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JNNP Online First, published on January 25, 2013 as 10.1136/jnnp-2012-304334 Neuropsychiatry
REVIEW
Improving delirium care through early intervention: from bench to bedside to boardroom Shane O’Hanlon,1,2 Niamh O’Regan,3 Alasdair M J MacLullich,4,5 Walter Cullen,1,6 Colum Dunne,1,6 Chris Exton,1,6 David Meagher1,6,7 1
Graduate Entry Medical School, University of Limerick, Ireland 2 Division of Geriatric Medicine, Department of Medicine, University Hospital Limerick, Limerick, Ireland 3 Centre for Gerontology and Rehabilitation, University College Cork, Cork 4 Edinburgh Delirium Research Group, Geriatric Medicine, Division of Health Sciences, School of Clinical Sciences, University of Edinburgh, Edinburgh, Scotland, UK 5 Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, Scotland, UK 6 Cognitive Impairment Research group (CIRG), Centre for Interventions in Infection, Inflammation & Immunity (4i), Graduate Entry Medical School, University of Limerick, Limerick, Ireland 7 Department of Psychiatry, University Hospital Limerick, Limerick, Ireland
ABSTRACT Delirium is a complex neuropsychiatric syndrome that impacts adversely upon patient outcomes and healthcare outcomes. Delirium occurs in approximately one in five hospitalised patients and is especially common in the elderly and patients who are highly morbid and/or have pre-existing cognitive impairment. However, efforts to improve management of delirium are hindered by gaps in our knowledge and issues that reflect a disparity between existing knowledge and real-world practice. This review focuses on evidence that can assist in prevention, earlier detection and more timely and effective pharmacological and non-pharmacological management of emergent cases and their aftermath. It points towards a new approach to delirium care, encompassing laboratory and clinical aspects and health services realignment supported by health managers prioritising delirium on the healthcare change agenda. Key areas for future research and service organisation are outlined in a plan for improved delirium care across the range of healthcare settings and patient populations in which it occurs.
Correspondence to Professor David Meagher, Graduate Entry Medical School, University of Limerick, Ireland;
[email protected]
DELIRIUM: A PRIME TARGET FOR EARLY INTERVENTION
Received 11 October 2012 Revised 10 December 2012 Accepted 12 December 2012
To cite: O’Hanlon S, O’Regan N, MacLullich AMJ, et al. J Neurol Neurosurg Psychiatry Published Online First: [ please include Day Month Year] doi:10.1136/ jnnp-2012-304334
Delirium is a serious neuropsychiatric syndrome that occurs in approximately one in five hospitalised patients, with rates of up to 90% reported among patients in palliative and intensive care settings.1 No other disorder has equivalent penetration across healthcare settings such that delirium has been likened to a ‘cognitive superbug’ that warrants the often effective preventative focus that infectious diseases have received in our healthcare environments.2 It is the commonest complication among hospitalised elderly and is associated with longer hospital stays, more complications, greater costs of care, reduced subsequent functional independence, and increased inhospital and subsequent mortality.1 3 Importantly, these adverse health and social outcomes are relatively independent of confounding factors such as morbidity level, baseline cognition, age and frailty. A quarter of older medical patients with delirium die within 1 month of its onset4 with a recent study estimating that the risk of mortality increases by 11% for every additional 48 h of delirium.5 In addition, delirium may be an accelerating and possibly causal factor in the development of dementia.6–9
O’Hanlon S, et al. J Article Neurol Neurosurg Psychiatry 2013;0:1–7. doi:10.1136/jnnp-2012-304334 Copyright author (or their employer) 2013. Produced
Despite this impact upon healthcare outcomes, delirium has been understudied in comparison with other neuropsychiatric conditions2 and there is much evidence to indicate that its management in everyday practice is suboptimal with inconsistent detection and treatment practices. Typically two-thirds of cases are undetected or misdiagnosed.1 10 Many cases are not formally recognised until symptoms have been present for days or weeks, presenting an avoidable delay in providing effective treatment. This reflects the challenges of recognising the often complex and fluctuating clinical presentation of delirium, but also relates to a lack of robust and consistently applied procedures for detecting and monitoring of delirium, even in patients at high risk. Non-detection is associated with especially poor outcomes including mortality.11 Non-detection also means that especially distressing aspects of delirium (such as hallucinations and delusions) are inadequately managed, and the lack of a clear explanation from professionals often provokes bewilderment and distress in carers.12 The frequency of delirium, its impact upon healthcare outcomes and evidence that delirium care can be substantially improved, all point towards delirium as a key target for improved practices.
BENCH: UNRAVELLING THE PSYCHOBIOLOGY OF DELIRIUM The clinical presentation of delirium includes a broad range of features indicative of widespread disturbance of brain function. In addition, the heterogeneous aetiology of delirium emphasises the connection between brain and body wellness. The principal pathophysiological theory of delirium emphasises the combined effect of brain insults (eg, hypoxia) with aberrant stress responses (eg, excess cortisol and exaggerated central nervous system (CNS) inflammation) perhaps inducing neurochemical (eg, relative cholinergic deficiency and dopaminergic excess) abnormalities that are expressed as delirium.13 The substantial interactions among cholinergic function, cognition and inflammatory processes suggest common mechanisms but their respective roles as predisposing or precipitating factors or merely epiphenomena requires clarification. Animal models of delirium can allow direct investigation of pathophysiology and testing of novel therapies. Trzepacz et al14 developed a hypocholinergic model based on atropine administration to rats that induces changes in EEG, behavioural
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Neuropsychiatry and maze performance that mirror features of human delirium. More recently, a model based upon activation of CNS inflammatory processes via peripheral inflammatory stimuli in animals with pre-existing neurodegenerative pathology has been used to explore the interaction between delirium and dementia. This work suggests that prior neurodegenerative pathology is associated with greater susceptibility to delirium due to an exaggerated response to systemic and CNS inflammatory signals due to factors such as microglial priming and synaptic loss at key areas of the brain (such as the hippocampus) which in turn are associated with heightened and more prolonged transcription of inflammatory mediators.15 Biomarkers can illuminate our understanding of delirium pathophysiology but can also assist in determining delirium proneness, allow for more accurate detection of delirium and assessment of illness severity, as well as monitoring of illness course and treatment response. Recent studies have identified evidence for serum, cerebrospinal fluid and genetic factors that (a) relate to increased baseline risk of delirium (APOE4 allele, low IGF-1), (b) link to the emergence of delirium (elevated C-reactive protein, cortisol, interleukin (IL)-8), (c) relate to delirium presence and course (IL-6, IL-8, IGF-1, chemokines) and (d) indicate neurotoxicity and possibly delirium severity (S-100B, NSE).16 17 Importantly, these studies take account of possible confounding factors such as age, prior cognitive function including dementia and severity of morbidity. Their integration into predictive models that include known clinical risk factors may allow for enhanced delirium prediction as well as illness monitoring. Other measures can also assist: the EEG shows generalised slowing in delirium and can help in distinguishing delirium from dementia, but this pattern lacks specificity18 and the practicalities of performing EEG on delirious patients limit widespread use. The few neuroimaging studies in delirium suggest that white matter disease may be an important predisposing factor for delirium.19 More recently, a small study of intensive care unit (ICU) patients found that duration of delirium correlated with degree of neurocognitive disturbance and white matter disruption at both 3- and 12-month follow-up.20 21 Other work has linked peripheral measures of anticholinergic activity (serum anticholinergic assay (SAA)) to delirium proneness but findings are inconsistent and SAA may not correlate closely with central cholinergic function.18 Melatonergic metabolism appears to be differentially affected in hypoactive versus hyperactive clinical subtypes of delirium22 highlighting the potential importance of circadian function as a key factor in delirium. Postoperative delirium is characterised by reduced serum levels of amino acids with low tryptophan (
