Delirium in advanced cancer patients

Palliative Medicine 2004; 18: 184 ¡/194

Delirium in advanced cancer patients Carlos Centeno Centro Regional de Cuidados Paliativos y Tratamiento del Dolor, Hospital Los Montalvos, ´ lvaro Sanz Servicio de OncologOá, Hospital ClOńico Universitario, Valladolid and Eduardo Bruera Salamanca, A Department of Palliative and Rehabilitation Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX Delirium in advanced cancer is often poorly identified and inappropriately managed. It is one of the most common causes for admission to clinical institutions and is the most frequently cited psychiatric disorder in terminal cancer. Diagnosis of delirium is defined as a disturbance of consciousness and attention with a change in cognition and/or perception. In addition, it develops suddenly and follows a fluctuating course and it is related to other causes, such as cancer, metabolic disorders or the effects of drugs. Delirium occurs in 26% to 44% of cancer patients admitted to hospital or hospice. Of all advanced cancer patients, over 80% eventually experience delirium in their final days. In advanced cancer, delirium is a multifactorial syndrome where opioids factor in almost 60% of episodes. Delirium in such patients, excluding terminal delirium, may be reversible in 50% of cases. Providing adequate end-of-life care for a patient with delirium is the main challenge. The family needs advice and it is important to create a relaxing environment for the patient. The primary therapeutic approach is to identify the reversible causes of delirium. Some therapeutic strategies have been shown to be effective: reduction or withdrawal of the psychoactive medication, opioid rotation, and hydration. Haloperidol is the most frequently used drug, and new neuroleptics such as risperidone or olanzapine are being tested with good results. Methylphenidate has been used for hypoactive delirium. Palliative Medicine 2004; 18: 184 ¡/194 Key words: cancer; cognition; dehydration; delirium; opioid/adverse effects; palliative care

in cancer patients, and to provide easy and practical guidelines on how to manage it.

Introduction Delirium is defined as an acute state of confusion which results from a diffuse organic brain dysfunction. 1 ¡ 4 Delirium is one of the most difficult syndromes to diagnose and treat and substantially deteriorates the quality of life for both the patient and their family in the final days of life. It is one of the main reasons for admission to Palliative Care Units 5 and one of the most frequent psychiatric disturbances in terminal disease.6 The acute state of confusion can be more striking than pain or other problems. Furthermore, it interferes with adequate clinical evaluation and impedes the patient from participating in decision making. Early detection of delirium and proper management may help to relieve and even to revert it. Delirium has been thoroughly studied in elderly patients with different grades of impairment in their mental functions, 7 in patients who have undergone surgery,8 or who suffer drug toxicity.9 This review intends to facilitate the detection and understanding of delirium Address for correspondence: Carlos Centeno, Centro Regional de Medicina Paliativa y Tratamiento del Dolor, Hospital Los Montalvos, 37192 Los Montalvos, Salamanca, Spain. E-mail: [email protected] # Arnold 2004

Concept The syndrome ‘delirium’ has been explained as ‘encephalopathy’, ‘acute confusional state’, ‘cognitive failure’, or even ‘brain failure’. All these terms are valid, but they are not clear enough because they only refer to partial aspects of the overall problem. The concept has been revised in order to clarify and unify the terminology.10 According to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition 11 (DSM-IV), delirium is classified as a cognitive disorder. Diagnostic criteria for delirium of the DSM-IV are shown in Table 1. Delirium is diagnosed when there is a disturbance in consciousness and attention, with a change in cognition or perception. It develops suddenly, usually over a period of hours to days, and follows a fluctuating course. Furthermore, clinical data suggest one or more causes, such as a known illness (cancer), a metabolic disturbance, or the side effects of drugs.1 2 As the end of life approaches, most patients experience diffuse brain dysfunction. Terminal agitation, an expres-

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Delirium in advanced cancer patients 185 Table 1 Diagnostic criteria for delirium due to multiple aetiologies A. Consciousness, alteration of (i.e., reduced clarity of awareness of the environment) with reduced ability to focus, sustain, or shift attention. B. A change in cognition (such as memory deficit, disorientation, language disturbance) or the development of a perceptual disturbance that is not better accounted for by a pre-existing, established or evolving dementia. C. The disturbance develops over a short period of time (usually hours to days) and tends to fluctuate during the course of the day. D. There is evidence from the case history, physical examination, or laboratory findings that the delirium has more than one aetiology (e.g., more than one aetiological general medical condition, a general medical condition plus substance intoxication or medication side effect).

sion of terminal delirium, may express the concept of the ‘delirium of final days’.1 3

Incidence and reversibility Among those cancer patients needing psychiatric evaluation, delirium is the second most frequent diagnosis (17%), only exceeded by adjustment disorders. 1 4 The incidence of delirium increases as performance status declines. In terminal cancer, delirium has a higher prevalence: of between 26% and 44% of all patients admitted to medical institutions such as hospitals or hospices (Table 2). Eventually, up to 83% of patients develop delirium in their final days, and 10% to 30% of them may require palliative terminal sedation.1 5,16 Delirium identified on admission to a Palliative Care Unit may be reversible through adopting a suitable therapeutic approach in almost 50% of cases.1 7 ¡ 1 9 This percentage rises when it is triggered by the use of drugs, or metabolic abnormalities such as dehydration or hypercalcaemia. The probability of response diminishes if there have been previous episodes, or if it is related to hypoxic or global metabolic encephalopathy.1 6 Delirium is usually irreversible when it appears in the final hours of life. In cancer patients, delirium is an independent factor of poor prognosis for short-term survival. One study shows that terminal cancer patients with delirium have a median survival of 21 days, compared to 39 days in those without. 20 Delirium can be added to other prognostic factors in order to more accurately define the probability of 30-day-survival in terminal cancer patients.21

disturbances, but it is more frequent in elderly people and in patients with a baseline brain dysfunction such as dementia. In terminally ill cancer patients, delirium may be due to organic failure although it may also be due to non-organic factors. It is unclear how a distant tumour may alter brain physiology, but both cytokines (such as interleukin or interferon) and other inflammatory mediators may contribute. 2 2 Among the hypotheses that try to explain the physiopathology of delirium (inflammation, infection, neurotransmission disorders, etc.), one of the most widely accepted is the cholinergic hypothesis. It contends that delirium is mediated by a deficit of acetylcholine or a predominance of dopamine.2 3 Delirium can be induced by anticholinergic drugs2 4 and can be reversed with cholinergic agonists such as physostigmine or neuroleptics. A deficiency of thiamine, hypoxia and hypoglycaemia also reduce acetylcholine. An excess of dopamine would explain why antidopaminergic drugs, such as haloperidol, can improve the symptoms of delirium. The GABA receptor seems to be involved in liver encephalopathy,25 and in midazolam-resistant agitated delirium.2 6 Delirium in advanced cancer is considered a multifactorial process. 2 Triggering factors act on a previously weakened organ (Table 3). A single cause of delirium can be identified for only one in three cancer patients that present a change in mental status. In the other two, several causes can be recognized: 27 opioids may be involved in 64% of the cases, metabolic disorders in 53%, infection in 46%, recent surgery in 32%, and structural lesions in 15%. Hyperactive delirium seems to be more frequent in liver failure, opioid toxicity or corticosteroid therapy.2 7 Delirium with a dominant hypoactive component has been associated with dehydration. A variety of drugs may be required for symptom control in terminally ill patients. However, drugs are the main precipitating factor of delirium in advanced cancer patients.9 Morphine metabolites may contribute to the development of delirium. There are also other drugs that may alter cognitive function and precipitate an acute state of confusion in the patient: metoclopramide, antihistamines, corticosteroids, quinolone, or anti-convulsants. Delirium might also be triggered by the withdrawal of psychoactive drugs.28

Clinical manifestations Pathophysiology Delirium has been considered as an unspecific and stereotyped response of the brain to different aggressions. It may appear in patients without previous brain

The severity of delirium varies from patient to patient, and even in the same patient may fluctuate over time. Some situations show very slight symptoms, almost unnoticeable for those unaccustomed to recognizing components of delirium in the changing symptoms of


186 C Centeno et al. Table 2 Incidence of delirium in elderly and advanced cancer patients Author and year

Pathology

N

Location

Diagnostic criteria

Percentage of patients with delirium

Francis, 19906 6

Elderly

229 ¡/

¡/

General Hospital

¡/

22%

Levkoff, 19926 7

Elderly

325 ¡/

Initial evaluation

Long Stay Centre DSM-III

10.5%

O‘Keeffe, 19976 8

Elderly

225 ¡/

Evaluation at admission

Emergency Room DSM-III

18%

Metitieri, 200069

Elderly, terminal illness 60

Admission

Hospice

MMSE DSM-IV

28%

Marcantonio, 200170

Elderly, hip surgery

126 79

Post-surgery, randomized

Traumatology Department

MMSE MDAS

32 ¡/50%

Bruera, 19921 5

Advanced cancer

47

¡/

Last two weeks of PCU life

MMSE

83%

Minagawa, 19966

Advanced cancer

93

¡/

First week after admission

General Hospital

MMSE DSM-III-R

28%

Cobb, 20005

Advanced cancer

210 ¡/

Retrospective, admission

Hospice

Clinical judgement

20%

Caraceni, 20002 0

Advanced cancer

393 ¡/

Transversal, multicentric

PCU

CAM

28%

Lawlor, 20001 7

Advanced cancer

104 62

Admission

PCU

MMSE, interview and DSM IV 42%

Sharnill, 2001

Advanced cancer

50

Admission

PCU

BCS

32%

Morita, 200144

Advanced cancer

237 ¡/

Structured protocol

86%

Age Time and type of evaluation

73

65

Prospective, during Hospice hospice stay

PCU: Palliative Care Unit. MMSE: Mini-Mental Status Examination. MDAS: Memorial Delirium Assessment Scale. CAM: Confusion Assessment Method. BCS: Bedside Confusion Scale.

patients. It can appear as restlessness, sleep difficulties or slowness in thinking. At the other extreme, there are cases of severe delirium in advanced cancer which should be considered as emergencies. The patient’s clinical appearance in delirium can initially confuse clinicians. Sometimes, psychomotor agitation clearly develops, but in others, it is characterized by hallucinations, illusions, and other abnormal perceptions, 29 with minimal cognitive failure. The patient’s ties with his surroundings grow weak and the patient seems scared and uncommunicative or perhaps upset and demanding. Clinically, delirium is often described in its most typical behavioural alteration as an ‘agitated patient’. The patient becomes uneasy, with repeated and constant limb movements, trying to get up, to undress, to throw off bed-covers, to disconnect the line, etc. Sometimes the only way to calm the patient down is physical contact, such as a caress or a whisper because any other stimulus may increase his restlessness and agitation. These manifestations characteristically appear or worsen at night and thus it becomes impossible for the patient to sleep.

Disinhibition may manifest itself as a constant repetition of the same name, a complaint about a pain or a noise or groaning. Behavioural disorders due to delirium do not always consist of pure agitation or a hypervigilant state. There are also hypoactive deliriums that are difficult to identify and in which the patient may appear reserved, postate, or very quiet, almost always somnolent or asleep, unable to focus attention. He may give monosyllabic answers to simple questions. A more thorough evaluation may reveal language disturbances, the inability to construct a sentence, reverberation, disorientation, somnolence, etc. In terminal cancer patients, it is difficult to distinguish between this hypoactive delirium and depression and although there are pure forms of hyperactive and hypoactive delirium, mixed types are frequent, with alternating hyper- and hypoactivity. Behaviour changes and attention alterations usually go together. As patients are unable to focus attention, they are unable to maintain interest in a single stimulus and shift to a different one. And, as they pay almost no


Delirium in advanced cancer patients 187 Table 3 Causes of delirium in advanced cancer Structural

Metastases or brain tumours Pre-existing dementia Advanced age Previous episodes of delirium Drugs Chemotherapy: methotrexate, ifosfamide, fluorouracil, vincristine, vinblastine, bleomycine, carmustine, cisplatin, procarbazine Psychoactive drugs: antidepressants, antiparkinsonian, antipsychotic, opioid, benzodiazepine, antiemetic (metoclopramide), antisecretor (hyoscine, scopolamine), antihistaminic Other drugs: corticosteroids, cimetidine, ranitidine, NSAID (COX-2 inhibitors included), antibiotics (quinolones), aciclovir, anticonvulsant, (phenobarbital, phenitoine, carbamazepine), digoxin, theophylline, nifedipine, alcohol Withdrawal syndromes: alcohol, opioids, corticosteroids, benzodiazepines Metabolic Fever Dehydration Hypoxic encephalopathy Uraemia Hepatic encephalopathy Hypoglycaemia Hypercalcaemia Hyponatraemia Hypernatraemia Haematological Anaemia Disseminated intravascular coagulation Infectious Infections in the nervous system Systemic infections (including embolic abscess)

attention to people close to them, communication becomes impossible. Sometimes, delirium is simply identified as ‘confusion’. This cognitive failure is another manifestation of the greater reality of delirium. The patient is disoriented to time, place and person. Confusion about daily events is frequent. He is unable to obey simple orders such as ‘open your eyes’ or ‘squeeze my hand’ as he cannot answer normal questions. Thinking becomes disorganized and language may be full of mistakes, neologisms, and chaos. A thorough examination may reveal inability in memory retention, difficulty in calculation, etc. Cognitive failure is often accompanied by perception disturbances, typically alternating with intervals of lucidity. Almost half of inpatients experience hallucinations (visual, tactile, auditory 3 0 ) in the last two weeks of life.3 1 They may be real hallucinations (perception without object) or illusions (erroneous perception of a real object). Delirium also overlaps with other clinical problems and interferes in the evaluation of other symptoms; for instance, ‘brain failure’ can be manifested as poorlydefined pain:3 2 when a patient reports pain ‘everywhere’ and is not able to indicate exactly where it hurts, we can suspect it is sign of a non-fully manifested delirium. Evidently, delirium causes suffering in the patient,3 3 as well as their family. The doctor may be under pressure to relieve this suffering. This emotional overload may lead to premature sedation of the patient to overcome this situation, in a process of a ‘destructive triangle’ (Figure 1).3 4,35

Identifying delirium Delirium is often apparent, but, in many cases, it may go undetected by the clinician. Some studies have shown that delirium was not detected in 22¡/50% of the cases.15 Factors related to this failure to recognize delirium include hypoactive delirium, pre-existing dementia, older age and the presence of sensorial alterations (such as failing or weak eyesight) in the patient. 36 The ability to identify delirium by nurses is characterized by high sensitivity (91% to 99%) but low specificity (15% to 30%). This ability can be improved by the correct use of terminology, the development of training programmes and the use of techniques of early recognition and other means of measuring cognitive function. 37 Delirium requires clinical diagnosis (Figure 2). A comparison with the baseline situation is crucial to detect any change in mental status. In the earliest evaluation, data should be collected from people close to the patient about the period prior to the onset of symptoms, in order to know if the patient was able to recognize their family, if they engaged in conversations, etc. To detect changes in mental state due to delirium, it is necessary to identify its most characteristic features: cognitive deficit and attention disorder. The ‘Mini-Mental State Examination’ (MMSE) 38 is a screening tool for cognitive impairment that includes shorter versions (MMSE-30). The cut-off point depends on formal education reached and age,39 and may change in different countries for elderly people. 40 Besides the MMSE, other instruments have been developed for the early recognition of delirium.


188 C Centeno et al.

Figure 1 Sedation as a consequence of a noncontrolled agitated delirium, inuenced by delirium-induced stress of proxies and overload in therapeutic team (’destructive triangle‘).

Other tools have been developed for screening or monitoring the course of delirium (Table 4). The use of any one of them depends on their availability, prior training and objective: detection, follow-up, or evaluation of the response to treatment. The Memorial Delirium Assessment Scale (MDAS) has been validated in advanced cancer patients,41 and is useful in palliative care.4 2 The Delirium Rating Scale (DRS) has been used to monitor delirium in terminal patients.18 ,4 3 Finally, the Communication Capacity Scale and the Agitation Distress Scale measure the impact of key symptoms of delirium. 4 4 Other possible causes for the change in mental state such as depression, dementia, and psychosis must be ruled out (Table 5). When delirium coexists with dementia or psychosis or depression it is very difficult to reach a definitive diagnosis. In these cases, sometimes the only choice is to treat delirium and later confirm one or several diagnoses, depending on the response and course of the disease.

Treatment of delirium Once delirium has been recognized, it must be treated (Figure 3). The main goals are to calm the patient and Table 4 Tools available to recognize or evaluate delirium in cancer patients Screening tools

Diagnostic tools Tools assessing intensity

Mini-Mental Status Examination (MMSE) Blessed Orientation Memory Concentration Test (BOMC) Bedside Confusion Scale (BSCS) Confusion Assessment Method (CAM) Memorial Delirium Assessment Scale (MDAS) Delirium Rating Scale (DRS) Communication Capacity Scale and Agitation Distress Scale (CCS & ADS)

Figure 2 patients.

Three steps approach to detect delirium in cancer

help recover his communication ability. The relief of suffering must not be delayed, as two thirds of patients whose delirium resolved recalled it as distressing, even those with hypoactive delirium. 33 Thus, the treatment of the symptoms of delirium, just as in severe pain and other distressing symptoms, must be initiated before or while searching for its cause. In severe cases, symptomatic therapy must be something more than sedation; like any other difficult symptom, sedation may be the recognition of our inability to control symptom. Nevertheless, when there is clinical evidence of terminal delirium and increased agitation, immediate sedation may be advisable. The suggestions for accurate recognition and management of delirium should be followed by the clinician according to his own experience and the clinical status of the patient (Figure 3). These efforts must be directed at identifying the causes, and simultaneously, towards initiating symptomatic control, improving the patient’s environment, giving advice to caregivers and using suitable medication. It is unrealistic to expect the situation to drastically improve with any single measure.


Delirium in advanced cancer patients 189 Table 5 Differential diagnosis of delirium Delirium

Dementia

Depression

Psychosis

Start

Acute

Insidious

Variable

Variable

Course

Quick and fluctuating

Slow and constantly progressive

Variation during the day

Variable

Reversibility

Some times

Non reversible

Reversible

Variable

Level of consciousness Obnubilated, disoriented and orientation

Lucid until the last stages

Generally normal

Intact, although the patient may be perplexed in the acute stage

Attention and memory

Poor short-term memory and constant inattention

Poor short-term memory, without inattention

Poor attention but intact memory

Poor attention but intact memory

Cognition

Focal cognitive failure

Global cognitive failure

Cognitive intact

Variable

Psychotics symptoms

Frequent; psychotic ideation Less frequent is brief and non-elaborated

EEG

Abnormalities in 80 ¡/90% Abnormalities in 80 ¡/90% Normal (most frequent: generalized (most frequent: generalized diffuse slowing) diffuse slowing)

Normal

Evaluation and treatment

Requests medical attention Needs chronic therapy and as an emergency adequate follow-up

Needs psychiatric evaluation and treatment

Identification and elimination of possible causes

Rare; psychotic ideation is Frequent; psychotic sympcomplex and related to the toms are complex and mood of the patient often paranoid

May need drug therapy and psychotherapy

Drugs. Drugs are the most frequent cause of delirium. Initially, it is important to keep a record of any drug that the patient may have been receiving in the past, as well as the changes in dose over preceding days (Table 3). It is common to find more than one type of medication potentially involved in the development of delirium. The next step should be to consider a reduction in the dose, withdrawal or substitution of the most likely substance, keeping in mind that sudden withdrawal may actually worsen delirium. When the patient is taking opioid drugs, an effective strategy is opioid rotation at an equianalgesic dose with a reduction of 20 ¡/30%. In this way, mental status can be improved without compromising analgesia.45 Active metabolites of morphine are hydrosoluble and tend to accumulate in renal failure or volume depletion. Making sure that patients receive adequate oral or parenteral (intravenous or subcutaneous 4 6 ) hydration may reduce the severity and duration of delirium. However, in delirium of the final hours, parenteral hydration does not seem appropriate.

Complementary evaluations. Complementary examinations should be evaluated depending on the patient’s prior wishes, clinical state and its reversibility, and available resources. The decision to further investigate the origin of delirium through special tests must be adapted to the same ethical criteria that govern other therapeutic decisions at the end of life. In any case, these evaluations must be guided by both the clinical history and the physical examination and they must be aimed at seeking reversible causes in order to design a therapeutic schedule. Blood tests may reveal metabolic abnormalities such as hypercalcaemia, hyponatraemia and hypoglycaemia, anaemia and indicators that may support suspicions of active infection. They may also provide information about other causes such as clotting disorders, disseminated intravascular coagulation, or renal or liver failure. Measurement of oxygen saturation is an easy and noninvasive way to reveal hypoxemia. Abnormalities in urine tests may point to a possible urinary tract infection. Chest X-ray may suggest pneumonia and heart failure. A CT-scan can rule out the presence of brain metastases.

Patient evaluation. Physical examination will try to identify neurological signs, fever, dehydration, signs of organic failure or other factors such as urine retention, constipation or faecal impaction. Physical evaluation permits the detection of signs of imminent death such as hypotension, death rattle, etc. which would advise against a more aggressive approach.

Nonpharmacological treatment: good care of the patient with delirium Delirium can be improved by changes in the approach to the patient, the environment and family support. These steps must be carried out at the same time as other symptomatic approaches.47


190 C Centeno et al.

Figure 3

Therapeutic approach to delirium in advanced cancer patients.

Approach to the patient. In the first stages of delirium, the patient may become aware of his own alterations and may suffer from being unable to control his own mind. Simple questions as ‘Do you feel confused?’ or ‘Do you feel disoriented?’ may help the patient become aware of his own confusion. At this moment it is important help the patient by reassuring him. One of the manifestations of delirium is attentiondeficit, usually accompanied by memory loss, more evident in short-term memory. Therefore, his long-term memory should be stimulated in order to re-establish trust and orientation. Nevertheless, when the patient is not able to remember something, he must not be overwhelmed by asking him the same question repeatedly. It is helpful to stimulate the patient to perform easy tasks, such as eating, but excessive demands should not be made, because emotional stability is weakened. It is advisable to maintain an empathic and respectful relationship, even if the patient displays a negative attitude. The patient may also be helped when manifesting

interest, trying to solve their fears, anxieties and perceptual disturbance. 48 Environmental issues. Providing a safe, comfortable and relaxing environment protects against delirium in patients with severe deterioration or advanced age.49 This results in the nervous system receiving a few, simple, well organized stimuli. It is advisable that the patient has people and objects he is familiar with around him, and carers use soft voice tones, and physical contact. The number of visits must be limited, as well as potentially annoying simultaneous conversations and distressing extreme sensorial experiences such as heat, cold, noise, lights, etc. To prevent further disorientation, the position of the bed should not be changed. Advice to the family. Decisions about a patient with delirium must be taken with the co-operation of the family. Nevertheless the appearance of delirium is worrisome for the family who may feel an emotional ambiguity as the patient may even be unable to recognize loved ones


Delirium in advanced cancer patients 191 and they may perceive this mental failure as a sign of imminent death. Therefore it is very important to explain that this is just ‘brain failure’, not necessarily a sign of death or that the patient is ‘losing their mind’, and that it may not necessarily be accompanied by pain or severe suffering. It is also necessary to inform of possible fluctuations in mental state. 50 In addition, the family should understand the risk of unusual and aggressive expressions and erratic and unspecific complaints, due to the loss of neural inhibitions. It is recommended that they recognize that the patient is disoriented without trying to immediately reorient him. It is important not to contradict what the patient is saying and not to challenge him. 4 At the same time an attitude that reduces sensorial stimuli and favours relaxation should be encouraged. Symptomatic therapy When the patient is agitated or has perceptual disturbances (illusions, hallucinations, nightmares), symptomatic therapy is mandatory. Actions should be taken in order to calm the patient down. Sedation could be a valid option if this is not possible. For instance, temporary deep sedation may be advisable while other therapies specifically directed at underlying causes take effect. Even hypoactive delirium, a calm situation with progressive somnolence and seclusion, can be distressing and needs adequate treatment. 3 3 Major tranquilizers. Haloperidol is effective for both hyperactive and hypoactive delirium5 1 and is the first choice in treatment. 5 2 This drug does not induce severe sedation: on the contrary, it helps treat agitation and allows the patient to rest once response is achieved. It is more effective for the ‘positive’ symptoms of delirium, such as agitation, abnormal ideation, or hallucinations, than for the ‘negative’ ones, like cognitive failure, that may improve more slowly. Haloperidol has few side effects, mainly extrapyramidal: muscle stiffness, early dyskinesia, and trembling. In prolonged treatment, other side effects, as late dyskinesia, can appear. Haloperidol can be administered orally, subcutaneously, intravenously, and intramuscularly. Oral bioavailability appears to be half that of parenteral.5 3 A practical guideline may be: initial dosage of 2.0 mg p.o. or 1.0 mg s.c. every six hours, with an additional dose every hour, as needed due to agitation or hallucinations.50 If severe agitation requires immediate control, haloperidol can be administered more frequently. Overall, most patients can be treated with daily doses under 20 mg. However, some patients may receive up to ten times this dose. For very agitated delirium, more sedative neuroleptics can be used, such as levomepromazine or chlorpromazine. Both of them can be administered subcutaneously, although chlorpromazine may induce local irritation. Levomepromazine has the advantage of analgesic proper-

ties but may induce excessive sedation and hypotension. 53 New neuroleptics such as risperidone and olanzapine are available. There are encouraging results on low doses of risperidone in brain tumour-induced behavioural disorders, 54 in elderly people,55 ,5 6 and in organic brain syndromes.57 Olanzapine may be useful in advanced cancer delirium due to its strength, its scarce pharmacological interactions, and its broad therapeutic scope. 58 Olanzapine has a more sedative effect and may be useful in single doses at the beginning of the night for the sleep ¡/ wake cycle disorder.59 These new neuroleptics are used in low dosages for the management of delirium in terminal patients, especially those with haloperidol-induced extrapyramidal effects: 0.5¡/1.0 mg every 12 hours for risperidone, 5 ¡/12 mg/day for olanzapine.6 0 Because of the important differences in secondary effects and individual susceptibility between neuroleptics, 6 0 a therapeutic trial might be advisable, changing drug when results are not satisfactory. Benzodiazepines are effective in the symptomatic treatment of delirium associated with convulsions or in those induced by alcohol or sedative withdrawal. Some researchers point out that when delirium does not respond to haloperidol, a trial with a benzodiazepine such as lorazepam is warranted.5 3 Lorazepam (0.5 to 1.0 mg every one or two hours) is recommended in cases of severe agitation, as it also prevents neurolepticinduced extrapyramidal effects. However, in a randomized study, lorazepam used as the only medication did not control delirium but actually worsened confusion and cognitive disturbance. 61 Use of sedative drugs. Direct sedation is the alternative to neuroleptics in agitated delirium in the final days. Delirium is presented by different authors as the most frequent cause of palliative terminal sedation;6 2 10% to 23% of patients in palliative care units require terminal sedation due to delirium. These differences might be explained not only by appealing to diverse delirium management, but also due to the inconsistencies in defining delirium and sedation, as well as to the different patient populations in diverse care settings. The dose-effect relation of benzodiazepines is more predictable than that of neuroleptics. Among benzodiazepines, midazolam has a rapid effect when inducing sedation6 3 and when reversing it, because of its short half-life, if in the meantime a treatable cause of delirium has been found. When indicated, sedation can be induced with an initial subcutaneous dose of 3 ¡/5 mg that can be repeated every six hours. Some complicated deliriums of the final days may not be solved even with midazolam and/or neuroleptics.26 In these cases, the patient will paradoxically look agitated and sedated at the same time. When there is no other way, anaesthetic medication may be used as a last resort. Phenobarbital is a useful agent


192 C Centeno et al. for inducing deep palliative sedation to control difficult and resistant terminal agitation.64 Propofol, a shortacting anaesthetic agent, has been used to control agitated patients with terminal delirium. Psychostimulants. Psychostimulants such as methylphenidate are effective in hypoactive delirium. 6 5 These drugs have also shown efficacy in depressive syndromes and in relieving asthenia in cancer patients.

Conclusion Delirium is a challenge for any clinician faced with a patient at the end of life. It is necessary to properly identify the moment in the evolution of the disease, to search for possible causes that may precipitate delirium, and to try to eliminate them and work fast with the symptomatology. Opioids and psychoactive medications are the source of many cases of delirium in cancer patients. More research needs to be done to establish a solid basis to scientifically support the diagnosis and treatment of delirium.

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