The pharmacotherapeutic management of postoperative delirium: an expert update

References

• Adamis D, Treloar A, Martin FC, et al. A brief review of the history of delirium as a mental disorder. Rev Int Hist Psychiatr. 2007;18(4):459–469.
   Google Scholar
• Muncie W. Postoperative states of excitement. Arch Neurol Psychiatr. 1932 Oct;32(4):681–703.
   Google Scholar
• American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Washington, DC: American Psychiatric Association; 2013.
   Google Scholar
• Marcantonio E, Ta T, Duthie E, et al. Delirium severity and psychomotor types: their relationship with outcomes after hip fracture repair. JAGS. 2002;50:850–857.
   PubMed Web of Science ®Google Scholar
• Robinson TN, Raeburn CD, Tran ZV, et al. Motor subtypes of postoperative delirium in older adults. Arch Surg. 2011;146(3):295–300.
   PubMedGoogle Scholar
• Marcantonio ER, Goldman L, Mangione CM, et al. Clinical prediction rule for delirium after elective non-cardiac surgery. JAMA. 1994;271(2):134–139.
   PubMed Web of Science ®Google Scholar
• Maldonado JR. Acute brain failure: pathophysiology, diagnosis, management, and sequelae of delirium. Crit Care Clin. 2017;33:461–519.
   PubMed Web of Science ®Google Scholar
• Oldroyd C, Scholz AFM, Hinchliffe RJ, et al. A systematic review and meta-analysis of factors for delirium in vascular surgical patients. J Vasc Surg. 2017;66:1269–1279.
   PubMed Web of Science ®Google Scholar
• Malik AT, Quatman CE, Phieffer LS, et al. Incidence, risk factors and clinical impact of postoperative delirium following open reduction and internal fixation (ORIF) for hip fractures: an analysis of 7859 patients from the ACS-NSQIP hip fracture procedure targeted database. Eur J Orthop Surg Tr. 2019;29:435–446.
   PubMedGoogle Scholar
• Cereghetti C, Siegemund M, Schaedelin S, et al. Independent predictors of the duration and overall burden of postoperative delirium after cardiac surgery in adults: an observational cohort study. J Cardiothorac Vasc Anesth. 2017;31:1966–1973.
   PubMed Web of Science ®Google Scholar
• Scholz AFM, Oldroyd C, McCarthy K, et al. Systematic review and meta-analysis of risk factors for postoperative delirium among older patients undergoing gastrointestinal surgery. BJS. 2016;103:e21–e28.
   Google Scholar
• Witlox J, Eurelings LS, deJonghe JF, et al. Delirium in elderly patients and the risk of postdischarge mortality, institutionalization, and dementia: a meta-analysis. JAMA. 2010 Jul;304(4):443–451.
   PubMed Web of Science ®Google Scholar
• Engel GL, Romano J. Delirium, a syndrome of cerebral insufficiency. J Chron Dis. 1959 Mar;9(3):260–277.
   PubMedGoogle Scholar
• Young JWS. The network model of delirium. Med Hypotheses. 2017;104:80–85.
   PubMed Web of Science ®Google Scholar
• Maldonado JR. Delirium pathophysiology: an updated hypothesis of the etiology of acute brain failure. Int J Geriatr Psychiatry. 2018;33:1428–1457.
   PubMed Web of Science ®Google Scholar
• Oh J, Shin JE, Yang KH, et al. Cortical and subcortical changes in resting-state functional connectivity before and during an episode of postoperative delirium. ANZJP. 2019;53(8):794–806.
   PubMed Web of Science ®Google Scholar
• Maldonado JR. Neuropathogenesis of delirium: review of current etiologic theories and common pathways. Am J Geriatr Psychiatry. 2013 Dec;21(12):1190–1222.
   PubMed Web of Science ®Google Scholar
• Sanders RD, Pandharipande PP, Davidson AJ, et al. Anticipating and managing postoperative delirium and cognitive decline in adults. BMJ. 2011;343:d4331.
   PubMedGoogle Scholar
• 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 Dec;286(21):2703–2710.
   PubMed Web of Science ®Google Scholar
• Alagiakrishnan K, Wiens CA. An approach to drug induced delirium in the elderly. Postgrad Med J. 2004 Jul;80(945):388–393.
   PubMed Web of Science ®Google Scholar
• van Gool WA, van de Beek D, Eikelenboom P. Systemic infection and delirium: when cytokines and acetylcholine collide. Lancet. 2010 Feb;375:773–775.
   PubMed Web of Science ®Google Scholar
• Inouye SK, Westendorp RGJ, Saczynski JS. Delirium in elderly people. Lancet. 2014 Mar;383:911–922.
   PubMed Web of Science ®Google Scholar
• Xie G, Deschamps A, Backman SB, et al. Critical involvement of the thalamus and precuneus during restoration of consciousness with physostigmine in humans during propofol anaesthesia: a positron emission tomography study. Br J Anaesth. 2011;106:548–557.
   PubMed Web of Science ®Google Scholar
• Brown KE, Mirrahimov AE, Yeddula K, et al. Propofol and the risk of delirium: exploring the anticholinergic properties of propofol. Med Hypotheses. 2013;81:536–539.
   PubMed Web of Science ®Google Scholar
• Liptzin B, Laki A, Garb JL, et al. Donepezil in the prevention and treatment of post-surgical delirium. Am J Geriatr Psychiatry. 2005;13(12):1100–1106.
   PubMed Web of Science ®Google Scholar
• Sampson EL, Raven PR, Ndhlovu PN, et al. A randomized, double-blind, placebo-controlled trial of donepezil hydrochloride (Aricept) for reducing the incidence of postoperative delirium after elective total hip replacement. Int J Geriatr Psychiatry. 2007;22(4):343–349.
   PubMed Web of Science ®Google Scholar
• Overshott R, Karim S, Burns A. Cholinesterase inhibitors for delirium (review). Cochrane Database Syst Rev. 2008;1:CD005317.
   Google Scholar
• Gamberini M, Bolliger D, Lurati Buse GA, et al. Rivastigmine for the prevention of postoperative delirium in elderly patients undergoing elective cardiac surgery—a randomized controlled trial. Crit Care Med. 2009;37(5):1762–1768.
   PubMed Web of Science ®Google Scholar
• Marcantonio ER, Palihnich KA, Appleton P, et al. Pilot randomized trial of donepezil hydrochloride for delirium after hip fracture. J Am Geriatr Soc. 2011 Nov;59(Suppl 2):S282–S288.
   PubMedGoogle Scholar
• Zaslavsky A, Haile M, Kline R, et al. Rivastigmine in the treatment of postoperative delirium: a pilot clinical trial. Int J Geriatr Psychiat. 2012 Sep;27(9):986–988.
   PubMed Web of Science ®Google Scholar
• van Eijk MMJ, Roes KCB, Honing MLH, et al. Effect of rivastigmine as an adjunct to usual care with haloperidol on duration of delirium and mortality in critically ill patients: a multicenter, double-blind, placebo-controlled randomized trial. Lancet. 2010 Nov;376:1829–1837.
   PubMed Web of Science ®Google Scholar
• Opdam FL, Oleksik AM, Westendorp RG. Cholinesterase inhibitor treatment in patients with delirium. Lancet. 2011 Mar;377:900–901.
   PubMedGoogle Scholar
• Maura G, Andrioli GC, Cavazzani P, et al. 5-Hydroxytryptamine, receptors sited on cholinergic ax on terminals of human cerebral cortex mediate inhibition of acetylcholine release. J Neurochem. 1992;58(6):2334–2337.
   PubMed Web of Science ®Google Scholar
• Papadopoulos G, Pouangare M, Papathanakos G, et al. The effect of ondansetron on postoperative delirium and cognitive function in aged orthopedic patients. Minerva Anesthesiol. 2013;80(4):444–451.
   PubMed Web of Science ®Google Scholar
• Tagarakis GI, Voucharas C, Tsolaki F, et al. Ondansetron versus haloperidol for the treatment of postcardiotomy delirium: a prospective, randomized, double-blinded study. J Cardiothorac Surg. 2012;7:25.
   PubMed Web of Science ®Google Scholar
• Bakri MH, Eman AI, Ibrahim A. Comparison of dexmedetomidine or ondansetron with haloperidol for treatment of postoperative delirium in trauma patients admitted to intensive care unit: randomized control trial. Anaesth, Pain Intens Care. 2015;19(2):118–123.
   Web of Science ®Google Scholar
• Haque N, Naqvi RM, Dasgupta M. Efficacy of ondansetron in the prevention or treatment of post-operative delirium—a systematic review. Can Geriatr J. 2019 Mar;22(1):1–6.
   PubMed Web of Science ®Google Scholar
• Larsen KA, Kelly SE, Stern TA, et al. Administration of olanzapine to prevent postoperative delirium in elderly joint-replacement patients: a randomized controlled trial. Psychosomatics. 2010 Sept-Oct;51(5):409–418.
   PubMed Web of Science ®Google Scholar
• Khan BA, Gutteridge D, Campbell NL. Update of pharmacotherapy for prevention and treatment of post-operative delirium: a systematic evidence review. Curr Anesthesiol Rep. 2015;5:57–64.
   PubMedGoogle Scholar
• 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 randomized, double-blind, placebo-controlled trial. Lance Respir Med. 2013 Sep;1(7):515–523.
   PubMed Web of Science ®Google Scholar
• Van den Boogaard M, Slooter AJC, Bruggermann 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(7):680–691.
   PubMed Web of Science ®Google Scholar
• Girard TD, Pandharipande PP, Carson SS, et al. Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: the MIND randomized, placebo-controlled trial. Crit Care Med. 2010 Feb;38(2):428–437.
   PubMed Web of Science ®Google Scholar
• Girard TD, Exline MC, Carson SS, et al. Haloperidol and ziprasidone for treatment of delirium in critical illness. N Engl J Med. 2018 Dec;379(26):2506–2516.
   PubMed Web of Science ®Google Scholar
• Zhang H, Lu Y, Lui M, et al. Strategies for prevention of postoperative delirium: a systematic review and meta-analysis of randomized trials. Crit Care. 2013;17:R47.
   PubMed Web of Science ®Google Scholar
• Teslyar P, Stock VM, Wilk CM, et al. Prophylaxis with antipsychotic medication reduces the risk of post-operative delirium in elderly patients: a meta-analysis. Psychosomatics. 2013;54:124–131.
   PubMed Web of Science ®Google Scholar
• Gilmore ML, Wolfe DJ. Antipsychotic prophylaxis in surgical patients modestly decreases delirium incidence – but not duration – in high-incidence samples: a meta-analysis. Gen Hosp Psychiatry. 2013;35:370–375.
   PubMed Web of Science ®Google Scholar
• Hirota T, Kishi T. Prophylactic antipsychotic use for postoperative delirium: a systematic review and meta-analysis. J Clin Psychiatry. 2013 Dec;74(12):e1136–1144.
   PubMed Web of Science ®Google Scholar
• Liu Y, Li XJ, Liang Y, et al. Pharmacological prevention of postoperative delirium: A systematic review and meta-analysis of randomized controlled trials. eCAM. 2019;9607129. DOI:10.1155/2019/9607129.
   Google Scholar
• Siddiqi N, Harrison JK, Clegg A, et al. Interventions for preventing delirium in hospitalized non-ICU patients (review). Cochrane Database Syst Rev. 2016;3:CD005563.
   PubMedGoogle Scholar
• Burry L, Mehta S, Perreault MM, et al. Antipsychotics for treatment of delirium in hospitalized non-ICU patients (review). Cochrane Database Syst Rev. 2018;6:CD005594.
   PubMedGoogle Scholar
• Herling SF, Greve IE, Vasilevskis EE, et al. Interventions for preventing intensive care unit delirium in adults (review). Cochrane Database Syst Rev. 2018;11:CD009783.
   PubMedGoogle Scholar
• Burry L, Hutton B, Williamson DR, et al. Pharmacological interventions for the treatment of delirium in critically ill adults (review). Cochrane Database Syst Rev. 2019;9:CD011749.
   PubMedGoogle Scholar
• Kaneko T, Cai J, Ishikura M, et al. Prophylactic consecutive administration of haloperidol can reduce the occurrence of postoperative delirium in gastrointestinal surgery. Yonago Acta Med. 1999;42(3):179–184.
   Google Scholar
• Kalisvaart KJ, DeJonghe JFM, Bogaards MJ, et al. Haloperidol prophylaxis for elderly hip-surgery patients at risk for delirium: a randomized placebo-controlled study. J Am Geriatr Soc. 2005;10:1658–1666.
   Google Scholar
• Prakanrattana U, Prapaitrakool S. Efficacy of risperidone for prevention of postoperative delirium in cardiac surgery. Anaesth Intens Care. 2007;35(5):714–719.
   PubMed Web of Science ®Google Scholar
• Devlin JW, Roberts RJ, Fong JJ, et al. Efficacy and safety of quetiapine in critically ill patients with delirium: a prospective, multicenter, randomized, double-blind, placebo-controlled pilot study. Crit Care Med. 2010;38(2):419–427.
   PubMed Web of Science ®Google Scholar
• Wang W, Li H-L, Wang D-X, et al. Haloperidol prophylaxis decreases delirium incidence in elderly patients after non-cardiac surgery: a randomized controlled trial. Crit Care Med. 2012;40(3):731–739.
   PubMed Web of Science ®Google Scholar
• Fukata S, Kawabata Y, Fujishiru K, et al. Haloperidol prophylaxis for preventing aggravation of postoperative delirium in elderly patients: a randomized, open-label prospective trial. Surg Today. 2017 Jul;47(7):815–826.
   PubMed Web of Science ®Google Scholar
• Devlin JW, Skrobik Y, Gelinas C, et al. Clinical practice guidelines for the prevention and management of pain, agitation/ sedation,delirium, immobility, sleep disruption in adults patients in the ICU. Crit Care Med. 2018 Sep;46(9):e825–e873.
   PubMed Web of Science ®Google Scholar
• Claustrat B, Brun J, Chazot G. The basic physiology and pathophysiology of melatonin. Sleep Med Rev. 2005;9(1):11–24.
   PubMed Web of Science ®Google Scholar
• Radogna F, Diederich M, Ghibelli L. Melatonin: a pleiotropic molecule regulating inflammation. Biochem Pharmacol. 2010;80:1844–1852.
   PubMed Web of Science ®Google Scholar
• Shigeta H, Yasui A, Yuji N, et al. Postoperative delirium and melatonin levels in elderly patients. Am J Surg. 2001;182:449–454.
   PubMed Web of Science ®Google Scholar
• Balan S, Leibovitz A, Zila SO, et al. The relation between the clinical subtypes of delirium and the urinary level of 6-SMT. J Neuropsychiatry Clin Neurosci. 2003;15(3):363–366.
   PubMed Web of Science ®Google Scholar
• Sultan SS. Assessment of role of perioperative melatonin in prevention and treatment of postoperative delirium after hip arthroplasty under spinal anesthesia in the elderly. Saudi J Anaesth. 2010;4:169–173.
   PubMedGoogle Scholar
• Artemiou P, Bily B, Bilecova-Rabajdova M, et al. Melatonin treatment in the prevention of postoperative delirium in cardiac surgery patients. Kardiochir Torakochirurgia Pol. 2015;12:126–133.
   PubMedGoogle Scholar
• De Jonghe A, van Munster BC, Goslings C, et al. Effect of melatonin on incidence of delirium among patients with hip fracture: a multicentre, double-blind randomized controlled trial. CMAJ. 2014;186:e547–e556.
   PubMed Web of Science ®Google Scholar
• Robinson TN, Dunn CL, Adams JC, et al. Tryptophan supplementation and postoperative delirium: a randomized controlled trial. J Am Geriatr Soc. 2014;62:1764–1771.
   PubMed Web of Science ®Google Scholar
• Campbell AM, Axon DR, Martin JR, et al. Melatonin for the prevention of postoperative delirium in older adults: a systematic review and meta-analysis. BMC Geriatr. 2019;19:272.
   PubMed Web of Science ®Google Scholar
• Baumgartner L, Lam K, Lai J, et al. Effectiveness of melatonin for the prevention of intensive care unit delirium. Pharmacotherapy. 2019 Mar;39(3):280–287.
   PubMed Web of Science ®Google Scholar
• Cusimano JM, Welch S, Perez-Protto S, et al. Factors associated with delirium in surgical intensive care unit patients treated with supplemental melatonin: a case-cohort study. Clin Neuropharmacol. 2019 May/June;42(3):67–72.
   PubMed Web of Science ®Google Scholar
• Hatta K, Kishi Y, Wada K, et al. Preventive effects of ramelteon on delirium: a randomized placebo-controlled trial. JAMA Psychiatry. 2014;71(4):397–403.
   PubMed Web of Science ®Google Scholar
• Lu Y, Li YW, Wang L, et al. Promoting sleep and circadian health may prevent postoperative delirium: a systematic review and meta-analysis of randomized clinical trials. Sleep Med Rev. 2019 Dec;48:101207.
   PubMed Web of Science ®Google Scholar
• Dillon ST, Vasunilashorn SM, Ngo L, et al. Higher C-reactive protein levels predict postoperative delirium in older patients undergoing major elective surgery: a longitudinal nested case-control study. Biol Psychiatry. 2017;81(2):145–153.
   PubMed Web of Science ®Google Scholar
• Liu X, Yu Y, Zhu S. Inflammatory markers in postoperative delirium (POD) and cognitive dysfunction (POCD): a meta-analysis of observational studies. PLoS One. 2018;13(4):e0195659.
   PubMed Web of Science ®Google Scholar
• Knaak C, Vorderwulbecke GSpies C, C-reactive protein for risk prediction of post-operative delirium and post-operative neurocognitive disorder. Acta Anaesthesiol Scand. 2019 Nov;63(10):1282–1289.
   PubMed Web of Science ®Google Scholar
• Ayob F, Lam E, Ho G, et al. Pre-operative biomarkers and imaging tests as predictors of post-operative delirium in non-cardiac surgical patients: a systematic review. BMC Anesthesiol. 2019;19:25.
   PubMed Web of Science ®Google Scholar
• Mardani D, Bigdelian H. Prophylaxis of dexamethasone protects patients from further post-operative delirium after cardiac surgery: a randomized trial. J Res Med Sci. 2013 Feb;18(2):137–143.
   PubMed Web of Science ®Google Scholar
• Sauer AM, Slooter AJ, Veldhuijzen DS, et al. Intraoperative dexamethasone and delirium after cardiac surgery: a randomized clinical trial. Anesth Analg. 2014;119(5):1046–1052.
   PubMed Web of Science ®Google Scholar
• Li-Qin L, Wang C, Fang MD, et al. Effects of dexamethasone of post-operative cognitive dysfunction and delirium in adults following general anaesthesia: a meta-analysis of randomized controlled trials. BMC Anesthesiol. 2019;19:113.
   PubMed Web of Science ®Google Scholar
• Mason SE, Noel-Storr A, Ritchie CW. The impact of general and regional anesthesia on the incidence of post-operative cognitive dysfunction and post-operative delirium: a systematic review of meta-analysis. J Alzheimers Dis. 2010;22(Suppl 3):67–79.
   PubMed Web of Science ®Google Scholar
• Williams-Russo P, Sharrock NE, Mattis S, et al. Cognitive effects after epidural vs general anesthesia in older adults. JAMA. 1995 Jul;274(1):44–50.
   PubMed Web of Science ®Google Scholar
• Chen X, Zhao M, White PF, et al. The recovery of cognitive function after general anesthesia in elderly patients: a comparison of desflurane and sevoflurane. Anesth Analg. 2001;93:1489–1494.
   PubMed Web of Science ®Google Scholar
• Mahajan VA, Ni Chonghaile M, Bokhari SA, et al. Recovery of older adults undergoing ambulatory anaesthesia with isoflurane or sevoflurane. Eur J Anaesthesiol. 2007;24:505–510.
   PubMed Web of Science ®Google Scholar
• Kinjo S, Lim E, Magsaysay MV, et al. Volatile anaesthetics and postoperative delirium in older surgical patients—A secondary analysis of prospective cohort studies. Acta Anaesthesiol Scand. 2019;63:18–26.
   PubMed Web of Science ®Google Scholar
• Matchett GA, Allard MW, Martin RD, et al. Neuroprotective effect of volatile anesthetic agents: molecular mechanisms. Neurol Res. 2009;31:128–134.
   PubMed Web of Science ®Google Scholar
• Zuo Z. Are volatile anesthetics neuroprotective or neurotoxic? Med Gas Res. 2012;2:10.
   PubMedGoogle Scholar
• Deng J, Lei C, Chen Y, et al. Neuroprotective gases – fantasy or reality for clinical use? Prog Neurobiol. 2014;115:210–245.
   PubMed Web of Science ®Google Scholar
• Radtke FM, Franck M, Lendner J, et al. Monitoring depth of anaesthesia in a randomized trial decreases the rate of postoperative delirium but not postoperative cognitive dysfunction. Br J Anaesth. 2013;110(S1):i98–i105..
   PubMedGoogle Scholar
• Fritz BA, Maybrier HR, Avidan MS. Intraoperative electroencephalogram suppression at lower volatile anaesthetic concentrations predicts postoperative delirium occurring in the intensive care unit. BJA. 2018;121(1):241–248.
   Google Scholar
• Punjasawadwong Y, Chau-In W, Laopaiboon M, et al. Processed electroencephalogram and evoked potential techniques for amelioration of postoperative delirium and cognitive dysfunction following non-cardiac and non-neurosurgical procedures in adults. Cochrane Database Syst Rev. 2018 May;15(5):CD011283.
   Google Scholar
• 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;321:473–483.
   PubMed Web of Science ®Google Scholar
• Hudetz JA, Patterson KM, Iqbal Z, et al. Ketamine attenuates delirium after cardiac surgery with cardiopulmonary bypass. J Cardiothorac Vasc Anesth. 2009;23:651–657.
   PubMed Web of Science ®Google Scholar
• 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, randomized clinical trial. Lancet. 2017 July;390:267–275.
   PubMed Web of Science ®Google Scholar
• Riegger H, Hollinger A, Seifert B, et al. Baden prevention and reduction of incidence of postoperative trial (PRIDe): a phase IV multicenter, randomized, placebo-controlled, double-blind clinical trial of ketamine versus haloperidol for prevention of postoperative delirium. Trials. 2018 Feb;19(1):142.
   PubMedGoogle Scholar
• 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 Jan;104(1):21–26.
   PubMed Web of Science ®Google Scholar
• Lonergan E, Luxenberg J, Areosa Sastre A. Benzodiazepines for delirium (review). Cochrane Database Syst Rev. 2009;4:CS006379.
   Google Scholar
• Amato L, Minozzi S, Vecchi S, et al. Benzodiazepines for alcohol withdrawal (review). Cochrane Database Syst Rev. 2010;3:CD005063.
   Google Scholar
• Kowark A, Rossaint R, Keszei AP, et al. Impact of PReOperative Midazolam on OuTcome of Elderly patients (I-PROMOTE): study protocol for a multicentre randomized controlled trial. Trials. 2019;20:430.
   PubMedGoogle Scholar
• Swart LM, van der Zanden V, Spies PE, et al. The comparative risk of delirium with different opioids: a systematic review. Drugs Aging. 2017;34:437–443.
   PubMed Web of Science ®Google Scholar
• Mantz J, Josserand J, Hamada S. Dexmedetomidine: new insights. Eur J Anaesthesiol. 2011;28:3–6.
   PubMed Web of Science ®Google Scholar
• Lee S. Dexmedetomidine: present and future directions. Korean J Anesthesiol. 2019 Aug;72(4):323–330.
   PubMed Web of Science ®Google Scholar
• Wang DS, Kaneshwaran K, Lei G, et al. Dexmedetomidine prevents excessive gamma-aminobutyric acid type A receptor function after anesthesia. Anesthesiology. 2018;129:477–489.
   PubMed Web of Science ®Google Scholar
• Pandharipande PP, Pun BT, Herr DL, et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients. JAMA. 2007;209(22):2644–2653.
   Google Scholar
• Maldonado JR, Wysong A, van der Starre PJ, et al. Dexmedetomidine and the reduction of postoperative delirium after cardiac surgery. Psychosomatics. 2009;50:206–217.
   PubMed Web of Science ®Google Scholar
• Shehabi Y, Grant P, Wolfenden H, et al. Prevalence of delirium with dexmedetomidine compared with morphine based therapy after cardiac surgery: a randomized controlled trial (DEXmedetomidine COmpared to Morphine—DEXCOM study). Anesthesiology. 2009;111:1075–1084.
   PubMed Web of Science ®Google Scholar
• Duan X, Coburn M, Rossaint R, et al. Efficacy of perioperative dexmedetomidine on postoperative delirium: systematic review and meta-analysis with trial sequential analysis of randomised controlled trials. Br J Anaesth. 2018 Aug;121(2):384–397.
   PubMed Web of Science ®Google Scholar
• Shi C, Jin J, Qiao L, et al. Effect of perioperative administration of dexmedetomidine on delirium after cardiac surgery in elderly patients: a double-blinded, multi-center, randomized study. Clin Interv Aging. 2019;14:571–575.
   PubMed Web of Science ®Google Scholar
• Pan H, Liu C, Ma X, et al. Perioperative dexmedetomidine reduces delirium in elderly patients after non-cardiac surgery: a systematic review and meta-analysis of randomized-controlled trials. Can J Anesth. 2019 Dec;66(12):1489–1500.
   PubMed Web of Science ®Google Scholar
• Shankar P, Mueller A, Packiasabapathy S, et al. Dexmedetomidine and intravenous acetaminophen for the prevention of postoperative delirium following cardiac surgery (DEXACET trial): protocol for a prospective randomized controlled trial. Trials. 2018;19:326.
   PubMed Web of Science ®Google Scholar
• 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 Feb;321(7):686–696.
   PubMed Web of Science ®Google Scholar
• National Clinical Guideline Centre (UK). Delirium: diagnosis, prevention and management [Internet]. London: Royal College of Physicians (UK); 2010 Jul. (NICE Clinical Guidelines, No. 103.)
   Google Scholar
• 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 Jan;47(1):3–14.
   PubMed Web of Science ®Google Scholar
• Carli F, Zavorsky GS. Optimizing functional exercise capacity in the elderly surgical population. Curr Opin Clin Nutr Metab Care. 2005;8:23–32.
   PubMed Web of Science ®Google Scholar
• Moran J, Guinan E, McCormick P, et al. The ability of prehabilitation to influence postoperative outcome after intra-abdominal operation: a systematic review and meta-analysis. Surgery. 2016;160:1189–1201.
   PubMed Web of Science ®Google Scholar
• Luther A, Gabriel J, Watson RP, et al. The impact of total body prehabilitation on post-operative outcomes after major abdominal surgery: a systematic review. World J Surg. 2018;42:2781–2791.
   PubMed Web of Science ®Google Scholar
• Cavallari M, Dai W, Guttmann CRG, et al. Neural substrates of vulnerability to postsurgical delirium as revealed by presurgical diffusion MRI. Brain. 2016;139(4):1282–1294.
   PubMedGoogle Scholar
• Cavallari M, Dai W, Guttmann CRG, et al. Longitudinal diffusion changes following postoperative delirium in older people without dementia. Neurology. 2017 Sept;89(10):1020–1027.
   PubMed Web of Science ®Google Scholar
• Hight DF, Sleigh J, Winders JD, et al. Inattentive delirium vs. disorganized thinking: a new axis to subcategorize PACU delirium. Front Syst Neurosci. 2018 May;12:22.
   PubMed Web of Science ®Google Scholar
• Wongviriyawong T, Sura-Arunsumrit P, Chaiwat O, et al. Diagnosis of postoperative delirium in older adults using the confusion assessment method for the intensive care unit in non-intensive care unit settings: a test modification might improve its diagnostic performance. Geriatr Gerontol Int. 2019 Aug;19(8):762–767.
   PubMed Web of Science ®Google Scholar
• Waddington CH. Canalisation of development and the inheritance of acquired characters. Nature. 1942;150:563–564.
   Google Scholar
• Reinhold AK, Jentho E, Schafer ST, et al. Epigenetics: important for anesthetists, pain and intensive care. Anaesthesist. 2018 Apr;67(4):246–254.
   PubMed Web of Science ®Google Scholar
• Holtkamp C, Koos B, Unterberg M, et al. A novel understanding of postoperative complications: in vitro study of the impact of propofol on epigenetic modifications in cholinergic genes. PloS One. 2019 May;14(5):e0217269.
   PubMed Web of Science ®Google Scholar
• Nekrosius D, Kaminskaite M, Jokubka R, et al. Association of COMT Val158 Met polymorphism with delirium risk and outcomes after traumatic brain injury. J Neuropsychiatry Clin Neurosci. 2019;31(4):298–305.
   PubMed Web of Science ®Google Scholar
• Vasunilasborn SM, Ngo LH, Jones RN, et al. The association between c-reactive protein and postoperative delirium differs by catechol-o-methyltransferase genotype. Am J Geriatr Psychiatry. 2019 Jan;27:1.
   PubMed Web of Science ®Google Scholar
• Oldham MA. Refining postoperative delirium: the case of a gene x protein interaction. Am J Geriatr Psychiatry. 2019 Jan;27(1):9–11.
   PubMed Web of Science ®Google Scholar
• Mahanna-Gabrielli E, Miano TA, Augoustides JG, et al. Does the melatonin receptor 1B gene polymorphism have a role in postoperative delirium? PLoS One. 2018 Nov;13(1):e02007941.
   Google Scholar
• Kawada K, Ohta T, Tanaka K, et al. Addition of suvorexant to ramelteon therapy for improved sleep quality with reduced delirium risk in acute stroke patients. J Stroke Cerebrovasc Dis. 2019 Jan;28(1):142–148.
   PubMed Web of Science ®Google Scholar
• Weinstock M, Gorodetsky E, Poltyrev T, et al. A novel cholinesterase and brain-selective monoamine oxidase inhibitor for the treatment of dementia comorbid with depression and Parkinson’s disease. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27:555–561.
   PubMed Web of Science ®Google Scholar
• Schneider LS, Geffen Y, Rabinowitz J, et al. Low-dose ladostigil for mild cognitive impairment. Neurology. 2019;93:e1474–e1484.
   PubMed Web of Science ®Google Scholar
• Maruyama W, Weinstock M, Youdim MB, et al. Anti-apoptotic action of anti-Alzheimer drug, TV3326 [(N-propargyl)-(3R) aminoindan-5-yl]-ethyl methyl carbamate, a novel cholinesterase-monoamine oxidase inhibitor. Neurosci Lett. 2003;341:233–236.
   PubMed Web of Science ®Google Scholar
• Weinstock M, Luques L, Poltyrev T, et al. Ladostigil prevents age-related glial activation and spatial memory deficits in rats. Neurobiol Aging. 2011;32:1069–1078.
   PubMed Web of Science ®Google Scholar
• Shoham S, Linial M, Weinstock M. Age-induced spatial memory deficits in rats are correlated with specific brain region alterations in microglial morphology and gene expression. J Neuroimmune Pharm. 2019;14:251–262.
   PubMed Web of Science ®Google Scholar
• Howland RH. Pimavanserin an inverse agonist antipsychotic drug. J Psych Nurs Men. 2016;54(6):21–24.
   Web of Science ®Google Scholar
• Cummings J, Isaacson S, Mills R, et al. Pimavanserin for patients with Parkinson’s disease psychosis: a randomized, placebo-controlled phase 3 trial. Lancet. 2014;383(9916):533–540.
   PubMed Web of Science ®Google Scholar
• Patel N, LeWitt P, Neikrug AB, et al. Nighttime sleep and daytime sleepiness improved with pimavanserin during treatment of Parkinson’s disease psychosis. Clin Neuropharmacol. 2018 Nov/Dec;41(6):210–215.
   PubMed Web of Science ®Google Scholar
• Brown CH 4th, Jones EL, Lin C, et al. Shaping anesthetic techniques to reduce post-operative delirium (SHARP) study: a protocol for a prospective pragmatic randomized controlled trial to evaluate spinal anesthesia with targeted sedation compared with general anesthesia in older adults undergoing lumbar spine fusion surgery. BMC Anesthesiol. 2019 Oct;19(1):192.
   PubMed Web of Science ®Google Scholar
• Halliwell B. The antioxidant paradox: less paradoxical now? Br J Clin Pharmacol. 2012;75:637–644.
   Web of Science ®Google Scholar
• Sanford AM, Flaherty JH. Do nutrients play a role in delirium? Curr Opin Clin Nutr Metab Care. 2014;17:45–50.
   PubMed Web of Science ®Google Scholar
• Skvarc DR, Dean OM, Byrne LK, et al. The post-anaesthesia N-acetylcysteine cognitive evaluation (PANACEA) trial: study protocol for a randomized controlled trial. Trials. 2016 Aug;17:395.
   PubMed Web of Science ®Google Scholar