Essential Readings

General reviews and education

• Wilson JE, Mart MF, Cunningham C, et al. Delirium. Nat Rev Dis Primers 2020;6:90.
• Marcantonio ER. Delirium in Hospitalized Older Adults. N Engl J Med 2017;377:1456-66.
• Oh ES, Fong TG, Hshieh TT, et al. Delirium in Older Persons: Advances in Diagnosis and Treatment. JAMA 2017;318:1161-74.
• Oldham MA, Flanagan NM, Khan A, Boukrina O, Marcantonio ER. Responding to Ten Common Delirium Misconceptions With Best Evidence: An Educational Review for Clinicians. J Neuropsychiatry Clin Neurosci 2018;30:51-7.
• Inouye SK, Westendorp RG, Saczynski JS. Delirium in elderly people. Lancet 2014;383:911-22.

Reviews of pathophysiology and biomarkers

• Maldonado JR. Delirium pathophysiology: An updated hypothesis of the etiology of acute brain failure. Int J Geriatr Psychiatry 2018;33:1428-57.
• Maldonado JR. Acute Brain Failure: Pathophysiology, Diagnosis, Management, and Sequelae of Delirium. Crit Care Clin 2017;33:461-519.
• Khan BA, Perkins AJ, Prasad NK, et al. Biomarkers of Delirium Duration and Delirium Severity in the ICU. Crit Care Med 2020;48:353-61.

Intervention trials

• Inouye SK, Bogardus ST, Jr., Charpentier PA, et al. A multicomponent intervention to prevent delirium in hospitalized older patients. The New England journal of medicine 1999;340:669-76.

Seminal RCT of non-pharm interventions to prevent delirium: positive

• Pandharipande PP, Pun BT, Herr DL, et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA 2007;298:2644-53.

RCT of dexmedetomidine vs lorazepam in ventilated ICU patients: dex superior

• Girard TD, Kress JP, Fuchs BD, et al. Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial. Lancet 2008;371:126-34.

RCT of ABC on critical care outcomes: positive

• Riker RR, Shehabi Y, Bokesch PM, et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: A randomized trial. JAMA 2009;301:489-99.

RCT of dexmedetomidine vs midazolam in ventilated ICU patients: dex superior

• van Eijk MM, Roes KC, Honing ML, et al. Effect of rivastigmine as an adjunct to usual care with haloperidol on duration of delirium and mortality in critically ill patients: a multicentre, double-blind, placebo-controlled randomised trial. Lancet 2010;376:1829-37.

Placebo-controlled RCT of adjunctive rivastigmine added to haloperidol: halted for safety concerns

• Page VJ, Ely EW, Gates S, et al. Effect of intravenous haloperidol on the duration of delirium and coma in critically ill patients (Hope-ICU): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med 2013;1:515-23.

Placebo-controlled RCT of haloperidol for ventilated ICU patients: negative

• Agar MR, Lawlor PG, 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.

Placebo-controlled RCT of risperidone & haloperidol for delirium symptoms in palliative care: negative

• Avidan MS, Maybrier HR, Abdallah AB, et al. Intraoperative ketamine for prevention of postoperative delirium or pain after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial. Lancet 2017;390:267-75.

RCT of single intraoperative dose of ketamine on postop delirium & pain: negative

• van den Boogaard M, Slooter AJC, Bruggemann RJM, et al. Effect of Haloperidol on Survival Among Critically Ill Adults With a High Risk of Delirium: The REDUCE Randomized Clinical Trial. JAMA 2018;319:680-90.

Placebo-controlled RCT of haloperidol on ICU survival: no association found

• Girard TD, Exline MC, Carson SS, et al. Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness. N Engl J Med 2018;379:2506-16.

Placebo-controlled RCT of haloperidol & ziprasidone for ICU delirium: negative

• Pun BT, Balas MC, Barnes-Daly MA, et al. Caring for Critically Ill Patients with the ABCDEF Bundle: Results of the ICU Liberation Collaborative in Over 15,000 Adults. Crit Care Med 2019;47:3-14.

Prospective study of A-to-F bundle adherence on ICU outcomes (n = 15,226): positive

• Wildes TS, Mickle AM, Ben Abdallah A, et al. Effect of Electroencephalography-Guided Anesthetic Administration on Postoperative Delirium Among Older Adults Undergoing Major Surgery: The ENGAGES Randomized Clinical Trial. JAMA 2019;321:473-83.

RCT of EEG-guided anesthesia on postop delirium: negative

• Subramaniam B, Shankar P, Shaefi S, et al. Effect of Intravenous Acetaminophen vs Placebo Combined With Propofol or Dexmedetomidine on Postoperative Delirium Among Older Patients Following Cardiac Surgery: The DEXACET Randomized Clinical Trial. JAMA 2019;321:686-96.

4-arm RCT (acetaminophen vs placebo; propofol vs dexmedetomidine) on post-cardiotomy delirium: positive for acetaminophen

• Hughes CG, Mailloux PT, Devlin JW, et al. Dexmedetomidine or Propofol for Sedation in Mechanically Ventilated Adults with Sepsis. N Engl J Med 2021;384:1424-36.

RCT of dexmedetomidine vs propofol for sedation in ventilated ICU patients: no clear superiority

Reviews of interventions

• Prevention:Oh ES, Needham DM, Nikooie R, et al. Antipsychotics for Preventing Delirium in Hospitalized Adults: A Systematic Review. Ann Intern Med 2019.
• Treatment: Nikooie R, Neufeld KJ, Oh ES, et al. Antipsychotics for Treating Delirium in Hospitalized Adults: A Systematic Review. Ann Intern Med 2019.

Key validation studies

• CAM: Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. Clarifying confusion: the confusion assessment method. A new method for detection of delirium. Annals of internal medicine 1990;113:941-8.
• CAM-S: Inouye SK, Kosar CM, 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;160:526-33.
• 3D-CAM:Marcantonio ER, Ngo LH, O’Connor M, et al. 3D-CAM: derivation and validation of a 3-minute diagnostic interview for CAM-defined delirium: a cross-sectional diagnostic test study. Annals of internal medicine 2014;161:554-61.
• 3D-CAM-S: Vasunilashorn SM, Devinney MJ, Acker L, et al. A New Severity Scoring Scale for the 3-Minute Confusion Assessment Method (3D-CAM). J Am Geriatr Soc 2020;68:1874-6.
• RASS: Ely EW, Truman B, Shintani A, et al. Monitoring sedation status over time in ICU patients: reliability and validity of the Richmond Agitation-Sedation Scale (RASS). JAMA 2003;289:2983-91.
• CAM-ICU:Ely EW, Margolin R, Francis J, et al. Evaluation of delirium in critically ill patients: validation of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Crit Care Med 2001;29:1370-9.
• CAM-ICU:Ely EW, Inouye SK, Bernard GR, et al. Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). JAMA 2001;286:2703-10.
• CAM-ICU-7:Khan BA, Perkins AJ, Gao S, et al. The Confusion Assessment Method for the ICU-7 Delirium Severity Scale: A Novel Delirium Severity Instrument for Use in the ICU. Crit Care Med 2017;45:851-7.
• MDAS: Breitbart W, Rosenfeld B, Roth A, et al. The Memorial Delirium Assessment Scale. J Pain Symptom Manage 1997;13:128-37.
• DRS-R-98: Trzepacz PT, Mittal D, Torres R, et al. Validation of the Delirium Rating Scale-Revised-98: Comparison with the delirium rating scale and the cognitive test for delirium. J Neuropsychiatry Clin Neurosci 2001;13:229-42.
• 4-AT: Bellelli G, Morandi A, Davis DH, et al. Validation of the 4AT, a new instrument for rapid delirium screening: a study in 234 hospitalised older people. Age Ageing 2014;43:496-502.
• bCAM: 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;62:457-65.

Natural history studies

• Mortality:Ely EW, Shintani A, Truman B, et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA 2004;291:1753-62.
• Long-term cognitive impairment: Girard TD, Jackson JC, Pandharipande PP, et al. Delirium as a predictor of long-term cognitive impairment in survivors of critical illness. Crit Care Med 2010;38:1513-20.
• 3-year trajectory: Inouye SK, Marcantonio ER, Kosar CM, et al. The short-term and long-term relationship between delirium and cognitive trajectory in older surgical patients. Alzheimers Dement 2016;12:766-75.
• Neuropathological associations:Davis DH, Muniz-Terrera G, Keage HA, et al. Association of Delirium With Cognitive Decline in Late Life: A Neuropathologic Study of 3 Population-Based Cohort Studies. JAMA Psychiatry 2017;74:244-51.

Key findings

• Dose-dependent relationship between benzodiazepines and delirium:Pandharipande P, Shintani A, Peterson J, et al. Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients. Anesthesiology 2006;104:21-6.
• Annual costs: Leslie DL, Marcantonio ER, Zhang Y, et al. One-year health care costs associated with delirium in the elderly population. Arch Intern Med 2008;168:27-32.
• BRAIN-ICU Study: Pandharipande PP, Girard TD, Jackson JC, et al. Long-term cognitive impairment after critical illness. N Engl J Med 2013;369:1306-16.
• Costs after surgery:Yun Gou R, Hshieh TT, Marcantonio ER, et al. One-year Medicare costs associated with delirium in older patients undergoing major elective surgery. JAMA Surg. 2021;156:430-42.

Research agenda

• AGS/NIA Delirium Conference Writing Group PC, Faculty. The American Geriatrics Society/National Institute on Aging Bedside-to-Bench Conference: Research Agenda on Delirium in Older Adults. J Am Geriatr Soc 2015;63:843-52.
• Khachaturian AS, Hayden KM, Devlin JW, et al. International drive to illuminate delirium: A developing public health blueprint for action. Alzheimers Dement 2020;16:711-25.
• Oh ES, Akeju O, Avidan MS, et al. A roadmap to advance delirium research: Recommendations from the NIDUS Scientific Think Tank. Alzheimers Dement 2020;16:726-33.

Best practice standards and core outcome sets

• Best practice:Amgarth-Duff I, Hosie A, Caplan G, Agar M. Toward best practice methods for delirium biomarker studies: An international modified Delphi study. Int J Geriatr Psychiatry 2020.
• Critical care core outcomes: Rose L, Burry L, Agar M, et al. A Core Outcome Set for Research Evaluating Interventions to Prevent and/or Treat Delirium in Critically Ill Adults: An International Consensus Study (Del-COrS). Crit Care Med 2021.
• Acute care core outcomes: Rose L, Burry L, Agar M, et al. A core outcome set for studies evaluating interventions to prevent and/or treat delirium for adults requiring an acute care hospital admission: an international key stakeholder informed consensus study. BMC Med 2021;19:143.

Statements and ADS-sponsored publications

• Rudolph JL, Boustani M, Kamholz B, Shaughnessey M, Shay K, American Delirium S. Delirium: a strategic plan to bring an ancient disease into the 21st century. J Am Geriatr Soc 2011;59 Suppl 2:S237-40.
• European Delirium Association, American Delirium Society. The DSM-5 criteria, level of arousal and delirium diagnosis: inclusiveness is safer. BMC Med 2014;12:141.
• Evered L, Silbert B, Knopman, et al. Recommendations for the nomenclature of cognitive change associated with anaesthesia and surgery-2018. Anesthesiology 2018;129:872-9.
• Slooter AJC, Otte WM, Devlin JW, et al. Updated nomenclature of delirium and acute encephalopathy: statement of ten Societies. Intensive Care Med 2020;46:1020-2.

Classic papers

• Romano J, Engel GL. Delirium I. Electroencephalographic data. Arch NeuroPsych 1944;51:356-77.
• Engel GL, Romano J. Delirium, a syndrome of cerebral insufficiency. J Chronic Dis 1959;9:260-77.

Books

• Lipowski ZJ. Delirium: Acute Brain Failure in Man. Springfield, IL: Charles C Thomas; 1980.
• Lipowski ZJ. Delirium: Acute Confusional States. New York: Oxford University Press; 1990.
• Caraceni A, Grassi L. Delirium: Acute Confusional States in Palliative Medicine: OUP Oxford; 2011.
• Page VJ, Ely EW. Delirium in Critical Care: Cambridge University Press; 2015.
• Isik AT, Grossberg GT. Delirium in Elderly Patients: Springer International Publishing; 2017.
• Bourgeois JA. Delirium: Prevention, Symptoms and Treatment: Nova Science Publishers, Incorporated; 2017.
• Hughes CG, Pandharipande PP, Ely EW. Delirium: Acute Brain Dysfunction in the Critically Ill: Springer International Publishing; 2020.
• Rahman S. Essentials of Delirium: Everything You Really Need to Know for Working in Delirium Care: Jessica Kingsley Publishers; 2020.

Guidelines (last decade)

• Association of Scientific Medical Societies of Germany: Martin J, Heymann A, Basell K, et al. Evidence and consensus-based German guidelines for the management of analgesia, sedation and delirium in intensive care–short version. Ger Med Sci 2010;8:Doc02.
• National Institute for Health and Clinical Excellence: O’Mahony R, Murthy L, Akunne A, Young J, Guideline Development G. Synopsis of the National Institute for Health and Clinical Excellence guideline for prevention of delirium. Ann Intern Med 2011;154:746-51.
• American Geriatrics Society: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;63:142-50.
• European Society of Anaesthesiology: Aldecoa C, Bettelli G, Bilotta F, et al. European Society of Anaesthesiology evidence-based and consensus-based guideline on postoperative delirium. Eur J Anaesthesiol 2017;34:192-214.
• Society for Critical Care Medicine:Devlin JW, Skrobik Y, Gelinas C, et al. 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;46:e825-e73.
• Cochrane Review: Burry L, Hutton B, D. W, et al. Medicines to treat delirium in critically ill adult patients. Cochrane Database Syst Rev 2019:CD011749.
• Scottish Intercollegiate Guidelines Network: The Scottish Intercollegiate Guidelines Network (SIGN) 157: Risk Reduction and Management of Delirium.
• Japanese Psycho-Oncology Society/Japanese Association of Supportive Care in Cancer: Matsuda Y, Tanimukai H, Inoue S, et al. JPOS/JASCC clinical guidelines for delirium in adult cancer patients: a summary of recommendation statements. Jpn J Clin Oncol 2020;50:586-93.