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Symptom Management and Supportive Care
The Assessment and Management of Delirium in Cancer Patients HIRLEY H. BUSH,a,b,c,d EDUARDO BRUERA
aDepartment of Palliative Care & Rehabilitation Medicine, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA; bMcCulloch House, Southern Health Care Network, Melbourne, Victoria, Australia; cFaculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia; dDivision of Palliative Care, University of Ottawa, Ottawa, Ontario, Canada Key Words. Delirium • Neoplasms • Palliative care • Diagnostic techniques and procedures • Antipsychotic agents
Shirley H. Bush: None; Eduardo Bruera: None.
Section editor Russell Portenoy has disclosed no financial relationships relevant to the content of this article.
The paper discusses s.c. administration of the parenteral preparation of olanzapine.
The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and freefrom commercial bias.
After completing this course, the reader will be able to: 1. Summarize the current evidence regarding strategies for the assessment and management of delirium in advanced 2. Outline the medications most commonly implicated for drug-induced delirium.
3. Compare the various pharmacological agents available for use in managing cancer-related delirium.
This article is available for continuing medical education credit at CME.TheOncologist.com.
Delirium remains the most common and distressing neu-
lirium, and the diagnosis and management of opioid-in-
ropsychiatric complication in patients with advanced can-
duced neurotoxicity. The early symptoms and signs of
cer. Delirium causes significant distress to patients and
delirium and the use of delirium-specific assessment tools
their families, and continues to be underdiagnosed and un-
for routine delirium screening and monitoring in clinical
dertreated. The most frequent, consistent, and, at the same
practice are summarized. Finally, management options
time, reversible etiology is drug-induced delirium result-
are reviewed, including pharmacological symptomatic
ing from opioids and other psychoactive medications. The
management and also the provision of counseling support
objective of this narrative review is to outline the causes of
to both patients and their families to minimize distress. The
delirium in advanced cancer, especially drug-induced de-
Correspondence: Shirley Bush, M.B.B.S., M.R.C.G.P., Division of Palliative Care, Bruyère Continuing Care, 43 Bruyère Street, Ottawa,Ontario, K1N 5C8, Canada. Telephone: 613-562-6262; Fax: 613-562-6371; e-mail: [email protected] Received June 18, 2009; ac- cepted for publication September 14, 2009; first published online in The Oncologist Express on October 6, 2009. AlphaMed Press
1083-7159/2009/$30.00/0 doi: 10.1634/theoncologist.2009-0122
The Oncologist 2009;14:1039 –1049 www.TheOncologist.com
Assessment and Management of Delirium in Cancer Patients lirium are more likely to receive psychotropic medications "Most delirious patients are considered either dull, stupid, and may have a better prognosis than patients with hypoac- ignorant, or uncooperative. It is only when their behaviour tive delirium . Hypoactive delirium may be more resis- and content of thought are grossly deviant that an abnormal tant to pharmacological treatment . The majority of mental state is recognised, although ids [sic] not always delirium episodes are either of the hypoactive or mixed sub- correctly identified as delirium" .
type [22, 23]. Lawlor et al. , in a prospective study, Despite the passage of time since Engel and Romano's de- found that delirium was mixed in 48 of 71 (68%) patients.
scription of delirium caused by global brain dysfunction in The hyperactive and mixed subtypes are highly associated their classic paper in 1959, delirium continues to be frequently with drug-induced delirium, whereas predominantly hypo- underdiagnosed or misdiagnosed by health care professionals active delirium is associated with dehydration and enceph- [2– 4] and continues to be inadequately treated .
Delirium remains the most common and devastating The differential diagnosis of delirium includes dementia neuropsychiatric complication in patients with advanced and depression, and other psychiatric disorders. In demen- cancer [2, 6], although a delirium episode is reversible in up tia, in contrast to delirium, there is little or no clouding of to 50% of cases [7, 8]. Delirium causes significant distress consciousness, and the onset is insidious. However, the to patients and their families [9, 10]. In a recent study of 99 symptoms of Lewy Body dementia (comprising cognitive patients with advanced cancer who had recovered from de- impairment, visual hallucinations, delusions, and parkin- lirium, 74% remembered their delirium episode . Pa- sonism) do fluctuate. Patients with dementia may also com- tients who recalled their delirium episode reported a monly present with a superimposed delirium. Hypoactive higher level of distress than patients with no recall .
delirium, with somnolence and withdrawal, may be mis- Delirium impairs patient communication, thus challeng- diagnosed as depression. Hyperactive delirium may be ing the assessment of pain and other symptoms . De- mistaken for manic and psychotic episodes, anxiety, or lirium also causes significant morbidity, increasing the akathisia. Increased expression of pain in an agitated pa- length of hospital stay and also increasing the risk for tient may be misinterpreted and inappropriately treated falls and associated sustained injuries [12, 13]. The de- as a pain syndrome, with the resulting increased opioid velopment of delirium prognosticates a greater likeli- administration exacerbating the delirium severity , hood of death .
rather than correctly identified as disinhibition because The purpose of this review is to update oncologists on of delirium.
the clinical assessment and management of this syndrome, with a focus on drug-induced delirium.
PATHOPHYSIOLOGY AND CAUSES
The cholinergic hypothesis describes a deficiency of ace-
DEFINITION AND PREVALENCE
tylcholine and an excess of dopamine as mediators for de- Delirium is defined as a disturbance of consciousness with lirium . Other neurotransmitter hypotheses postulate reduced ability to focus, sustain, or shift attention, with the role of glutamate, serotonin, cortisol, and endogenous changes in cognition or perceptual disturbances that occur opioid [3, 28, 29]. The role of cytokines is attracting recent over a short period of time and tend to fluctuate over the interest, especially interleukin (IL)-1, IL-6, and IL-8, and course of the day, with an organic etiology .
also interferon and tumor necrosis factor [30, 31]. It has Delirium is present in 26%– 44% of advanced cancer been suggested that IL-6 has a role in hyperactive delirium patients at the time of admission to an acute care hospital or . Transient thalamic dysfunction has been postulated as palliative care unit, and ⬎80% of patients with advanced a mechanism for drug-induced delirium . Future re- cancer develop delirium in the last hours and days before search may identify pathophysiological mechanisms spe- death [8, 16, 17].
cific for other delirium subtypes.
According to the level of psychomotor activity, three The organic etiology of delirium is usually multifacto- clinical delirium subtypes have been described: hyperac- rial, with a median of three (range, one to six) precipitants tive, hypoactive, and mixed (with alternating features of per delirium episode  (Fig. 1).
both hyperactive and hypoactive delirium) [18, 19]. How- On multivariate analysis, one small prospective study in ever, in many studies to date, the true nature of the psy- 145 oncology admissions found the following five risk fac- chomotor abnormality has been difficult to determine tors for the development of delirium: advanced age, cogni- because of its fluctuation (observed more in longitudinal tive impairment, low albumin, bone metastases, and studies) and also the potentially confounding effect of med- hematological malignancy . However, often a specific ications used to treat delirium. Patients with hyperactive de- cause remains unidentified. Predisposing factors increase a CANCER BYPRODUCTS,
anticholinergics, e.g., primary and corticosteroids, metastatic brain tumor, antidepressants, leptomeningeal disease, benzodiazepines, Electrolyte imbalance
Side effects of
Other medical conditions
e.g., withdrawal syndromes Organ failure
(alcohol, medication, nicotine), nutritional deficiencies, coagulopathy, anemia Infection
e.g., pneumonia, e.g., hypoglycemia, Figure 1. Factors contributing to delirium in cancer patients.
patient's baseline susceptibility for developing delirium.
Table 1. Medications that contribute to delirium [7, 25,
Examples are pre-existing cognitive impairment, such as dementia, and reduced sensory input because of poor vision or deafness.
antidepressants, selective serotonin The most commonly implicated medications are opioids reuptake inhibitors, neuroleptics,nonbenzodiazepine hypnotics (see section below on opioid-induced neurotoxicity), corti- costeroids, benzodiazepines, and anticholinergics [7, 25, Corticosteroids, antihistamines, H 35, 36] (Table 1). In addition to delirium, other features of blockers, antibiotics (quinolones), anticholinergic drug toxicity are mydriasis, hyperthermia, fever with no sweating, flushed appearance, dry skin, and certain antivirals urinary retention.
In a prospective cohort study in 261 cancer hospital in- patients, Gaudreau et al.  found that the risk for delir-ium doubled if the daily dose equivalent (DDE) of s.c.
agement of cancer pain, produces a high rate of neurotox- morphine was ⬎90 mg/day or if the DDE of lorazepam icity because approximately 60% of it is metabolized to was ⬎2 mg/day. A DDE ⬎15 mg/day of oral dexameth- normeperidine. Leipzig et al.  found that 77% of cancer asone led to a 2.7 higher risk for the development of de- patients receiving opioids had an impaired mental status.
lirium, but no association with anticholinergics was The features of OIN are severe sedation, hallucinations, found in that study .
cognitive impairment, delirium, myoclonus, seizures, hy- Opioid-induced neurotoxicity (OIN) is a syndrome of peralgesia, and allodynia. These symptoms can develop as a neuropsychiatric side effects seen with opioid therapy. Ta- single feature or in any combination and order. Hallucina- ble 2 outlines the risk factors for this syndrome. OIN can tions tend to be visual or tactile, with visual hallucinations occur with all known opioid agonists that are used in cancer occurring in almost half of hospice inpatients . Patients pain management, including morphine, hydromorphone, with a history of seizures, cerebral metastases, or metabolic oxycodone, fentanyl, and methadone [37, 38]. Meperidine, abnormalities may have a predisposition to developing an opioid analgesic that is not recommended for the man- tonic-clonic OIN-associated seizures. The oncologist must
Assessment and Management of Delirium in Cancer Patients (Small intestine mucosa) (Proximal renal tubule) NO binding to opioid • morphine ethereal ACTIVE metabolite (? ANTIANALGESIC) Cognitive impairment/ Neurotoxic properties (especially if high-dose morphine or prolonged RENAL EXCRETION – related to Creatinine Clearance Figure 2. Morphine metabolism [37, 41, 44]. aThe percentage breakdown of metabolites remains the same for all routes of ad-
Abbreviations: M-3-G, morphine-3-glucuronide; M-6-G, morphine-6-glucuronide.
remain vigilant because any patient prescribed opioids is at patients receiving high-dose or prolonged treatment with potential risk for developing OIN.
morphine. It is unknown to what extent morphine-6-gluc- Opioid-induced central nervous system (CNS) adverse uronide (M-6-G) contributes to OIN.
effects are related to the anticholinergic actions of opioids, Opioid neurotoxicity is also thought to involve endocy- with inhibition of central cholinergic activity in multiple tosis of opioid receptors and also activation of N-methyl- cortical and subcortical regions of the brain, in addition to D-aspartate receptors, where the neurotransmitter is an imbalance in CNS cholinergic and dopaminergic sys- glutamate . It has been suggested that inhibition of gly- tems . The accumulation of toxic opioid metabolites cine in dorsal horn neurons leads to myoclonus and hyper- has also been implicated (Fig. 2). Using the example of algesia . It has also been proposed that the neurotoxic morphine as the "gold standard" opioid, the major metabo- effect of opioids may occur via a nonopioid receptor–me- lite (44%–55%), morphine-3-glucuronide (M-3-G), has no diated mechanism .
-opioid binding and consequently no analgesic properties[37, 41]. M-3-G is thought to be responsible for the cluster of OIN symptoms described above. However, the evidence For didactic purposes, we separately discuss the clinical for this is conflicting. Gong et al. , in 1992, reported that features and assessment of delirium and the evaluation of M-3-G did not produce excitatory and antianalgesic effects contributory factors. However, in daily clinical practice, in rats, and Penson et al.  more recently, in 2001, did not this process takes place in a fully integrated fashion.
induce neurotoxicity when small i.v. doses of M-3-G wereinjected into healthy volunteers. Normorphine, another Clinical Features of Delirium
nonopioid-binding neurotoxic metabolite, accounts for Early diagnosis is important, because this enables not only only approximately 5% of morphine metabolism .
earlier treatment but also provision of education and sup- However, this mediator may play a more prominent role in port to the patient and family.
55]. Some instruments, such as the Confusion Assessment Table 2. Factors predisposing to opioid-induced
Method (CAM) , are diagnostic only and used mainly neurotoxicity (OIN) for screening. Such tools cannot be used to monitor patients Opioid factors—large dose, extended treatment time, because they do not give a severity rating. Instruments that rapid dose escalation, reduced nociceptive input measure delirium severity, in addition to being diagnostic tools, include the Memorial Delirium Assessment Scale (MDAS) [57, 58] and the brief observational Nursing De- lirium Screening Scale (NuDESC) , derived from the Borderline cognitive impairment/delirium Confusion Rating Scale (CRS) .
Use of other psychoactive drugs, e.g., benzodiazepine A brief description of three delirium assessment tools and nonbenzodiazepine hypnotics, tricyclicantidepressants used in clinical practice follows.
Previous episode of OIN CAM
The CAM  is based on the DSM-III-R criteria. Al-
though it is a brief, four-item diagnostic algorithm that
takes ⬍5 minutes to administer, it does require training in
An essential feature for the clinical diagnosis of delir- its use. It has recently been validated in the palliative care ium of the Diagnostic and Statistical Manual of Mental setting .
Disorders IV-TR (DSM-IV-TR) criteria is a disturbance ofconsciousness . Noncore clinical features of delirium include sleep–wake cycle disturbance, altered psychomotor The MDAS  is a 10-item, four-point, clinician-rated in- activity, and emotional lability. Patients may exhibit pro- strument (possible range, 0 –30). It was originally designed dromal features including anxiety, restlessness, irritability, to measure severity but can be used as a diagnostic tool us- disorientation, and sleep disturbances . Patients may ing a cutoff total MDAS score ⱖ7 of 30 . This is a val- have disorganized thinking and disjointed unintelligible idated instrument . The objective cognitive testing speech. The altered perceptions that may occur include mis- items (items 2, 3, and 4) should be completed first because perceptions, illusions, delusions, and hallucinations .
this achieves a higher rate of completion and allows as- Clinical features include neurological motor abnormalities: sessment time for the more observational or subjective tremor, asterixis, myoclonus, and tone and reflex changes . Dysgraphia may also occur . Other neurologicalabnormalities that may be present include constructional apraxia, dysnomia, and aphasia . Generalized slowing The NuDESC  is an observational five-item scale (pos- of the electroencephalogram is a classic finding .
sible range, 0 –10) that includes the four items of the CRS and an additional assessment of psychomotor retar- Delirium Assessment Tools
dation. Each symptom (disorientation, inappropriate be- Delirium is frequently underdiagnosed in the clinical set- havior, inappropriate communication, illusions, or ting, even by experienced physicians and nurses . One hallucinations, as well as psychomotor retardation) is rated study reported that physicians and nurses missed the diag- 0 –2 according to its presence and severity. It is a low bur- nosis 23% and 20% of the time, respectively . A similar den tool that takes ⬍2 minutes to complete, and can be used underdiagnosis may occur in patients admitted to clinical for screening and monitoring delirium severity. The Nu- trials .
DESC has been validated and is reported to have a sensitiv- Historically, the Mini-Mental State Examination ity of 85.7% and a specificity of 86.8% .
(MMSE)  was used in multiple studies on cognitivefailure in cancer patients with delirium [2, 8, 51–53]. How- Further Clinical Assessment
ever, the MMSE only assesses cognitive function. For ex- The assessment of delirium also includes the investigation ample, two delirious patients with an MMSE score of 14 of of all potential precipitating factors for the delirium episode 30 can range from being completely lethargic to completely (as shown in Fig. 1) in order to identify reversible causes.
agitated and unmanageable. Better tools are needed to as- Medication history for both new and continuing drugs sess perceptual abnormalities, psychomotor changes, delu- should be reviewed. Predisposing factors that increase the sions, and other delirium features. Multiple validated patient's baseline susceptibility for developing delirium delirium-specific assessment tools are now available [54, may also be identified, such as pre-existing cognitive im-
Assessment and Management of Delirium in Cancer Patients fects of OIN resolve within 3–5 days of introduction of opi- Table 3. Management of opioid-induced neurotoxicity
oid rotation and hydration. There have been some case reports examining the effect of treatment of opioid-induced Initial opioid selection (e.g., avoid opioids with active delirium with acetylcholinesterase inhibitors , but cur- metabolites in patients with known renal failure) rently there is no supporting evidence for their effectiveness Hydration (oral/parenteral: i.v. or s.c.) from controlled trials .
Opioid dose reduction with or without Pharmacological Treatment of
Opioid switch/rotation The equianalgesic dose of the new opioid should bereduced by 30%–50%, e.g., morphine 3 There is limited research evidence from clinical trials, so hydromorphone, oxycodone, methadone, or fentanyl this review reports current best practice. Neuroleptics are Stop contributing drugs, e.g., hypnotics considered to be first-line agents [20, 70]. They are usually 75%–80% of episodes of drug-induced delirium resolve used as a short-term measure to relieve perceptual distur- by action of opioid rotation and discontinuation of other bance or agitation while reversible causes are investigated and treated, and include haloperidol and atypical antipsy- Psychostimulants chotics (Table 4) [20, 68 – 80]. There is no research evi- Symptomatic treatment with neuroleptics, e.g., dence to date to support particular dosing schedules and Consider benzodiazepine for myoclonus, e.g., practice. Clinical trials are needed to better inform current Reassurance and explanation Haloperidol is the most commonly used and the most studied neuroleptic [70, 81]. It is a potent dopamine D re- ceptor antagonist with few anticholinergic side effects.
However, there is limited randomized controlled trial evi- pairment or reduced sensory input with poor vision or deaf- dence for its use in the management of delirium . In the ness. Urinary retention and constipation may aggravate 2004 Cochrane review on drug therapy for delirium in ter- agitation, especially in the elderly.
minally ill patients, only one study met the review criteria In addition to the use of a delirium-specific tool, a mul- . This was the seminal double-blind, randomized com- tidimensional assessment of the patient's symptom burden, parison trial by Breitbart et al.  of haloperidol, chlor- using a validated instrument such as the Edmonton Symp- promazine, and lorazepam in the treatment of delirium in 30 tom Assessment System  enables the identification and hospitalized AIDS patients. Chlorpromazine and haloperi- quantification of other significant symptoms that are im- dol were found to be equally effective. There was a small pacting the delirium episode.
but significant decline in cognitive function over time withchlorpromazine. This study highlighted the importance of not treating delirium with a benzodiazepine as a single The multimodal management of delirium includes nonphar- agent, unless delirium is secondary to sedative or alcohol macological and environment management strategies, in addi- withdrawal, because the lorazepam arm was stopped early because of side effects (excessive sedation, increased con- simultaneously identifying and treating underlying causes fusion, disinhibition, and ataxia).
when appropriate. Comprehensive management should in- By 2007, there were three studies eligible for the Cochrane volve a multidisciplinary team. The patient's delirium severity review examining antipsychotics in delirium , comparing and response to treatment need to be monitored regularly.
haloperidol with risperidone, olanzapine, and placebo. The re-view concluded that haloperidol at a dose of ⬍3.5 mg/day, ris- Treatment of Underlying Causes
peridone, and olanzapine were equally effective.
Because 50% of delirium episodes in advanced cancer are Haloperidol has the advantage of versatile routes of ad- reversible, possible contributors to delirium (as shown in ministration: oral, s.c., i.m., and i.v. It is rarely sedating. Be- Fig. 1) should be appropriately treated. For drug-induced cause the average oral bioavailability of haloperidol is delirium, all implicated medications should be discontin- approximately 60% , parenteral doses are about twice ued or undergo a dose reduction if cessation of the impli- as potent as oral doses. High concentrations of haloperidol cated medication is not possible. Opioid rotation should be and reduced-haloperidol, the active metabolite of haloperi- instigated if opioid discontinuation is not possible [64 – 66].
dol, increase the frequency and severity of extrapyramidal See Table 3 for further management of OIN . Most ef- side effects (EPSs) . Parenteral administration of halo- Olanzapine has a common side effect of sedation, which Table 4. Guide to medications used for symptomatic
may be potentially beneficial in a hyperalert, hyperaroused treatment of delirium in advanced cancer patients patient with delirium. In addition, metabolic syndrome can Conventional neuroleptics [22, 72] occur with olanzapine , but the significance of this is unclear when used short term, as in the management of de- lirium. In an open, prospective trial of oral olanzapine for the treatment of delirium in 79 hospitalized cancer patients, Breitbart et al.  found that patients ⬎70 years of age, Atypical antipsychotics [22, 73] with hypoactive delirium, delirium of "severe" intensity (defined in their study as an MDAS score ⬎23 of 30), and a history of dementia, cerebral metastatic disease, and hyp- oxia had a poorer response to treatment. The parenteral olanzapine preparation for i.m. injection has been well tol- erated, with no injection site toxicity when administered by Methylphenidate hydrochloride  the s.c. route in some units .
A higher risk for cerebrovascular events in elderly de- mentia patients has been reported with atypical antipsy- Cholinesterase inhibitors [68, 69] chotics, especially risperidone . In a 2006 meta- Cholinomimetics  analysis assessing the adverse events associated with the use of atypical antipsychotics in the management of behav- Dexmedetomidine  ioral disturbances in patients with Alzheimer disease or other dementia , the duration of the 15 identified randomized, placebo-controlled trials was in the range of 6 –26 weeks. This None of these medications are currently recommended for the routine management of delirium. At present, they is as opposed to the usual short-term use of antipsychotics in are being investigated in the clinical setting.
the management of delirium. The use of atypical and typicalantipsychotics in the elderly has also been associated with ahigher risk for mortality [97, 98]. U.S. Food and Drug Admin- peridol reduces the risk for EPSs. However, there is marked istration (FDA) alerts have been issued for both classes of neu- variation in patient sensitivity to EPS development. In com- roleptics [99, 100].
parison with parkinsonism, neuroleptic-induced parkinson- In addition to EPSs, other adverse effects have been re- ism consists of the triad of bradykinesia, tremor, and ported with neuroleptics. QTc interval prolongation can occur, rigidity, with a predilection for the upper limbs, and with with the risk for sudden cardiac death, including with atypical gait change being mild .
antipsychotics [84, 101]. If the QTc interval is ⬎450 msec, or Clinical guidelines recommend starting haloperidol doses increases ⬎25% from baseline, then the dose of haloperidol of 0.5–2 mg, with varying frequency and routes of administra- and any other contributory medications should be re- tion [86, 87]. Most studies to date report dose ranges of 2–10 duced or ceased . In 2007, the FDA recommended mg/day [52, 88, 89]. Some authors also suggest using regular electrocardiogram monitoring when i.v. haloperidol is low-dose haloperidol for the management of hypoactive delir- given . Most reported cases of neuroleptic malig- ium [47, 90]. However, further research in the form of ran- nant syndrome have occurred in patients receiving par- domized, double-blind, placebo-controlled trials is needed in enteral haloperidol, although it may also occur with other the advanced cancer population to determine appropriate dos- neuroleptics, including atypical antipsychotics .
ing schedules for all delirium subtypes.
More recently, atypical antipsychotics, such as olanza- pine, risperidone, quetiapine, and aripiprazole, have been Simple environmental measures may help in the manage- used in the management of delirium in patients with cancer ment of patients with delirium . Education should be [20, 21, 91–93]. The reduced frequency of EPSs with this provided to the family and bedside nurse on the nature and class of antipsychotics is a result of 5-HT prognosis of delirium, and on measures required to mini- onism and muscarinic M receptor antagonism mitigating mize patient stimulation (Table 5).
D2 receptor blockade . EPSs can still occur with atyp- Up to 75% of patients recall their own symptoms after ical antipsychotics at higher doses, especially risperidone at delirium resolution . Patients require reassurance to doses ⬎6 mg/day .
help reduce their significant associated distress, with hypo-
Assessment and Management of Delirium in Cancer Patients not hastening death. Medications that have been used for PS Table 5. Summary of nonpharmacological management
include midazolam, lorazepam, phenobarbitol (phenobar- bitone), propofol, and methotrimeprazine (levomeproma- Physically safe for patient, and also for staff and family zine) (not available in the U.S.) [109 –112]. Consultation Minimize noise, excessive light, and excessive with a palliative care specialist is strongly recommended before initiating PS .
Streamline the patient's environment Call bell and other essential items visible and CLINICAL COURSE AND PROGNOSIS
Although approximately 50% of delirium episodes are re- Simple, clear, and concise communication versible, episodes are significantly more reversible if the Glasses, hearing aid, dentures where needed precipitating factor is opioids and other psychoactive drugs Explain each intervention prior to instituting care and hypercalcemia [7, 25]. Opioid rotation and discontinu- Orient patient frequently ation of other drugs results in resolution of approximately Provide a clock and calendar that are visible from 75%– 80% of episodes of drug-induced delirium. Delirium is less likely to improve in patients with underlying demen- Name of nurse also visible from the bed tia  or if the delirium is related to hypoxic or global met- Presence of familiar objects abolic encephalopathy, or disseminated intravascular Enlist the family to assist with reorientation coagulation [7, 25].
The presence of delirium is an independent factor in pre- dicting short-term survival of patients with advanced can- cer [14, 113]. Similarly, delirium is associated with greater Other health care providers mortality in medical inpatients [12, 86]. In 121 palliative care inpatients with delirium, Leonard et al.  found that patients with more advanced age, greater cognitive im- Patient, after delirium resolution pairment, and organ failure had significantly shorter sur-vival. In patients ⬎50 years old, persistent delirium isfrequent and associated with poorer outcomes, includinggreater mortality .
active delirium being just as distressing to patients as hy- peractive delirium [9, 11].
Family caregivers observe patient behaviors and expe- Studies are required on delirium predictors that are specific to rience distress more frequently than health care profession- patients with advanced cancer and on the efficacy of multimo- als [9, 11], and require ongoing education (especially dal preventative interventions in this patient population, as regarding patient disinhibition) and psychosocial support compared with trials that have been conducted in the elderly from the interprofessional team [10, 105]. Expressive sup- . There remains limited information from pharmacological portive therapy  is often helpful in reducing family randomized controlled trials to guide practice in evidence- member distress.
based neuroleptic administration to cancer and palliative carepatients. Further research is needed to determine efficacious REFRACTORY AGITATED DELIRIUM
and safe neuroleptic dosing schedules according to the differ- This often necessitates the use of more sedative drugs for ent delirium subtypes and etiologies, and also on the role of patient comfort and symptomatic relief . Palliative se- nonpharmacological and environment management strategies dation (PS) has been defined as the monitored use of pro- to improve the comprehensive multifaceted management of portionate sedative medication to reduce the patient's this distressing syndrome.
awareness of intractable and refractory symptoms near theend of life when other interventions have failed to control them . Refractory agitated delirium is the most com- In advanced cancer patients, the high frequency of delirium ac- mon indication for PS. Other indications for PS include se- companied by the frequent underdiagnosis of this syndrome vere dyspnea or respiratory distress, pain, hemorrhage, strongly suggests that regular screening for delirium should be severe seizures, and uncontrolled myoclonus. Appropri- conducted using validated tools in order to reach an earlier di- ately titrated PS in the dying is an ethically and legally ac- agnosis. Although delirium in this population is often associ- cepted intervention, with the aim of relieving suffering and ated with a poor prognosis, 50% of patients can improve with appropriate management of contributing etiologies, especially Eduardo Bruera is supported in part by National Insti- if opioids and other psychoactive drugs are precipitating fac- tutes of Health Grant numbers: RO1NR010162-01A1, tors, and involvement of the interprofessional team. Patients, RO1CA122292-01, and RO1CA124481-01.
family, and staff require ongoing support to reduce the impactof this potentially devastating condition.
The authors would like to thank Kathy R. King for her sec- Conception/Design: Shirley H. Bush, Eduardo Bruera
Manuscript writing: Shirley H. Bush, Eduardo Bruera
retarial assistance in the preparation of this manuscript.
Final approval of manuscript: Shirley H. Bush, Eduardo Bruera
Massie MJ, Holland J, Glass E. Delirium in terminally ill cancer patients.
Am J Psychiatry 1983;140:1048 –1050.
Engel GL, Romano J. Delirium, a syndrome of cerebral insufficiency.
J Chronic Dis 1959;9:260 –277.
Liptzin B, Levkoff SE. An empirical study of delirium subtypes. Br J Psy- chiatry 1992;161:843– 845.
Bruera E, Miller L, McCallion J et al. Cognitive failure in patients with terminal cancer: A prospective study. J Pain Symptom Manage 1992;7: Meagher D, Moran M, Raju B et al. A new data-based motor subtype schema for delirium. J Neuropsychiatry Clin Neurosci 2008;20:185–193.
Inouye SK. Delirium in older persons. N Engl J Med 2006;354:1157–1165.
Seitz DP, Gill SS, van Zyl LT. Antipsychotics in the treatment of delirium: A systematic review. J Clin Psychiatry 2007;68:11–21.
Braiteh F, El Osta B, Palmer JL et al. Characteristics, findings, and out- comes of palliative care inpatient consultations at a comprehensive cancer Breitbart W, Tremblay A, Gibson C. An open trial of olanzapine for the center. J Palliat Med 2007;10:948 –955.
treatment of delirium in hospitalized cancer patients. Psychosomatics Breitbart W, Bruera E, Chochinov H et al. Neuropsychiatric syndromes and psychological symptoms in patients with advanced cancer. J Pain Alici-Evcimen Y, Breitbart W. An update on the use of antipsychotics in Symptom Manage 1995;10:131–141.
the treatment of delirium. Palliat Support Care 2008;6:177–182.
Lawlor PG, Bruera ED. Delirium in patients with advanced cancer. He- Spiller JA, Keen JC. Hypoactive delirium: Assessing the extent of the prob- matol Oncol Clin North Am 2002;16:701–714.
lem for inpatient specialist palliative care. Palliat Med 2006;20: 17–23.
Lawlor PG, Gagnon B, Mancini IL et al. Occurrence, causes, and outcome Lawlor P, Gagnon B, Mancini I et al. Phenomenology of delirium and its of delirium in patients with advanced cancer: A prospective study. Arch subtypes in advanced cancer patients: A prospective study [abstract]. J Intern Med 2000;160:786 –794.
Palliat Care 1998;14:106.
Pereira J, Hanson J, Bruera E. The frequency and clinical course of cognitive Morita T, Tei Y, Tsunoda J et al. Underlying pathologies and their asso- impairment in patients with terminal cancer. Cancer 1997;79:835– 842.
ciations with clinical features in terminal delirium of cancer patients. J Pain Symptom Manage 2001;22:997–1006.
Breitbart W, Gibson C, Tremblay A. The delirium experience: Delirium re- call and delirium-related distress in hospitalized patients with cancer, their Bruera E, Fainsinger RL, Miller MJ et al. The assessment of pain intensity spouses/caregivers, and their nurses. Psychosomatics 2002;43:183–194.
in patients with cognitive failure: A preliminary report. J Pain Symptom Morita T, Hirai K, Sakaguchi Y et al. Family-perceived distress from de- lirium-related symptoms of terminally ill cancer patients. Psychosomatics Trzepacz PT. Is there a final common neural pathway in delirium? Focus on acetylcholine and dopamine. Semin Clin Neuropsychiatry 2000;5:132–148.
Agar M, Lawlor P. Delirium in cancer patients: A focus on treatment- Bruera E, Bush SH, Willey J et al. Impact of delirium and recall on the induced psychopathology. Curr Opin Oncol 2008;20:360 –366.
level of distress in patients with advanced cancer and their family care- givers. Cancer 2009;115:2004 –2012.
Vella-Brincat J, Macleod AD. Adverse effects of opioids on the central nervous systems of palliative care patients. J Pain Palliat Care Pharmaco- Siddiqi N, House AO, Holmes JD. Occurrence and outcome of delirium in medical in-patients: A systematic literature review. Age Ageing 2006;35: de Rooij SE, van Munster BC, Korevaar JC et al. Cytokines and acute phase response in delirium. J Psychosom Res 2007;62:521–525.
Pautex S, Herrmann FR, Zulian GB. Factors associated with falls in patients with cancer hospitalized for palliative care. J Palliat Med 2008;11:878 – 884.
Adamis D, Lunn M, Martin FC et al. Cytokines and IGF-I in delirious and non-delirious acutely ill older medical inpatients. Age Ageing 2009;38:326 – Caraceni A, Nanni O, Maltoni M et al. Impact of delirium on the short term prognosis of advanced cancer patients. Italian Multicenter Study Group on Palliative Care. Cancer 2000;89:1145–1149.
van Munster BC, Korevaar JC, Zwinderman AH et al. Time-course of cy- tokines during delirium in elderly patients with hip fractures. J Am Geriatr Delirium due to a general medical condition. In: American Psychiatric As- Soc 2008;56:1704 –1709.
sociation (APA). Diagnostic and Statistical Manual of Mental Disorders, Text Revision, Fourth Edition. Washington, DC: American Psychiatric Gaudreau JD, Gagnon P. Psychotogenic drugs and delirium pathogenesis: The central role of the thalamus. Med Hypotheses 2005;64:471– 475.
Centeno C, Sanz A, Bruera E. Delirium in advanced cancer patients. Pal- Ljubisavljevic V, Kelly B. Risk factors for development of delirium liat Med 2004;18:184 –194.
among oncology patients. Gen Hosp Psychiatry 2003;25:345–352.
Assessment and Management of Delirium in Cancer Patients Gaudreau JD, Gagnon P, Harel F et al. Psychoactive medications and risk of tique of current tools and suggestions for future development. J Psycho- delirium in hospitalized cancer patients. J Clin Oncol 2005;23:6712– 6718.
som Res 2008;65:255–259.
Han L, McCusker J, Cole M et al. Use of medications with anticholinergic Inouye SK, van Dyck CH, Alessi CA et al. Clarifying confusion: The con- effect predicts clinical severity of delirium symptoms in older medical in- fusion assessment method. A new method for detection of delirium. Ann patients. Arch Intern Med 2001;161:1099 –1105.
Intern Med 1990;113:941–948.
Bruera E, Pereira J. Neuropsychiatric toxicity of opioids. In: Jensen TS, Breitbart W, Rosenfeld B, Roth A et al. The Memorial Delirium Assess- Turner JA, Wiesenfeld-Hallin Z, eds. Proceedings of the 8th World Con- ment Scale. J Pain Symptom Manage 1997;13:128 –137.
gress on Pain: Progress in Pain Research and Management, Volume 8.
Lawlor PG, Nekolaichuk C, Gagnon B et al. Clinical utility, factor anal- Seattle: IASP Press, 1997:717–738.
ysis, and further validation of the Memorial Delirium Assessment Scale in Mercadante S. Opioid rotation for cancer pain: Rationale and clinical as- patients with advanced cancer: Assessing delirium in advanced cancer.
pects. Cancer 1999;86:1856 –1866.
Cancer 2000;88:2859 –2867.
Leipzig RM, Goodman H, Gray G et al. Reversible, narcotic-associated Gaudreau JD, Gagnon P, Harel F et al. Fast, systematic, and continuous mental status impairment in patients with metastatic cancer. Pharmacol- delirium assessment in hospitalized patients: The nursing delirium screen- ing scale. J Pain Symptom Manage 2005;29:368 –375.
Fountain A. Visual hallucinations: A prevalence study among hospice in- Gagnon P, Allard P, Mâsse B et al. Delirium in terminal cancer: A pro- patients. Palliat Med 2001;15:19 –25.
spective study using daily screening, early diagnosis, and continuous monitoring. J Pain Symptom Manage 2000;19:412– 426.
Sjøgren P, Eriksen J. Opioid analgesics. In: Bruera E, Higginson IJ, Ri- pamonti C et al., eds. Textbook of Palliative Medicine. London: Hodder Ryan K, Leonard M, Guerin S et al. Validation of the confusion assess- Arnold, 2006:380 –389.
ment method in the palliative care setting. Palliat Med 2009;23:40 – 45.
Gong QL, Hedner J, Björkman R et al. Morphine-3-glucuronide may Fadul N, Kaur G, Zhang T et al. Evaluation of the Memorial Delirium As- functionally antagonize morphine-6-glucuronide induced antinociception sessment Scale (MDAS) for the screening of delirium by means of simu- and ventilatory depression in the rat. Pain 1992;48:249 –255.
lated cases by palliative care health professionals. Support Care Cancer Penson RT, Joel SP, Clark S et al. Limited phase I study of morphine-3- glucuronide. J Pharm Sci 2001;90:1810 –1816.
Bruera E, Kuehn N, Miller MJ et al. The Edmonton Symptom Assessment System (ESAS): A simple method for the assessment of palliative care pa- Sjøgren P. Clinical implications of morphine metabolites. In: Portenoy tients. J Palliat Care 1991;7:6 –9.
RK, Bruera E, eds. Topics in Palliative Care, Volume 1. New York: Ox- ford University Press, 1997:163–175.
de Stoutz ND, Bruera E, Suarez-Almazor M. Opioid rotation for toxicity reduction in terminal cancer patients. J Pain Symptom Manage 1995;10: Mercadante S, Ferrera P, Villari P et al. Hyperalgesia: An emerging iat- rogenic syndrome. J Pain Symptom Manage 2003;26:769 –775.
Indelicato RA, Portenoy RK. Opioid rotation in the management of re- Gupta N, de Jonghe J, Schieveld J et al. Delirium phenomenology: What fractory cancer pain. J Clin Oncol 2002;20:348 –352.
can we learn from the symptoms of delirium? J Psychosom Res 2008;65: Mercadante S, Bruera E. Opioid switching: A systematic and critical re- view. Cancer Treat Rev 2006;32:304 –315.
Breitbart W, Chochinov HM, Passik SD. Psychiatric symptoms in pallia- tive medicine. In: Doyle D, Hanks G, Cherny NI et al., eds. Oxford Text- Eisele JH Jr, Grigsby EJ, Dea G. Clonazepam treatment of myoclonic con- book of Palliative Medicine, Third Edition. New York: Oxford University tractions associated with high-dose opioids: Case report. Pain 1992;49: Press, 2004:746 –771.
Macleod AD, Whitehead LE. Dysgraphia and terminal delirium. Palliat Slatkin N, Rhiner M. Treatment of opioid-induced delirium with acetyl- cholinesterase inhibitors: A case report. J Pain Symptom Manage 2004; 27:268 –273.
Bruera E, Spachynski K, MacEachern T et al. Cognitive failure in cancer patients in clinical trials [letter]. Lancet 1993;341:247–248.
Overshott R, Karim S, Burns A. Cholinesterase inhibitors for delirium.
Cochrane Database Syst Rev 2008:(1):CD005317. DOI: 10.1002/ Folstein MF, Folstein SE, McHugh PR. "Mini-mental state." A practical method for grading the cognitive state of patients for the clinician. J Psy- chiatr Res 1975;12:189 –198.
Attard A, Ranjith G, Taylor D. Delirium and its treatment. CNS Drugs 2008;22:631– 644.
Bruera E, Franco JJ, Maltoni M et al. Changing pattern of agitated im- paired mental status in patients with advanced cancer: Association with Bourne RS, Tahir TA, Borthwick M et al. Drug treatment of delirium: cognitive monitoring, hydration, and opioid rotation. J Pain Symptom Past, present and future. J Psychosom Res 2008;65:273–282.
Twycross R, Wilcock A, eds. Hospice and Palliative Care Formulary Breitbart W, Marotta R, Platt MM et al. A double-blind trial of haloperi- USA. Nottingham: Palliativedrugs.com, 2006:103–104.
dol, chlorpromazine, and lorazepam in the treatment of delirium in hospi- Boettger S, Breitbart W. Atypical antipsychotics in the management of de- talized AIDS patients. Am J Psychiatry 1996;153:231–237.
lirium: A review of the empirical literature. Palliat Support Care 2005;3: Hjermstad M, Loge JH, Kaasa S. Methods for assessment of cognitive failure and delirium in palliative care patients: Implications for practice Gagnon B, Low G, Schreier G. Methylphenidate hydrochloride improves and research. Palliat Med 2004;18:494 –506.
cognitive function in patients with advanced cancer and hypoactive delirium: Smith MJ, Breitbart WS, Platt MM. A critique of instruments and methods to A prospective clinical study. J Psychiatry Neurosci 2005;30:100 –107.
detect, diagnose, and rate delirium. J Pain Symptom Manage 1995;10:35–77.
Breitbart W, Alici Y. Agitation and delirium at the end of life: "We Kean J, Ryan K. Delirium detection in clinical practice and research: Cri- couldn't manage him." JAMA 2008;300:2898 –2910.
Hanania M, Kitain E. Melatonin for treatment and prevention of postop- chotic drug treatment for dementia: Meta-analysis of randomized placebo- erative delirium. Anesth Analg 2002;94:338 –339.
controlled trials. JAMA 2005;294:1934 –1943.
Nakamura K, Kurasawa M, Tanaka Y. Apomorphine-induced hypoatten- Wang PS, Schneeweiss S, Avorn J et al. Risk of death in elderly users of tion in rats and reversal of the choice performance impairment by anirac- conventional vs. atypical antipsychotic medications. N Engl J Med 2005; etam. Eur J Pharmacol 1998;342:127–138.
Bourgeois JA, Koike AK, Simmons JE et al. Adjunctive valproic acid for U.S. Food and Drug Administration. Deaths With Antipsychotics in El- delirium and/or agitation on a consultation-liaison service: A report of six derly Patients With Behavioral Disturbances. Silver Spring, MD: U.S.
cases. J Neuropsychiatry Clin Neurosci 2005;17:232–238.
Food and Drug Administration, 2005. Available at http://www.fda.gov/ Riker RR, Shehabi Y, Bokesch PM et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: A randomized trial. JAMA 2009;301: September 2, 2009.
489 – 499.
100 U.S. Food and Drug Administration. Conventional Antipsychotics – Bayindir O, Gu¨den M, Akpinar B et al. Ondansetron hydrochloride for the Healthcare Professional Sheet Text Version. Silver Spring, MD: U.S.
treatment of delirium after coronary artery surgery. J Thorac Cardiovasc Food and Drug Administration, 2008. Available at http://www.fda.gov/ Surg 2001;121:176 –177.
September 2, 2009.
Lacasse H, Perreault MM, Williamson DR. Systematic review of antipsy- chotics for the treatment of hospital-associated delirium in medically or 101 Ray WA, Chung CP, Murray KT et al. Atypical antipsychotic drugs and surgically ill patients. Ann Pharmacother 2006;40:1966 –1973.
the risk of sudden cardiac death. N Engl J Med 2009;360:225–235.
Jackson KC, Lipman AG. Drug therapy for delirium in terminally ill pa- 102 U.S. Food and Drug Administration. Haloperidol (Marketed as Haldol, tients. Cochrane Database Syst Rev 2004;(2):CD004770. DOI: 10.1002/ Haldol Decanoate and Haldol Lactate). Silver Spring, MD: U.S. Food and Drug Administration, 2007. Available at http://www.fda.gov/Drugs/ Lonergan E, Britton AM, Luxenberg J. Antipsychotics for delirium. Co- tember 2, 2009.
chrane Database Syst Rev 2007;(2):CD005594. DOI: 10.1002/ 103 Seitz DP, Gill SS. Neuroleptic malignant syndrome complicating antipsy- chotic treatment of delirium or agitation in medical and surgical patients: Vella-Brincat J, Macleod AD. Haloperidol in palliative care. Palliat Med Case reports and a review of the literature. Psychosomatics 2009;50:8 –15.
104 Zimberg M, Berenson S. Delirium in patients with cancer: Nursing assess- Hassin-Baer S, Sirota P, Korczyn AD et al. Clinical characteristics of neu- ment and intervention. Oncol Nurs Forum 1990;17:529 –538.
roleptic-induced parkinsonism. J Neural Transm 2001;108:1299 –1308.
105 Gagnon P, Charbonneau C, Allard P et al. Delirium in advanced cancer: A American Psychiatric Association (APA). Practice guideline for the treat- psychoeducational intervention for family caregivers. J Palliat Care 2002; ment of patients with delirium. Am J Psychiatry 1999;156(suppl 5):1–20.
Casarett DJ, Inouye SK. Diagnosis and management of delirium near the 106 Spiegel D. Essentials of psychotherapeutic intervention for cancer pa- end of life. Ann Intern Med 2001;135:32– 40.
tients. Support Care Cancer 1995;3:252–256.
Akechi T, Uchitomi Y, Okamura H et al. Usage of haloperidol for delirium 107 Elsayem A, Curry Iii E, Boohene J et al. Use of palliative sedation for in- in cancer patients. Support Care Cancer 1996;4:390 –392.
tractable symptoms in the palliative care unit of a comprehensive cancer Olofsson SM, Weitzner MA, Valentine AD et al. A retrospective study of center. Support Care Cancer 2009;17:53–59.
the psychiatric management and outcome of delirium in the cancer patient.
108 de Graeff A, Dean M. Palliative sedation therapy in the last weeks of life: Support Care Cancer 1996;4:351–357.
A literature review and recommendations for standards. J Palliat Med Platt MM, Breitbart W, Smith M et al. Efficacy of neuroleptics for hypo- 2007;10:67– 85.
active delirium. J Neuropsychiatry Clin Neurosci 1994;6:66 – 67.
109 Chater S, Viola R, Paterson J et al. Sedation for intractable distress in the Horikawa N, Yamazaki T, Miyamoto K et al. Treatment for delirium with dying—a survey of experts. Palliat Med 1998;12:255–269.
risperidone: Results of a prospective open trial with 10 patients. Gen Hosp 110 Burke AL, Diamond PL, Hulbert J et al. Terminal restlessness—its man- Psychiatry 2003;25:289 –292.
agement and the role of midazolam. Med J Aust 1991;155:485– 487.
Shinno H, Matsuoka T, Yamamoto O et al. Successful treatment with 111 Stirling LC, Kurowska A, Tookman A. The use of phenobarbitone in the quetiapine for delirium in terminally ill cancer patients. Psychogeriatrics management of agitation and seizures at the end of life. J Pain Symptom 2007;7:64 – 68.
Straker DA, Shapiro PA, Muskin PR. Aripiprazole in the treatment of de- 112 Lundström S, Zachrisson U, Fu¨rst CJ. When nothing helps: Propofol as lirium. Psychosomatics 2006;47:385–391.
sedative and antiemetic in palliative cancer care. J Pain Symptom Manage Jayaram MB, Hosalli P, Stroup S. Risperidone versus olanzapine for 2005;30:570 –577.
schizophrenia. Cochrane Database Syst Rev 2006;(2):CD005237. DOI: 113 Maltoni M, Caraceni A, Brunelli C et al. Prognostic factors in advanced cancer patients: Evidence-based clinical recommendations–a study by the Delgado-Guay M, Curry E, Bruera E et al. Subcutaneous olanzapine for Steering Committee of the European Association for Palliative Care.
hyperactive or mixed delirium in a comprehensive cancer center [abstract J Clin Oncol 2005;23:6240 – 6248.
191]. Palliat Med 2008;22:457.
114 Leonard M, Raju B, Conroy M et al. Reversibility of delirium in terminally ill Schneider LS, Dagerman K, Insel PS. Efficacy and adverse effects of patients and predictors of mortality. Palliat Med 2008;22:848 – 854.
atypical antipsychotics for dementia: Meta-analysis of randomized, pla- 115 Cole MG, Ciampi A, Belzile E et al. Persistent delirium in older hospital cebo-controlled trials. Am J Geriatr Psychiatry 2006;14:191–210.
patients: A systematic review of frequency and prognosis. Age Ageing Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsy- 2009;38:19 –26.
The Assessment and Management of Delirium in Cancer Patients
Shirley H. Bush and Eduardo Bruera The Oncologist 2009;14;1039-1049; originally published online October 6, 2009; This information is current as of July 24, 2011
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