem resulting in altered levels of consciousness and impaired attention is pathognomonic ofdelirium. This arousal disturbance is, in part, the basis for classifying delirium into several subtypes.

Subtypes of Delirium

Three clinical subtypes of delirium, based on arousal disturbance and psychomotor behavior, havebeen described. These include the hyperactive subtype (hyperaroused, hyperalert, or agitated), thehypoactive subtype (hypoaroused, hypoalert, or lethargic), and a mixed subtype with alternatingfeatures of hyperactive and hypoactive delirium.[33,34] Research suggests that the hyperactivesubtype is more frequently characterized by hallucinations, delusions, agitation, and disorientation,whereas the hypoactive subtype is characterized by confusion and sedation, and less frequentlyaccompanied by hallucinations or delusions.[35]In addition, there is evidence suggesting that the subtypes of delirium may result from specificetiologies, demonstrate unique pathophysiologies, and display differential responses totreatment.[36,37] An estimated 67% of cases of delirium are either the hypoactive or mixedsubtype. The prototypical agitated delirium most familiar to clinicians actually occurs in a minority ofcases.[33-35]

Differential Diagnosis

Many of the clinical features and symptoms of delirium may be associated with other psychiatricdisorders including depression, mania, psychosis, or dementia. A patient with delirium may exhibitmood disturbances such as anxiety, fear, depression, irritability, anger, euphoria, apathy, or moodlability.• Depression and Mania—Delirium, particularly the hypoactive subtype, is often initiallymisdiagnosed as depression. Symptoms of major depression, including altered level of activity(hypoactivity), insomnia, impaired concentration, depressed mood, and suicidal ideation, mayoverlap with symptoms of delirium, making an accurate diagnosis more difficult. To differentiatedelirium from depression, particularly in the context of advanced disease, an evaluation of the onsetand temporal sequencing of depressive and cognitive symptoms is particularly helpful. Importantly,the degree of cognitive impairment in delirium is more severe, pervasive, and abrupt in onset thanthat associated with depression. Most notably, in delirium, a disturbance in arousal or consciousnessis present. Arousal disturbance is not characteristic of depression.Similarly, a manic episode may share some features of delirium, particularly the hyperactive ormixed subtype. Again, the temporal onset and course of symptoms, as well as the presence of anarousal disturbance associated with cognitive impairment, assist in differentiating these disorders.•Psychosis—Delirium characterized by vivid hallucinations and delusions must be distinguishedfrom a variety of psychotic disorders. In delirium, psychotic symptoms occur in the context of adisturbance in consciousness or arousal associated with memory impairment and disorientation.These features are not present in other psychotic disorders. The delusions associated with deliriumtend to be poorly organized and abrupt in onset. Visual and tactile hallucinations predominate indelirium, in contrast to the auditory hallucinations more characteristic of schizophrenia. Finally, thedevelopment of these psychotic symptoms in the context of advanced medical illness makesdelirium a more likely diagnosis.• Dementia—A common diagnostic task is to differentiate delirium from dementia or deliriumsuperimposed upon a preexisting dementia. Both delirium and dementia are cognitive impairmentdisorders, sharing clinical features such as impaired memory, disordered thinking, limited judgment,and disorientation. However, the patient with dementia is alert without the disturbance ofconsciousness or arousal characteristic of delirium. The temporal onset of symptoms in dementia issubacute and chronically progressive, and the patient's sleepwake cycle is less disrupted. The mostprominent disturbances in dementia include short- and long-term memory deficits, impaired

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judgment, reduced capacity for abstract thinking, and alterations in higher cortical functions(aphasia and apraxia).In contrast to dementia, delirium is typically conceptualized as a reversible process. Delirium isfrequently reversible even in patients with advanced illness. However, delirium may not bereversible in the last 24 to 48 hours of life. This is most likely due to irreversible processes includingmultiple organ failure. Delirium occurring in these last days of life is sometimes referred to as"terminal" delirium in the palliative care literature. TABLE 2

Tools for Assessing Delirium in Cancer Patients

Delirium Screening/Diagnostic Scales

Numerous scales or instruments have been developed to aid the clinician in rapidly screening forcognitive impairment disorders (dementia or delirium), or in establishing a diagnosis of delirium (seeTable 2).[38- 46] Such scales have been described, and their relative strengths and weaknessesreviewed elsewhere.[43,47] Perhaps most helpful to clinicians are the Mini-Mental State Examination(a cognitive impairment screening tool) and several delirium diagnostic and severity rating scales,including the Delirium Rating Scale, the Delirium Rating Scale-Revised-98, the Confusion AssessmentMethod, the Abbreviated Cognitive Test for Delirium, and the Memorial Delirium Assessment Scale.These tools are briefly described in the subsections below.• Mini-Mental State Examination— The Mini-Mental State Examination (MMSE)[45] is useful inscreening for cognitive failure but does not distinguish between delirium and dementia. The MMSEprovides a quantitative assessment of the patient's cognitive performance and capacity, measuringthe severity of cognitive impairment. It is most sensitive to cortical dementias such as Alzheimer'sdisease and less sensitive in detecting subcortical deficits such as those found in AIDS dementia.The MMSE assesses five general cognitive areas: orientation, registration, attention/calculation,delayed recall, and language. Traditionally, a score of 23 or less is considered indicative of cognitiveimpairment. However, a multitiered system is frequently utilized, with a score of 24- 30 indicating noimpairment, a score of 18-23 indicating mild impairment, and a score of 0-17 indicating severeimpairment.• Delirium Rating Scale—The Delirium Rating Scale (DRS), developed by Trzepacz andcolleagues[47] is a 10-item clinician-rated symptom rating scale for diagnosing delirium. Based onDSM-III-R (third edition, revised) diagnostic criteria for delirium, the scale is designed to be used bythe clinician to identify delirium and distinguish it reliably from dementia and other neuropsychiatricdisorders. Each item is scored by choosing the best rating, which has a numerical weight designed todistinguish the phenomenologic characteristics of delirium. A score of 12 or greater is diagnostic ofdelirium.• Delirium Rating Scale-Revised 98—A revision of the Delirium Rating Scale (DRS), the DeliriumRating Scale-Revised 98 (DRS-R-98) has 13 severity and 3 diagnostic items with descriptive anchorsfor each rating level. Although it was designed for phenomenologic and treatment research, thescale may be used clinically. Indeed, the DRS-R-98 is a valid, sensitive, and reliable instrument forthe rating of delirium severity. It has advantages over the original DRS for repeated measures andphenomenologic studies due to its enhanced breadth of symptoms and separation into severity and

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diagnostic subscales.[48]• Confusion Assessment Method— The Confusion Assessment Method (CAM)[49] is a nine-itemdelirium diagnostic scale utilizing the DSMIII- R criteria for delirium, which can be administeredrapidly by a trained clinician. The CAM may be administered using a simplified diagnostic algorithmthat includes only four items designed for rapid identification of delirium by nonpsychiatrists. Thefouritem algorithm requires an acute onset and a fluctuating course with inattention and eitherdisorganized thinking or altered level of consciousness.• Abreviated Cognitive Test for Delirium—Abreviated Cognitive Test for Delirium (CTD)[50] wasrecently developed as a tool to identify delirium in patients in the intensive care unit setting whohave limited ability to communicate verbally. This brief tool utilizes visualization span andrecognition memory of pictures. It reliably identifies delirium and discriminates delirium fromdementia, depression, and schizophrenia. TABLE 3

Items From the Memorial Delirium Assessment Scale (MDAS)

• Memorial Delirium Assessment Scale—Memorial Delirium Assessment Scale (MDAS) is a10-item delirium assessment tool (see Table 3), validated among hospitalized inpatients withadvanced cancer and AIDS.[39] The MDAS is both a good delirium diagnostic screening tool as wellas a reliable tool for assessing delirium severity among patients with advanced disease. A cutoffscore of 13 is diagnostic of delirium. The MDAS has advantages over other delirium tools in that it isboth a diagnostic and a severity measure ideal for repeated assessments and for treatmentintervention trials. Recently, Lawlor and colleagues[51] further examined the clinical utility andvalidation of the MDAS in a population of advanced cancer patients in a palliative care unit. Theinvestigators demonstrated the usefulness of the MDAS in this select population. A cutoff score of 7out of 30 yielded the highest sensitivity (98%) and specificity (76%) for a delirium diagnosis in thispalliative care population.

Management of Delirium in the Terminally Ill

The standard approach to managing delirium in the medically ill, including patients with advanceddisease, requires an investigation of the etiologies, correction of the contributing factors, andmanagement of symptoms. The desired and frequently achievable outcome is a patient who isawake, alert, calm, cognitively intact, not psychotic, and able to communicate coherently with familyand staff. In the terminally ill patient who develops delirium in the last days of life, the managementof delirium is unique, presents a number of dilemmas, and may alter the desired clinical outcome.

Assessment of Etiologies of Delirium

Formulation of a differential diagnosis of the etiologies of delirium in a terminally ill or dying patientis useful. Controversy exists regarding the appropriate extent of diagnostic evaluation to be pursuedin a dying patient with terminal delirium.[52,53] Most palliative care clinicians undertake diagnosticstudies only if a clinically suspected etiology may be readily identified with minimal use of invasiveprocedures and effectively treated with simple interventions that minimize risk and limit distress tothe patient. Diagnostic work-up in pursuit of an etiology for delirium may be limited by eitherpractical constraints such as the setting (home, hospice) or the focus on patient comfort, so thatunpleasant or painful diagnostic procedures are avoided. However, more often the etiology ofterminal delirium is multifactorial or indeterminate.Bruera and colleagues[2] reported that an etiology is discovered in less than 50% of terminally illpatients with delirium. If a distinct cause is responsible for delirium in the terminally ill, it isfrequently irreversible or difficult to treat. Studies in patients with earlier stages of advanced cancer,however, have demonstrated the potential utility of a thorough diagnostic assessment.[2,22] Whensuch diagnostic information is available, a specific therapy may be able to reverse delirium. Onestudy found that 68% of delirium in cancer patients could be improved, despite a 30-day mortality of

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31%.[54] Another study found that 33% of episodes of cognitive failure improved if an evaluationyielded a specific etiology.[2]In a prospective study of delirium in patients on a palliative care unit,[29] investigators reported thatthe etiology of delirium was multifactorial in the majority of cases. Despite the occurrence of deliriumin 88% of dying patients in the last week of life, delirium was reversible in approximately 50% ofcases. The causes of delirium most associated with reversibility included dehydration andpsychoactive or opioid medications. Hypoxic and metabolic encephalopathies were less likely to bereversible in terminal delirium.A diagnostic evaluation includes an assessment of potentially reversible causes of delirium. A fullphysical examination should examine for evidence of sepsis, dehydration, or major organ failure.Medications that contribute to delirium should be identified. A laboratory assessment identifiesmetabolic abnormalities including hypercalcemia, hypoxia, or disseminated intravascular coagulationthat may cause delirium. Radiographic imaging studies of the brain and lumbar puncture forexamination of cerebrospinal fluid may be appropriate in some instances. TABLE 4

Causes of Delirium in Patients With Advanced Disease

• Potential Etiologies—Delirium has multiple potential etiologies (Table 4). In patients withadvanced cancer, delirium may be due either to direct effects on the central nervous system (CNS)or to indirect CNS effects of the disease or treatments (medications, electrolyte imbalance, majororgan failure, infection, or vascular complications).[2,29]Due to fragile physiologic functioning and the prescription of numerous medications, advancedcancer patients are more vulnerable to the development of delirium with routinely prescribedhypnotics. Narcotic analgesics including levorphanol (Levo-Dromoran), morphine, and meperidineare common causes of delirium in the elderly and terminally ill. Chemotherapeutic agents known tocause delirium include methotrexate, fluorouracil, vincristine, vinblastine, bleomycin, carmustine(BiCNU, Gliadel), cisplatin, asparaginase (Elspar), procarbazine (Matulane), ifosfamide (Ifex), andglucocorticosteroids[ 8,23,27,55-60]; as well as the immunotherapeutic agents interleukin-2 andinterferon.Most patients receiving chemotherapeutic agents will not develop prominent central nervous systemeffects unless dexamethasone or prednisone is included in the regimen. The spectrum ofdisturbances related to steroids includes anxiety, mood lability, major affective disorders (mania ordepression), cognitive impairment (reversible dementia), and delirium (steroid psychosis). Theincidence of steroid-induced disorders ranges from 3% to 57% in noncancer populations, withincreased prevalence at higher doses. Symptoms typically develop within the first 2 weeks ofadministration but may occur at any time, with any dose, and even during the tapering phase.[22]These disorders are frequently rapidly reversible upon dose reduction or discontinuation.[22]

Nonpharmacologic Interventions

In addition to identifying and correcting the etiologies of delirium, symptomatic and supportivetherapies are important.[3,4,20,53] In fact, symptomatic and supportive treatment may be the onlyinterventions in a dying patient. Maintaining fluid and electrolyte balance, providing nutrition,supplementing vitamins, reducing anxiety and disorientation, and continuing comforting, reassuringinteractions with family members may be helpful. Providing structure, routine, and familiarity willreduce anxiety and disorientation. Ensuring that the patient has a quiet, well-lit room with familiarobjects, a visible clock or calendar, and the presence of family will provide comfort. Judicious use ofphysical restraints or one-to-one nursing observation may be appropriate, beneficial, and necessary.

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Inouye and colleagues[61] reported on a successful multicomponent intervention program to preventdelirium in hospitalized older patients. They focused on a set of risk factors that were highlypredictive of delirium in the elderly, including preexisting cognitive impairment, visual impairment,hearing impairment, sleep deprivation, immobility, dehydration, and severe illness. Interventionsdirected at constant reorientation, correction of hearing and visual impairment, reversal ofdehydration, and early mobilization appeared to significantly reduce the number and duration ofepisodes of delirium in hospitalized older patients. The applicability of these interventions and thelikelihood that they would prevent delirium in the terminally ill, particularly in the last days of life, isminimal.

Pharmacologic Interventions

TABLE 5

Medications Used to Manage Delirium in Patients With AdvancedDisease

Supportive techniques alone are frequently ineffective in managing symptoms of delirium, andsymptomatic treatment with neuroleptics or sedative medications may be necessary (Table 5).Neuroleptic drugs (dopamine- blocking drugs) such as haloperidol, are utilized frequently asantiemetics in the medical setting. However, only 0.5% to 2% of hospitalized cancer patients, forinstance, receive haloperidol for the management of delirium.[62,63] In terminally ill populations, asfew as 17% receive an antipsychotic for agitation, despite an estimated prevalence of deliriumranging from 25% in hospitalized cancer patients to 85% in the terminally ill.[64,65]• Neuroleptics—Haloperidol, a neuroleptic with potent dopamine blockade, is frequently used in thetreatment of delirium in patients with advanced disease.[65-73] Haloperidol in low doses (1 to 3mg/d) is usually effective in targeting agitation, paranoia, and hallucinations. Haloperidol, 0.5 to 1.0mg (po, IV, IM, SC), may be administered with repeated doses every 45 to 60 minutes titratedupward to relieve target symptoms.[52,74] An intravenous route facilitates rapid onset of action. Ifintravenous access is unavailable, an intramuscular or subcutaneous route of administration may beused and switched to oral administration when possible.The majority of delirious patients can be managed with oral haloperidol. Parenteral doses areapproximately twice as potent as oral doses. Many palliative care practitioners deliver haloperidol bythe subcutaneous route.[21,75] A low dose of neuroleptic is typically sufficient to treat delirium inelderly, terminally ill patients. In general, doses need not exceed 20 mg of haloperidol in a 24-hourperiod. There are clinicians who advocate high doses (up to 250 mg of haloperidol intravenously over24 hours) in selected cases.[69]A common strategy in the management of delirium is the addition of parenteral lorazepam to aregimen of haloperidol.[76,77] Lorazepam (0.5 to 1.0 mg every 1 to 2 hours orally or intravenously),administered with haloperidol may provide effective sedation for the agitated delirious patient andminimize extrapyramidal side effects associated with haloperidol.[77] An alternative strategy is toswitch from haloperidol to a more sedating neuroleptic such as chlorpromazine.In a double-blind, randomized comparison trial of haloperidol, chlorpromazine, and lorazepam,Breitbart and colleagues demonstrated that lorazepam alone, in doses up to 8 mg in a 12-hourperiod, was ineffective in the treatment of delirium. Lorazepam used alone exacerbated delirium andincreased cognitive impairment.[1] Both haloperidol and chlorpromazine administered in low doses(haloperidol at 2 mg or its equivalent every 24 hours), were highly effective in managing symptomsof delirium (significant improvement in DRS scores) and improving cognitive function (significant

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improvement in MMSE scores). In addition, both haloperidol and chlorpromazine significantlyimproved symptoms of delirium in both subtypes, ie, hypoactive and hyperactive.[1]Methotrimeprazine, a phenothiazine neuroleptic with properties similar to chlorpromazine, is oftenutilized parenterally (intravenously or by subcutaneous infusion) to control confusion and agitation interminal delirium.[78] Doses range from 12.5 to 50 mg every 4 to 8 hours up to 300 mg/24 hours forthe majority of patients. Hypotension and excessive sedation are potential limitations of this drug.Methotrimeprazine has the advantage of analgesic properties, equipotent to morphine, throughnonopioid mechanisms.[78]• Atypical Neuroleptics—Several new, atypical, antipsychotic agents with less risk ofextrapyramidal side effects are currently available and include such agents as clozapine, risperidone(Risperdal), and olanzapine (Zyprexa).[79-83] Risperidone demonstrated usefulness in the treatmentof dementia and psychosis in AIDS patients at doses of 1 to 6 mg/d, suggesting safe use in patientswith delirium.[ 82] A limited number of published studies have addressed the use of these agents inthe treatment of delirium.[80-83] In a recent doubleblind comparative delirium intervention studyassessing the efficacy of haloperidol vs risperidone, Han and Kim demonstrated in a small sample of24 patients that there was no significant difference in clinical efficacy or response rate.[84]Breitbart and colleagues[80] published a large (N = 82) open trial of olanzapine for the treatment ofdelirium in hospitalized patients with advanced cancer, and the drug proved highly effective.Delirium resolved in 76% of patients, without incidence of extrapyramidal side effects. Severalfactors were found to be significantly associated with poorer response to olanzapine, including ageover 70, history of dementia, and the hypoactive subtype of delirium. The average starting dose was2.5 to 5 mg and patients were given up to 20 mg daily. Sedation was the most common side effect.Many palliative care clinicians use risperidone (eg, 0.5-1 mg twice daily) and olanzapine (2.5-20mg/d in divided doses) in the management of delirium in terminally ill patients, particularly thosewho have demonstrated intolerance to extrapyramidal side effects of the typical neuroleptics.[85] Acurrent limitation on the use of atypical neuroleptics is the lack of availability in parenteralformulations. While neuroleptics are most effective in reducing agitation, clearing the sensorium, and improvingcognition in the delirious patient, this outcome may not be possible in delirium that complicates thelast days of life. Processes causing delirium may be persistent and irreversible during the activedying phase. Ventafridda et al[86] and Fainsinger et al[23] reported that 10% to 20% of terminally illpatients experience delirium that necessitates management by sedation, resulting in significantlyreduced arousal and decreased level of consciousness.The goal of treatment with midazolam, propofol (Diprivan), or methotrimeprazine is quiet sedation.Midazolam, administered by subcutaneous or intravenous infusion in doses ranging from 30 to 100mg over 24 hours may be effectively used to control agitation related to delirium in the terminalstages.[87] Propofol, a short-acting anesthetic agent, has also been utilized primarily as a sedatingagent for the control of agitated patients with terminal delirium. In several case reports, propofol hasbeen used in terminal care with an intravenous loading dose of 20 mg followed by a continuousinfusion at initial doses ranging from 10 to 70 mg/h, with titration upward to a maximum of 400 mg/hover a period of hours to days, to control severely agitated patients.[ 88,89] Propofol has theadvantage of more readily titrated sedation and more rapid recovery by tapering the rate ofinfusion.[88]

Controversies in the Management of Terminal Delirium

REFERENCE GUIDE Therapeutic Agents

Mentioned in This Article Asparaginase (Elspar)

Bleomycin

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Carmustine (BiCNU, Gliadel)

Chlorpromazine

Cisplatin

Clozapine

Dexamethasone

Fluorouracil (5-FU)

Haloperidol

Ifosfamide (Ifex)

Interleukin-2 (IL-2, Proleukin)

Levorphanol (Levo-Dromoran)

Lorazepam

Meperidine

Methotrexate

Methotrimeprazine (Levoprome)

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Midazolam

Morphine

Olanzapine (Zyprexa)

Prednisone

Procarbazine (Matulane)

Propofol (Diprivan)

Risperidone (Risperdal)

Vinblastine

Vincristine

Brand names are listed in parentheses only if a drug is not available generically and is marketed as no more than two trademarked or registered products. More familiar alternative generic designations may also be included parenthetically.

Several aspects of the use of neuroleptics and other pharmacologic agents in the management ofdelirium in the dying patient remain controversial. Some clinicians contend that pharmacologicinterventions with neuroleptics or benzodiazepines are inappropriate for delirium in the dyingpatient. Clinicians may hesitate to intervene, as they view delirium as an integral component of thedying process.In particular, some palliative care clinicians consider dying patients' hallucinations and delusionsinvolving communication with predeceased relatives welcoming them to heaven as an importantevent in the transition from life to death. Given that some patients experience hallucinations anddelusions as pleasant and comforting, clinicians may doubt the appropriateness of pharmacologicintervention or the necessity of perceived aggressive treatment in the actively dying patient.Moreover, parenteral neuroleptics or sedatives may mistakenly be avoided secondary toexaggerated fears of hastening death through hypotension or respiratory depression. Many cliniciansare unnecessarily pessimistic about the possibility of effective results of neuroleptics in thesymptomatic relief of terminal delirium. Some practitioners argue that as the underlyingpathophysiologic process is irreversible, no improvement will be expected in the patient's mentalstatus. Others are concerned that neuroleptics or sedatives may exacerbate delirium by further

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confusion or sedation.Clinical experience in terminal delirium suggests that the use of neuroleptics in the management ofagitation, paranoia, hallucinations, and altered sensorium is safe, effective, and frequentlyappropriate.[76] Management of delirium on a case-by-case basis is wisest. An agitated, deliriousdying patient should receive neuroleptics to restore calm. A "wait-and-see" approach, prior tointervening with neuroleptics, may be appropriate for patients who are lethargic, somnolent, orexperiencing pleasant, comforting hallucinations. That said, such a waitand- see approach mustrecognize that a lethargic or hypoactive delirium may rapidly and unexpectedly transform into anagitated or hyperactive delirium that threatens the serenity and safety of the patient, family, andstaff.Recent evidence suggests that neuroleptics effectively reduce the symptoms of delirium in bothhyperactive and hypoactive subtypes of delirium.[ 1] Neuroleptics improve the arousal disturbanceand cognitive function in patients with hypoactive delirium. Some clinicians suggest that thehypoactive delirium subtype responds to psychostimulants or combinations of neuroleptics andpsychostimulants.[54]• Need for Sedation—Perhaps the most challenging clinical problem is management of the dyingpatient with a terminal delirium that is unresponsive to standard neuroleptics, whose symptoms canonly be controlled by sedation to the point of a significantly decreased level of consciousness. Beforeundertaking interventions such as midazolam or propofol infusions, in which the goal is a calm,comfortable, but sedated, unresponsive patient, the clinician must first take several steps.The clinician must have a discussion with the family (and the patient if he or she appears to have thecapacity during lucid moments) to elicit concerns and wishes for the type of care that best honors adesire to provide comfort and symptom control during the dying process. The clinician shoulddescribe the optimal achievable goals of therapy as they currently exist. Family members should beinformed that the goal of sedation is to provide comfort and symptom control, not to hasten death.They should also be told to anticipate that sedation may result in a premature sense of loss and thatthey may feel their loved one is in some sort of limbo state, not yet dead, but no longer alive in thevital sense.The distress and confusion that family members can experience during such a period may beameliorated by including the family in the decision- making process and emphasizing the sharedgoals of care. Sedation in such patients is not always complete or irreversible. Some patients haveperiods of wakefulness despite sedation, and many clinicians will periodically lighten sedation toreassess the patient's condition.Ultimately, the clinician must always keep in mind the goals of care and communicate these goals tothe staff, patients, and family members. The clinician must consider these issues in the managementof the dying patient who presents with delirium in such a way that preserves and respects thedignity and values of that individual and family.Financial Disclosure: Dr. Breitbart has been on the speakers’ bureaus and acted as a consultantfor Eli Lilly, Cephalon, Ortho Biotech, Janssen, Johnson & Johnson, and Purdue Pharma. He has beenon the speakers' bureau for Bristol-Myers Squibb. References: 1. Breitbart W, Marotta R, Platt M: A doubleblind comparison trial of haloperidol,chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients. Am JPsychiatry 153:231-237, 1996.2. Bruera E, Miller L, McCallion J: Cognitive failure in patients with terminal cancer: A prospectivestudy. J Pain Symptom Manage 7:192-195, 1992.3. Fainsinger R, Young C: Cognitive failure in a terminally ill patient. J Pain Symptom Manage6:492-494, 1991.4. Leipzig R, Goodman H, Gray G: Reversible narcotic associated mental status impairment inpatients with metastatic cancer. Pharmacology 35:47-54, 1987.5. Levine P, Silberfarb P, Lipowski Z: Mental disorders in cancer patients: A study of 100 psychiatricreferrals. Cancer 42:1385-1391, 1978.6. Massie M, Holland J, Glass E: Delirium in terminally ill cancer patients. Am J Psychiatry140:1048-1050, 1983.7. Murray G: Confusion, delirium, and dementia, in Hackett T, Cassem N (eds): MassachusettsGeneral Hospital Handbook of General Hospital Psychiatry, pp 84-115. Littleton, Mass, PSGPublishing, 1987.8. Posner J: Delirium and exogenous metabolic brain disease, in Beeson P, McDermott W,

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