Often under-recognised or misdiagnosed, delirium is also known as ‘acute and fluctuating confusional state’. A serious condition, it can cause significant patient, family and healthcare distress. It is associated overall with poorer outcomes leading to increased morbidity, mortality and longer hospitalisations.^1,2

Delirium can affect between 28-88% of patients with advanced cancer, with an incidence of 3-45% in specialist palliative care inpatients.^1,3 The incidence increases as end of life approaches.⁴

Delirium can be challenging to recognise and subsequently manage particularly in the palliative care population at end of life. Distinguishing it from dementia, especially when they co-exist, can cause clinical management dilemmas for healthcare professionals. This review article will look at how to assess and manage delirium, principally focusing on the palliative care population.

Diagnosis

Delirium is diagnosed on the basis of the DSM IV diagnostic criteria:

• Inattention

• Disorganised thinking

• At least two of the following:

– reduced level of consciousness

– perceptual disturbance

– disturbance in sleep-wake cycle

– disorientation to time, place or person

– memory impairment.

• Short history and fluctuation.

An important step in diagnosing delirium is to distinguish it from dementia. This can be a challenge clinically and certain features can be helpful (see Table 1 below).

There are three clinical subtypes of delirium based on psychomotor features: 

• Hyperactive
• Hypoactive
• Mixed.

Hyperactive delirium is associated with heightened arousal, leading to restless, agitated and aggressive behaviours. 

Identifying hypoactive and mixed delirium can be more challenging.² In the palliative care setting, hypoactive delirium is often more common and hence under-recognised. 

Hypoactive delirium is denoted by withdrawn, quiet and somnolent features. It is often associated with dehydration and global encephalopathy, and patients are at increased risks of falls, longer hospitalisations and poorer outcomes.^2,3

Hyperactive and mixed deliriums are more likely to be associated with medication as a consequence of side-effects, substance intoxication or withdrawal.

Screening tools have been established to aid in the diagnosis. The CAM (Confusion Assessment Method) is a diagnostic algorithm that is both sensitive (94%) and specific (89%) for the diagnosis of delirium especially when applied by specialists (see Figure 1).⁵

The algorithm is based on the cardinal features of delirium:
(1) Acute onset with fluctuating course and (2) Impaired ability to focus or sustain attention, ie. distractibility
and either (3) Disorganised thinking or (4) Altered cognition (see Figure 2).

Recent research in developing screening tools shows that simple attention tests are useful in delirium screening. The MOTYB (ie. naming the months of the year backwards) is the best individual screening test for delirium especially in the elderly.⁶

Certain patient groups are more susceptible to developing a delirium. In particular elderly patients, those with cognitive impairment or reduced sensory input (visual impairment/deafness) and exposure to certain medications all increase the risk of delirium.⁷

 (click to enlarge)

Figure 1. Confusion assessment (CAM) shortened version of worksheet (adapted from: Inouye SK et al. Clarifying confusion: The confusion assessment method. A new method for detection of delirium. Ann Intern Med 1990; 113: 941-8)(click to enlarge)

Figure 2. Cardinal features of delirium(click to enlarge)

Aetiology

The aetiology of delirium is often multifactorial. A list of potential causes is outlined in Table 2. 

The medications used in achieving symptom control in palliative care patients may also be causing or exacerbating the delirium. Anticholinergics in particular can cause a delirium and therefore caution is needed when introducing, combining or titrating these drugs (opioids, steroids, SSRIs, atropine, glycopyrolate and tricyclic antidepressants.⁸

 (click to enlarge)

Management

A multifaceted approach required in the management of delirium. As with all symptoms in palliative care, management is tailored to the individual based on likely causes, potential reversibility, consideration of overall performance status, their recent illness trajectory and goals of treatment.⁹

The first step in managing a patient with delirium is to identify all potential reversible or contributory factors.² A thorough history and examination followed by appropriate investigations will help in identifying potential reversible causes. If indicated the following should be arranged: baseline blood tests (to check full blood count, renal  function, liver function, corrected calcium), urinanlysis( +/- MSU) and imaging if indicated, eg. chest x-ray, CT brain. Where appropriate any underlying cause should be corrected. Examples include sepsis, dehydration or electrolyte disturbances. Review and consider the role of drugs that may be aggravating or causing delirium, eg. anticholinergics, steroids. Recognition and management of opioid toxicity in particular and opioid induced neurotoxicity is essential in this population.

When reversibility is not possible, then delirium is a relatively reliable predictor of approaching death. It is important to recognise this situation, ie. an end-of-life delirium, so the transition of care can be made for the multidisciplinary team and the family and to enable a change in the focus of care to one of comfort measures. This needs to be discussed and communicated clearly with the family so they are aware of the significance.¹⁰

Management of delirium involves both non-pharmacological and pharmacological approaches. Better outcomes are achieved when drug and non-pharmacological interventions are combined.^2,11 An interdisciplinary approach to optimising environmental factors so as to promote cognition and safety, and the provision of information to and involvement of family members is key.¹

A delirious patient requires:

• Simple communication
• Reality orientation
• Adequate lighting 
• One-to-one care.

Antipsychotics

Antipsychotics remain the cornerstone of pharmacological treatment of delirium (oral or parenteral). The 2010 NICE guidance on delirium supports the use of antipsychotics, either typical or atypical, in the pharmacological management of delirium, despite the lack of evidence. Ideally, the lowest dose antipsychotic is used for the shortest possible time.²

Guidance from the 2007 Cochrane review on the use of antipsychotics in delirium highlights some areas of note:¹²

Haloperidol, risperidone and olanzapine all have similar clinical effect in managing delirium. Low-dose haloperidol has no increased incidence of adverse effects when compared to low-dose atypical antipsychotics. Studies support the use of haloperidol at low dose for a short period in delirious patients. Haloperidol at < 3mg/day is effective in reducing severity and duration of delirium. With higher doses of haloperidol, there is increased risk of extrapyramidal side-effects (eg. Parkinsonism, tremor, rigidity, akathisia/restlessness and tardive dyskinesia) and cardiac toxicity (prolonged QT interval). In patients requiring higher doses, use of atypical antipsychotics may lead to fewer adverse effects

The newer atypical antipsychotics, eg. olanzapine and risperidone, have been associated with increased risk of stroke, especially in older people with dementia, when used at high doses

Quetiapine is being used more frequently in managing delirium in palliative care patients. Although it can cause extra-pyramidal side effects, its use in the management of delirium is favoured as studies to date showed no extra-pyramidal side effect in the delirious patients treated. However, these studies were limited by absence of a control group and further research in its use in delirium is needed.¹²

Levomepromazine is an antipsychotic drug that is widely used in palliative care. In addition to its antipsychotic properties, it also has anxiolytic, antiemetic and sedative effects.¹³ It is indicated as an adjunct in the relief of pain with accompanying anxiety or distress. As a result of its additional sedative effect, it is often used in the management of hyperactive or mixed delirium at end of life.

Benzodiazepines

Although benzodiazepines are not recommended as first-line in the management of delirium, their role in the management of delirium due to alcohol or acute benzodiazepine withdrawal is acknowledged.^2,12 In the palliative care setting, they have the potential to precipitate a paradoxical agitation and therefore should be used with caution.¹⁴

In hyperactive delirium, benzodiazepines may be used as an adjunct to antipsychotics, either orally or subcutaneously, eg. midazolam and haloperidol.¹⁵

Methylphenidate

Methylphenidate is a psycho-stimulant originally used for the treatment of attention deficit disorder. It inhibits neuronal neurotransmitter transporters involved in the uptake of dopamine and norepinephrine at the level of the synapse. This leads to increased concentrations of dopamine and norepinephrine in the synapse resulting in increased alertness.¹⁵ The stimulant effect of methylphenidate has been used for the treatment of major depression, post-stroke depression, fatigue, delirium and sedation associated with opioid use. 

Three studies examining the role of methylphenidate in advanced cancer patients with a hypoactive delirium showed improved end-of-life cognitive function and wakefulness.¹⁶ It is typically commenced at doses of 2.5mg twice daily or 5mg once daily and may be titrated to 15mg twice daily, once tolerated by blood pressure and heart rate. 

Conclusion

Delirium is an increasingly common condition encountered in the palliative care patient population. It can be difficult to recognise and is associated with poorer outcomes for patients, particularly if it is not reversible. It can be distressing for the patient, family member and healthcare workers. 

Earlier recognition can be aided by using diagnostic tools. Management requires both non-pharmacological and pharmacological approaches. Potential reversible causes should be first identified and corrected. Antipsychotic medications remain the mainstay of pharmacological treatment and greater understanding of their use and tolerability is emerging. 

References

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