Regular Research Articles| Volume 26, ISSUE 9, P913-924, September 2018

Download started.


Refining Delirium: A Transtheoretical Model of Delirium Disorder with Preliminary Neurophysiologic Subtypes


      • The immense clinical and neurophysiologic diversity in delirium suggests that the current one-size-fits-all approach may be misguided.
      • We propose a refined model of delirium disorder composed of interactive elements that elucidates key relationships and clarifies delirium nomenclature.
      • Our transtheoretical model highlights delirium neurophysiology as a novel treatment target.
      • We introduce a preliminary list of delirium disorder subtypes based on underlying neurophysiologic disturbance(s).
      The development of delirium indicates neurophysiologic disruption and predicts unfavorable outcomes. This relationship between delirium and its outcomes has inspired a generation of studies aimed at identifying, predicting, and preventing both delirium and its associated sequelae. Despite this, evidence on delirium prevention and management remains limited. No medication is approved for the prevention or treatment of delirium or for its associated psychiatric symptoms. This unmet need for effective delirium treatment calls for a refined approach. First, we explain why a one-size-fits-all approach based on a unitary biological model of delirium has contributed to variance in delirium studies and prevents further advance in the field. Next, in parallel with the shift from dementia to “major neurocognitive disorder,” we propose a transtheoretical model of “delirium disorder” composed of interactive elements—precipitant, neurophysiology, delirium phenotype, and associated psychiatric symptoms. We explore how these relate both to the biopsychosocial factors that promote healthy cognition (“procognitive factors”) and to consequent neuropathologic sequelae. Finally, we outline a preliminary delirium typology of specific neurophysiologic disturbances. Our model of delirium disorder offers several avenues for novel insights and clinical advance: it univocally differentiates delirium disorder from the phenotype of delirium, highlights delirium neurophysiology as a treatment target, separates the core features of delirium from associated psychiatric symptoms, suggests how procognitive factors influence the core elements of delirium disorder, and makes intuitive predictions about how delirium disorder leads to neuropathologic sequelae and cognitive impairment. Ultimately, this model opens several avenues for modern neuroscience to unravel this disease of antiquity.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to The American Journal of Geriatric Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Girard T.D.
        • Jackson J.C.
        • Pandharipande P.P.
        • et al.
        Delirium as a predictor of long-term cognitive impairment in survivors of critical illness.
        Crit Care Med. 2010; 38: 1513-1520
        • MacLullich A.M.
        • Beaglehole A.
        • Hall R.J.
        • et al.
        Delirium and long-term cognitive impairment.
        Int Rev Psychiatry. 2009; 21: 30-42
        • Salluh J.I.
        • Wang H.
        • Schneider E.B.
        • et al.
        Outcome of delirium in critically ill patients: systematic review and meta-analysis.
        BMJ. 2015; 350: h2538
        • Newman M.W.
        • O'Dwyer L.C.
        • Rosenthal L.
        Predicting delirium: a review of risk-stratification models.
        Gen Hosp Psychiatry. 2015; 37: 408-413
        • van Meenen L.C.
        • van Meenen D.M.
        • de Rooij S.E.
        • et al.
        Risk prediction models for postoperative delirium: a systematic review and meta-analysis.
        J Am Geriatr Soc. 2014; 62: 2383-2390
        • American Geriatrics Society Expert Panel on Postoperative Delirium in Older Adults
        American Geriatrics Society abstracted clinical practice guideline for postoperative delirium in older adults.
        J Am Geriatr Soc. 2015; 63: 142-150
        • Siddiqi N.
        • Stockdale R.
        • Britton A.M.
        • et al.
        Interventions for preventing delirium in hospitalised patients.
        Cochrane Database Syst Rev. 2007; (CD005563)
        • Lipowski Z.J.
        Delirium: Acute Brain Failure in Man.
        Charles C Thomas, Springfield, IL1980
        • Lipowski Z.J.
        Delirium: Acute Confusional States.
        Oxford University Press, New York1990
        • Pandharipande P.
        • Banerjee A.
        • McGrane S.
        • et al.
        Liberation and animation for ventilated ICU patients: the ABCDE bundle for the back-end of critical care.
        Crit Care. 2010; 14: 157
        • Abraha I.
        • Trotta F.
        • Rimland J.M.
        • et al.
        Efficacy of non-pharmacological interventions to prevent and treat delirium in older patients: a systematic overview. The SENATOR project ONTOP Series.
        PLoS ONE. 2015; 10 (e0123090)
        • Agar M.R.
        • Lawlor P.G.
        • Quinn S.
        • et al.
        Efficacy of oral risperidone, haloperidol, or placebo for symptoms of delirium among patients in palliative care: a randomized clinical trial.
        JAMA Intern Med. 2017; 177: 34-42
        • Robinson T.N.
        • Raeburn C.D.
        • Tran Z.V.
        • et al.
        Postoperative delirium in the elderly: risk factors and outcomes.
        Ann Surg. 2009; 249: 173-178
        • Pisani M.A.
        • Murphy T.E.
        • Araujo K.L.
        • et al.
        Factors associated with persistent delirium after intensive care unit admission in an older medical patient population.
        J Crit Care. 2010; 25 (e1–7): 540
        • Marcantonio E.R.
        • Simon S.E.
        • Bergmann M.A.
        • et al.
        Delirium symptoms in post-acute care: prevalent, persistent, and associated with poor functional recovery.
        J Am Geriatr Soc. 2003; 51: 4-9
        • Quinn T.J.
        Forward thinking: where next for delirium prevention research?.
        Cochrane Database Syst Rev. 2016; (ED000110)
        • Harwood R.H.
        • Teale E.
        Where next for delirium research?.
        Int J Geriatr Psychiatry. 2017; (Epub ahead of print)
        • Heckers S.
        The value of psychiatric diagnoses.
        JAMA Psychiatry. 2015; 72: 1165-1166
        • Stein D.J.
        • Phillips K.A.
        • Bolton D.
        • et al.
        What is a mental/psychiatric disorder? From DSM-IV to DSM-V.
        Psychol Med. 2010; 40: 1759-1765
        • Engel G.L.
        • Romano J.
        Delirium, a syndrome of cerebral insufficiency. 1959.
        J Neuropsychiatry Clin Neurosci. 2004; 16: 526-538
        • Maclullich A.M.
        • Ferguson K.J.
        • Miller T.
        • et al.
        Unravelling the pathophysiology of delirium: a focus on the role of aberrant stress responses.
        J Psychosom Res. 2008; 65: 229-238
        • Maldonado J.R.
        Neuropathogenesis of delirium: review of current etiologic theories and common pathways.
        Am J Geriatr Psychiatry. 2013; 21: 1190-1222
        • Gupta N.
        • de Jonghe J.
        • Schieveld J.
        • et al.
        Delirium phenomenology: what can we learn from the symptoms of delirium?.
        J Psychosom Res. 2008; 65: 215-222
        • Trzepacz P.T.
        The neuropathogenesis of delirium. A need to focus our research.
        Psychosomatics. 1994; 35: 374-391
        • Isabelle C.
        • Warner A.
        Long-term heavy use of diphenhydramine without anticholinergic delirium.
        Am J Health Syst Pharm. 1999; 56: 555-557
        • Piva S.
        • McCreadie V.A.
        • Latronico N.
        Neuroinflammation in sepsis: sepsis associated delirium.
        Cardiovasc Hematol Disord Drug Targets. 2015; 15: 10-18
        • Shim J.
        • DePalma G.
        • Sands L.P.
        • et al.
        Prognostic significance of postoperative subsyndromal delirium.
        Psychosomatics. 2015; 56: 644-651
        • Marcantonio E.R.
        • Rudolph J.L.
        • Culley D.
        • et al.
        Serum biomarkers for delirium.
        J Gerontol A Biol Sci Med Sci. 2006; 61: 1281-1286
        • Hall R.J.
        • Watne L.O.
        • Cunningham E.
        • et al.
        CSF biomarkers in delirium: a systematic review.
        Int J Geriatr Psychiatry. 2017; (Epub ahead of print)
        • Neufeld K.J.
        • Yue J.
        • Robinson T.N.
        • et al.
        Antipsychotic medication for prevention and treatment of delirium in hospitalized adults: a systematic review and meta-analysis.
        J Am Geriatr Soc. 2016; 64: 705-714
      1. Kendler K.S., Kupfer D., Narrow W., et al: Guidelines for making changes to DSM-V (Report to DSM-5 Work Groups), Arlington, VA.

        • Avidan M.S.
        • Evers A.S.
        Review of clinical evidence for persistent cognitive decline or incident dementia attributable to surgery or general anesthesia.
        J Alzheimers Dis. 2011; 24: 201-216
        • Nadelson M.R.
        • Sanders R.D.
        • Avidan M.S.
        Neurotoxicity of general anaesthesia is hypothetical.
        Br J Anaesth. 2015; 114: 344-345
        • Klein Klouwenberg P.M.
        • Zaal I.J.
        • Spitoni C.
        • et al.
        The attributable mortality of delirium in critically ill patients: prospective cohort study.
        BMJ. 2014; 349: g6652
        • Al-Qadheeb N.S.
        • Balk E.M.
        • Fraser G.L.
        • et al.
        Randomized ICU trials do not demonstrate an association between interventions that reduce delirium duration and short-term mortality: a systematic review and meta-analysis.
        Crit Care Med. 2014; 42: 1442-1454
        • Anderson B.J.
        • Mikkelsen M.E.
        Duration of delirium and patient-centered outcomes: embracing the short- and long-term perspective.
        Crit Care Med. 2014; 42: 1558-1559
        • Inouye S.K.
        • Kosar C.M.
        • Tommet D.
        • et al.
        The CAM-S: development and validation of a new scoring system for delirium severity in 2 cohorts.
        Ann Intern Med. 2014; 160: 526-533
        • Meagher D.J.
        • Leonard M.
        • Donnelly S.
        • et al.
        A longitudinal study of motor subtypes in delirium: relationship with other phenomenology, etiology, medication exposure and prognosis.
        J Psychosom Res. 2011; 71: 395-403
        • Koch C.
        • Massimini M.
        • Boly M.
        • et al.
        Neural correlates of consciousness: progress and problems.
        Nat Rev Neurosci. 2016; 17: 307-321
        • Shioiri A.
        • Kurumaji A.
        • Takeuchi T.
        • et al.
        A decrease in the volume of gray matter as a risk factor for postoperative delirium revealed by an atlas-based method.
        Am J Geriatr Psychiatry. 2016; 24: 528-536
        • Shafi M.M.
        • Santarnecchi E.
        • Fong T.G.
        • et al.
        Advancing the Neurophysiological Understanding of Delirium.
        J Am Geriatr Soc. 2017; 65: 1114-1118
        • Choi S.H.
        • Lee H.
        • Chung T.S.
        • et al.
        Neural network functional connectivity during and after an episode of delirium.
        Am J Psychiatry. 2012; 169: 498-507
        • Singhal A.B.
        • Topcuoglu M.A.
        • Koroshetz W.J.
        Diffusion MRI in three types of anoxic encephalopathy.
        J Neurol Sci. 2002; 196: 37-40
        • Iadecola C.
        The pathobiology of vascular dementia.
        Neuron. 2013; 80: 844-866
        • Thomas T.
        • Miners S.
        • Love S.
        Post-mortem assessment of hypoperfusion of cerebral cortex in Alzheimer's disease and vascular dementia.
        Brain. 2015; 138: 1059-1069
        • Sanford A.M.
        • Flaherty J.H.
        Do nutrients play a role in delirium?.
        Curr Opin Clin Nutr Metab Care. 2014; 17: 45-50
        • van de Rest O.
        • Berendsen A.A.
        • Haveman-Nies A.
        • et al.
        Dietary patterns, cognitive decline, and dementia: a systematic review.
        Adv Nutr. 2015; 6: 154-168
        • Dauncey M.J.
        Nutrition, the brain and cognitive decline: insights from epigenetics.
        Eur J Clin Nutr. 2014; 68: 1179-1185
        • Sfera A.
        • Cummings M.
        • Osorio C.
        Dehydration and cognition in geriatrics: a hydromolecular hypothesis.
        Front Mol Biosci. 2016; 3: 18
        • Riebl S.K.
        • Davy B.M.
        The hydration equation: update on water balance and cognitive performance.
        ACSMs Health Fit J. 2013; 17: 21-28
        • Basner M.
        • Rao H.
        • Goel N.
        • et al.
        Sleep deprivation and neurobehavioral dynamics.
        Curr Opin Neurobiol. 2013; 23: 854-863
        • Goel N.
        • Basner M.
        • Rao H.
        • et al.
        Circadian rhythms, sleep deprivation, and human performance.
        Prog Mol Biol Transl Sci. 2013; 119: 155-190
        • Oldham M.A.
        • Lee H.B.
        • Desan P.H.
        Circadian rhythm disruption in the critically Ill: an opportunity for improving outcomes.
        Crit Care Med. 2016; 44: 207-217
        • Kuehn B.M.
        Resetting the circadian clock might boost metabolic health.
        JAMA. 2017; 317: 1303-1305
        • Logan R.W.
        • Sarkar D.K.
        Circadian nature of immune function.
        Mol Cell Endocrinol. 2012; 349: 82-90
        • Tsang A.H.
        • Astiz M.
        • Friedrichs M.
        • et al.
        Endocrine regulation of circadian physiology.
        J Endocrinol. 2016; 230: R1-R11
        • Schultz D.P.
        Sensory Restriction: Effects on Behavior.
        Academic Press, New York1965
        • Weisman A.D.
        • Hackett T.P.
        Psychosis after eye surgery; establishment of a specific doctor-patient relation in the prevention and treatment of black-patch delirium.
        N Engl J Med. 1958; 258: 1284-1289
        • Scheydt S.
        • Muller Staub M.
        • Frauenfelder F.
        • et al.
        Sensory overload: a concept analysis.
        Int J Ment Health Nurs. 2017; 26: 110-120
        • Schweickert W.D.
        • Pohlman M.C.
        • Pohlman A.S.
        • et al.
        Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial.
        Lancet. 2009; 373: 1874-1882
        • Stillman C.M.
        • Cohen J.
        • Lehman M.E.
        • et al.
        Mediators of physical activity on neurocognitive function: a review at multiple levels of analysis.
        Front Hum Neurosci. 2016; 10: 626
        • Wong R.Y.
        Physical exercise, cognition, and function in older people.
        J Am Med Dir Assoc. 2017; 18: 282-283
        • Morley J.E.
        • Cruz-Oliver D.M.
        Cognitive stimulation therapy.
        J Am Med Dir Assoc. 2014; 15: 689-691
        • Foroughi C.K.
        • Monfort S.S.
        • Paczynski M.
        • et al.
        Placebo effects in cognitive training.
        Proc Natl Acad Sci USA. 2016; 113: 7470-7474
        • Gatz M.
        Educating the brain to avoid dementia: can mental exercise prevent Alzheimer disease?.
        PLoS Med. 2005; 2: e7
        • Ruthirakuhan M.
        • Luedke A.C.
        • Tam A.
        • et al.
        Use of physical and intellectual activities and socialization in the management of cognitive decline of aging and in dementia: a review.
        J Aging Res. 2012; 2012 (384875)
        • Hilton D.A.
        • Shivane A.G.
        Basic pathologic reactions.
        in: Hilton D.A. Shivane A.G. Neuropathology Simplified: A Guide for Clinicians and Neuroscientists. Springer, Switzerland2015: 17-28
        • Maldonado J.R.
        Delirium pathophysiology: an updated hypothesis of the etiology of acute brain failure.
        Int J Geriatr Psychiatry. 2017; (Epub ahead of print)
        • Abraha I.
        • Rimland J.M.
        • Trotta F.
        • et al.
        Non-pharmacological interventions to prevent or treat delirium in older patients: clinical practice recommendations the SENATOR-ONTOP series.
        J Nutr Health Aging. 2016; 20: 927-936
        • Davis D.H.
        • Muniz-Terrera G.
        • Keage H.A.
        • et al.
        Association of delirium with cognitive decline in late life: a neuropathologic study of 3 population-based cohort studies.
        JAMA Psychiatry. 2017; 74: 244-251
        • Cizginer S.
        • Marcantonio E.
        • Vasunilashorn S.
        • et al.
        The cognitive reserve model in the development of delirium: the successful aging after elective surgery study.
        J Geriatr Psychiatry Neurol. 2017; 30: 337-345
        • Sepulveda E.
        • Franco J.G.
        • Trzepacz P.T.
        • et al.
        Delirium diagnosis defined by cluster analysis of symptoms versus diagnosis by DSM and ICD criteria: diagnostic accuracy study.
        BMC Psychiatry. 2016; 16: 167
        • Titulaer M.J.
        • McCracken L.
        • Gabilondo I.
        • et al.
        Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study.
        Lancet Neurol. 2013; 12: 157-165
        • Dharmarajan K.
        • Swami S.
        • Gou R.Y.
        • et al.
        Pathway from delirium to death: potential in-hospital mediators of excess mortality.
        J Am Geriatr Soc. 2017; 65: 1026-1033
        • Hill A.B.
        The environment and disease: association or causation?.
        Proc R Soc Med. 1965; 58: 295-300
        • Skelly D.
        • Griffin E.W.
        • Murra C.
        • et al.
        Acute transient cognitive dysfunction and acute brain injury induced by systemic inflammation occur by dissociable IL-1-dependent mechanisms.
        Mol Psychiatry. 2018;
        • Slor C.J.
        • Adamis D.
        • Jansen R.W.
        • et al.
        Delirium motor subtypes in elderly hip fracture patients: risk factors, outcomes and longitudinal stability.
        J Psychosom Res. 2013; 74: 444-449
        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders.
        American Psychiatric Association, Washington, DC2013
        • Chae J.H.
        • Miller B.J.
        Beyond Urinary Tract Infections (UTIs) and delirium: a systematic review of UTIs and neuropsychiatric disorders.
        J Psychiatr Pract. 2015; 21: 402-411
        • Blennow K.
        • Hardy J.
        • Zetterberg H.
        The neuropathology and neurobiology of traumatic brain injury.
        Neuron. 2012; 76: 886-899
        • Ponsford J.
        • Janzen S.
        • McIntyre A.
        • et al.
        INCOG recommendations for management of cognition following traumatic brain injury, part I: posttraumatic amnesia/delirium.
        J Head Trauma Rehabil. 2014; 29: 307-320
        • Giacino J.T.
        • Whyte J.
        • Bagiella E.
        • et al.
        Placebo-controlled trial of amantadine for severe traumatic brain injury.
        N Engl J Med. 2012; 366: 819-826
        • Heidland A.
        • Sebekova K.
        • Klassen A.
        • et al.
        Mechanisms of acute uremic encephalopathy: early activation of Fos and Fra-2 gene products in different nuclei/areas of the rat brain.
        J Ren Nutr. 2010; 20: S44-S50
        • Shirvani N.
        • Jimenez X.F.
        Cystocerebral syndrome: a case report and review of literature and mechanisms.
        J Am Geriatr Soc. 2015; 63: 2645-2647
        • Butterworth R.F.
        Pathogenesis of hepatic encephalopathy in cirrhosis: the concept of synergism revisited.
        Metab Brain Dis. 2016; 31: 1211-1215
        • Lewis C.
        • Deshpande A.
        • Tesar G.E.
        • et al.
        Valproate-induced hyperammonemic encephalopathy: a brief review.
        Curr Med Res Opin. 2012; 28: 1039-1042
        • Vossler D.G.
        • Wilensky A.J.
        • Cawthon D.F.
        • et al.
        Serum and CSF glutamine levels in valproate-related hyperammonemic encephalopathy.
        Epilepsia. 2002; 43: 154-159
        • Brusilow S.W.
        • Maestri N.E.
        Urea cycle disorders: diagnosis, pathophysiology, and therapy.
        Adv Pediatr. 1996; 43: 127-170
        • Michinaga S.
        • Koyama Y.
        Pathogenesis of brain edema and investigation into anti-edema drugs.
        Int J Mol Sci. 2015; 16: 9949-9975
        • Maldonado J.R.
        Acute brain failure: pathophysiology, diagnosis, management, and sequelae of delirium.
        Crit Care Clin. 2017; 33: 461-519
        • Rudberg M.A.
        • Pompei P.
        • Foreman M.D.
        • et al.
        The natural history of delirium in older hospitalized patients: a syndrome of heterogeneity.
        Age Ageing. 1997; 26: 169-174
        • Cole M.G.
        • Ciampi A.
        • Belzile E.
        • et al.
        Persistent delirium in older hospital patients: a systematic review of frequency and prognosis.
        Age Ageing. 2009; 38: 19-26
        • King F.
        • Morris N.A.
        • Schmahmann J.D.
        Delayed posthypoxic leukoencephalopathy: improvement with antioxidant therapy.
        Case Rep Neurol. 2015; 7: 242-246