Taking care of the terminally ill cancer patient: delirium as a symptom of terminal disease

Transcription

1 Annals of Oncology 15 (Supplement 4): iv199 iv203, 2004 doi: /annonc/mdh927 Taking care of the terminally ill cancer patient: delirium as a symptom of terminal disease L. Michaud 1,2, B. Burnand 1,3 & F. Stiefel 2 1 Centre of Clinical Epidemiology and 3 Health Care Evaluation Unit, Institute of Social and Preventive Medicine, University of Lausanne, Lausanne; 2 Psychiatry Service, University Hospital, Lausanne, Switzerland Introduction Delirium remains under-recognized and undertreated in oncology, especially in the terminally ill [1 3]. While delirium is often associated with a considerable burden of suffering for the patient and his relatives, it also causes distress among health care professionals [4]. Delirium is not an unavoidable consequence of disease or of the process of dying; indeed it can be successfully treated, even in the terminally ill cancer patient [5, 6]. Definition and mode of presentation of delirium According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) [7], delirium is characterized by a diminished level of consciousness, an inability to shift, focus or maintain attention, and a disturbance of cognition and perception, which develop over a short period of time, usually hours or days, and tends to fluctuate during the course of the day. Delirium has an acute onset and is often reversible with or without treatment; it may, however, persist over extensive periods (days and weeks). Three clinical subtypes have been identified: hypoactive, mixed and hyperactive [8, 9]. Hyperactive delirium, often associated with agitation, aggressiveness and hallucination, is more often diagnosed and treated than the two other subtypes. Patients with hypoactive delirium are often sleepy and withdrawn, and are therefore more difficult to identify. Different outcomes and risks may be associated with these subtypes, but it remains to be confirmed whether hyperactive or hypoactive delirium is associated with the worst outcome [10, 11]. While the definition of delirium is well established, its symptoms may show a considerable intra- and inter-individual variability, especially in the terminally ill patient. In some patients, delirium may start with subtle changes in mood (feeling tense or anxious, crying spells), while in others, visual or auditory hallucinations, changes of sleep patterns and of the sleep wake cycle, disorientation, incoherent thought processes, psychomotor agitation or retardation, irritability and aggressiveness, inability to concentrate, loss of memory or difficulties in verbal expression may represent its first signs [12]. The variability of the symptoms of delirium, its fluctuating course and the overlapping symptoms with other psychiatric disorders, such as dementia or depressive and anxious states, often hamper the correct diagnosis of delirium, especially in the early phase of its manifestation. Evaluation, diagnosis and differential diagnosis of delirium Repeated evaluations of the patient, possibly complemented by the use of questionnaires, are the key to the diagnosis of delirium. This implies a close observation of the level of consciousness (has the patient a slightly diminished level of consciousness? Is he sometimes sleepy or even impossible to wake?), of the capacity to maintain, focus or shift attention (is he able to follow a conversation? To concentrate on a text? Or to fulfil different tasks, such as washing himself in a coherent way?), as well as of cognitive functioning and perception (has he difficulty in remembering relevant issues? Is he disorientated in time or space or is he seeing or hearing strange things?). If such deterioration occurs rapidly in an otherwise mentally healthy individual, if these changes have an acute onset, and if they fluctuate over the course of the day, the diagnosis of delirium is most probable. The difficulty in diagnosing delirium in oncology may be due to a variety of factors, such as busy clinical practice, lack of familiarity with its manifestation, heterogeneity and fluctuation of the clinical presentation, the difficulty of evaluating psychological symptoms and asking obvious questions (what is the date today? Can you tell me where we are? Can you tell me who I am?), or the underestimation of the impact of delirium on patients, their families and health care professionals. Screening instruments, such as the Mini Mental State Exam [13] or the Blessed Orientation-Memory-Concentration [14], may help to improve the recognition of delirium. Instruments to grade its severity, like the Memorial Delirium Assessment Scale [15, 16], which has been developed for cancer patients, may be useful to monitor its treatment. However, evidence to support their routine use is lacking and many questions, such as the frequency of screening during hospitalization, remain unanswered. Differential diagnosis includes dementia (which shows similar symptoms, but has a slow onset and gradual deterioration over months), anxiety and depression (which are not associated with a diminished level of consciousness and severe cognitive impairment), psychotic and manic states q 2004 European Society for Medical Oncology

2 iv200 (which usually have a longstanding history), and organic hallucinatory states (which are monosymptomatic). It may be appropriate to request a psychiatric consultation for patients with a prior psychiatric history, a psychiatric comorbidity or for whom the diagnosis remains unclear. Epidemiology and risk factors of delirium in the terminal cancer patient In studies of cancer patients, prevalence rates of delirium ranging from 8 to 85% have been reported, depending largely on age as well as on severity and stage of disease [17]. Most epidemiological studies have major methodological weaknesses and longitudinal studies with repeated measurements are lacking; in addition, diagnostic criteria as well as standardized diagnostic instruments have been evolving over the last decades, hampering comparison and replication of studies. Again, the probability of developing delirium during a stay in a palliative care unit has been found to vary between 34 and 88% [17 21], frequent assessment being clearly associated with a higher prevalence [5]. Clinical experiences indicate that mild forms of delirium may affect almost all of the patients at some time during the terminal stage of their illness [22]. General risk factors for delirium were explored in a number of prospective studies, which were systematically reviewed [23]. In the elderly, a model separating predisposing and precipitating factors was proposed and validated [24, 25]. Predisposing factors set the baseline vulnerability, while precipitating factors are thought to trigger the occurrence of delirium during the hospitalization. This model is most probably also valid for the population of terminally ill cancer patients. Predisposing factors such as advanced age, cognitive impairment and severity of disease were clearly identified [23]. Studies of the role of visual and hearing impairment, depression, alcohol abuse, electrolyte disorders, and dehydration in the development of delirium produced heterogeneous results; these factors should therefore be considered as possibly predisposing. Several studies clearly identified the number of medications added during hospitalization as a precipitating factor [25 27]. The number of iatrogenic events, malnutrition and physical restraints were found to possibly precipitate delirium [25, 27], and one study identified changes of room and the absence of clocks, calendars and glasses as aggravating factors [28]. In oncology and in the palliative care setting, only a few studies have addressed the issue of risk factors for delirium. In a prospective study including 113 patients admitted to a general oncology ward, advanced age and cognitive impairment were found to be independent predictors of delirium [29]. Low albumin levels, bone metastases and the presence of a hematological malignancy were also identified, but these may represent a mark of illness severity, and not be independent risk factors for delirium. A recent study in patients with advanced cancer found psychotropic medication and non-respiratory infections to be predictive of the reversibility of delirium, while hypoxic encephalopathy (as defined by oxymetry levels by the authors) was associated with nonreversibility [5]. Table 1. Etiology of delirium in terminal cancer patients [1, 57, 58] Causal category Organ failure Medications Psychoactive Others Intracranial processes Infections Metabolic disease Withdrawal Main causes Heart, renal, liver, pulmonary failure Benzodiazepines, anticholinergics Steroids, chemotherapeutics, opioids Brain metastases, hemorrhage Urinary, pulmonary and any other infections Dehydration, hypoxia, hypercalcemia Alcohol, benzodiazepines withdrawal Etiology of delirium in terminal cancer patients While a variety of causes are listed in review articles and textbooks, only a few studies have attempted to identify etiological factors of delirium (Table 1). Defining a potential cause of delirium is a difficult task, since experimental studies (e.g. reversal or deliberate application of a putative risk factor) cannot be conducted for practical and ethical reasons. The few studies addressing etiology in patients with advanced cancer concluded that multiple causes were responsible for the development of delirium [20, 30]. In a subsequent study, hepatorenal dysfunction, fluid and electrolyte imbalances were thought to be the most common causes [31]. Brain metastases, metabolic impairment, infections, cerebral infarctions and hemorrhage, nutritional deficits and drug effects (opioid treatment, corticosteroids, benzodiazepines and tricyclic antidepressants) are often thought to cause delirium in terminal cancer patients [32, 33]. Several hypotheses concerning the pathogenesis of delirium have been suggested in the literature; among them, neurotransmitter changes (relative imbalance between acetylcholin and dopamine), cerebral hypoxia or stress-induced hormonal changes (corticosteroids) [34]. Prevention, non-pharmacological and pharmacological treatment of delirium Three systematic reviews [35 37] have addressed the issue of preventive strategies to reduce the incidence of delirium. Despite the current lack of evidence, they support the implementation of non-pharmacological interventions to prevent delirium in surgical and medical inpatients. The interventions are intended to focus on patients at-risk with predisposing and precipitating factors, and consist of measures comparable to the non-pharmacological treatments detailed below (Table 2). One recent randomized controlled trial using a preventive intervention targeted at the elderly demonstrated significant and cost-effective results [38, 39]. Treatment of delirium is always directed at the identification and elimination of the underlying causal agent [1, 20, 40]; this also applies to the terminally ill cancer patients. However, it may not always be possible, since the burden of diagnostic investigations and treatments in patients with

3 iv201 Table 2. Prevention, and treatment of delirium [58] (A) Non-pharmacological interventions Interventions Orientation Dehydration Mobilization Information Sleep Environment Sensory regulation Examples Provide clocks and calendars; reorient the patient about hospitalization, persons and actions Encourage oral fluids Early mobilization protocols Provide concise information to the patient and proxies regarding the nature and treatment of delirium Promote sleep using protocols (warm drink before sleeping, massage, relaxation, etc.) Provide a stable environment (room and staff); allow the patient and proxies to personalize the room Provide glasses and hearing devices; reduce noise (B) Pharmacological interventions Drug category Indications Examples Antipsychotics First-line treatment Haloperidol mg two to three times daily Second-line treatment Olanzapine mg orally once daily; risperidone 0.5 mg orally twice daily Combined treatment with antipsychotics and benzodiazepines Aggressive and/or agitated patients Haloperidol and lorazepam mg three times daily advanced disease have to be balanced with the expected benefit for the quality of life. Nevertheless, some investigations should be considered even in the terminally ill: examination of the patient s medical history, a detailed review of treatment, especially with regard to the introduction or withdrawal of psychotropic drugs, the study of the medical chart to identify predisposing and precipitating factors, as well as possible causal agents may direct management of delirium. A physical examination with special attention to neurological focal signs, evidence of fever, or symptoms of alcohol or substance abuse completes the investigation. Routine laboratory exams to detect organ failure or electrolyte imbalance and complementary exams, such as X-rays or computed tomography scan, must be carefully balanced against the possible distress that such investigation may cause. Electroencephalogram, certainly not considered as a routine tool, may exceptionally be necessary to distinguish delirium from dementia, or from nonconvulsive status epilepticus and temporal lobe epilepsy. Identification of vitamin deficiency may be necessary to differentiate delirium from Wernicke s disease [41, 42]. The challenge of the management of delirium in palliative care is to find an intermediate between an unduly fatalistic stance and an inappropriately aggressive medical investigation and treatment. Close involvement of family members in medical decisions is needed, since the possibility of obtaining informed consent from a delirious patient is most often non-existent. If detection and elimination of the underlying cause is not possible or while investigations are under way, the patient should benefit from non-pharmacological and pharmacological treatments. Non-pharmacological interventions have not yet been firmly evaluated, but are nevertheless recommended, based on modest evidence, clinical experience and the lack of side-effects [35, 37, 43]. Their aim is to reduce factors that may aggravate delirium and to provide a reassuring environment with an adequate level of stimulation. Non-pharmacological interventions include such measures as regular reorientation of the patient (by offering clocks, calendars and other means), comprehensive information regarding the way the family should communicate with the patient (avoiding over- and understimulation), mobilization, restoration of glasses and hearing devices, the provision of a stable environment (same room, same nurses) and renouncement of restraints [41, 42]. Pharmacological treatment of delirium has traditionally been based on the use of low doses of haloperidol (e.g mg two to three times a day) [42]. Haloperidol is a highpotency dopamine-blocking agent with low anticholinergic and sedative properties, a short half-life, no active metabolites and minimal cardiovascular side-effects [44]. Some evidence suggests that atypical neuroleptics, such as risperidone and olanzapine, could also be useful [1, 40, 45]. In case of nonresponse of aggressive and agitated patients to higher doses of haloperidol (e.g. 5 mg three times a day), the third author s clinical experience and existing guidelines [42] support the use of a combination of haloperidol and benzodiazepines with a short half-life and without active metabolites (e.g. lorazepam mg three times a day). Benzodiazepines without neuroleptics are nevertheless only indicated in withdrawal and hepatic encephalopathy; it has to be remembered that they can worsen confusion and induce paradoxical excitement in the elderly [46, 47]. In rare cases of important agitation or severe psychological distress, sedation with a continuous subcutaneous infusion of midazolam (e.g. 1 mg/h) may become necessary if other treatments fail [48]. If opioids are thought to cause or contribute to a delirious state [49], opioid rotation (i.e. rotating between different types of opioid to avoid accumulation of active metabolites) should be considered,

4 iv202 even though two studies have shown contradictory results in the palliative care setting [50, 51]; however, a recent systematic review has demonstrated overall reduction of various sideeffects with opioid rotation [52]. Methodologically sound studies on pharmacological treatment of delirium in terminal cancer patients are still lacking, especially in cases of hypoactive delirium, for which different hypotheses concerning the pathogenesis and possible treatments have been suggested [53]. Conclusions If untreated, delirium causes psychological suffering and functional decline in the overwhelming majority of patients. In addition, family members are often shocked by the patient s symptoms and the inability to engage in meaningful conversations and relationships. Health care professionals may also experience distress, especially in cases of aggressiveness and hyperactive delirium. Delirious patients may harm themselves, through falls or self-inflected injuries. The few prospective studies that have been conducted to determine outcomes have demonstrated that delirium is an independent predictor of diminished survival in the elderly [54, 55] and the terminally ill [56]. While the risk of diminished survival may not be an issue in palliative care, effective symptom management, especially the treatment of pain, are hampered in delirious patients. Using effective strategies, delirium can be successfully prevented and treated. In this way, it is of utmost importance for oncologists to be familiar with its management. References 1. Mazzocato C, Stiefel F, Buclin T, Berney A. Psychopharmacology in supportive care of cancer: a review for the clinician: II. Neuroleptics. Support Care Cancer 2000; 8: Roth-Roemer S, Fann J, Syrjala K. The importance of recognizing and measuring delirium. J Pain Symptom Manage 1997; 13: Breitbart W, Bruera E, Chochinov H, Lynch M. Neuropsychiatric syndromes and psychological symptoms in patients with advanced cancer. J Pain Symptom Manage 1995; 10: Breitbart W, Gibson C, Tremblay A. The delirium experience: delirium recall and delirium-related distress in hospitalized patients with cancer, their spouses/caregivers, and their nurses. Psychosomatics 2002; 43: Lawlor PG, Gagnon B, Mancini IL et al. Occurrence, causes, and outcome of delirium in patients with advanced cancer A prospective study. Arch Intern Med 2000; 160: Lawlor PG, Fainsinger RL, Bruera ED. Delirium at the end of life: critical issues in clinical practice and research. JAMA 2000; 284: Diagnostic and Statistical Manual of Mental Disorder, Text Revision, 4th edition. Washington, DC: American Psychiatric Association Lipowski ZJ. Delirium (acute confusional states). JAMA 1987; 258: Camus V, Burtin B, Simeone I et al. Factor analysis supports the evidence of existing hyperactive and hypoactive subtypes of delirium. Int J Geriatr Psychiatry 2000; 15: Marcantonio E, Ta T, Duthie E, Resnick NM. Delirium severity and psychomotor types: their relationship with outcomes after hip fracture repair. J Am Geriatr Soc 2002; 50: O Keeffe ST, Lavan JN. Clinical significance of delirium subtypes in older people. Age Ageing 1999; 28: Meagher DJ, Trzepacz PT. Delirium phenomenology illuminates pathophysiology, management, and course. J Geriatr Psychiatry Neurol 1998; 11: Folstein MF, Folstein SE, McHugh PR. Mini-mental state. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12: Katzman R, Brown T, Fuld P et al. Validation of a short Orientation- Memory-Concentration Test of cognitive impairment. Am J Psychiatry 1983; 140: Breitbart W, Rosenfeld B, Roth A et al. The Memorial Delirium Assessment Scale. J Pain Symptom Manage 1997; 13: Lawlor PG, Nekolaichuk C, Gagnon B et al. Clinical utility, factor analysis, and further validation of the memorial delirium assessment scale in patients with advanced cancer: Assessing delirium in advanced cancer. Cancer 2000; 88: Derogatis LR, Morrow GR, Fetting J et al. The prevalence of psychiatric disorders among cancer patients. JAMA 1983; 249: Conill C, Verger E, Henriquez I et al. Symptom prevalence in the last week of life. J Pain Symptom Manage 1997; 14: Minagawa H, Uchitomi Y, Yamawaki S, Ishitani K. Psychiatric morbidity in terminally ill cancer patients: a prospective study. Cancer 1996; 78: Bruera E, Miller L, McCallion J et al. Cognitive failure in patients with terminal cancer: a prospective study. J Pain Symptom Manage 1992; 7: Massie MJ, Holland J, Glass E. Delirium in terminally ill cancer patients. Am J Psychiatry 1983; 140: de Stoutz N, Stiefel F. Delirium in cancer patients: etiology, assessemnt and therapeutic proceedings. In Portenoy RK, Bruera E (eds): Topics in Palliative Care, Vol. 1. New York, NY: Oxford University Press 1997; Elie M, Cole MG, Primeau FJ, Bellavance F. Delirium risk factors in elderly hospitalized patients. J Gen Inter Med 1998; 13: Inouye SK. Predisposing and precipitating factors for delirium in hospitalized older patients. Dement Geriatr Cogn Disord 1999; 10: Inouye SK, Charpentier PA. Precipitating factors for delirium in hospitalized elderly persons. Predictive model and interrelationship with baseline vulnerability. JAMA 1996; 275: Dai YT, Lou MF, Yip PK, Huang GS. Risk factors and incidence of postoperative delirium in elderly Chinese patients. Gerontology 2000; 46: Martin NJ, Stones MJ, Young JE, Bedard M. Development of delirium: A prospective cohort study in a community hospital. Int Psychogeriatr 2000; 12: McCusker J, Cole M, Abrahamowicz M et al. Environmental risk factors for delirium in hospitalized older people. J Am Geriatr Soc 2001; 49: Ljubisavljevic V, Kelly B. Risk factors for development of delirium among oncology patients. Gen Hosp Psychiatry 2003; 25: Pereira J, Hanson J, Bruera E. The frequency and clinical course of cognitive impairment in patients with terminal cancer. Cancer 1997; 79: Morita T, Tei Y, Tsunoda J et al. Underlying pathologies and their associations with clinical features in terminal delirium of cancer patients. J Pain Symptom Manage 2001; 22:

5 iv Stiefel FC, Breitbart WS, Holland JC. Corticosteroids in cancer: neuropsychiatric complications. Cancer Invest 1989; 7: Stiefel F, Holland J. Delirium in cancer patients. Int Psychogeriatr 1991; 3: Trzepacz PT, van der Mast RC. The neuropathophysiology of delirium. In Lindesay J, Rockwood K, Macdonald AJ (eds): Delirium in Old Age, Oxford University Press, New York, NY: 2002; Cole MG, Primeau FJ, Elie LM. Delirium: prevention, treatment, and outcome studies. J Geriatr Psychiatry Neurol 1998; 11: Cole MG, Primeau F, McCusker J. Effectiveness of interventions to prevent delirium in hospitalized patients: a systematic review. CMAJ 1996; 155: Britton A, Russell R. Multidisciplinary team interventions for delirium in patients with chronic cognitive impairment (update of Cochrane Database Syst Rev 2000; 2). Cochrane Database Syst Rev 2001; 1: CD Rizzo JA, Bogardus ST Jr, Leo-Summers L et al. Multicomponent targeted intervention to prevent delirium in hospitalized older patients: what is the economic value? Med Care 2001; 39: Inouye SK, Bogardus ST, Charpentier PA et al. A multicomponent intervention to prevent delirium in hospitalized older patients. N Engl J Med 1999; 340: de Stoutz ND, Tapper M, Fainsinger RL. Reversible delirium in terminally ill patients. J Pain Symptom Manage 1995; 10: British Geriatrics Society. Delirium guidelines. [On-line]. org.uk (6 September 2004, date last accessed). 42. Trzepacz P, Breitbart W, Franklin J, et al. Practice guideline for the treatment of patients with delirium. American Psychiatric Association Practice Guidelines for the Treatment of Psychiatric Disorders: Compendium Washington, DC: American Psychiatric Association 2002; Stiefel F, Razavi D. Common psychiatric disorders in cancer patients II. Anxiety and acute confusional states. Support Care Cancer 1994; 2: Marder S, Van Kammen D. Biological therapies. In Sadock BJ, Sadock V (eds): Kaplan & Sadock s Comprehensive Textbook of Psychiatry. Lippincott Williams & Wilkins, New York, NY: 2000; Tune L. The role of antipsychotics in treating delirium. Curr Psychiatry Rep 2002; 4: Breitbart W, Marotta R, Platt MM et al. A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients. Am J Psychiatry 1996; 153: Fernandez F, Levy JK, Mansell PW. Management of delirium in terminally ill AIDS patients. Int J Psychiatry Med 1989; 19: Sykes N, Thorns A. Sedative use in the last week of life and the implications for end-of-life decision making. Arch Intern Med 2003; 163: Stiefel F, Morant R. Morphine intoxication during acute reversible renal insufficiency. J Palliat Care 1991; 7: Morita T, Tei Y, Inoue S. Agitated terminal delirium and association with partial opioid substitution and hydration. J Palliat Med 2003; 6: Bruera E, Franco JJ, Maltoni M et al. Changing pattern of agitated impaired mental status in patients with advanced cancer: association with cognitive monitoring, hydration, and opioid rotation. J Pain Symptom Manage 1995; 10: McNicol E, Horowicz-Mehler N, Fisk RA et al. Management of opioid side effects in cancer-related and chronic noncancer pain: a systematic review. J Pain 2003; 4: Stiefel F, Bruera E. Psychostimulants for hypoactive-hypoalert delirium? J Palliat Care 1991; 7: McCusker J, Kakuma R, Abrahamowicz M. Predictors of functional decline in hospitalized elderly patients: a systematic review. J Gerontol A Biol Sci Med Sci 2002; 57: M569 M McCusker J, Cole M, Abrahamowicz M et al. Delirium predicts 12-month mortality. Arch Intern Med 2002; 162: Caraceni A, Nanni O, Maltoni M et al. Impact of delirium on the short term prognosis of advanced cancer patients. Cancer 2000; 89: Lawlor PG, Bruera ED. Delirium in patients with advanced cancer. Hematol Oncol Clin North Am 2002; 16: Casarett DJ, Inouye SK. Diagnosis and management of delirium near the end of life. Ann Intern Med 2001; 135: