The Biochemical Basis of Delirium

  • Matthew Umholtz
  • Nader D. NaderEmail author
Part of the Neuromethods book series (NM, volume 150)


Delirium is an important clinical diagnosis that is common in the post-operative period and in critically ill patients. It is associated with an increase in morbidity, mortality and resource utilization. Though the pathogenesis of delirium has been increasingly recognized for its importance and has been an intensively studied in recent years, the biochemical mechanism for its development is still debated. This review scrutinized a number of studies in order to better characterize the biochemical basis for delirium, with particular focus paid to the interactions of the cholinergic system, the cholinergic anti-inflammatory pathway, the immune system and neuroinflammation. Despite the clinical impact of delirium, evidence-based protocols for the prevention and treatment are still lacking. Several previous trials have attempted to prevent or treat delirium by modulation of the cholinergic system with acetylcholinesterase inhibitors, the results of which have been largely ambiguous at best. As the biochemical basis of delirium becomes more clearly defined, future research into therapeutics based on immune modulation and treatment of neuroinflammation may prove to be very promising.

Key words

Postoperative delirium Postoperative cognitive dysfunction Neuroinflammation Cholinergic system Anesthetic complications 


  1. 1.
    Inouye SK (2006) Delirium in older persons. N Engl J Med 354:1157–1165CrossRefGoogle Scholar
  2. 2.
    Inouye SK, Ferrucci L (2006) Elucidating the pathophysiology of delirium and the interrelationship of delirium and dementia. J Gerontol A Biol Sci Med Sci 61:1277–1280CrossRefGoogle Scholar
  3. 3.
    Hshieh TT, Fong TG, Marcantonio ER et al (2008) Cholinergic deficiency hypothesis in delirium: a synthesis of current evidence. J Gerontol A Biol Sci Med Sci 63:764–772CrossRefGoogle Scholar
  4. 4.
    Benarroch EE (2010) Acetylcholine in the cerebral cortex: effects and clinical implications. Neurology 75:659–665CrossRefGoogle Scholar
  5. 5.
    Han L, McCusker J, Cole M et al (2001) Use of medications with anticholinergic effect predicts clinical severity of delirium symptoms in older medical inpatients. Arch Intern Med 161:1099–1105CrossRefGoogle Scholar
  6. 6.
    Tune LE, Damlouji NF, Holland A et al (1981) Association of postoperative delirium with raised serum levels of anticholinergic drugs. Lancet 2:651–653CrossRefGoogle Scholar
  7. 7.
    Bartus RT, Dean RL III, Beer B et al (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217:408–414CrossRefGoogle Scholar
  8. 8.
    Deiner S, Silverstein JH (2009) Postoperative delirium and cognitive dysfunction. Br J Anaesth 103(Suppl 1):i41–i46CrossRefGoogle Scholar
  9. 9.
    Siedlecki KL, Stern Y, Reuben A et al (2009) Construct validity of cognitive reserve in a multiethnic cohort: the Northern Manhattan Study. J Int Neuropsychol Soc 15:558–569CrossRefGoogle Scholar
  10. 10.
    Blass JP, Gibson GE (1999) Cerebrometabolic aspects of delirium in relationship to dementia. Dement Geriatr Cogn Disord 10:335–338CrossRefGoogle Scholar
  11. 11.
    Gibson GE, Blass JP (1976) Impaired synthesis of acetylcholine in brain accompanying mild hypoxia and hypoglycemia. J Neurochem 27:37–42CrossRefGoogle Scholar
  12. 12.
    Pratico C, Quattrone D, Lucanto T et al (2005) Drugs of anesthesia acting on central cholinergic system may cause post-operative cognitive dysfunction and delirium. Med Hypotheses 65:972–982CrossRefGoogle Scholar
  13. 13.
    Mackie K (2008) Cannabinoid receptors: where they are and what they do. J Neuroendocrinol 20(Suppl 1):10–14CrossRefGoogle Scholar
  14. 14.
    Kearns IR, Morton RA, Bulters DO et al (2001) Opioid receptor regulation of muscarinic acetylcholine receptor-mediated synaptic responses in the hippocampus. Neuropharmacology 41:565–573CrossRefGoogle Scholar
  15. 15.
    Flood P, Ramirez-Latorre J, Role L (1997) Alpha 4 beta 2 neuronal nicotinic acetylcholine receptors in the central nervous system are inhibited by isoflurane and propofol, but alpha 7-type nicotinic acetylcholine receptors are unaffected. Anesthesiology 86:859–865CrossRefGoogle Scholar
  16. 16.
    Yamakura T, Harris RA (2000) Effects of gaseous anesthetics nitrous oxide and xenon on ligand-gated ion channels. Comparison with isoflurane and ethanol. Anesthesiology 93:1095–1101CrossRefGoogle Scholar
  17. 17.
    Westphalen RI, Hemmings HC Jr (2003) Effects of isoflurane and propofol on glutamate and GABA transporters in isolated cortical nerve terminals. Anesthesiology 98:364–372CrossRefGoogle Scholar
  18. 18.
    Nakagawasai O (2005) Behavioral and neurochemical alterations following thiamine deficiency in rodents: relationship to functions of cholinergic neurons. Yakugaku Zasshi 125:549–554CrossRefGoogle Scholar
  19. 19.
    Barclay LL, Gibson GE, Blass JP (1981) Impairment of behavior and acetylcholine metabolism in thiamine deficiency. J Pharmacol Exp Ther 217:537–543PubMedGoogle Scholar
  20. 20.
    Butterworth RF, Giguere JF, Besnard AM (1985) Activities of thiamine-dependent enzymes in two experimental models of thiamine-deficiency encephalopathy: 1. The pyruvate dehydrogenase complex. Neurochem Res 10:1417–1428CrossRefGoogle Scholar
  21. 21.
    Butterworth RF, Giguere JF, Besnard AM (1986) Activities of thiamine-dependent enzymes in two experimental models of thiamine-deficiency encephalopathy. 2. Aalpha-Ketoglutarate dehydrogenase. Neurochem Res 11:567–577CrossRefGoogle Scholar
  22. 22.
    Szutowicz A, Tomaszewicz M, Bielarczyk H (1996) Disturbances of acetyl-CoA, energy and acetylcholine metabolism in some encephalopathies. Acta Neurobiol Exp (Wars) 56:323–339Google Scholar
  23. 23.
    Robinson TN, Raeburn CD, Tran ZV et al (2009) Postoperative delirium in the elderly: risk factors and outcomes. Ann Surg 249:173–178CrossRefGoogle Scholar
  24. 24.
    Gibson GE, Duffy TE (1981) Impaired synthesis of acetylcholine by mild hypoxic hypoxia or nitrous oxide. J Neurochem 36:28–33CrossRefGoogle Scholar
  25. 25.
    Jevtovic-Todorovic V, Todorovic SM, Mennerick S et al (1998) Nitrous oxide (laughing gas) is an NMDA antagonist, neuroprotectant and neurotoxin. Nat Med 4:460–463CrossRefGoogle Scholar
  26. 26.
    Leung JM, Sands LP, Vaurio LE et al (2006) Nitrous oxide does not change the incidence of postoperative delirium or cognitive decline in elderly surgical patients. Br J Anaesth 96:754–760CrossRefGoogle Scholar
  27. 27.
    Tost H, Alam T, Meyer-Lindenberg A (2010) Dopamine and psychosis: theory, pathomechansims and Intermediate Phenotypes. Neurosci Biobehav Rev 34(5):689–700CrossRefGoogle Scholar
  28. 28.
    Seamans JK, Floresco SB, Phillips AG (1998) D1 receptor modulation of hippocampal-prefrontal cortical circuits integrating spatial memory with executive functions in the rat. J Neurosci 18:1613–1621CrossRefGoogle Scholar
  29. 29.
    Broderick PA, Gibson GE (1998) Dopamine and serotonin in rat striatum during in vivo hypoxic-hypoxia. Metab Brain Dis 4:143–153CrossRefGoogle Scholar
  30. 30.
    Alagiakrishnan K, Wiens CA (2004) An approach to drug induced delirium in the elderly. Post Grad Med J 80:388–393CrossRefGoogle Scholar
  31. 31.
    Takeuchi A, Ahern TL, Henderson SO (2011) Excited delirium. West J Emerg Med 12(1):77–83PubMedPubMedCentralGoogle Scholar
  32. 32.
    Console S, Bertorelli R, Russi G et al (1994) Serotonergic facilitation of acetylcholine release in vivo from rat dorsal hippocampus via serotonin 5-HT3 Receptors. J Neurochem 62(6):2254–2261CrossRefGoogle Scholar
  33. 33.
    Izumi J, Washizuka M, Miura N et al (1994) Hippocampal serotonin 5-HT1A receptor enhances acetylcholine release in conscious rats. J Neurochem 62(5):1804–1808CrossRefGoogle Scholar
  34. 34.
    Consolo S, Arnaboldi S, Giorgi S et al (1994) 5-HT4 receptor stimulation facilitates acetylcholine release in rat frontal cortex. Neuroreport 5(10):1230–1232CrossRefGoogle Scholar
  35. 35.
    Gillet G, Ammor S, Fillion G (1985) Serotonin inhibits acetylcholine release from rat striatum slices: evidence for a presynaptic receptor mediated effect. J Neurochem 45(6):1687–1691CrossRefGoogle Scholar
  36. 36.
    Jackson D, Stachowiak MK, Bruno JP et al (1988) Inhibition of striatal acetylcholine release by endogenous serotonin. Brain Res 457(2):259–266CrossRefGoogle Scholar
  37. 37.
    Robinson TN, Raeburn CD, Angles EM et al (2008) Low tryptophan levels are associated with post-operative delirium in the elderly. Am J Surg 196(5):670–674CrossRefGoogle Scholar
  38. 38.
    Tomas CD, Salluh J, Soares M et al (2015) Baseline acetylcholinesterase activity and serotonin plasma levels are not associated with delirium in critically ill patients. Rev Bras Ter Intens 27(2):170–177Google Scholar
  39. 39.
    Cerejeira J, Firmino H, Vaz-Serra A et al (2010) The neuroinflammatory hypothesis of delirium. Acta Neuropathol 119:737–754CrossRefGoogle Scholar
  40. 40.
    Cerejeira J, Nogueira V, Luis P et al (2012) The cholinergic system and inflammation: common pathways in delirium pathophysiology. J Am Geriatr Soc 60:669–675CrossRefGoogle Scholar
  41. 41.
    Fasick V, Spengler RN, Samankan S et al (2015) The hippocampus and TNF: common links between chronic pain and depression. Neurosci Biobehav Rev 53:139–159CrossRefGoogle Scholar
  42. 42.
    Parrish WR, Rosas-Ballina M, Gallowitsch-Puerta M et al (2008) Modulation of TNF release by choline requires alpha7 subunit nicotinic acetylcholine receptor-mediated signaling. Mol Med 14:567–574CrossRefGoogle Scholar
  43. 43.
    Porhomayon J, Kolesnikov S, Nader ND (2014) The impact of stress hormones on post-traumatic stress disorders symptoms and memory in cardiac surgery patients. J Cardiovasc Thorac Res 6:79–84PubMedPubMedCentralGoogle Scholar
  44. 44.
    Tracey KJ (2009) Reflex control of immunity. Nat Rev Immunol 9:418–428CrossRefGoogle Scholar
  45. 45.
    Pol RA, van Leeuwen BL, Izaks GJ et al (2014) C-reactive protein predicts postoperative delirium following vascular surgery. Ann Vasc Surg 28:1923–1930CrossRefGoogle Scholar
  46. 46.
    de Waal Malefyt R, Abrams J, Bennett B et al (1991) Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med 174:1209–1220CrossRefGoogle Scholar
  47. 47.
    Blalock JE, Smith EM (2007) Conceptual development of the immune system as a sixth sense. Brain Behav Immun 21:23–33CrossRefGoogle Scholar
  48. 48.
    Pugh RC, Fleshner M, Watkins LR et al (2001) The immune system and memory consolidation: a role for the cytokine IL-1beta. Neurosci Biobehav Rev 25:29–41CrossRefGoogle Scholar
  49. 49.
    Roytblat L, Talmor D, Rachinsky M et al (1998) Ketamine attenuates the interleukin-6 response after cardiopulmonary bypass. Anesth Analg 87:266–271PubMedGoogle Scholar
  50. 50.
    Borovikova LV, Ivanova S, Zhang M et al (2000) Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405:458–462CrossRefGoogle Scholar
  51. 51.
    Andersson U, Tracey KJ (2012) Neural reflexes in inflammation and immunity. J Exp Med 209:1057–1068CrossRefGoogle Scholar
  52. 52.
    Saravia F, Homo-Delarche F (2003) Is innervation an early target in autoimmune diabetes? Trends Immunol 24:574–579CrossRefGoogle Scholar
  53. 53.
    Straub RH, Rauch L, Fassold A et al (2008) Neuronally released sympathetic neurotransmitters stimulate splenic interferon-gamma secretion from T cells in early type II collagen-induced arthritis. Arthritis Rheum 58:3450–3460CrossRefGoogle Scholar
  54. 54.
    van Maanen MA, Lebre MC, van der Poll T et al (2009) Stimulation of nicotinic acetylcholine receptors attenuates collagen-induced arthritis in mice. Arthritis Rheum 60:114–122CrossRefGoogle Scholar
  55. 55.
    Zhang P, Han D, Tang T et al (2008) Inhibition of the development of collagen-induced arthritis in Wistar rats through vagus nerve suspension: a 3-month observation. Inflamm Res 57:322–328CrossRefGoogle Scholar
  56. 56.
    Abou-Hatab K, Nixon LS, O'Mahony MS et al (1999) Plasma esterases in cystic fibrosis: the impact of a respiratory exacerbation and its treatment. Eur J Clin Pharmacol 54:937–941CrossRefGoogle Scholar
  57. 57.
    Hubbard RE, O'Mahony MS, Calver BL et al (2008) Plasma esterases and inflammation in ageing and frailty. Eur J Clin Pharmacol 64:895–900CrossRefGoogle Scholar
  58. 58.
    Locatelli FM, Kawano T (2017) Postoperative cognitive dysfunction: preclinical highlights and perspectives on preventative strategies. Curr Topics Anesthesiol. In: Erbay RH (ed) InTech, London. Scholar
  59. 59.
    Macdonald A, Adamis D, Treloar A et al (2007) C-reactive protein levels predict the incidence of delirium and recovery from it. Age Ageing 36:222–225CrossRefGoogle Scholar
  60. 60.
    White S, Eeles E, O'Mahony S et al (2008) Delirium and C-reactive protein. Age Ageing 37:123–124. author reply 124CrossRefGoogle Scholar
  61. 61.
    Wilson CJ, Finch CE, Cohen HJ (2002) Cytokines and cognition—the case for a head-to-toe inflammatory paradigm. J Am Geriatr Soc 50:2041–2056CrossRefGoogle Scholar
  62. 62.
    Bartsch T, Wulff P (2015) The hippocampus in aging and disease: From plasticity to vulnerability. Neuroscience 309:1–16CrossRefGoogle Scholar
  63. 63.
    Ball MJ (1977) Neuronal loss, neurofibrillary tangles and granulovacuolar degeneration in the hippocampus with ageing and dementia. A quantitative study. Acta Neuropathol 37:111–118CrossRefGoogle Scholar
  64. 64.
    West MJ, Coleman PD, Flood DG et al (1994) Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer’s disease. Lancet 344:769–772CrossRefGoogle Scholar
  65. 65.
    Murray CA, Lynch MA (1998) Evidence that increased hippocampal expression of the cytokine interleukin-1 beta is a common trigger for age- and stress-induced impairments in long-term potentiation. J Neurosci 18:2974–2981CrossRefGoogle Scholar
  66. 66.
    Cape E, Hall RJ, van Munster BC et al (2014) Cerebrospinal fluid markers of neuroinflammation in delirium: a role for interleukin-1beta in delirium after hip fracture. J Psychosom Res 77:219–225CrossRefGoogle Scholar
  67. 67.
    Cibelli M, Fidalgo AR, Terrando N et al (2010) Role of interleukin-1beta in postoperative cognitive dysfunction. Ann Neurol 68:360–368CrossRefGoogle Scholar
  68. 68.
    Terrando N, Monaco C, Ma D et al (2010) Tumor necrosis factor-alpha triggers a cytokine cascade yielding postoperative cognitive decline. Proc Natl Acad Sci U S A 107:20518–20522CrossRefGoogle Scholar
  69. 69.
    Aloisi F (2001) Immune function of microglia. Glia 36:165–179CrossRefGoogle Scholar
  70. 70.
    Xanthos DN, Sandkuhler J (2014) Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity. Nat Rev Neurosci 15:43–53CrossRefGoogle Scholar
  71. 71.
    Murchison EP, Hannon GJ (2004) miRNAs on the move: miRNA biogenesis and the RNAi machinery. Curr Opin Cell Biol 16:223–229CrossRefGoogle Scholar
  72. 72.
    Wang G, Huang Y, Wang LL et al (2016) MicroRNA-146a suppresses ROCK1 allowing hyperphosphorylation of tau in Alzheimer’s disease. Sci Rep 6:26697CrossRefGoogle Scholar
  73. 73.
    Yu X, Liu S, Li J et al (2015) MicroRNA-572 improves early post-operative cognitive dysfunction by down-regulating neural cell adhesion molecule 1. PLoS One 10:e0118511CrossRefGoogle Scholar
  74. 74.
    Gamberini M, Bolliger D, Lurati Buse GA et al (2009) Rivastigmine for the prevention of postoperative delirium in elderly patients undergoing elective cardiac surgery—a randomized controlled trial. Crit Care Med 37:1762–1768CrossRefGoogle Scholar
  75. 75.
    Youn YC, Shin HW, Choi BS et al (2016) Rivastigmine patch reduces the incidence of postoperative delirium in older patients with cognitive impairment. Int J Geriatr Psychiatry 32(10):1079–1084CrossRefGoogle Scholar
  76. 76.
    Wang H, Liao H, Ochani M et al (2004) Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat Med 10:1216–1221CrossRefGoogle Scholar
  77. 77.
    van Eijk MM, Roes KC, Honing ML et al (2010) 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 376:1829–1837CrossRefGoogle Scholar
  78. 78.
    Hevesi ZG, Hammel LL (2012) Geriatric dDisorders. In: Stoelting RK, Hines RL, Marschall KE (eds) Stoelting’s anesthesia and co-existing disease. Saunders/Elsevier, Philadelphia, PA, p 674Google Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2020

Authors and Affiliations

  1. 1.Department of AnesthesiologyBrandon Regional HospitalBrandonUSA
  2. 2.Department of AnesthesiologyUniversity at BuffaloBuffaloUSA
  3. 3.Anesthesiology SvVA Western NY Healthcare SystemBuffaloUSA
  4. 4.Department of AnesthesiologyJacobs School of Medicine and Biomedical ScienceBuffaloUSA

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