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Palliating delirium in patients with cancer
Review
Palliating delirium in patients with cancer Augusto Caraceni, Fabio Simonetti Lancet Oncol 2009; 10: 164–72 Palliative Care (Pain Therapy, Rehabilitation), Fondazione IRCCS, National Cancer Institute, Milan, Italy (A Caraceni MD, F Simonetti MD) Correspondence to: Dr Augusto Caraceni, Palliative Care (Pain Therapy, Rehabilitation), National Cancer Institute, 20133 Milan, Italy augusto.caraceni@ istitutotumori.mi.it
Delirium is a frequent complication in oncology. Its definition as a disorder of consciousness, attention, and cognition is useful to elaborate a rational framework of its pathophysiology and to interpret the role of different aetiological factors and therapeutic interventions. Many aetiologies and an interaction between risk and predisposing factors have been shown to contribute to most cases of delirium. A screening of potential aetiologies is always mandatory to benefit reversible cases. The palliative treatment of symptoms of delirium includes non-pharmacological, environmental, and preventive interventions and the use of haloperidol. If haloperidol fails to control delirium, sedation with other drugs can be necessary. Specific attention to the qualitative aspects of care and to the effect of delirium on family members should be given in the overall assessment of the patient in his or her cancer trajectory.
Introduction Delirium (figure 1) is one of the most common neurological complications seen in hospitalised patients with cancer.1 Its frequency in oncology compared with other medically ill populations is shown in table 1,2–11 which highlights how elderly individuals and patients with advanced or terminal cancer are especially at risk from this complication. The probability of developing delirium is determined by the combined effect of predisposing or vulnerability factors, such as previous cognitive failure or dementia and age,4,12 incident factors, such as drug toxicity and metabolic abnormalities, and other conditions that are more often associated with the severity of the underlying illness (figure 1). Delirium in cancer can be a challenging diagnosis, because it can be a reversible complication, it can herald the progression of the disease to the brain, and it can be irreversible as part of the terminal evolution of an incurable disease. The aims of this Review are to clarify the definition of delirium, assess the pathophysiological aspects useful for its understanding and rational therapeutic strategy, and investigate specific aspects of its aetiology and management in patients with cancer. The comprehensive description of specific conditions, such as postoperative delirium and alcohol withdrawal syndrome, is not within the scope of this Review.
Definition and clinical findings Diagnostic definition of delirium Delirium is a brain syndrome only rarely associated with a specific brain lesion. The Diagnostic and Statistical Manual of Mental Disorders IV—Treatment Revision (panel 1) established the most commonly used diagnostic definition of delirium,12 which highlights a few core concepts—delirium is a disorder of consciousness and attention combined with abnormalities of cognition and perception. Delirium is an acute syndrome as opposed to dementia, and an organic cause affecting the brain is usually identified or likely.
Consciousness and attention A definition of consciousness can be addressed from a semantic, philosophical, and neurophysiological perspective.13–15 In clinical practice, it is useful to assess the 164
level of consciousness and the content of consciousness— ie, the brain functions that allow an individual to be awake and aware of self and of the environment. The level of consciousness is behaviourally equivalent to the degree of wakefulness, often described, in neurological language, as the level of brain arousal.13,15 The normal degree of wakefulness varies from asleep to awake, and has been described as the degree of sensory stimulation needed to keep the patient awake and vigilant.15 The content of consciousness and cognition can be assessed only if at least a certain degree of wakefulness and alertness are preserved. Patients with delirium can be defined as hypoalert or hyperalert (hypovigilant and hypervigilant can be used synonymously).15 The level of consciousness and awareness can be affected separately or concurrently in different brain disorders. In the vegetative states, awareness can be lost, whereas control of the level of consciousness is preserved. In delirium, the level of both consciousness and awareness are abnormal. In coma, awareness is absent because the patient cannot be woken. The function of the brain that focuses mental activity on internal or external stimuli, making it possible to concentrate on these stimuli and to shift from one to another, is attention. Attention has been defined as “the sentry at the gate of consciousness”.13,16 If the level of consciousness and attention are abnormal, changes in perception of internal and external stimuli can occur, thereby compromising awareness. Attention abnorIncident factors: Toxic Metabolic Brain lesion
Delirium
Predisposing factors: Age Dementia
Figure 1: Schematic of delirium pathophysiology
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Population (age in years Prevalence at Incidence or medical category) admission, % during admission, %
Panel 1: DSM IV criteria for diagnosing delirium due to a general medical condition12
Francis2
16·0
16·0
≥70
Levfkoff3
10·5
31·3
≥65
Inouye4
NA
25·0
≥70
Inouye5
NA
18·0
≥70
Ljubisavjevic6 NA
18·0
Medical oncology
Gaudreau7
NA
16·5
Medical oncology
A Disturbance of consciousness (ie, reduced clarity of awareness of the evironment) with reduced ability to focus, sustain, and shift attention B A change in cognition (ie, memory deficit, disorientation, and language disturbances) or perception disturbances not better explained 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 history, physical examination, or laboratory findings that the disturbance is caused by the direct physiological consequences of a general medical condition
Minagawa8
28·0
NA
Hospice
Lawlor9
42·0
45·0
Hospital palliative-care unit
Caraceni10
28·0
NA
Palliative-care programme including homecare
Massie11
NA
85·0
Patients dying from cancer
NA=not available.
Table 1: Prevalence of delirium at admission and incidence of delirium during admission in hospital—comparison of the elderly medically ill population with patients undergoing palliative care or with cancer
malities are core symptoms in delirium, and they can be identified by distractibility and perseveration. Attention can be formally tested by simple bedside mental-status assessment tools.7,17,18
Cognitive and psychotic symptoms Cognitive failure is another essential feature of delirium. Some of the cognitive symptoms that occur in delirium depend on the effect of altered consciousness and attention on cognitive performances (ie, memory recall, orientation, calculations, writing, drawing, and language),16 as a study has shown.18 This study also showed that psychotic symptoms, such as hallucinations and delusions, are found less frequently than cognitive symptoms, (out of 100 patients, 50 had hallucinations and 31 had delusions), and are not correlated with the impairment of attention and cognition.18
Other symptoms Other important symptoms are often associated with impairment of consciousness, cognitive failure, and psychotic symptoms. These symptoms include disorders of the sleep–wakefulness cycle, vivid dreams, abnormal thought, motor abnormalities (ie, hypoactivity or hyperactivity), and mood changes (panel 2). From a behavioural point of view, delirium can be classified as hypoactive, hyperactive (ie, associated with the hypovigilant or hypervigilant level of consciousness), or mixed.19,20 Patients with hypoactive delirium are often misdiagnosed, or receive late diagnoses, due to the belief that hyperactivity alone is the hallmark of delirium.21
Pathophysiology and aetiology The pathophysiology of delirium remains to be fully elucidated, but the reticular formation of the brainstem, with its connection with the hypothalamus, thalamus, www.thelancet.com/oncology Vol 10 February 2009
DSM IV=Diagnostic and Statistical Manual of Mental Disorders, fourth edition. Reprinted with permission from reference 12.
Panel 2: Symptoms and signs of delirium Altered level of consciousness=level of wakefulness or arousal • Hyperalert (hypervigilant) in the hyperactive deliria • Hypoalert (hypovigilant) in the hypoactive deliria • Transitions from one state to another on a continuum from awake and hypervigilant to somnolent or drowsy with fluctuations also in the short time period are frequent in the mixed hyper-hypoactive deliria Impaired attention Altered sleep–wakefulness cycle regulation Motor changes (hyperactivity or hypoactivity) Affective changes Hallucinations Delusions Cognitive performance failure at formal testing • Orientation • Memory • Visual spatial abilities • Calculation • Writing • Reading Involuntary movements • Asterixis • Myoclonus
and diffuse effects on the cortex—regulating normal wakefulness and sleep—is thought to have a significant role. The neurotransmitters and receptors that are important for wakefulness and consciousness functions, 165
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Panel 3: Brain centres and neurotransmitters active in maintaining and modulating normal wakefulness and level of consciousness—pathophysiological role in delirium, possible pharmacological interventions, and toxicity Acetylcholine • Promotes wakefulness and cognition • Inhibition by drugs produces sedation, cognitive impairment, and delirium (eg, atropine, opioids, and tricyclic antidepressants) • A major role of cholinergic pathways dysfunction is likely in many cases of delirium Dopamine • Promotes wakefulness • Hyperactivation can be responsible for delusion, hallucinations, and psychomotor agitation in delirium • Neuroleptics (haloperidol) are used in delirium, mainly for their inhibitory activity on these receptors to obtain tranquillisation without sedation Norepinephine • Promotes wakefulness • Hyperactivation can be important for agitated deliria, especially in alcohol and other substance withdrawal • Alpha 2 adrenergic agents (eg, clonidine) can inhibit this pathway, are useful in sedation, and can be used in hyperactive delirium, such as delirium tremens due to alcohol withdrawal Serotonin • Modulates sleep–wakefulness cycle • Excessive serotonergic activity is associated with delirium (serotonergic syndrome) • Delirium can be caused by serotonergic drugs, such as many antidepressants, some antiemetics, and analgesics • New-generation neuroleptics have setotonin inhibitory effects on subsets of serotonin receptors Histamine • Promotes wakefulness, inhibition causes sedation • Antihistamine drugs are sedative (eg, promethazine) Orexin (hypocretin) • Promotes wakefulness and attention in cooperation with the histaminergic and cholinergic systems • In cases of excessive sedation due to drug toxicity or other factors, drugs acting on orexin receptors (modafinil) can improve arousal and vigilance Gamma-aminobutyric acid • The final common pathway of all sleep-promoting neurotransmitters • Sedative effects of benzodiazepines, barbiturates, and general anaesthetics are all mediated by GABA receptors • Level of consciousness is reduced and risk of developing delirium is increased electively by benzodiazepines
and for toxic and pharmacological effects, are listed in panel 3.15,22–24 Among the neurotransmitters, a central role in the pathogenesis of delirium has been advocated for acetylcholine. All drugs or toxic effects that affect CNS cholinergic neurons are candidates for causing delirium. This theory would also explain the higher risk of developing delirium in patients with dementia and with cognitive decline due to brain ageing, who already have an impaired cholinergic system.22,23,25 166
Multiple risk factors As anticipated, the most relevant risk factors for developing delirium are age and dementia (table 2). Elderly patients with delirium, present with this condition in response to relatively mild incident factors that exert an anticholinergic effect.5,23,25 Indeed, empirical evidence shows that many aetiologies are often implied,1,9 and a multiple-factor model explains the risk of developing delirium in elderly patients, as confirmed also by the efficacy of risk-modifying interventions in preventing its onset.26,27 This means that the classic cause–effect mechanistic approach might fail to explain many cases of delirium.19,23
Patient assessment Assessment of cognitive functions A formal assessment of cognitive function is needed in patients who develop acute mental status changes and would be desirable in routine monitoring of patients who are at an especially high risk of developing delirium. Although there are a plethora of assessment instruments that are potentially useful,24 the most interesting and practically useful are restricted to a few. The Mini-mental State Exam is sensitive to changes in cognition and includes items that explore temporal orientation and other performances sensitive to changes in the level of consciousness and attention.28 It is not specific for delirium and cannot be used to differentiate delirium from dementia. The Delirium Rating Scale29 and the Memorial Delirium Assessment Scale30 are both specific for delirium, but not specifically designed to diagnose delirium. The Confusion Assessment Method, however, is a diagnostic algorithm that is both sensitive (94%) and specific (89%) for the diagnosis of delirium, but only when applied by specialists.31 The Nursing Delirium Screening Scale is a new and promising screening method with reasonable sensitivity (86%) and specificity (87%) in the hands of nurses, and we would advocate studies to test its potential as a routine method for the assessment of populations at risk.32
Differential diagnosis Dementia can be difficult to differentiate from delirium. In delirium, cognitive failure occurs acutely and in association with a disturbance of consciousness. In dementia, cognitive failure is slow and progressive, and it occurs, until terminal stage, without changes in the level of consciousness. When delirium is superimposed on a pre-existing dementia, the diagnosis is especially difficult.33 The increasing number of elderly patients attending oncology clinics will continue to pose these difficult dilemmas.34 The two main differential diagnoses of acute changes in level of consciousness and cognition in patients with cancer, not due to delirium, are seizures and acute psychoses. When seizures occur without or with minor motor activities (ie, convulsions), such as in non-convulsive status epilepticus, the clinical presentation www.thelancet.com/oncology Vol 10 February 2009
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Advanced age
Patients with cancer
General medical population
Postsurgical patients
+
+
+ +
Previously impaired cognition
+
+
Severity of illness
+
+
Benzodiazepines
+
+
Functional impairment
+
+
Metabolic abnormalities
+
+
Low albumin
+
Bone metastases
+
Liver metastases
+
Haematological malignancies
+
History of delirium
+
Metastases to brain or meninges
+
Opiods (dose related)
+
Corticosteroids (dose related)
+
Visual or hearing impairment
+
Infection
+
Alcohol abuse
+
Type of surgery (cardiac thoracic surgery bears a higher risk).
Table 2: Factors associated with the risk of developing delirium according to multivariate analysis in at least one study2–7,23,24
will mimic delirium.35 The diagnosis in patients with primary psychiatric disease can also be challenging when symptoms are acute and mainly involve communication and behaviour, such as in catatonia.36 The possibility of acute psychosis should not be disregarded in young patients with a severe affective impact of their disease and a history of psychological morbidity.
Aetiological assessment The most common aetiologies should always be reviewed (panel 4). Many aetiological factors are usually present, and their respective roles are difficult to differentiate. In patients with cancer, it is also important to exclude spread of the disease to the brain or the meninges; in a series of 140 consecutive patients, a structural brain lesion was the sole cause of delirium in 15% of patients, and had a contributory role in 36%.37 We treated a male patient with rhinopharyngeal carcinoma and bone metastases, who was undergoing chemotherapy while on an opioid regimen for bone pain (100 μg/h transdermal fentanyl administration). Due to slight changes in his behaviour, a brain MRI was requested and was negative. The patient was admitted and given intravenous morphine titrated up to 400 mg/24 h for pain control, without significant side-effects. A few days later he developed pneumonia with a high fever (up to 40°C) and acute delirium (ie, severe disorientation, delusions, hallucinations, and psychomotor agitation), which required intravenous infusion of haloperidol (12 mg/day) and lorazepam www.thelancet.com/oncology Vol 10 February 2009
Panel 4: Causes of delirium in patients with cancer • Drug toxicity • Non-metastatic complications of cancer • Metabolic encephalopathy due to hepatic, renal, or pulmonary failure • Infections • Electrolyte abnormalities • Glucose abnormalities • Haematological abnormalities • Paraneoplastic neurological syndromes (rare) • Toxic effects of antineoplastic therapies • Chemotherapy • Biological therapy (monoclonal antibodies) • Radiation to brain • Nutritional deficiency (including thiamine, folic acid, vitamin B12 deficiency) • CNS tumour, brain metastases, meningeal metastases • Other diseases/conditions not related to cancer • CNS diseases (including cerebrovascular disease, infection, vasculitis, or trauma) • Cardiac disease • Lung disease • Endocrinopathy • Alcohol or drug withdrawal (benzodiazepine and nicotine most common)
(12 mg/day). Examination of the cerebrospinal fluid was negative for malignant cells. Antibiotics were also given, and after a few days the fever remitted and the pneumonia improved, with full recovery of the acute symptoms of delirium and persistent fluctuating disorientation to space and time. Lorazepam and haloperidol were discontinued. An MRI taken after this episode showed diffused dural enhancement due to meningeal neoplastic infiltration not visible in the MRI obtained a month before (figure 2). This case highlights the difficulty in assessing the aetiological role of one of many factors that present at the same time—ie, meningeal disease, high-dose opioids, and sepsis. Other more rare examples of aetiological factors that are typical of cancer include: CNS lesions associated with paraneoplastic disease;38 infection (figure 3);39 toxic leucoencephalopathy;40 and meningeal or brain metastases causing delirium as the only sign of CNS involvement (figure 4).37,41
Treatment and management Non-pharmacological interventions Screening potentially reversible aetiological factors is a mandatory initial step in all cases of delirium. Even in the advanced phase of cancer, 50% of delirium episodes are reversible, especially when associated with drug toxicity.9 It is important to remember that providing safety, companionship, orientation, a quiet environment, emotional support to both the patient and the care-givers, 167
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Figure 2: Meningeal metastases and multiple aetiologies in delirium A patient with rhynopharingeal carcinoma, bone metastases, and pneumonia, who was receiving high-dose intravenous morphine infusion, developed delirium. MRI, done after recovery of pneumonia and delirium, shows meningeal enhancement in the more central and cranial part of the dura mater layers (arrow).
and a caring relationship can avoid pharmacological and eventually physical restraint in many patients with mild to moderate symptoms, and will probably improve the outcome of therapy in all cases.42–45
Prevention Evidence supports the role of multidisciplinary interventions in decreasing the risk of developing delirium in hospitalised elderly patients, but this finding has not been confirmed in patients with cancer.26,42 It is likely that the risk factors identified in the elderly population are more homogeneous and amenable to modification than those affecting patients with cancer (table 2).
Pharmacological management Haloperidol The treatment of delirium lacks well-established, evidence-based guidelines. Most guidelines and specialists consider haloperidol, a high-potency antipsychotic, as the first-line treatment. This recommendation is, at best, partially supported by a few randomised controlled trials and by neuropharmacological rationale (panel 3), but no placebo-controlled clinical trial is available.46–49 Benzodiazepines have a primary role, alone, or in combination with other drugs, such as haloperidol and clonidine, only in alcohol-withdrawal delirium.45,50 In all other cases, unless 168
Figure 3: Limbic encephalitis presenting as delirium in a patient who underwent bone-marrow transplant for non-Hodgkin lymphoma Coronal MRI shows high signal (white) bilaterally in the temporal lobes in the areas corresponding to the hypocampal uncus. The surrounding white matter shows oedema (arrows). The CSF examination confirmed diagnosis of herpes 6 virus encephalitis.
sedation is specifically desired, benzodiazepines should be avoided, because they increase the frequency and worsen the symptoms of delirium.7,51,52 The paucity of well-controlled clinical trials leaves the dosing recommendation of haloperidol to be based on clinical experience from case series. Guidelines45 suggest that in elderly patients, and in mild to moderately agitated deliria, haloperidol can be started at low doses—ie, 0·5 mg (orally) twice to three times a day—and then be titrated to obtain an effect. Such a dose will not suffice in more severe cases and in younger patients, as often seen in oncology. The most common emergency situation is due to hyperactive delirium with psychomotor agitation. In this condition, rapid tranquillisation is needed. Recommended parenteral doses are 1–2 mg in young patients and 0·25–0·5 mg in elderly patients (≥60 years), to be repeated after 1–2 h as needed until tranquillisation is achieved.19 Therapy can then be converted into an oral equivalent dose of 1·5 to two-times the parenteral dose. In young patients with no liver disease, acute intramuscular doses of 5–10 mg have been used to control aggressive dangerous behaviour due to different psychiatric diseases.19,53 With such doses, www.thelancet.com/oncology Vol 10 February 2009
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there is a definite, but low, risk of acute extrapyramidal side-effects, such as torticollis, oculogyric crisis, and tongue and laryngeal spasm, which must be treated with anticholinergic or antihistamine drugs.53 Akechi and co-workers54 used a 30-min interval titration protocol in patients with cancer, with doses given orally or parenterally according to feasibility (0·5 mg for three doses, 1 mg for three doses, 2 mg for three doses, and 5 mg for three doses). In this way, a maximum 25·5 mg dose could be reached in 6 h in patients with refractory disease. By applying this protocol to ten patients, the mean dose reached on the first day was 6 mg (SD 4; range 0·5–11) and in the whole follow-up period until recovery the mean dose reached was 5·4 mg (SD 3·4; 0·5–10·5). In another study55 of hyperactive delirium in 54 patients with cancer, low daily doses of haloperidol (mean 2·5 mg) were used in 61% of patients, intermediate doses (mean 15 mg) in 32%, and high doses (mean 30 mg) in 7%. These dosing examples confirm the need for titration. Haloperidol alone often fails to control agitation. Although insufficient titration cannot be ruled out, one case series of patients with advanced cancer reported that only 60% of patients could be managed with haloperidol alone. A combination with benzodiazepines or more sedative neuroleptics was considered necessary in the other patients.56
B
A
Figure 4: Meningeal metastases causing tetraventricular hydrocephalus Sagittal (A) and axial (B) brain MRI views showing tetraventricular hydrocephalus, a skull lesion (arrow), which invades the dura and is adjacent to the cortex and leptomeningeal covering, and a typical leptomeningeal lesion of the frontal lobe (arrowhead). The patient had a lung carcinoma and presented with delirium with disorientation of space and time, perseveration, and somnolence. Headache, meningismus, papilloedema, and focal signs were absent. CSF examination showed malignant cells. Reproduced with permission from Oxford University Press 2003.
Haloperidol
D1
D2
D4
Alpha 1
+
+++
++
+
5-HT2c
++
++ +++
+
+++
++
+
+++
+
++
+
+++
+
+
+
+
++
+
++
++
+
Promethazine† + +
Newer, atypical, antipsychotics (table 3) have also been assessed for the management of delirium. Doses of risperidone are usually low (around 1 mg/day), whereas olanzapine has been administered in doses ranging from 4·5–8·2 mg/day. Quetiapine was administered to a small number of patients at a mean daily dose of 25–75 mg.46,57–59 Risperidone can be initiated in elderly individuals at a dose of 0·25 mg twice a day, olanzapine at a dose of 1·25–2·5 mg/day, and quetiapine at a dose of 12·5–50 mg/day. These drugs were as effective as low-dose haloperidol in the available comparative studies.46 The older phenotiazine neuroleptics (promazine, levomepromazine, and chorpromazine) are seldom used in delirium for their anticholinergic effects. Levomepromazine (methotrimeprazine) is a phenotiazine with strong sedative properties, which is available in some countries also as a parenteral formulation. It is used to obtain sedation in the practice of palliative care at centres in the USA and UK, also via subcutaneous administration.60,61
Quetiapine
++
M
+
++
Olanzapine
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5-HT2a
Levomepromazine* Risperidone
Table 3 shows the action of different neuroleptic drugs on CNS receptors and their side-effects.61,62 A very rare, but life-threatening, side-effect of these drugs is the neuroleptic malignant syndrome manifested by catatonia, rigidity, and hyerpyrexia.
Hi 1
Chlorpromazine
Other neuroleptics
Side-effects of neuroleptics
Alpha 2
+++
++ **
**
++ ++ +++
D=dopamine receptors subtypes: antagonism has antipsychotic effects and extrapyramidal side-effects. Alpha 1=type 1 adrenergic receptors: antagonism leads to orthostatic hypotension. Alpha 2=type 2 adrenergic receptors: antagonism leads to sedation and hypotension. Hi=histamine receptors: antagonism is associated with sedation. 5-HT2a and 5-HT2c=subtypes of serotonin receptors: antagonism has antipsychotic effects. M=muscarinic cholinergic receptors: antagonism is responsible for sedation and other anticholinergic effects (xerostomia, constipation, cognitive failure, and delirium). *Data on receptor selectivity of levomepromazine are older, but show its binding capacity to 5-HT2, H1, alpha 1, and alpha 2 receptors. †Originally studied as a neuroleptic, promethazine is, as shown, mainly an antihistamine agent.
Table 3: Most important receptor activities blocked by neuroleptic drugs
Newer neuroleptics used in elderly patients to treat aggressive behaviour in those with dementia have been associated with an increased risk of cerebrovascular accidents and mortality. Whether this risk should limit their use in the general and younger populations with delirium is unknown and questionable.45 All typical antipsychotic drugs, especially those with low potency (ie, chlorpromazine and thioridazine) and some atypical antipsychotic drugs (ie, olanzapine and clozapine) have quinidine-like effects, and can induce prolongation of the QT interval and cardiac arrhythmia. A baseline cardiogram is required by guidelines and by national regulatory agency recommendations.45 When a substantial prolongation of the QT interval is noted (ie, >450 ms or a 25% increase compared with previous ECG), antipsychotic discontinuation should be considered. Commonly used 169
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antipsychotics can lower the seizure threshold, but this is seen more often with low-potency drugs (see above) than with haloperidol.63 Most neuroleptic drugs have some anticholinergic effects (table 3) and can themselves cause delirium.
Non-neuroleptic sedating drugs In the cases of agitated delirium refractory to neuroleptic therapy, it is common clinical practice to add a non-neuroleptic sedative drug to control agitation, hallucinations, and dangerous behaviour. Benzodiazepines can be used for this purpose, with lorazepam considered as the first choice.50 Lorazepam can be given in doses of 2 mg intravenously or intramuscularly, which can be repeated after a safe period of time (15–30 min after intravenous administration and 60 min after intramuscular administration) to obtain slight sedation. The use of higher doses requires monitoring and availability of airway patency equipment and expertise. In alcohol-withdrawal delirium, it is common to associate haloperidol with lorazepam in an attempt to reach tranquillisation without excessive sedation.46,51 The role of other drugs with sedative properties, such as antihistamines and alpha-2-adrenergic agonists, has not been assessed in delirium. Antihistamines are sedative drugs without respiratory depressant effects, and, although they have anticholinergic effects, their primary sedative activity (panel 3) can be important to improve night-time sleep. Promethazine proved efficacious to control agitated behaviour in patients treated with high-dose (5–10 mg) injections of haloperidol.53 The alpha-2-adrenergic agonists, clonidine and dexmedetomidine, are used for their central sedative activity, produced via inhibition of the activation of the cortex by noradrenergic projections (panel 3) in patients in intensive care. Additionally, these drugs are devoid of respiratory depressant effects.64 The role of these drugs in the management of patients with delirium and, in particular, of patients with delirium that is refractory to first-line treatments with neuroleptics and benzodiazepines, needs to be specifically addressed. An absence of response to standard treatments should trigger referral to liason psychiatry or palliative care.
Night-time control of sleep The attempt to normalise night-time sleep is a specific and often challenging task in cases of hyperactive or mixed deliria. Night-time sleep is disturbed in most patients with delirium, and agitation with disruptive behaviour can occur at night, complicating insomnia. If use of haloperidol is not enough to calm the patient, substitution with quetiapine or the addition of promethazine are choices that we have found useful. The role of benzodiazepines is questionable. If the sedation obtained with benzodiazepines is not deep and continuous enough, the risk of worsening the delirium is substantial. 170
Sedation for refractory delirium When delirium occurs in the setting of advanced cancer, it is an independent prognostic sign of a shortened life expectancy.10,65 When aetiological and more conservative drug management fail, delirium is one of the most frequent indications for sedation as a strategy to control symptoms and distress at the end of life.66 This type of sedation should not be the result of therapeutic nihilism. In fact, 50% of delirium episodes occurring in patients with advanced cancer are still reversible.9 However, it should be a deliberate choice at the end of a rational decisional process.66–69 Guidelines for treatment are the same as for other cases of delirium, and haloperidol should be considered the first choice in combination with benzodiazepines or a more sedating neuroleptic, such as methotrimeprazine, or antihistamines, such as promethazine. Among benzodiazepines, midazolam is often preferred at the end of life for its good subcutaneous absorption.67 The scope of sedation is symptom control, therefore it should be achieved with the minimally effective doses and monitored in depth to provide comfort. It is possible to induce and maintain sedation in this setting without shortening life and with very low risks of respiratory depression.66,67 The practice of sedation at the end of life should therefore be clearly distinguished from the practice of euthanasia.70 However, a multidisciplinary team approach with the contribution of specific palliativecare expertise is to be strongly encouraged.69
Effect of delirium on family and care-givers Delirium is regarded by family and care-givers as a difficult experience to witness.71 In one study, high levels of distress were reported by spouses and by the nurses caring for patients with delirium.72 In a multicentre Japanese study, 50% of family members reported being emotionally distressed about the experience of terminal delirium.73,74 The same researchers also identified some aspects of care that were perceived as important in this situation by family members, including: respect for the patient’s subjective perceptions and experiences; coordination of care to enhance communication; and improving communication to explain the reasons for delirium and its course. The presence of a care-giver with the patient was associated with lower family emotional distress, emphasising one of the oldest palliative-care tenets: “to be there”. The relatives of patients with cancer who perceived the patient as being delirious developed persistently higher anxiety levels than relatives of patients with cancer without delirium, independently of other disease-related factors.75
Conclusion Delirium is a demanding clinical condition that complicates the history of patients with cancer. Strategies for early detection, prevention, and management are still insufficient. Careful diagnostic assessment and www.thelancet.com/oncology Vol 10 February 2009
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Search strategy and selection criteria Articles for this Review were identified by a search of Medline, Current Content, and Pubmed by use of the search terms “delirium”, “cancer”, and “delirium and neoplasm”, and by a hand search of major textbooks and three monographic books on delirium. References from identified articles were selected for relevance, with priority given to systematic reviews and meta-analyses. Only articles published in English between 1990, and 2008, were included, unless necessary to support specific statements.
13 14 15 16 17
18
19 20
appropriate care should be combined to meet the needs of patients with different clinical perspectives and disease burden. An interdisciplinary approach to the clinical management and research of delirium would enhance our understanding of a syndrome that covers many disciplines of medicine, including psychiatry, oncology, neurology, geriatrics, and palliative care. Elaborating on the experience of delirium occurring at the end of life, it is tempting to assume that a palliativecare approach and insight could be very helpful in generally managing patients with advanced cancer and specifically managing patients with cancer and delirium, as well as other patients affected by many other conditions characterised by heavy symptom burden and a limited prognosis.
21 22 23 24 25
26
27
28
Conflicts of interest The authors declared no conflicts of interest. References 1 Clouston PD, De Angelis L, Posner JB. The spectrum of neurological disease in patients with systemic cancer. Ann Neurol 1992; 31: 268–73. 2 Francis J, Martin D, Kapoor WN. A prospective study of delirium in hospitalized elderly. JAMA 1990; 263: 1097–101. 3 Levkoff SE, Evans DA, Lipzin B, et al. Delirium. The occurrence and persistence of symptoms among elderly hospitalized patients. Arch Intern Med 1992; 152: 334–40. 4 Inouye SK, Viscoli CM, Horwitz RI, Hurst LD, Tinetti ME. A predictive model for delirium in hospitalized elderly medical patients based on admission characteristics. Ann Intern Med 1993; 119: 474–81. 5 Inouye SK, Charpentier PA. Precipitating factors for delirium in hospitalized elderly persons. Predictive model and interrelationship with baseline vulnerability. JAMA 1996; 275: 852–57. 6 Ljubisavjevic V, Kelly B. Risk factors for development of delirium among oncology patients. Gen Hosp Psychiatry 2003; 25: 345–52. 7 Gaudreau J, Gagnon P, Roy M, Tremblay A. Psychoactive medications and risk of delirium in hospitalized cancer patients. J Clin Oncol 2005; 23: 6712–18. 8 Minagawa H, Yosuke U, Yamawaki S, Ishitani K. Psychiatric morbidity in terminally ill cancer patients. Cancer 1996; 78: 1131–37. 9 Lawlor PG, Gagnon B, Mancini IL, et al. Occurrence, causes and outcome of delirium in patients with advanced cancer. Arch Intern Med 2000; 160: 786–94. 10 Caraceni A, Nanni O, Maltoni M, et al. The impact of delirium on the short-term prognosis of advanced cancer patients. Cancer 2000; 89: 1145–48. 11 Massie MJ, Holland JC, Glass E. Delirium in terminally ill cancer patients. Am J Psychiatry 1983; 140: 1048–50. 12 American Psychiatric Association. Diagnostic and statistical manual of mental disorders, fourth edition. Text revision. DSM IV–TR. Washington: American Psychiatric Press, 2000.
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Weitzener MA, Olofson SM, Forman AD. Patients with malignant meningitis presenting with neuropsychiatric manifestations. Cancer 1995; 76: 1804–08. Gagnon PR. Treatment of delirium in supportive and palliative care. Curr Opin Support Palliat Care 2008; 2: 60–66. American Psychiatric Association. Practice guidelines for the treatment of patients with delirium. Am J Psychiatry 1999; 156 (5 suppl): 1–20. Casarett D, Inouye S. Diagnosis and management of delirium near the end of life. Ann Intern Med 2001; 135: 32–42. Canadian Coalition for Seniors’ Mental Health. National guidelines for seniors’ mental health: the assessment and treatment of delirium. http://www.ccsmh.ca/en/guidelinesusers.cfm (accessed Nov 3, 2008). Lonergan E, Britton A, Wyller T. Antipsychotics for delirium. Cochrane Database of Syst Rev 2007; 2: CD005594. Seitz D, Gill S, van Zyl L. Antipsychotics in the treatment of delirium: a systematic review. J Clin Psychiatry 2007; 68: 11–21. Lacasse H, Perreault M, Williamson D. Systematic review of antipsychotics for the treatment of hospital-associated delirium in medically or surgically ill patients. Ann Pharmacother 2006; 40: 1966–73. Jackson K, Lipman A. Drug therapy for delirium in terminally ill patients. Cochrane Database of Syst Rev 2004; 2: CD004770. Mayo-Smith MF, Beecher L, Fischer T, et al. Management of alcohol withdrawal delirium. An evidence-based practice guideline. Arch Intern Med 2004; 164: 1405–12. Pandharipande P, Shintay A, Peterson J, et al. Lorazepam is an independent risk factor for transitioning to delirium in intensive care patients. Anesthesiology 2006; 104: 21–26. Breitbart W, Marotta R, Platt MM, Weisman H, Derevenco M, Grau C. A double-blind trial of haloperidol, chlorpromazine and lorazepam in the treatment of delirium in hospitalized AIDS patients. Am J Psychiatry 1996; 153: 231–37. Huf G, Coutinho E, Adams C, for the TREC Collaborative Group. Rapid tranquillisation in psychiatric emergency settings in Brazil: pragmatic randomized controlled trial of intramuscular haloperidol versus intramuscular haloperidol plus promathazine. BMJ 2007; 335: 869–72. Akechi T, Uchitomi Y, Okamura H, et al. Usage of haloperidol for delirium in cancer patients. Support Care Cancer 1996; 4: 390–92. Olofson SM, Weitzener MA, Valentine AD, Baile WF, Meyers CA. A retrospective study of the psychiatric management and outcome of delirium in the cancer patient. Support Care Cancer 1996; 4: 351–57. Stiefel F, Fainsinger R, Bruera E. Acute confusional states in patients with advanced cancer. J Pain Symptom Manage 1992; 7: 94–98. Breitbart W, Tremblay A, Gibson C. An open trial of olanzapine for the treatment of delirium in hospitalized cancer patients. Psychosomatics 2002; 43: 175–82. Schwartz TL, Masand P. Treatment of delirium with quetiapine. Prim Care Companion J Clin Psychiatry 2000; 2: 10–12.
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Sasaki Y, Matsuyama T, Inoue S, et al. A prospective, open label, flexible-dose study of quetiapine in the treatment of delirium. J Clin Psychiatry 2003; 64: 1316–21. Oliver OJ. The use of methotrimeprazine in terminal care. Br J Clin Pract 1985; 39: 339–40. Green B, Pettit T, Faith L, Seaton K. Focus on levomepromazine. Curr Med Res Opin 2004; 20: 1877–81. Preskorn SH. Classification of neuropsychiatric medications by principal mechanism of action: a meaningful way to anticipate pharmacodynamically mediated drug interactions. J Psychiatr Pract 2003; 9: 376–84. Alldredge B. Seizures risk associated with psychotropic drugs: clinical and pharmacokinetic considerations. Neurology 1999; 53 (suppl 2): S68–75. Mirski M, Hemstreet M. Critical care sedation for neuroscience patients. J Neurol Sci 2007; 261: 16–34. Viganò A, Dorgan M, Buckingham J, Bruera E, Suarez-Almazor ME. Survival prediction in terminal cancer patients: a systematic review of the literature. Palliat Med 2001; 11: 363–74. Sykes N, Thorns A. The use of opioids and sedatives at the end of life. Lancet Oncol 2003; 4: 312–18. Morita T, Chinone Y, Ikenaga M, et al. Efficacy and safety of palliative sedation therapy: a multicenter, prospective, observational study conducted on specialized palliative care units in Japan. J Pain Symptom Manage 2005; 30: 320–28. Morita T, Chinone Y, Ikenaga M, et al. Ethical validity of palliative sedation therapy: a multicenter, prospective, observational study conducted on specialized palliative care units in Japan. J Pain Symptom Manage 2005; 30: 308–19. De Graef A, Dean M. Palliative sedation in the last weeks of life: a literature review and recommednation for standards. J Palliat Med 2007; 10: 67–85. Matersvedt LJ, Clark D, Ellershaw J, et al. Euthanasia and physicianassisted suicide: a view from an EAPC ethics task force. Palliat Med 2003; 17: 97–101. Brajtman S. The impact on the family of terminal restlessness and its management. Palliat Med 2003; 17: 454–60. Breitbart W, Gibson C, Tremblay A. The delirium experience: delirium recall and delirium-related distress in hospitalized patients with cancer, their spouse/caregivers and nurses. Psychosomatics 2002; 43: 183–94. Morita T, Akechi T, Ikenaga M, et al. Terminal delirium: recommendations from bereaved families. J Pain Symptom Manage 2007; 34: 579–89. Morita T, Hirai K, Sakaguchi Y, Tsuneto S, Shima Y. Familyperceived distress from delirium-related symptoms of terminally ill cancer patients. Psychosomatics 2004; 45: 2107–13. Buss M, Vaderwerker L, Inouye SK, Zhang B, Block S, Prigeson H. Association between caregiver-perceived delirium in patients with cancer and generalized anxiety in their caregivers. J Palliat Med 2007; 10: 1083–92.
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Palliating delirium in patients with cancer Augusto Caraceni, Fabio Simonetti Lancet Oncol 2009; 10: 164–72 Palliative Care (Pain Therapy, Rehabilitation), Fondazione IRCCS, National Cancer Institute, Milan, Italy (A Caraceni MD, F Simonetti MD) Correspondence to: Dr Augusto Caraceni, Palliative Care (Pain Therapy, Rehabilitation), National Cancer Institute, 20133 Milan, Italy augusto.caraceni@ istitutotumori.mi.it
Delirium is a frequent complication in oncology. Its definition as a disorder of consciousness, attention, and cognition is useful to elaborate a rational framework of its pathophysiology and to interpret the role of different aetiological factors and therapeutic interventions. Many aetiologies and an interaction between risk and predisposing factors have been shown to contribute to most cases of delirium. A screening of potential aetiologies is always mandatory to benefit reversible cases. The palliative treatment of symptoms of delirium includes non-pharmacological, environmental, and preventive interventions and the use of haloperidol. If haloperidol fails to control delirium, sedation with other drugs can be necessary. Specific attention to the qualitative aspects of care and to the effect of delirium on family members should be given in the overall assessment of the patient in his or her cancer trajectory.
Introduction Delirium (figure 1) is one of the most common neurological complications seen in hospitalised patients with cancer.1 Its frequency in oncology compared with other medically ill populations is shown in table 1,2–11 which highlights how elderly individuals and patients with advanced or terminal cancer are especially at risk from this complication. The probability of developing delirium is determined by the combined effect of predisposing or vulnerability factors, such as previous cognitive failure or dementia and age,4,12 incident factors, such as drug toxicity and metabolic abnormalities, and other conditions that are more often associated with the severity of the underlying illness (figure 1). Delirium in cancer can be a challenging diagnosis, because it can be a reversible complication, it can herald the progression of the disease to the brain, and it can be irreversible as part of the terminal evolution of an incurable disease. The aims of this Review are to clarify the definition of delirium, assess the pathophysiological aspects useful for its understanding and rational therapeutic strategy, and investigate specific aspects of its aetiology and management in patients with cancer. The comprehensive description of specific conditions, such as postoperative delirium and alcohol withdrawal syndrome, is not within the scope of this Review.
Definition and clinical findings Diagnostic definition of delirium Delirium is a brain syndrome only rarely associated with a specific brain lesion. The Diagnostic and Statistical Manual of Mental Disorders IV—Treatment Revision (panel 1) established the most commonly used diagnostic definition of delirium,12 which highlights a few core concepts—delirium is a disorder of consciousness and attention combined with abnormalities of cognition and perception. Delirium is an acute syndrome as opposed to dementia, and an organic cause affecting the brain is usually identified or likely.
Consciousness and attention A definition of consciousness can be addressed from a semantic, philosophical, and neurophysiological perspective.13–15 In clinical practice, it is useful to assess the 164
level of consciousness and the content of consciousness— ie, the brain functions that allow an individual to be awake and aware of self and of the environment. The level of consciousness is behaviourally equivalent to the degree of wakefulness, often described, in neurological language, as the level of brain arousal.13,15 The normal degree of wakefulness varies from asleep to awake, and has been described as the degree of sensory stimulation needed to keep the patient awake and vigilant.15 The content of consciousness and cognition can be assessed only if at least a certain degree of wakefulness and alertness are preserved. Patients with delirium can be defined as hypoalert or hyperalert (hypovigilant and hypervigilant can be used synonymously).15 The level of consciousness and awareness can be affected separately or concurrently in different brain disorders. In the vegetative states, awareness can be lost, whereas control of the level of consciousness is preserved. In delirium, the level of both consciousness and awareness are abnormal. In coma, awareness is absent because the patient cannot be woken. The function of the brain that focuses mental activity on internal or external stimuli, making it possible to concentrate on these stimuli and to shift from one to another, is attention. Attention has been defined as “the sentry at the gate of consciousness”.13,16 If the level of consciousness and attention are abnormal, changes in perception of internal and external stimuli can occur, thereby compromising awareness. Attention abnorIncident factors: Toxic Metabolic Brain lesion
Delirium
Predisposing factors: Age Dementia
Figure 1: Schematic of delirium pathophysiology
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Population (age in years Prevalence at Incidence or medical category) admission, % during admission, %
Panel 1: DSM IV criteria for diagnosing delirium due to a general medical condition12
Francis2
16·0
16·0
≥70
Levfkoff3
10·5
31·3
≥65
Inouye4
NA
25·0
≥70
Inouye5
NA
18·0
≥70
Ljubisavjevic6 NA
18·0
Medical oncology
Gaudreau7
NA
16·5
Medical oncology
A Disturbance of consciousness (ie, reduced clarity of awareness of the evironment) with reduced ability to focus, sustain, and shift attention B A change in cognition (ie, memory deficit, disorientation, and language disturbances) or perception disturbances not better explained 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 history, physical examination, or laboratory findings that the disturbance is caused by the direct physiological consequences of a general medical condition
Minagawa8
28·0
NA
Hospice
Lawlor9
42·0
45·0
Hospital palliative-care unit
Caraceni10
28·0
NA
Palliative-care programme including homecare
Massie11
NA
85·0
Patients dying from cancer
NA=not available.
Table 1: Prevalence of delirium at admission and incidence of delirium during admission in hospital—comparison of the elderly medically ill population with patients undergoing palliative care or with cancer
malities are core symptoms in delirium, and they can be identified by distractibility and perseveration. Attention can be formally tested by simple bedside mental-status assessment tools.7,17,18
Cognitive and psychotic symptoms Cognitive failure is another essential feature of delirium. Some of the cognitive symptoms that occur in delirium depend on the effect of altered consciousness and attention on cognitive performances (ie, memory recall, orientation, calculations, writing, drawing, and language),16 as a study has shown.18 This study also showed that psychotic symptoms, such as hallucinations and delusions, are found less frequently than cognitive symptoms, (out of 100 patients, 50 had hallucinations and 31 had delusions), and are not correlated with the impairment of attention and cognition.18
Other symptoms Other important symptoms are often associated with impairment of consciousness, cognitive failure, and psychotic symptoms. These symptoms include disorders of the sleep–wakefulness cycle, vivid dreams, abnormal thought, motor abnormalities (ie, hypoactivity or hyperactivity), and mood changes (panel 2). From a behavioural point of view, delirium can be classified as hypoactive, hyperactive (ie, associated with the hypovigilant or hypervigilant level of consciousness), or mixed.19,20 Patients with hypoactive delirium are often misdiagnosed, or receive late diagnoses, due to the belief that hyperactivity alone is the hallmark of delirium.21
Pathophysiology and aetiology The pathophysiology of delirium remains to be fully elucidated, but the reticular formation of the brainstem, with its connection with the hypothalamus, thalamus, www.thelancet.com/oncology Vol 10 February 2009
DSM IV=Diagnostic and Statistical Manual of Mental Disorders, fourth edition. Reprinted with permission from reference 12.
Panel 2: Symptoms and signs of delirium Altered level of consciousness=level of wakefulness or arousal • Hyperalert (hypervigilant) in the hyperactive deliria • Hypoalert (hypovigilant) in the hypoactive deliria • Transitions from one state to another on a continuum from awake and hypervigilant to somnolent or drowsy with fluctuations also in the short time period are frequent in the mixed hyper-hypoactive deliria Impaired attention Altered sleep–wakefulness cycle regulation Motor changes (hyperactivity or hypoactivity) Affective changes Hallucinations Delusions Cognitive performance failure at formal testing • Orientation • Memory • Visual spatial abilities • Calculation • Writing • Reading Involuntary movements • Asterixis • Myoclonus
and diffuse effects on the cortex—regulating normal wakefulness and sleep—is thought to have a significant role. The neurotransmitters and receptors that are important for wakefulness and consciousness functions, 165
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Panel 3: Brain centres and neurotransmitters active in maintaining and modulating normal wakefulness and level of consciousness—pathophysiological role in delirium, possible pharmacological interventions, and toxicity Acetylcholine • Promotes wakefulness and cognition • Inhibition by drugs produces sedation, cognitive impairment, and delirium (eg, atropine, opioids, and tricyclic antidepressants) • A major role of cholinergic pathways dysfunction is likely in many cases of delirium Dopamine • Promotes wakefulness • Hyperactivation can be responsible for delusion, hallucinations, and psychomotor agitation in delirium • Neuroleptics (haloperidol) are used in delirium, mainly for their inhibitory activity on these receptors to obtain tranquillisation without sedation Norepinephine • Promotes wakefulness • Hyperactivation can be important for agitated deliria, especially in alcohol and other substance withdrawal • Alpha 2 adrenergic agents (eg, clonidine) can inhibit this pathway, are useful in sedation, and can be used in hyperactive delirium, such as delirium tremens due to alcohol withdrawal Serotonin • Modulates sleep–wakefulness cycle • Excessive serotonergic activity is associated with delirium (serotonergic syndrome) • Delirium can be caused by serotonergic drugs, such as many antidepressants, some antiemetics, and analgesics • New-generation neuroleptics have setotonin inhibitory effects on subsets of serotonin receptors Histamine • Promotes wakefulness, inhibition causes sedation • Antihistamine drugs are sedative (eg, promethazine) Orexin (hypocretin) • Promotes wakefulness and attention in cooperation with the histaminergic and cholinergic systems • In cases of excessive sedation due to drug toxicity or other factors, drugs acting on orexin receptors (modafinil) can improve arousal and vigilance Gamma-aminobutyric acid • The final common pathway of all sleep-promoting neurotransmitters • Sedative effects of benzodiazepines, barbiturates, and general anaesthetics are all mediated by GABA receptors • Level of consciousness is reduced and risk of developing delirium is increased electively by benzodiazepines
and for toxic and pharmacological effects, are listed in panel 3.15,22–24 Among the neurotransmitters, a central role in the pathogenesis of delirium has been advocated for acetylcholine. All drugs or toxic effects that affect CNS cholinergic neurons are candidates for causing delirium. This theory would also explain the higher risk of developing delirium in patients with dementia and with cognitive decline due to brain ageing, who already have an impaired cholinergic system.22,23,25 166
Multiple risk factors As anticipated, the most relevant risk factors for developing delirium are age and dementia (table 2). Elderly patients with delirium, present with this condition in response to relatively mild incident factors that exert an anticholinergic effect.5,23,25 Indeed, empirical evidence shows that many aetiologies are often implied,1,9 and a multiple-factor model explains the risk of developing delirium in elderly patients, as confirmed also by the efficacy of risk-modifying interventions in preventing its onset.26,27 This means that the classic cause–effect mechanistic approach might fail to explain many cases of delirium.19,23
Patient assessment Assessment of cognitive functions A formal assessment of cognitive function is needed in patients who develop acute mental status changes and would be desirable in routine monitoring of patients who are at an especially high risk of developing delirium. Although there are a plethora of assessment instruments that are potentially useful,24 the most interesting and practically useful are restricted to a few. The Mini-mental State Exam is sensitive to changes in cognition and includes items that explore temporal orientation and other performances sensitive to changes in the level of consciousness and attention.28 It is not specific for delirium and cannot be used to differentiate delirium from dementia. The Delirium Rating Scale29 and the Memorial Delirium Assessment Scale30 are both specific for delirium, but not specifically designed to diagnose delirium. The Confusion Assessment Method, however, is a diagnostic algorithm that is both sensitive (94%) and specific (89%) for the diagnosis of delirium, but only when applied by specialists.31 The Nursing Delirium Screening Scale is a new and promising screening method with reasonable sensitivity (86%) and specificity (87%) in the hands of nurses, and we would advocate studies to test its potential as a routine method for the assessment of populations at risk.32
Differential diagnosis Dementia can be difficult to differentiate from delirium. In delirium, cognitive failure occurs acutely and in association with a disturbance of consciousness. In dementia, cognitive failure is slow and progressive, and it occurs, until terminal stage, without changes in the level of consciousness. When delirium is superimposed on a pre-existing dementia, the diagnosis is especially difficult.33 The increasing number of elderly patients attending oncology clinics will continue to pose these difficult dilemmas.34 The two main differential diagnoses of acute changes in level of consciousness and cognition in patients with cancer, not due to delirium, are seizures and acute psychoses. When seizures occur without or with minor motor activities (ie, convulsions), such as in non-convulsive status epilepticus, the clinical presentation www.thelancet.com/oncology Vol 10 February 2009
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Advanced age
Patients with cancer
General medical population
Postsurgical patients
+
+
+ +
Previously impaired cognition
+
+
Severity of illness
+
+
Benzodiazepines
+
+
Functional impairment
+
+
Metabolic abnormalities
+
+
Low albumin
+
Bone metastases
+
Liver metastases
+
Haematological malignancies
+
History of delirium
+
Metastases to brain or meninges
+
Opiods (dose related)
+
Corticosteroids (dose related)
+
Visual or hearing impairment
+
Infection
+
Alcohol abuse
+
Type of surgery (cardiac thoracic surgery bears a higher risk).
Table 2: Factors associated with the risk of developing delirium according to multivariate analysis in at least one study2–7,23,24
will mimic delirium.35 The diagnosis in patients with primary psychiatric disease can also be challenging when symptoms are acute and mainly involve communication and behaviour, such as in catatonia.36 The possibility of acute psychosis should not be disregarded in young patients with a severe affective impact of their disease and a history of psychological morbidity.
Aetiological assessment The most common aetiologies should always be reviewed (panel 4). Many aetiological factors are usually present, and their respective roles are difficult to differentiate. In patients with cancer, it is also important to exclude spread of the disease to the brain or the meninges; in a series of 140 consecutive patients, a structural brain lesion was the sole cause of delirium in 15% of patients, and had a contributory role in 36%.37 We treated a male patient with rhinopharyngeal carcinoma and bone metastases, who was undergoing chemotherapy while on an opioid regimen for bone pain (100 μg/h transdermal fentanyl administration). Due to slight changes in his behaviour, a brain MRI was requested and was negative. The patient was admitted and given intravenous morphine titrated up to 400 mg/24 h for pain control, without significant side-effects. A few days later he developed pneumonia with a high fever (up to 40°C) and acute delirium (ie, severe disorientation, delusions, hallucinations, and psychomotor agitation), which required intravenous infusion of haloperidol (12 mg/day) and lorazepam www.thelancet.com/oncology Vol 10 February 2009
Panel 4: Causes of delirium in patients with cancer • Drug toxicity • Non-metastatic complications of cancer • Metabolic encephalopathy due to hepatic, renal, or pulmonary failure • Infections • Electrolyte abnormalities • Glucose abnormalities • Haematological abnormalities • Paraneoplastic neurological syndromes (rare) • Toxic effects of antineoplastic therapies • Chemotherapy • Biological therapy (monoclonal antibodies) • Radiation to brain • Nutritional deficiency (including thiamine, folic acid, vitamin B12 deficiency) • CNS tumour, brain metastases, meningeal metastases • Other diseases/conditions not related to cancer • CNS diseases (including cerebrovascular disease, infection, vasculitis, or trauma) • Cardiac disease • Lung disease • Endocrinopathy • Alcohol or drug withdrawal (benzodiazepine and nicotine most common)
(12 mg/day). Examination of the cerebrospinal fluid was negative for malignant cells. Antibiotics were also given, and after a few days the fever remitted and the pneumonia improved, with full recovery of the acute symptoms of delirium and persistent fluctuating disorientation to space and time. Lorazepam and haloperidol were discontinued. An MRI taken after this episode showed diffused dural enhancement due to meningeal neoplastic infiltration not visible in the MRI obtained a month before (figure 2). This case highlights the difficulty in assessing the aetiological role of one of many factors that present at the same time—ie, meningeal disease, high-dose opioids, and sepsis. Other more rare examples of aetiological factors that are typical of cancer include: CNS lesions associated with paraneoplastic disease;38 infection (figure 3);39 toxic leucoencephalopathy;40 and meningeal or brain metastases causing delirium as the only sign of CNS involvement (figure 4).37,41
Treatment and management Non-pharmacological interventions Screening potentially reversible aetiological factors is a mandatory initial step in all cases of delirium. Even in the advanced phase of cancer, 50% of delirium episodes are reversible, especially when associated with drug toxicity.9 It is important to remember that providing safety, companionship, orientation, a quiet environment, emotional support to both the patient and the care-givers, 167
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Figure 2: Meningeal metastases and multiple aetiologies in delirium A patient with rhynopharingeal carcinoma, bone metastases, and pneumonia, who was receiving high-dose intravenous morphine infusion, developed delirium. MRI, done after recovery of pneumonia and delirium, shows meningeal enhancement in the more central and cranial part of the dura mater layers (arrow).
and a caring relationship can avoid pharmacological and eventually physical restraint in many patients with mild to moderate symptoms, and will probably improve the outcome of therapy in all cases.42–45
Prevention Evidence supports the role of multidisciplinary interventions in decreasing the risk of developing delirium in hospitalised elderly patients, but this finding has not been confirmed in patients with cancer.26,42 It is likely that the risk factors identified in the elderly population are more homogeneous and amenable to modification than those affecting patients with cancer (table 2).
Pharmacological management Haloperidol The treatment of delirium lacks well-established, evidence-based guidelines. Most guidelines and specialists consider haloperidol, a high-potency antipsychotic, as the first-line treatment. This recommendation is, at best, partially supported by a few randomised controlled trials and by neuropharmacological rationale (panel 3), but no placebo-controlled clinical trial is available.46–49 Benzodiazepines have a primary role, alone, or in combination with other drugs, such as haloperidol and clonidine, only in alcohol-withdrawal delirium.45,50 In all other cases, unless 168
Figure 3: Limbic encephalitis presenting as delirium in a patient who underwent bone-marrow transplant for non-Hodgkin lymphoma Coronal MRI shows high signal (white) bilaterally in the temporal lobes in the areas corresponding to the hypocampal uncus. The surrounding white matter shows oedema (arrows). The CSF examination confirmed diagnosis of herpes 6 virus encephalitis.
sedation is specifically desired, benzodiazepines should be avoided, because they increase the frequency and worsen the symptoms of delirium.7,51,52 The paucity of well-controlled clinical trials leaves the dosing recommendation of haloperidol to be based on clinical experience from case series. Guidelines45 suggest that in elderly patients, and in mild to moderately agitated deliria, haloperidol can be started at low doses—ie, 0·5 mg (orally) twice to three times a day—and then be titrated to obtain an effect. Such a dose will not suffice in more severe cases and in younger patients, as often seen in oncology. The most common emergency situation is due to hyperactive delirium with psychomotor agitation. In this condition, rapid tranquillisation is needed. Recommended parenteral doses are 1–2 mg in young patients and 0·25–0·5 mg in elderly patients (≥60 years), to be repeated after 1–2 h as needed until tranquillisation is achieved.19 Therapy can then be converted into an oral equivalent dose of 1·5 to two-times the parenteral dose. In young patients with no liver disease, acute intramuscular doses of 5–10 mg have been used to control aggressive dangerous behaviour due to different psychiatric diseases.19,53 With such doses, www.thelancet.com/oncology Vol 10 February 2009
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there is a definite, but low, risk of acute extrapyramidal side-effects, such as torticollis, oculogyric crisis, and tongue and laryngeal spasm, which must be treated with anticholinergic or antihistamine drugs.53 Akechi and co-workers54 used a 30-min interval titration protocol in patients with cancer, with doses given orally or parenterally according to feasibility (0·5 mg for three doses, 1 mg for three doses, 2 mg for three doses, and 5 mg for three doses). In this way, a maximum 25·5 mg dose could be reached in 6 h in patients with refractory disease. By applying this protocol to ten patients, the mean dose reached on the first day was 6 mg (SD 4; range 0·5–11) and in the whole follow-up period until recovery the mean dose reached was 5·4 mg (SD 3·4; 0·5–10·5). In another study55 of hyperactive delirium in 54 patients with cancer, low daily doses of haloperidol (mean 2·5 mg) were used in 61% of patients, intermediate doses (mean 15 mg) in 32%, and high doses (mean 30 mg) in 7%. These dosing examples confirm the need for titration. Haloperidol alone often fails to control agitation. Although insufficient titration cannot be ruled out, one case series of patients with advanced cancer reported that only 60% of patients could be managed with haloperidol alone. A combination with benzodiazepines or more sedative neuroleptics was considered necessary in the other patients.56
B
A
Figure 4: Meningeal metastases causing tetraventricular hydrocephalus Sagittal (A) and axial (B) brain MRI views showing tetraventricular hydrocephalus, a skull lesion (arrow), which invades the dura and is adjacent to the cortex and leptomeningeal covering, and a typical leptomeningeal lesion of the frontal lobe (arrowhead). The patient had a lung carcinoma and presented with delirium with disorientation of space and time, perseveration, and somnolence. Headache, meningismus, papilloedema, and focal signs were absent. CSF examination showed malignant cells. Reproduced with permission from Oxford University Press 2003.
Haloperidol
D1
D2
D4
Alpha 1
+
+++
++
+
5-HT2c
++
++ +++
+
+++
++
+
+++
+
++
+
+++
+
+
+
+
++
+
++
++
+
Promethazine† + +
Newer, atypical, antipsychotics (table 3) have also been assessed for the management of delirium. Doses of risperidone are usually low (around 1 mg/day), whereas olanzapine has been administered in doses ranging from 4·5–8·2 mg/day. Quetiapine was administered to a small number of patients at a mean daily dose of 25–75 mg.46,57–59 Risperidone can be initiated in elderly individuals at a dose of 0·25 mg twice a day, olanzapine at a dose of 1·25–2·5 mg/day, and quetiapine at a dose of 12·5–50 mg/day. These drugs were as effective as low-dose haloperidol in the available comparative studies.46 The older phenotiazine neuroleptics (promazine, levomepromazine, and chorpromazine) are seldom used in delirium for their anticholinergic effects. Levomepromazine (methotrimeprazine) is a phenotiazine with strong sedative properties, which is available in some countries also as a parenteral formulation. It is used to obtain sedation in the practice of palliative care at centres in the USA and UK, also via subcutaneous administration.60,61
Quetiapine
++
M
+
++
Olanzapine
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5-HT2a
Levomepromazine* Risperidone
Table 3 shows the action of different neuroleptic drugs on CNS receptors and their side-effects.61,62 A very rare, but life-threatening, side-effect of these drugs is the neuroleptic malignant syndrome manifested by catatonia, rigidity, and hyerpyrexia.
Hi 1
Chlorpromazine
Other neuroleptics
Side-effects of neuroleptics
Alpha 2
+++
++ **
**
++ ++ +++
D=dopamine receptors subtypes: antagonism has antipsychotic effects and extrapyramidal side-effects. Alpha 1=type 1 adrenergic receptors: antagonism leads to orthostatic hypotension. Alpha 2=type 2 adrenergic receptors: antagonism leads to sedation and hypotension. Hi=histamine receptors: antagonism is associated with sedation. 5-HT2a and 5-HT2c=subtypes of serotonin receptors: antagonism has antipsychotic effects. M=muscarinic cholinergic receptors: antagonism is responsible for sedation and other anticholinergic effects (xerostomia, constipation, cognitive failure, and delirium). *Data on receptor selectivity of levomepromazine are older, but show its binding capacity to 5-HT2, H1, alpha 1, and alpha 2 receptors. †Originally studied as a neuroleptic, promethazine is, as shown, mainly an antihistamine agent.
Table 3: Most important receptor activities blocked by neuroleptic drugs
Newer neuroleptics used in elderly patients to treat aggressive behaviour in those with dementia have been associated with an increased risk of cerebrovascular accidents and mortality. Whether this risk should limit their use in the general and younger populations with delirium is unknown and questionable.45 All typical antipsychotic drugs, especially those with low potency (ie, chlorpromazine and thioridazine) and some atypical antipsychotic drugs (ie, olanzapine and clozapine) have quinidine-like effects, and can induce prolongation of the QT interval and cardiac arrhythmia. A baseline cardiogram is required by guidelines and by national regulatory agency recommendations.45 When a substantial prolongation of the QT interval is noted (ie, >450 ms or a 25% increase compared with previous ECG), antipsychotic discontinuation should be considered. Commonly used 169
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antipsychotics can lower the seizure threshold, but this is seen more often with low-potency drugs (see above) than with haloperidol.63 Most neuroleptic drugs have some anticholinergic effects (table 3) and can themselves cause delirium.
Non-neuroleptic sedating drugs In the cases of agitated delirium refractory to neuroleptic therapy, it is common clinical practice to add a non-neuroleptic sedative drug to control agitation, hallucinations, and dangerous behaviour. Benzodiazepines can be used for this purpose, with lorazepam considered as the first choice.50 Lorazepam can be given in doses of 2 mg intravenously or intramuscularly, which can be repeated after a safe period of time (15–30 min after intravenous administration and 60 min after intramuscular administration) to obtain slight sedation. The use of higher doses requires monitoring and availability of airway patency equipment and expertise. In alcohol-withdrawal delirium, it is common to associate haloperidol with lorazepam in an attempt to reach tranquillisation without excessive sedation.46,51 The role of other drugs with sedative properties, such as antihistamines and alpha-2-adrenergic agonists, has not been assessed in delirium. Antihistamines are sedative drugs without respiratory depressant effects, and, although they have anticholinergic effects, their primary sedative activity (panel 3) can be important to improve night-time sleep. Promethazine proved efficacious to control agitated behaviour in patients treated with high-dose (5–10 mg) injections of haloperidol.53 The alpha-2-adrenergic agonists, clonidine and dexmedetomidine, are used for their central sedative activity, produced via inhibition of the activation of the cortex by noradrenergic projections (panel 3) in patients in intensive care. Additionally, these drugs are devoid of respiratory depressant effects.64 The role of these drugs in the management of patients with delirium and, in particular, of patients with delirium that is refractory to first-line treatments with neuroleptics and benzodiazepines, needs to be specifically addressed. An absence of response to standard treatments should trigger referral to liason psychiatry or palliative care.
Night-time control of sleep The attempt to normalise night-time sleep is a specific and often challenging task in cases of hyperactive or mixed deliria. Night-time sleep is disturbed in most patients with delirium, and agitation with disruptive behaviour can occur at night, complicating insomnia. If use of haloperidol is not enough to calm the patient, substitution with quetiapine or the addition of promethazine are choices that we have found useful. The role of benzodiazepines is questionable. If the sedation obtained with benzodiazepines is not deep and continuous enough, the risk of worsening the delirium is substantial. 170
Sedation for refractory delirium When delirium occurs in the setting of advanced cancer, it is an independent prognostic sign of a shortened life expectancy.10,65 When aetiological and more conservative drug management fail, delirium is one of the most frequent indications for sedation as a strategy to control symptoms and distress at the end of life.66 This type of sedation should not be the result of therapeutic nihilism. In fact, 50% of delirium episodes occurring in patients with advanced cancer are still reversible.9 However, it should be a deliberate choice at the end of a rational decisional process.66–69 Guidelines for treatment are the same as for other cases of delirium, and haloperidol should be considered the first choice in combination with benzodiazepines or a more sedating neuroleptic, such as methotrimeprazine, or antihistamines, such as promethazine. Among benzodiazepines, midazolam is often preferred at the end of life for its good subcutaneous absorption.67 The scope of sedation is symptom control, therefore it should be achieved with the minimally effective doses and monitored in depth to provide comfort. It is possible to induce and maintain sedation in this setting without shortening life and with very low risks of respiratory depression.66,67 The practice of sedation at the end of life should therefore be clearly distinguished from the practice of euthanasia.70 However, a multidisciplinary team approach with the contribution of specific palliativecare expertise is to be strongly encouraged.69
Effect of delirium on family and care-givers Delirium is regarded by family and care-givers as a difficult experience to witness.71 In one study, high levels of distress were reported by spouses and by the nurses caring for patients with delirium.72 In a multicentre Japanese study, 50% of family members reported being emotionally distressed about the experience of terminal delirium.73,74 The same researchers also identified some aspects of care that were perceived as important in this situation by family members, including: respect for the patient’s subjective perceptions and experiences; coordination of care to enhance communication; and improving communication to explain the reasons for delirium and its course. The presence of a care-giver with the patient was associated with lower family emotional distress, emphasising one of the oldest palliative-care tenets: “to be there”. The relatives of patients with cancer who perceived the patient as being delirious developed persistently higher anxiety levels than relatives of patients with cancer without delirium, independently of other disease-related factors.75
Conclusion Delirium is a demanding clinical condition that complicates the history of patients with cancer. Strategies for early detection, prevention, and management are still insufficient. Careful diagnostic assessment and www.thelancet.com/oncology Vol 10 February 2009
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Search strategy and selection criteria Articles for this Review were identified by a search of Medline, Current Content, and Pubmed by use of the search terms “delirium”, “cancer”, and “delirium and neoplasm”, and by a hand search of major textbooks and three monographic books on delirium. References from identified articles were selected for relevance, with priority given to systematic reviews and meta-analyses. Only articles published in English between 1990, and 2008, were included, unless necessary to support specific statements.
13 14 15 16 17
18
19 20
appropriate care should be combined to meet the needs of patients with different clinical perspectives and disease burden. An interdisciplinary approach to the clinical management and research of delirium would enhance our understanding of a syndrome that covers many disciplines of medicine, including psychiatry, oncology, neurology, geriatrics, and palliative care. Elaborating on the experience of delirium occurring at the end of life, it is tempting to assume that a palliativecare approach and insight could be very helpful in generally managing patients with advanced cancer and specifically managing patients with cancer and delirium, as well as other patients affected by many other conditions characterised by heavy symptom burden and a limited prognosis.
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26
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