Introduction
Delirium is an acute, fluctuating change in mental status, with inattention, disorganized thinking, and altered levels of consciousness.[1]Inouye SK, Schlesinger MJ, Lydon TJ. Delirium: a symptom of how hospital care is failing older persons and a window to improve quality of hospital care. Am J Med. 1999 May;106(5):565-73.
http://www.ncbi.nlm.nih.gov/pubmed/10335730?tool=bestpractice.com
It is a potentially life-threatening disorder characterized by high morbidity and mortality. Guidelines address recognition, risk factors, and treatment for delirium.[2]Devlin JW, Skrobik Y, Gélinas C, et al; American College of Critical Care Medicine. Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. Crit Care Med. 2018 Sep;46(9):e825-e73.
https://journals.lww.com/ccmjournal/Fulltext/2018/09000/Clinical_Practice_Guidelines_for_the_Prevention.29.aspx
http://www.ncbi.nlm.nih.gov/pubmed/23269131?tool=bestpractice.com
[3]National Institute for Health and Care Excellence. Delirium: prevention, diagnosis and management in hospital and long-term care. Jan 2023 [internet publication].
https://www.nice.org.uk/guidance/cg103
Adverse sequelae
Mortality for those diagnosed with delirium in the hospital is twice that of patients with similar medical conditions without delirium and rises as high as 14% within 1 month of diagnosis.[4]Cole MG, Primeau FJ. Prognosis of delirium in elderly hospital patients. CMAJ. 1993 Jul 1;149(1):41-6.
http://www.ncbi.nlm.nih.gov/pubmed/8319153?tool=bestpractice.com
Delirium occurs in >20% of hospitalizations annually and is the most common hospital-related complication in the US.[5]Brown TM, Boyle MF. Delirium. BMJ. 2002 Sep 21;325(7365):644-7.
https://www.doi.org/10.1136/bmj.325.7365.644
http://www.ncbi.nlm.nih.gov/pubmed/12242179?tool=bestpractice.com
[6]US Department of Health and Human Services. 2004 CMS Statistics. Washington, DC: Centers for Medicare and Medicaid Services, 2004:34. (CMS Publication No 03445) Delirium is common in the intensive care unit especially among mechanically ventilated patients. In critically ill patients, it is associated with an increased length of stay and increased mortality.[7]Cavallazzi R, Saad M, Marik PE. Delirium in the ICU: an overview. Ann Intensive Care. 2012 Dec 27;2(1):49.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3539890
http://www.ncbi.nlm.nih.gov/pubmed/23270646?tool=bestpractice.com
Studies have demonstrated a 12% prevalence of delirium in older emergency department patients.[8]Han JH, Wilson A, Vasilevskis EE, et al. Diagnosing delirium in older emergency department patients: validity and reliability of the delirium triage screen and the brief confusion assessment method. Ann Emerg Med. 2013 Nov;62(5):457-65.
http://www.ncbi.nlm.nih.gov/pubmed/23916018?tool=bestpractice.com
Despite its frequency, delirium is frequently under-recognized given the fluctuating nature of symptoms and an overall underappreciation of its significance by healthcare providers. Moreover, delirium has also been associated with elevated risks for functional and cognitive decline, poor rehabilitation potential, institutionalization, and rehospitalization.[1]Inouye SK, Schlesinger MJ, Lydon TJ. Delirium: a symptom of how hospital care is failing older persons and a window to improve quality of hospital care. Am J Med. 1999 May;106(5):565-73.
http://www.ncbi.nlm.nih.gov/pubmed/10335730?tool=bestpractice.com
[9]Kiely DK, Bergmann MA, Murphy KM, et al. Delirium among newly admitted postacute facility patients: prevalence, symptoms, and severity. J Gerontol A Biol Sci Med Sci. 2003 May;58(5):441-5.
http://www.ncbi.nlm.nih.gov/pubmed/12730254?tool=bestpractice.com
[10]Murray AM, Levkoff SE, Wetle T, et al. Acute delirium and functional decline in the hospitalized elderly patient. J Gerontol. 1993 Sep;48(5):M181-6.
http://www.ncbi.nlm.nih.gov/pubmed/8366260?tool=bestpractice.com
[11]Marcantonio ER, Simon SE, Bergmann MA, et al. Delirium symptoms in post-acute care: prevalent, persistent, and associated with poor functional recovery. J Am Geriatr Soc. 2003 Jan;51(1):4-9.
http://www.ncbi.nlm.nih.gov/pubmed/12534838?tool=bestpractice.com
[12]van den Boogaard M, Schoonhoven L, Evers AW, et al. Delirium in critically ill patients: impact on long-term health-related quality of life and cognitive functioning. Crit Care Med. 2012 Jan;40(1):112-8.
http://www.ncbi.nlm.nih.gov/pubmed/21926597?tool=bestpractice.com
While delirium is generally considered reversible, studies suggest that delirium symptoms can last for weeks to months following onset.[13]Roche V. Southwestern Internal Medicine Conference. Etiology and management of delirium. Am J Med Sci. 2003 Jan;325(1):20-30.
http://www.ncbi.nlm.nih.gov/pubmed/12544081?tool=bestpractice.com
Persistent delirium has been found to be frequent in older hospitalized patients, and associated with adverse outcomes.[14]Cole MG, Ciampi A, Belzile E, et al. Persistent delirium in older hospital patients: a systematic review of frequency and prognosis. Age Ageing. 2009 Jan;38(1):19-26.
http://ageing.oxfordjournals.org/content/38/1/19.long
http://www.ncbi.nlm.nih.gov/pubmed/19017678?tool=bestpractice.com
Classification
The Diagnostic and Statistical Manual of Mental Disorders (DSM-5-TR) notes that in order to be diagnosed with delirium, a patient must show all 4 of the following features.[15]American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 5th ed., text revision (DSM-5-TR). Washington, DC: American Psychiatric Publishing; 2022
A disturbance in attention (i.e., reduced clarity of awareness of the environment) is evident, with reduced ability to focus, sustain, or shift attention. This disturbance in consciousness might be subtle, initially presenting solely as lethargy or distractibility, and might be frequently dismissed by clinicians and/or family members as being related to the primary illness.
A change in cognition (such as memory deficit, disorientation, language disturbance) or the development of a perceptual disturbance not better accounted for by a pre-existing or evolving dementia.
The disturbance develops over a short period of time (usually hours to days), represents an acute change from baseline, and tends to fluctuate during the course of the day.
There is evidence from the history, physical examination, or laboratory findings that the disturbance is caused by the direct physiologic consequences of a general medical condition, substance intoxication, or substance withdrawal. The changes in attention and cognition must not occur in the context of a severely reduced level of arousal, such as coma.
Three clinical subtypes of delirium have been identified.[16]Potter J, George J; Guideline Development Group. The prevention, diagnosis and management of delirium in older people: concise guidelines. Clin Med. 2006 May-June;6(3):303-8.
http://www.ncbi.nlm.nih.gov/pubmed/16826866?tool=bestpractice.com
[17]Gupta N, de Jonghe J, Schieveld J, et al. Delirium phenomenology: what can we learn from the symptoms of delirium? J Psychosom Res. 2008 Sep;65(3):215-22.
http://www.ncbi.nlm.nih.gov/pubmed/18707943?tool=bestpractice.com
[18]Meagher DJ, Leonard M, Donnelly S, et al. A longitudinal study of motor subtypes in delirium: frequency and stability during episodes. J Psychosom Res. 2012 Mar;72(3):236-41.
http://www.ncbi.nlm.nih.gov/pubmed/22325705?tool=bestpractice.com
These include:
Hyperactive delirium - a condition where a patient might have heightened arousal, with restlessness, agitation, hallucinations, and inappropriate behavior
Hypoactive delirium - a condition where a patient might display lethargy, reduced motor activity, incoherent speech, and lack of interest
Mixed delirium - a combination of hyperactive and hypoactive signs and symptoms.
The term subsyndromal delirium has also been used to define partially resolved or incomplete forms of delirium.
Epidemiology
The prevalence of delirium in the community is believed to be 1% to 2%, a figure that increases to 14% for patients age >85 years.[13]Roche V. Southwestern Internal Medicine Conference. Etiology and management of delirium. Am J Med Sci. 2003 Jan;325(1):20-30.
http://www.ncbi.nlm.nih.gov/pubmed/12544081?tool=bestpractice.com
Prevalence of delirium ranges from 10% to 40% in older hospitalized patients.[5]Brown TM, Boyle MF. Delirium. BMJ. 2002 Sep 21;325(7365):644-7.
https://www.doi.org/10.1136/bmj.325.7365.644
http://www.ncbi.nlm.nih.gov/pubmed/12242179?tool=bestpractice.com
Delirium affects up to 30% of people on medical floors.[3]National Institute for Health and Care Excellence. Delirium: prevention, diagnosis and management in hospital and long-term care. Jan 2023 [internet publication].
https://www.nice.org.uk/guidance/cg103
Prevalence ranges from 14% to 24% in the emergency department, 15% to 53% for postoperative patients, and 70% to 87% for intensive care patients.[19]Inouye SK. Delirium in hospitalized older patients. Clin Geriatr Med. 1998 Nov;14(4):745-64.
http://www.ncbi.nlm.nih.gov/pubmed/9799477?tool=bestpractice.com
[20]Pisani MA, McNicoll L, Inouye SK. Cognitive impairment in the intensive care unit. Clin Chest Med. 2003 Dec;24(2):727-37.
http://www.ncbi.nlm.nih.gov/pubmed/14710700?tool=bestpractice.com
[21]Neufeld KJ, Thomas C. Delirium: definition, epidemiology, and diagnosis. J Clin Neurophysiol. 2013 Oct;30(5):438-42.
http://www.ncbi.nlm.nih.gov/pubmed/24084176?tool=bestpractice.com
Pathophysiology
The pathophysiology of delirium remains relatively unclear. In general, neuroimaging studies reveal disruptions in higher cortical functioning in multiple disparate areas of the brain, including the prefrontal cortex, subcortical structures, thalamus, basal ganglia, lingual gyri, and frontal, fusiform and temporoparietal cortex.[22]Singer GG, Brenner BM. Fluid and electrolyte disturbances. In: Kasper DL, Fauci AS, Longo DL, et al. eds. Harrison's Principles of Internal Medicine, 16th ed. New York, NY: McGraw Hill; 2005:252-63.[23]Choi SH, Lee H, Chung TS, et al. Neural network functional connectivity during and after an episode of delirium. Am J Psychiatry. 2012 May;169(5):498-507.
http://www.ncbi.nlm.nih.gov/pubmed/22549209?tool=bestpractice.com
Electroencephalographic (EEG) studies also show diffuse slowing of cortical activity.
Theories on the pathogenesis of delirium point to the role of neurotransmitters, inflammation, and chronic stress on the brain. For example, the role of cholinergic deficiency in inducing delirium is strengthened by the clear association of anticholinergic drug use with increased incidence.[24]Trzepacz P, van der Mast R. The neuropathophysiology of delirium. In: Lindesay J, Rockwood K, Macdonald A, eds. Delirium in old age. Oxford, UK: Oxford University Press; 2002:51-90. Studies in surgical patients have demonstrated a dysfunctional interaction between the cholinergic and immune systems in patients who developed postoperative delirium.[25]Cerejeira J, Nogueira V, Luís P, et al. The cholinergic system and inflammation: common pathways in delirium pathophysiology. J Am Geriatr Soc. 2012 Apr;60(4):669-75.
http://www.ncbi.nlm.nih.gov/pubmed/22316182?tool=bestpractice.com
Dopaminergic excess is also believed to contribute. Evidence does not appear to support the use of antipsychotic medications (dopamine antagonists) for the prevention or treatment of delirium, but is not entirely consistent.[26]Oh ES, Needham DM, Nikooie R, et al. Antipsychotics for preventing delirium in hospitalized adults: a systematic review. Ann Intern Med. 2019 Oct 1;171(7):474-84.
https://www.doi.org/10.7326/M19-1859
http://www.ncbi.nlm.nih.gov/pubmed/31476766?tool=bestpractice.com
[27]Janssen TL, Alberts AR, Hooft L, et al. Prevention of postoperative delirium in elderly patients planned for elective surgery: systematic review and meta-analysis. Clin Interv Aging. 2019;14:1095-117.
https://www.doi.org/10.2147/CIA.S201323
http://www.ncbi.nlm.nih.gov/pubmed/31354253?tool=bestpractice.com
[28]Siddiqi N, Harrison JK, Clegg A, et al. Interventions for preventing delirium in hospitalised non-ICU patients. Cochrane Database Syst Rev. 2016 Mar 11;3:CD005563.
https://www.doi.org/10.1002/14651858.CD005563.pub3
http://www.ncbi.nlm.nih.gov/pubmed/26967259?tool=bestpractice.com
[29]Nikooie R, Neufeld KJ, Oh ES, et al. Antipsychotics for treating delirium in hospitalized adults: a systematic review. Ann Intern Med. 2019 Oct 1;171(7):485-95.
https://www.doi.org/10.7326/M19-1860
http://www.ncbi.nlm.nih.gov/pubmed/31476770?tool=bestpractice.com
[30]Zayed Y, Barbarawi M, Kheiri B, et al. Haloperidol for the management of delirium in adult intensive care unit patients: a systematic review and meta-analysis of randomized controlled trials. J Crit Care. 2019 Apr;50:280-6.
https://www.doi.org/10.1016/j.jcrc.2019.01.009
http://www.ncbi.nlm.nih.gov/pubmed/30665181?tool=bestpractice.com
[31]Burry L, Hutton B, Williamson DR, et al. Pharmacological interventions for the treatment of delirium in critically ill adults. Cochrane Database Syst Rev. 2019 Sep 3;9:CD011749.
https://www.doi.org/10.1002/14651858.CD011749.pub2
http://www.ncbi.nlm.nih.gov/pubmed/31479532?tool=bestpractice.com
[32]Kishi T, Hirota T, Matsunaga S, et al. Antipsychotic medications for the treatment of delirium: a systematic review and meta-analysis of randomised controlled trials. J Neurol Neurosurg Psychiatry. 2016 Jul;87(7):767-74.
https://www.doi.org/10.1136/jnnp-2015-311049
http://www.ncbi.nlm.nih.gov/pubmed/26341326?tool=bestpractice.com
[33]Finucane AM, Jones L, Leurent B, et al. Drug therapy for delirium in terminally ill adults. Cochrane Database Syst Rev. 2020 Jan 21;1(1):CD004770.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984445
http://www.ncbi.nlm.nih.gov/pubmed/31960954?tool=bestpractice.com
Other neurotransmitters implicated in the pathophysiology of delirium include norepinephrine, serotonin, gamma-aminobutyric acid, glutamate, and melatonin.
Evidence also points to the role of cytokines such as interleukins 1 and 2 and TNF-alpha and interferon in contributing to delirium.[34]Cerejeira J, Lagarto L, Mukaetova-Ladinska EB. The immunology of delirium. Neuroimmunomodulation. 2014;21(2-3):72-8.
http://www.ncbi.nlm.nih.gov/pubmed/24557038?tool=bestpractice.com
Finally, chronic hypercortisolism, as induced by chronic stress secondary to illness or trauma, may also contribute to delirium initiation.[35]Inouye SK. Delirium in older persons. N Engl J Med. 2006 Mar 16;354(11):1157-65.
http://www.ncbi.nlm.nih.gov/pubmed/16540616?tool=bestpractice.com
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