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If the patient is not agitated, cyanosed nor imminently dying, a trial of methylphenidate dextroamphetamine Delirium and
(Dexedrine®) 2.5–5.0mg once or twice daily in the morning may help. Tolerance develops to these drugs and may limit their role. A newer CNS stimulant, modafinil (Alertec®) may be tried. Its mechanism of action is not entirely Studies report that this symptom, which varies clear, but it has central 1-adrenergic receptor from mild to severe, occurs in 25–85% of patients agonism. It also may have a different site of action with advanced cancer(7). Gagnon reported a in the hypothalamus rather than the cortex as in prevalence of delirium in 52% of patients(8). On methylphenidate(5). As such, its adverse effect occasion, however, a few patients will remain profile is also different and lower. Although coherent until within minutes or hours of death. officially approved only for use in narcolepsy, it Lawlor et al(9) reported that, on admission to a has been found helpful in cancer-related fatigue, palliative care unit, delirium was initially diagnosed in Alzheimer's disease and as an adjuvant in in 42% of patients, and later developed in a further depression(6). Dosage is 100–200mg morning or 45%, with 12% having no delirium at any point. divided at morning and noon.
Terminal delirium occurred in 88% of deaths. Confusion about Confusion In a Cochrane collaborative review, delirium is stated to be a common disorder that often complicates treatment in patients with life-limiting disease. Delirium is described using a variety of terms such as agitation, acute confusional state, encephalopathy, organic mental disorders and terminal restlessness(10).
Chang(11), in an editorial entitled The Confusion About Confusion, also notes various terms that are used but have different meanings, including confusion, altered mental state, cognitive impairment, acute brain syndrome, restlessness, dementia and delirium. Even then, ‘confusion' could represent delirium, pain, a psychiatric condition, dysphasia, dementia or disorientation(12). ‘Altered mental status' could be agitation or anger, coma, seizures or delusions(13). ‘Delirium' and ‘dementia' are more closely defined using DSM-IV or ICD-10 coding. The criteria for delirium by DSM-IV are listed in Chapter 17 Etiology and Assessment Psychosocial Care, and by ICD-10 is shown in Table 14.1(14).
Acute brain syndrome(15) was often previously Delirium is one of the most prevalent symptoms used but delirium has now replaced it(16).
in palliative care and, since it may present in Dementia will be briefly discussed later but, different shades of altered cognition, the routine use in comparison to delirium, has the following of screening instruments is recommended(18).
As with all symptoms, careful assessment • Often irreversible is necessary in determining the etiology of • Consciousness level usually not affected confusion. Much can be gained by careful review • Hallucinations not common of recent history, current medications and physical • Usually deterioration of all cognitive and examination. Table 14.2 outlines the general causes intellectual functions of confusion in advanced disease.
Although the following data relates to a study Delirium in dementia appears to have similar (physicians, social workers)(11), Inouye et al report that hospice nurses have difficulty recognizing N.B. For the purposes of this book, delirium will delirium, with a sensitivity of 18% (15–31%) generally be used in place of confusion, and dementia but specificity of 95%(20). This means that they used as it implies.
were accurate in knowing when delirium was not present, but significantly under-recognized it when ICD-10 Diagnostic Guidelines for Delirium
For a definite diagnosis, symptoms of mild or severe should be present in the following areas:• Impairment of • On a continuum from clouding to coma • Reduced ability to direct, focus, sustain and shift attention • Global disturbance • Perceptual distortions, illusions and hallucinations, most often visual • Impairment of abstract thinking and comprehension, with or without delusions, but typically with some degree of incoherence • Impairment of immediate recall and of recent memory but with relatively intact remote memory • Disorientation for time as well as, in more severe cases, for place and person • Hypo- or hyperactivity and unpredictable shifts from one to the other • Increased reaction time • Increased or decreased flow of speech • Enhanced startle reaction • Disturbance of • Insomnia or, in severe cases, total sleep loss or reversal of the sleep-wake cycle • Daytime drowsiness • Nocturnal worsening of symptoms • Disturbing dreams or nightmares, which may continue as hallucinations after wakening • Examples - depression, anxiety or fear, irritability, euphoria, apathy or wondering perplexity • The onset is usually rapid, the course diurnally fluctuating, and the total duration of the condition less than six months. • The above clinical picture is so characteristic that a fairly confident diagnosis of delirium can be made even if the underlying cause is not clearly established.
• In addition to a history of an underlying physical or brain disease, evidence of cerebral dysfunction (e.g. EEG) may be required if the diagnosis is in doubt.
• Acute brain syndrome • Acute confusional state • Acute infective psychosis • Acute organic reaction • Acute psycho-organic syndrome Table 14.1. ICD-10 Diagnostic Guidelines for Delirium. With permission WHO(14).
Causes of Delirium
There are many possible assessment tools used Physical
• Tumor burden or location e.g. brain for assessing cognitive and affective aspects of • Infection, sepsis delirium(21,22), although usual medical and nursing assessments may have similar outcomes(23). Of • Hypercalcemia those, several are more often used in palliative • Hepatic encephalopathy • Hypo- or hyperglycemia One of the most widely used tools for assessing • Cardiorespiratory cognition is the Folstein Mini Mental State Exam (MMSE)(24,25), but it is not specific for delirium. The Delirium Rating Scale (DRS)(26,27) has • Cerebrovascular – e.g. stroke(19) value in screening and monitoring the severity of delirium(21), as has the Memorial Delirium • Subdural hematoma Assessment Scale (MDAS)(28,29).
• General discomfort Screening tools, i.e. not for full assessment, Drug Effects • Idiosyncratic
which could be used in various settings include • Drug accumulation Confusion Assessment Method (CAM)(8,30-34) • Physical decline, decreased renal or hepatic clearance and Bedside Confusion Scale (BCS)(35). Even • Accidental or intentional overdose then, use of these without some training reduces • Drug withdrawal their sensitivity(36). CAM assesses 10 areas: acute onset, inattention, disorganized thinking, altered • Other medications e.g. steroid level of consciousness, disorientation, memory impairment, perceptual disturbances, psychomotor Table 14.2. Causes of Delirium. M Downing
agitation, psychomotor retardation and altered a patient was delirious. Four independent risk factors sleep-wake cycle. The CAM (short form) uses for under-recognition were identified: hypoactive 4 factors: acute onset and fluctuating course, delirium, age 80 years and older, vision impairment, inattention, disorganized thinking and altered level and dementia. Under-recognition increased with of consciousness.
the number of risk factors present from 2% (0 risk factors) – 6% (1 risk factor), 15% (2 risk factors), Delirium Sub-types and 44% (3 or 4 risk factors). Patients with 3 or 4 Two types of delirium are of particular note as risk factors had a 20-fold risk for under-recognition. each is seen in end-of-life care(37). As the terms Recognition of delirium can be enhanced with imply, hyperactive delirium involves an agitated, education in delirium features, cognitive assessment, hyperalert stage, and hypoactive delirium involves and factors associated with poor recognition(20).
being lethargic. Table 14.3 shows distinguishing Any decision to carry out investigations must be weighed against the value which will Among older adults, especially those in long- be gained from the results and the expected term care situations, delirium may not appear to improvement from treatment based on those be very different from previous episodes observed tests, as well as the morbidity and 'usefulness' of when the resident experienced an infection, pursuing investigations in a patient who may be exacerbation of a chronic condition, anxiety, pain deteriorating quickly and close to death.
or adverse drug reactions. However, delirium at the end of life is usually multifactorial and exacerbated by the progressive multiple system failure. Sandberg et al(38) reported that in the elderly, although episodes of delirium in general occur in the afternoon, evening or night, in fact 47% of the delirious patients in a residential facility had morning delirium. Further, nearly 26% were classified as having hypoactive, 30% as having hyperactive, and 42% as having mixed delirium(39). Hypoactive delirium is often misdiagnosed in the elderly as depression or simply not recognized(40, It is a major challenge to discern whether one should pursue investigations or not. If the cause The experience of delirium is highly distressful could be identified easily, with minimal invasion to most. In a recall study, Breitbart et al(42) found and be readily treated with resulting improvement, several important points: then many would want this as this is a distressing • Patients who could recall delirium (about 53%) ranked their distress level at average 3.2 (scale Physicians always face the dilemma of how 0–4) with delusions being the most distressful aggressively to intervene in reversing delirium, and the following is a possible strategy(43): • Spouses/caregivers rated their distress at 3.75 • Identify the underlying cause (if possible) and • Nurses rated personal distress at 3.09 with assess its impact on the patient's quality of life symptom severity and perceptual disturbances • Rank the distress of delirium in the context of as most distressful the patient's overall symptom complex • Patients with hypoactive delirium were just as • Assess the potential problems associated with distressed as those with hyperactive type correcting the underlying causes and consequent • They concluded stating the necessity for timely impact on quality of life (e.g. using IV line for recognition and prompt treatment antibiotics, and patient pulling out) • Consider the advantages and disadvantages of intervention versus no intervention • Discuss treatment options with the patient (if mild cognitive impairment) and the family to allow informed decision-making and ultimately the development of a consensus on the appropriate level of intervention It is usually neither simple nor easy, and the causes are often multiple. When confronted with delirium in terminally ill or dying patients, health care professionals should always review a differential diagnosis and the likely factors involved. A firm Contrasting Features of Subtypes of Delirium
diagnosis may only be attainable in less than half of Hyperactive Delirium Hypoactive
cases(44). In the Lawlor study above(9) reversal of delirium was possible in 56% of first episodes, but • Hallucinations only 26% if a subsequent delirium developed. Factors associated with likely reversible delirium
were:
• Encephalopathies • Opioid-induced neurotoxicity • Psychoactive drugs benzodiazepines, • Benzodiazepine Pathophys- • Elevated or normal • Decreased
Factors associated with irreversibility:
cerebral metabolism • Hypoxic encephalopathy • EEG – fast or • Metabolic factors (e.g. hypercalcemia, • EEG – diffuse • Reduced activity in hyponatremia, renal insufficiency) • Overstimulation of • Non-respiratory infection Table 14.3. Contrasting Features of Subtypes of Delirium.
From Handbook of Psychiatry in Palliative Medicine, edited by HM Chochinov, W Breibart. With permission of Oxford University Press, Inc(37).
A valuable practical insight is that of a baseline hydration, bisphosphonates for hypercalcemia, vulnerability and superimposed precipitants. Age, oxygen, rotation of opioids, reduction or mental status, multi-system impairment, decreased discontinuing of other offending drugs.
nutritional status and decreased functional status At the same time, low dose neuroleptics may be provide a precarious baseline. Any superimposed started. The aim is not to sedate, which may tip the factor may then precipitate delirium, including situation to become irreversible, but rather to provide medications, dehydration, infection, metabolic sufficient medication to reduce agitation. Therefore, dysfunction or hypoxia.
one should use low-sedating neuroleptics and avoid The mortality rate in delirium varies of course by anxiolytics as possible.
the etiology and patient condition, and varies from 2. Intent to Relieve by Sedation Reversal may be unrealistic or unwanted. Treatment Approaches Latimer(46) used the term ‘sedation as therapy' Taking the above facts into consideration, there in recognizing that the goal may be reduction of are three approaches to consider in management as severity of delirium via use of sedative medication.
follows. Each of these have pros and cons, requiring Criteria for this approach include: team and family input as noted. • If delirium unpleasant and/or worsening Additionally, similar to the relationship of pain • If patient did not want active treatment and total pain, delirium has the underlying disease • If treatment is futile or unlikely to improve factors precipitating delirium, but there can be superimposed many other features, including • If conditions are unsafe for patient, family or unresolved fears, anxiety or spiritual journey. staff e.g. wild agitation, violence Cultural aspects may also be involved and respect for these are required as discussed in Chapters 17 In this approach, neuroleptics ± anxiolytics are Psychosocial Care and 18 Cultural and Spiritual titrated in the usual manner to provide acceptable control. Most patients will respond to this. This is The three possible treatment approaches include not palliative sedation per se, as that is intended the intent to reverse delirium, the intent to relieve only in severe refractory symptoms. Palliative with sedation and the intent to observe for the time sedation as a topic is discussed in Chapter 19 Death and Dying with its own criteria.
1. Intent to Relieve by Reversal In this approach, there is some likelihood of reversing delirium, particularly where the patient has a higher functional status.
Criteria for this include:• Known patient wish for intervention where possible, even if chances are low • If readily reversible • If potentially reversible e.g. opioid neurotoxicity• If not dying, i.e. earlier stages• If dying, trial attempts – only if patient had wanted active treatments and reverse is likely; otherwise no. Treatment examples – hydration, O , opioid rotation With this approach, some investigations and treatments will be carried out depending on the identified causes. Examples include antibiotics, 3. Intent to Observe Delirium Other Treatment Measures There are occasional times when, in known imminently dying patients, the patient develops Provide Education and Support: hallucinations, visions or physical movements which • Explanation (repeated) to patient, family and appear comforting(37), or at least not disturbing, and possibly have interpretable meaning to family. • Stress that the patient is not going ‘insane' This usually occurs in a hypoactive delirium, with its • There may be brief lucid periods for some quietness. Some view this mild restlessness, visions meaningful interaction and voices as a meaningful journey for the patient, with symbolism in the patient. Callanan's book Final Using More or Less Stimulation Gifts discusses such types of experiences wherein some family find comfort(47).
In these cases, it may be prudent to observe the Provide a safe and relaxing environment.
patient, provide support to family, but be prepared Patients with delirium need LESS stimulation: to initiate sedative therapy if circumstances change • Quiet, well-lit room to agitation. As Breitbart and Cohen(37) note, • Minimal staff changes "such a ‘wait and see' approach must, however, • Repeated reassurance, explanation be tempered by the knowledge that a lethargic • Calendars, clocks, observing sunshine, darkness, or hypoactive delirium may very quickly and unexpectedly become an agitated delirium that • Contacts with fewer people can threaten the serenity and safety of the patient, • Sedation as necessary family and staff." At the same time, in the study discussed Patients with dementia need MORE stimulation, but above(42), patients with hypoactive delirium who structured so as not to further disorient:
survived recalled that they were highly distressed • Constant reorientation to time, place during delirium. Guidance by the temporary • Familiar and constant surroundings substitute decision-maker and other family, along • Sedation often worsens disorientation with the palliative care team, is needed to determine the most appropriate course of management.
Use of Relaxation Techniques Some relaxation therapies may be helpful while others may worsen delirium. For example, massage, tub baths, gentle music, scripture, etc. may assist in calming the patient, while visualization or guided imagery can worsen hallucinations or deepen feelings of fear and dissociation from reality. Therefore, these need to be applied on an individual basis.
Drug Therapy in Delirium ‘hypoactive' delirium, and delirium of ‘severe' intensity. Another reported value in the elderly who were non-responsive to other neuroleptics(64). Two classes of drugs can be used as indicated, There have been two case reports of opioid-induced neuroleptics and anxiolytics. Neuroleptic drugs delirium while on olanzapine, so its role in the are the standard and quite effective(48–50). multiple etiologies in palliative care remains unclear There are the so-called ‘conventional' and ‘modern at present(65). Dosage is 2.5–10.0mg once to twice atypical' drugs with some being more sedating daily PO or by dissolvable wafer on the tongue(37) methotrimeprazine, and also as injectable.
olanzapine) and others less so (e.g. haloperidol, Methotrimeprazine is effective and used as
quetiapine). Drugs in both categories are used an alternative to haloperidol(66,67). It is a higher for delirium management as discussed here, and sedation drug at doses of 15mg or above. It can be also for intractable or refractory delirium as part given PO, SC, IV as well as SL. Very low doses are of palliative sedation as discussed in Chapter 19 used for nausea (0.5–2.5mg) but control of delirium Death and Dying. usually requires 10–15mg for mild and up to 50mg A Cochrane review(10) noted that evidence for severe delirium. These may be given q4–8h is scarce regarding this class of drugs in terminal initially, then less often once controlled(37).
care. Recognizing this limit, haloperidol is the most
Quetiapine may be an acceptable and safe
suitable drug therapy for the treatment of patients alternative(68) but there is little evidence in the with delirium near the end of life. Chlorpromazine
palliative field. Some have found it helpful at mean may be an acceptable alternative if a small risk of dosing of 93±23mg/day(69) or mean dosing of slight cognitive impairment is not a concern. This 44±30mg/day(70). Anecdotally, some have started was based mainly on a study by Breitbart(51) but at a low dose 6.25mg bid and increased as needed also with support from other case studies(52-56).
(71). For agitated dementia with delusions, an Haloperidol is generally considered the gold
expert panel's first-line recommendation is an standard. It is a longer acting drug(48) which antipsychotic drug: risperidone (0.5–2.0 mg/day) can be given PO, SC, IM or IV. In delirium, a was first line followed by quetiapine (50-150mg/day) suggested regimen is 0.5–1.5mg PO (mild), 1.5– and olanzapine (5.0–7.5mg/day) as high second-line 5.0mg PO (severe) or 10mg SC or IV (very severe) [one report of up to 250mg/24hr(57)]. These doses Other possible drugs are droperidol, risperidone, may be repeated q30–60 minutes until alleviation thioridazine or molindone.
(37,58). Once controlled, the maintenance dose In cases of hypoactive delirium, methylphenidate
suggested is 50% of amount to achieve control, may be effective(73-75). Neuroleptics in low doses usually between 1.5–20mg daily divided to 1–3 may also be effective alone(76) or in combination times daily. Typical doses in the first hour range with methylphenidate in improving hypoactive from 0.5–20mg (45). Caution is needed in elderly patients who may need as little as 0.25–0.5mg
q4h PRN(59), unless severe. The parenteral dose
should be 50% of the oral dose (48). It does have
a higher EPS profile and, if needed, benztropine
Benzodiazepine drugs do not clear the sensorium is usually effective or lorazepam in selected cases or improve cognition(45), and should not be where sedation is not an issue. Rare concerns used for delirium unless as an adjunct to primary are QT interval prolongation(59) or neuroleptic therapy with haloperidol or anther neuroleptic(48). Lorazepam alone appears to be ineffective and is Olanzapine is a newer atypical antipsychotic in fact associated with treatment-limiting adverse (61). It may be helpful where haloperidol is effects(78), but in combination may provide quicker contraindicated(62). It has a low EPS profile but and more effective control(78). Particular caution is more sedating. In one trial, 75% had complete should be used in the elderly or those with hepatic response(63). Of those with poorer response, factors included age >70 years, history of dementia, central The main role of this class is where haloperidol nervous system spread of cancer and hypoxia, fails to control delirium, as in severe agitation or terminal restlessness. The goal in these cases is quiet sedation only(38). In this situation, benzodiazepines give effective palliation of restlessness and, unlike haloperidol or other phenothiazines, do not exacerbate the existing tendency to myoclonus and convulsions(79). Lorazepam is often used. It has an intermediate
half-life, no active metabolites and several routes are Terminology and Etiology available (SL, PO, SC, IV). Doses vary widely from 0.5mg to 5mg. In mild cases of delirium, it should be This term is variously used in health care and avoided as noted above or used on a PRN only basis thus, is often unclear. It may be defined as(89): 1) for agitation until the neuroleptic provides overall inability to rest or relax or be still, 2) the quality of control, especially if the goal is reversal of delirium. being ceaselessly moving or active, or 3) a feeling of In severe delirium with agitation and/or violent agitation expressed in motion.
behavior, purposeful but hopefully temporary In the broader context of palliative care, there sedation is necessary, in which case both the are several categories in which restlessness may be neuroleptic and anxiolytic doses require escalation. Lorazepam may be 1–2–5mg SC q1h until control • Physical – pain, constipation, bladder retention,
of agitation, then reduced as quickly as possible on hypoxia, metabolic, organ failure, fever, etc.
a q4h basis.
• Drug effect – EPS akathisia, opioid-induced
Midazolam is also frequently used in delirium,
neurotoxicity, etc.
but is more helpful for the restlessness aspect(79). In • Psychosocial – personal suffering, existential
acute dosing, it is short-acting and rapidly effective. anguish, interpersonal conflict, spiritual journey, With longer-term infusion, the drug is widely worry, grief, etc.
redistributed and may result in prolonged effect(45). • Psychiatric – delirium of any cause, dementia,
Initial dosing may be 5–10mg SC then 2–5mg SC anxiety disorder, psychosis, etc.
PRN or by pump at 1–2–4mg/hr SC. Total daily • Imminently dying – any combination of above
doses have varied from 20–200mg/day(80,81).
with altered, fluctuating and declining state of In a review by Kehl(82), a number of studies demonstrated the effectiveness of other medications such as benzodiazepines (notably Kehl(82) lists several terms used in the literature midazolam and lorazepam) or phenothiazines, to describe the latter in dying patients, including either alone or in combinations. There is terminal delirium, terminal restlessness, terminal insufficient evidence to suggest that a single agitation, terminal anguish and confusion at end-of- medication or class of medications is appropriate for terminal restlessness. There is a clear need for As readily appreciated, each of these categories additional trials of neuroleptics, benzodiazepines, and sub-issues require assessment and, generally barbiturates and combination protocols to speaking, separate strategies for relief. Sometimes, determine which protocols are the most effective however, the strategy is even ‘not to relieve' per se, and have the least side-effects(82).
as this may reflect an important emotional process for the patient.
Propofol, a short-acting anesthetic, could also be
used. Suggested starting doses are 10mg IV bolus, then 10mg/hr(83), or 20mg stat then 10–70mg/hr(84, 85).
Phenobarbital may be helpful(86,76) or in
combination if midazolam fails to provide adequate sedation(67,88) in refractory cases.
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