Dr Andrew Clegg, MBBS BSc MRCP
Dunhill Medical Trust Research Fellow
Professor John Young, MBBS MSc MBA FRCP
Professor of Elderly Care Medicine
Bradford Institute for Health Research
Bradford Teaching Hospitals NHS Foundation Trust
Delirium is a common clinical problem that is characterised by the rapid onset of fluctuating confusion and impaired awareness.1 The National Institute for Health and Clinical Excellence (NICE) delirium guideline has recently been published to help healthcare professionals diagnose, prevent and manage delirium.2
Pharmacists have an important role in the implementation of the NICE delirium guideline. Firstly, effective prevention of delirium requires knowledge of the medications that are associated with an increased risk of the condition so that they can be avoided. Secondly, effective management of delirium requires knowledge of the agents that can be used to treat the symptoms of delirium, and when these agents are contraindicated. We will summarise the NICE delirium guideline, with particular reference to the role of pharmacists in its implementation.
Causes and consequences of delirium
Delirium occurs when a susceptible individual is exposed to often multiple precipitants such as infections, medications and severe pain.2 Age over 65, presence of a severe illness, acute hip fracture and presence of cognitive impairment or dementia increase the risk of delirium by approximately five fold.2 Clustering of these risk factors in individuals occurs throughout acute wards in hospitals and in long-term care. This explains the high rates of delirium in these healthcare settings. Delirium is particularly common in the intensive care unit (ICU) with approximately 70% of ICU patients developing delirium during their admission. Delirium is also common on general medicine, orthopaedic and vascular surgery wards, with around 30% of patients developing delirium during their stay. The point prevalence of delirium in long-term care is approximately 15%.2
Delirium is associated with important adverse health consequences and the symptoms of delirium, such as agitation and hallucinations, are distressing to patients. Development of delirium increases the risk of in-patient complications, length of hospital stay, risk of dementia, risk of admission to long-term care and risk of death.2 As delirium is common and these adverse health consequences are expensive, the economic impact of delirium is high. The total annual direct cost of delirium in the United States has been estimated as up to $154 billion, which rivals the total annual cost of diabetes care.3 Although delirium is common and associated with adverse health consequences, the detection of delirium by healthcare professionals is often poor.2 A recent well conducted UK study reported that the delirium detection rate was only 25% for older people presenting to a medical assessment unit.4
Prevention of delirium
Prevention of delirium is clearly desirable and pharmacological prophylaxis is one option. A large randomised controlled trial (RCT) investigated the effects of haloperidol for patients presenting with a fractured hip and reported a reduction in the severity and duration of delirium but not incidence.5
The best supported approach for delirium prevention relates to multicomponent interventions delivered to people at higher risk. Research studies internationally suggest it is possible to prevent delirium from developing in around 30% of cases.2 The NICE delirium guideline promotes the prevention of delirium in a two-stage process. Firstly, people who are at risk of developing delirium are identified at admission to hospital or long-term care if any of the important risk factors for delirium (age over 65, severe illness, hip fracture or presence of cognitive impairment/dementia) are present. Secondly, these higher risk people are then provided with a multicomponent delirium prevention intervention that is targeted at important clinical factors identified as potential precipitants of delirium. The clinical factors and associated preventative interventions are summarised in Table 1.
A medication review that takes into account the number and type of prescribed medications is an important part of the multicomponent delirium prevention intervention.2 Understanding of the pathophysiology of delirium and the medications that are associated with an increased risk of delirium is therefore important. Identification and management of pain is another important element of the multicomponent delirium prevention intervention, and particular knowledge of the complex association between opioid medications and delirium is required.
Pathophysiology of delirium
Multiple neurotransmitter pathways are involved in the development of delirium but particularly cholinergic and dopaminergic pathways.6 Many commonly prescribed medications have unintended cholinergic and dopaminergic activity and have been implicated in the development of delirium.7,8 Antihistamine H1 medications, H2 antagonists, steroids and digoxin exhibit anticholinergic activity; angiotensin converting enzyme (ACE) inhibitors, dihydropyridines and antiparkinson medications exhibit dopaminergic activity.7,9 Direct effects of medications on opioid and GABA receptors may also contribute to the complex pathophysiology of delirium. Reduced levels of hepatic esterases, important enzymes in medication metabolism, have been observed in frail older people and in acute illness and this may also contribute to the development of delirium.10
Medications to avoid in people at risk of delirium
A recent systematic review investigated the risk of delirium that is associated with individual medications.11 This systematic review identified evidence to suggest an approximately three fold increased risk of delirium associated with benzodiazepine medications and that these medications should therefore be avoided in people at risk of delirium where possible.
There is evidence to support a 2.5 fold increased risk of delirium with opioid medications and these medications should also be prescribed with caution in people at risk of delirium. However, opioids should not be avoided in people with acute severe pain as this can itself trigger delirium: a delicate clinical balance needs to be struck between effective pain control and too high a dose of opioids. Pethidine appears to be associated with a higher risk of delirium when compared to other opioids; oxycodone appears to be associated with a lower risk.
Lower quality evidence exists to suggest an increased risk of delirium with dihydropyridine and antihistamine H1 medications. Caution is advised when prescription of these medications for people at risk of delirium.
Reassuringly, good quality evidence exists to suggest that there is no increased risk of delirium associated with neuroleptic medications such as haloperidol. Low quality evidence exists to suggest no increased delirium risk with digoxin.
There remains significant uncertainty regarding the risk of delirium that is associated with H2 antagonists, tricyclic antidepressants, antiparkinson medications, steroids, NSAIDs and antimuscarinic agents. This uncertainty reflects an evidence absence due to underpowered cohort studies.
Which medications should be used to treat the symptoms of delirium?
The NICE delirium guidelines emphasise that the treatment of the underlying cause or combination of causes of delirium is the most important aspect of management. This includes considering antibiotic sensitivities when treating infection and adjusting the dose or stopping medications that may be contributing to delirium where appropriate. Effective communication and reorientation of people with delirium is also advocated.2
Given the unpleasant experience and distress associated with delirium, there could be strong argument for sedating pharmacological treatments. Also, as described above, delirium is in part a disturbance of neurotransmitter function and drugs might have a role in ameliorating the underlying neuropathophysiological processes. However, the evidence base is far from robust and the potential harms of sedating and antipsychotic medications need to be considered. For example, recent large scale observational studies have reported neurotoxicity with increased stroke risk associated with anti-psychotic drugs, especially for people with dementia (a common group to experience delirium). Hence, the NICE guideline has taken a considered and cautious approach to the use of pharmacological treatments for delirium.
If people with delirium are distressed, or are considered a risk to themselves or others the NICE guideline recommends that verbal and non-verbal techniques should first be used to de-escalate the situation.
If verbal and non-verbal de-escalation techniques are ineffective or inappropriate, the prescription of haloperidol or olanzapine should be considered. This should be short term (usually for one week or less) and the lowest clinically appropriate dose should be used, titrated cautiously according to symptoms. These medications should be used cautiously or not at all if people have conditions such as Parkinson’s disease or dementia with Lewy bodies because such treatment increases the risk of harms such as increased extrapyramidal symptoms and the neuroleptic malignant syndrome.2
Following a careful consideration of the evidence, the NICE delirium guideline does not support the use of benzodiazepine medications to treat the symptoms of delirium. A recent Cochrane review also noted an absence of evidence to support benzodiazepines in delirium and did not recommend them to treat delirium symptoms.12
Research recommendations highlighted in the NICE delirium guideline include investigation of the pharmacological prevention and treatment of delirium. A large randomised trial is recommended in hospitalised people at high risk to compare atypical neuroleptics, typical neuroleptics, benzodiazepines or acetylcholinesterase inhibitors with placebo, or with each other, for preventing delirium.2 A large randomised trial should also be conducted in people in hospital to compare atypical neuroleptics, typical neuroleptics or benzodiazepines with placebo or each other for the treatment of delirium.2
The uncertainties regarding the risk of delirium associated with individual medications are mainly due to an evidence absence owing to a lack of adequately powered, rigorously designed studies. A large prospective cohort study to investigate the risk of delirium with individual medications which controls for important confounding variables would help address these uncertainties.
The NICE delirium guideline highlights the early identification of people at risk of delirium and the delivery of a multicomponent delirium prevention intervention that includes a detailed medication review and review of pain management for those at risk. Information to support an evidence-based choice of medication to treat the symptoms of delirium is also provided in the guideline.
Pharmacists are therefore well placed to contribute to the successful implementation of this guideline. Identification of which medications to avoid in people at risk of delirium will help guide a detailed medications review – an important part of the multicomponent delirium prevention intervention. Through a detailed understanding of the complex relationship between opioid medications and delirium, pharmacists can help guide the considered individual decisions that are required to achieve the fine balance between adequate pain control and delirium risk. Guidance from pharmacists regarding selection of appropriate medications to treat the distressing symptoms of delirium will also facilitate evidence-based decision making. The involvement of pharmacists in the design and implementation of clinical trials to investigate the research questions identified by the NICE delirium guideline will help address important uncertainties that remain regarding the pharmacological prevention and treatment of delirium.
JY is chairman of the NICE delirium guideline development group. AC is a member of the NICE delirium guideline development group.
Conflict of interest
JY is Principal Investigator for a National Institute for Health research programme grant investigating delirium prevention in the English NHS. l
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