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 [20]. Hypoactive delirium may be more resis-
and content of thought are grossly deviant that an abnormal
tant to pharmacological treatment [21]. 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" [1].
type [22, 23]. Lawlor et al. [24], 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 [5].
alopathies [25].
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 [11]. 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 [11].
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 [2]. 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 [26],
hood of death [14].
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 [27]. 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 [15].
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
[32]. Transient thalamic dysfunction has been postulated as
palliative care unit, and ⬎80% of patients with advanced
a mechanism for drug-induced delirium [33]. 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 [7] (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 [34]. However, often a specific
ications used to treat delirium. Patients with hyperactive de-
cause remains unidentified. Predisposing factors increase a
CANCER BYPRODUCTS,
Medications
e.g., opioids,
Intracranial disease
anticholinergics,
e.g., primary and
corticosteroids,
metastatic brain tumor,
antidepressants,
leptomeningeal disease,
benzodiazepines,
Electrolyte imbalance
e.g., hypercalcemia,
hyponatremia,
Side effects of
Dehydration
Other medical conditions
e.g., withdrawal syndromes
Organ failure
(alcohol, medication, nicotine),
nutritional deficiencies,
coagulopathy, anemia
Infection
Endocrine
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. [35] 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. [39] 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 [35].
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 [40]. 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-
ministration.
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 [29]. It has been suggested that inhibition of gly-
tems [29]. 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 [29]. 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 [45].
-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. [42], 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. [43] 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 [44].
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) [56], 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) [59], derived from the
Borderline cognitive impairment/delirium
Confusion Rating Scale (CRS) [60].
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 [56] 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 [61].
Disorders IV-TR (DSM-IV-TR) criteria is a disturbance ofconsciousness [15]. Noncore clinical features of delirium
include sleep–wake cycle disturbance, altered psychomotor
The MDAS [57] 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 [46]. Patients may
ing a cutoff total MDAS score ⱖ7 of 30 [58]. This is a val-
have disorganized thinking and disjointed unintelligible
idated instrument [58]. 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 [47].
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
[47]. Dysgraphia may also occur [48]. Other neurologicalabnormalities that may be present include constructional
apraxia, dysnomia, and aphasia [47]. Generalized slowing
The NuDESC [59] is an observational five-item scale (pos-
of the electroencephalogram is a classic finding [1].
sible range, 0 –10) that includes the four items of the CRS[60] 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 [3]. 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 [2]. 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 [49].
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% [59].
(MMSE) [50] 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 [68], 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 [69].
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 [20]. 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-
[82]. This was the seminal double-blind, randomized com-
tidimensional assessment of the patient's symptom burden,
parison trial by Breitbart et al. [52] 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 [63] 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 [83], 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% [84], 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 [67]. Most ef-
side effects (EPSs) [84]. 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 [94], 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. [21] 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 [74]
the s.c. route in some units [95].
A higher risk for cerebrovascular events in elderly de-
mentia patients has been reported with atypical antipsy-
Cholinesterase inhibitors [68, 69]
chotics, especially risperidone [96]. In a 2006 meta-
Cholinomimetics [77]
analysis assessing the adverse events associated with the
use of atypical antipsychotics in the management of behav-
Dexmedetomidine [79]
ioral disturbances in patients with Alzheimer disease or other
dementia [96], 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 [85].
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 [86]. 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 [102]. 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 [103].
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 [104]. 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 [73]. 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 [11]. Patients require reassurance to
doses ⬎6 mg/day [22].
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 [108].
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 [3] 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. [114] 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 [115].
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-
[3]. There remains limited information from pharmacological
portive therapy [106] 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 [107]. 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 [108]. 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
including high-resolution figures, can be found at:
& Services
Source: http://www.e-sanitas.edu.co/Diplomados/paliativos/Modulo%206/documentos/Delirium%20Bruera.pdf
PROGRAMA NACIONAL DE FORMACIÓN EN MEDICINA INTEGRAL COMUNITARIA PLAN DE CLASE ASIGNATURA: Morfofisiología Humana III SEMANA: 8 FOE: Actividad Orientadora 10 MÉTODO: Expositivo Ilustrativo MEDIOS: Pizarra, Videoclase. TIEMPO: 100' TEMA: 1. Sistema endocrino. TÍTULO: Glándulas paratiroides
L-Type Calcium Channels: The Low Down Diane Lipscombe, Thomas D. Helton and Weifeng XuJ Neurophysiol 92:2633-2641, 2004. You might find this additional info useful. This article cites 135 articles, 77 of which can be accessed free at: This article has been cited by 60 other HighWire hosted articles, the first 5 are:
