1932

Abstract

Delirium, an acute disturbance in mental status due to another medical condition, is common and morbid in the intensive care unit. Despite its clear association with multiple common risk factors and important outcomes, including mortality and long-term cognitive impairment, both the ultimate causes of and ideal treatments for delirium remain unclear. Studies suggest that neuroinflammation, hypoxia, alterations in energy metabolism, and imbalances in multiple neurotransmitter pathways contribute to delirium, but commonly used treatments (e.g., antipsychotic medications) target only one or a few of these potential mechanisms and are not supported by evidence of efficacy. At this time, the optimal treatment for delirium during critical illness remains avoidance of risk factors, though ongoing trials may expand on the promise shown by agents such as melatonin and dexmedetomidine.

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2022-01-27
2024-05-04
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Literature Cited

  1. 1. 
    Adamis D, Treloar A, Martin FC, Macdonald AJ. 2007. A brief review of the history of delirium as a mental disorder. Hist. Psychiatry 18:72 Pt. 4459–69
    [Google Scholar]
  2. 2. 
    Am. Psychiatr. Assoc 2013. Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. Washington, DC: Am. Psychiatr. Assoc. Publ.
    [Google Scholar]
  3. 3. 
    Salluh JI, Wang H, Schneider EB et al. 2015. Outcome of delirium in critically ill patients: systematic review and meta-analysis. BMJ 350:h2538
    [Google Scholar]
  4. 4. 
    Ely EW, Shintani A, Truman B et al. 2004. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA 291:141753–62
    [Google Scholar]
  5. 5. 
    Girard TD, Exline MC, Carson SS et al. 2018. Haloperidol and ziprasidone for treatment of delirium in critical illness. N. Engl. J. Med. 379:262506–16
    [Google Scholar]
  6. 6. 
    Devlin JW, Marquis F, Riker RR et al. 2008. Combined didactic and scenario-based education improves the ability of intensive care unit staff to recognize delirium at the bedside. Crit. Care 12:1R19
    [Google Scholar]
  7. 7. 
    van den Boogaard M, Schoonhoven L, van der Hoeven JG et al. 2012. Incidence and short-term consequences of delirium in critically ill patients: a prospective observational cohort study. Int. J. Nurs. Stud. 49:7775–83
    [Google Scholar]
  8. 8. 
    Thomason JW, Shintani A, Peterson JF et al. 2005. Intensive care unit delirium is an independent predictor of longer hospital stay: a prospective analysis of 261 non-ventilated patients. Crit. Care 9:4R375–81
    [Google Scholar]
  9. 9. 
    Ely EW, Gautam S, Margolin R et al. 2001. The impact of delirium in the intensive care unit on hospital length of stay. Intensive Care Med 27:121892–900
    [Google Scholar]
  10. 10. 
    Pisani MA, Kong SY, Kasl SV et al. 2009. Days of delirium are associated with 1-year mortality in an older intensive care unit population. Am. J. Respir. Crit. Care Med. 180:111092–97
    [Google Scholar]
  11. 11. 
    Shehabi Y, Riker RR, Bokesch PM et al. 2010. Delirium duration and mortality in lightly sedated, mechanically ventilated intensive care patients. Crit. Care Med. 38:122311–18
    [Google Scholar]
  12. 12. 
    Milbrandt EB, Deppen S, Harrison PL et al. 2004. Costs associated with delirium in mechanically ventilated patients. Crit. Care Med. 32:4955–62
    [Google Scholar]
  13. 13. 
    Girard TD, Jackson JC, Pandharipande PP et al. 2010. Delirium as a predictor of long-term cognitive impairment in survivors of critical illness. Crit. Care Med. 38:71513–20
    [Google Scholar]
  14. 14. 
    Pandharipande PP, Girard TD, Jackson JC et al. 2013. Long-term cognitive impairment after critical illness. N. Engl. J. Med. 369:141306–16
    [Google Scholar]
  15. 15. 
    Brummel NE, Jackson JC, Pandharipande PP et al. 2014. Delirium in the ICU and subsequent long-term disability among survivors of mechanical ventilation. Crit. Care Med. 42:2369–77
    [Google Scholar]
  16. 16. 
    Norman BC, Jackson JC, Graves JA et al. 2016. Employment outcomes after critical illness: an analysis of the bringing to light the risk factors and incidence of neuropsychological dysfunction in ICU survivors cohort. Crit. Care Med. 44:112003–9
    [Google Scholar]
  17. 17. 
    Persico I, Cesari M, Morandi A et al. 2018. Frailty and delirium in older adults: a systematic review and meta-analysis of the literature. J. Am. Geriatr. Soc. 66:102022–30
    [Google Scholar]
  18. 18. 
    Davis DHJ, Skelly DT, Murray C et al. 2015. Worsening cognitive impairment and neurodegenerative pathology progressively increase risk for delirium. Am. J. Geriatr. Psychiatry 23:4403–15
    [Google Scholar]
  19. 19. 
    Hasel P, Dando O, Jiwaji Z et al. 2017. Neurons and neuronal activity control gene expression in astrocytes to regulate their development and metabolism. Nat. Commun. 8:15132
    [Google Scholar]
  20. 20. 
    Hennessy E, Griffin EW, Cunningham C 2015. Astrocytes are primed by chronic neurodegeneration to produce exaggerated chemokine and cell infiltration responses to acute stimulation with the cytokines IL-1β and TNF-α. J. Neurosci. 35:228411–22
    [Google Scholar]
  21. 21. 
    Sweeney MD, Kisler K, Montagne A et al. 2018. The role of brain vasculature in neurodegenerative disorders. Nat. Neurosci. 21:101318–31
    [Google Scholar]
  22. 22. 
    Engel GL, Romano J. 1959. Delirium, a syndrome of cerebral insufficiency. J. Chronic Dis. 9:3260–77
    [Google Scholar]
  23. 23. 
    Kealy J, Murray C, Griffin EW et al. 2020. Acute inflammation alters brain energy metabolism in mice and humans: role in suppressed spontaneous activity, impaired cognition, and delirium. J. Neurosci. 40:295681–96
    [Google Scholar]
  24. 24. 
    Wood MD, Maslove DM, Muscedere JG et al. 2017. Low brain tissue oxygenation contributes to the development of delirium in critically ill patients: a prospective observational study. J. Crit. Care 41:289–95
    [Google Scholar]
  25. 25. 
    Sejling AS, Kjaer TW, Pedersen-Bjergaard U et al. 2015. Hypoglycemia-associated changes in the electroencephalogram in patients with type 1 diabetes and normal hypoglycemia awareness or unawareness. Diabetes 64:51760–69
    [Google Scholar]
  26. 26. 
    Virkamaki A, Puhakainen I, Koivisto VA et al. 1992. Mechanisms of hepatic and peripheral insulin resistance during acute infections in humans. J. Clin. Endocrinol. Metab. 74:3673–79
    [Google Scholar]
  27. 27. 
    Meltzer CC, Zubieta JK, Brandt J et al. 1996. Regional hypometabolism in Alzheimer's disease as measured by positron emission tomography after correction for effects of partial volume averaging. Neurology 47:2454–61
    [Google Scholar]
  28. 28. 
    Semmler A, Hermann S, Mormann F et al. 2008. Sepsis causes neuroinflammation and concomitant decrease of cerebral metabolism. J. Neuroinflamm. 5:38
    [Google Scholar]
  29. 29. 
    Maclullich AM, Ferguson KJ, Miller T et al. 2008. Unravelling the pathophysiology of delirium: a focus on the role of aberrant stress responses. J. Psychosom. Res. 65:3229–38
    [Google Scholar]
  30. 30. 
    Cape E, Hall RJ, van Munster BC et al. 2014. Cerebrospinal fluid markers of neuroinflammation in delirium: a role for interleukin-1β in delirium after hip fracture. J. Psychosom. Res. 77:3219–25
    [Google Scholar]
  31. 31. 
    Skelly DT, Griffin EW, Murray CL et al. 2019. Acute transient cognitive dysfunction and acute brain injury induced by systemic inflammation occur by dissociable IL-1-dependent mechanisms. Mol. Psychiatry 24:101533–48
    [Google Scholar]
  32. 32. 
    Feng X, Valdearcos M, Uchida Y et al. 2017. Microglia mediate postoperative hippocampal inflammation and cognitive decline in mice. JCI Insight 2:7e91229
    [Google Scholar]
  33. 33. 
    Munster BC, Aronica E, Zwinderman AH et al. 2011. Neuroinflammation in delirium: a postmortem case-control study. Rejuvenation Res 14:6615–22
    [Google Scholar]
  34. 34. 
    Varatharaj A, Galea I. 2017. The blood-brain barrier in systemic inflammation. Brain Behav. Immun. 60:1–12
    [Google Scholar]
  35. 35. 
    Itil T, Fink M. 1966. Anticholinergic drug-induced delirium: experimental modification, quantitative EEG and behavioral correlations. J. Nerv. Ment. Dis. 143:6492–507
    [Google Scholar]
  36. 36. 
    Gainetdinov RR, Jones SR, Caron MG. 1999. Functional hyperdopaminergia in dopamine transporter knock-out mice. Biol. Psychiatry 46:3303–11
    [Google Scholar]
  37. 37. 
    Page CB, Duffull SB, Whyte IM, Isbister GK. 2009. Promethazine overdose: clinical effects, predicting delirium and the effect of charcoal. QJM 102:2123–31
    [Google Scholar]
  38. 38. 
    Fujii S, Tanimukai H, Kashiwagi Y. 2012. Comparison and analysis of delirium induced by histamine H2 receptor antagonists and proton pump inhibitors in cancer patients. Case Rep. Oncol. 5:2409–12
    [Google Scholar]
  39. 39. 
    Aston-Jones G, Cohen JD. 2005. An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. Annu. Rev. Neurosci. 28:403–50
    [Google Scholar]
  40. 40. 
    Deiner S, Lin HM, Bodansky D et al. 2014. Do stress markers and anesthetic technique predict delirium in the elderly?. Dement. Geriatr. Cogn. Disord. 38:5–6366–74
    [Google Scholar]
  41. 41. 
    Sanders RD. 2011. Hypothesis for the pathophysiology of delirium: role of baseline brain network connectivity and changes in inhibitory tone. Med. Hypotheses 77:1140–43
    [Google Scholar]
  42. 42. 
    Morandi A, Rogers BP, Gunther ML et al. 2012. The relationship between delirium duration, white matter integrity, and cognitive impairment in intensive care unit survivors as determined by diffusion tensor imaging: the VISIONS prospective cohort magnetic resonance imaging study. Crit. Care Med. 40:72182–89
    [Google Scholar]
  43. 43. 
    Cavallari M, Dai W, Guttmann CR et al. 2016. Neural substrates of vulnerability to postsurgical delirium as revealed by presurgical diffusion. MRI Brain 139:Pt. 41282–94
    [Google Scholar]
  44. 44. 
    van Montfort SJT, van Dellen E, van den Bosch AMR et al. 2018. Resting-state fMRI reveals network disintegration during delirium. Neuroimage Clin 20:35–41
    [Google Scholar]
  45. 45. 
    Inouye SK, Charpentier PA. 1996. Precipitating factors for delirium in hospitalized elderly persons. Predictive model and interrelationship with baseline vulnerability. JAMA 275:11852–57
    [Google Scholar]
  46. 46. 
    Wilson JE, Mart MF, Cunningham C et al. 2020. Delirium. Nat. Rev. Dis. Primers 6:190
    [Google Scholar]
  47. 47. 
    Jacobi J, Fraser GL, Coursin DB et al. 2002. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit. Care Med. 30:1119–41
    [Google Scholar]
  48. 48. 
    Page VJ, Ely EW, Gates S et al. 2013. 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. 1:7515–23
    [Google Scholar]
  49. 49. 
    van den Boogaard M, Slooter AJC, Bruggemann RJM et al. 2018. Effect of haloperidol on survival among critically ill adults with a high risk of delirium: the REDUCE randomized clinical trial. JAMA 319:7680–90
    [Google Scholar]
  50. 50. 
    Burry L, Hutton B, Williamson DR et al. 2019. Pharmacological interventions for the treatment of delirium in critically ill adults. Cochrane Database Syst. Rev. 9:CD011749
    [Google Scholar]
  51. 51. 
    Herling SF, Greve IE, Vasilevskis EE et al. 2018. Interventions for preventing intensive care unit delirium in adults. Cochrane Database Syst. Rev. 11:CD009783
    [Google Scholar]
  52. 52. 
    Devlin JW, Skrobik Y, Gelinas C et al. 2018. 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. 46:9e825–73
    [Google Scholar]
  53. 53. 
    Rea RS, Battistone S, Fong JJ, Devlin JW. 2007. Atypical antipsychotics versus haloperidol for treatment of delirium in acutely ill patients. Pharmacotherapy 27:4588–94
    [Google Scholar]
  54. 54. 
    Devlin JW, Roberts RJ, Fong JJ et al. 2010. Efficacy and safety of quetiapine in critically ill patients with delirium: a prospective, multicenter, randomized, double-blind, placebo-controlled pilot study. Crit. Care Med. 38:2419–27
    [Google Scholar]
  55. 55. 
    Pandharipande PP, Sanders RD, Girard TD et al. 2010. Effect of dexmedetomidine versus lorazepam on outcome in patients with sepsis: an a priori-designed analysis of the MENDS randomized controlled trial. Crit. Care 14:2R38
    [Google Scholar]
  56. 56. 
    Pandharipande PP, Pun BT, Herr DL et al. 2007. Effect of sedation with dexmedetomidine versus loraze-pam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA 298:222644–53
    [Google Scholar]
  57. 57. 
    Riker RR, Shehabi Y, Bokesch PM et al. 2009. Dexmedetomidine versus midazolam for sedation of critically ill patients: a randomized trial. JAMA 301:5489–99
    [Google Scholar]
  58. 58. 
    Reade MC, Eastwood GM, Bellomo R et al. 2016. Effect of dexmedetomidine added to standard care on ventilator-free time in patients with agitated delirium: a randomized clinical trial. JAMA 315:141460–68
    [Google Scholar]
  59. 59. 
    Skrobik Y, Duprey MS, Hill NS, Devlin JW. 2018. Low-dose nocturnal dexmedetomidine prevents ICU delirium. A randomized, placebo-controlled trial. Am. J. Respir. Crit. Care Med. 197:91147–56
    [Google Scholar]
  60. 60. 
    Shehabi Y, Howe BD, Bellomo R et al. 2019. Early sedation with dexmedetomidine in critically ill patients. N. Engl. J. Med. 380:262506–17
    [Google Scholar]
  61. 61. 
    Hughes CG, Mailloux PT, Devlin JW et al. 2021. Dexmedetomidine or propofol for sedation in mechanically ventilated adults with sepsis. N. Engl. J. Med. 384:151424–36
    [Google Scholar]
  62. 62. 
    Hudetz JA, Patterson KM, Iqbal Z et al. 2009. Ketamine attenuates delirium after cardiac surgery with cardiopulmonary bypass. J. Cardiothorac. Vasc. Anesth. 23:5651–57
    [Google Scholar]
  63. 63. 
    Avidan MS, Maybrier HR, Abdallah AB et al. 2017. Intraoperative ketamine for prevention of postoperative delirium or pain after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial. Lancet 390:10091267–75
    [Google Scholar]
  64. 64. 
    Morandi A, Hughes CG, Thompson JL et al. 2014. Statins and delirium during critical illness: a multicenter, prospective cohort study. Crit. Care Med. 42:81899–909
    [Google Scholar]
  65. 65. 
    Needham DM, Colantuoni E, Dinglas VD et al. 2016. Rosuvastatin versus placebo for delirium in intensive care and subsequent cognitive impairment in patients with sepsis-associated acute respiratory distress syndrome: an ancillary study to a randomised controlled trial. Lancet Respir. Med. 4:3203–12
    [Google Scholar]
  66. 66. 
    Page VJ, Casarin A, Ely EW et al. 2017. Evaluation of early administration of simvastatin in the prevention and treatment of delirium in critically ill patients undergoing mechanical ventilation (MoDUS): a randomised, double-blind, placebo-controlled trial. Lancet Respir. Med. 5:9727–37
    [Google Scholar]
  67. 67. 
    Vijayakumar HN, Ramya K, Duggappa DR et al. 2016. Effect of melatonin on duration of delirium in organophosphorus compound poisoning patients: a double-blind randomised placebo controlled trial. Indian J. Anaesth. 60:11814–20
    [Google Scholar]
  68. 68. 
    Gandolfi JV, Di Bernardo APA, Chanes DAV et al. 2020. The effects of melatonin supplementation on sleep quality and assessment of the serum melatonin in ICU patients: a randomized controlled trial. Crit. Care Med. 48:12e1286–93
    [Google Scholar]
  69. 69. 
    Nishikimi M, Numaguchi A, Takahashi K et al. 2018. Effect of administration of ramelteon, a melatonin receptor agonist, on the duration of stay in the ICU: a single-center randomized placebo-controlled trial. Crit. Care Med. 46:71099–105
    [Google Scholar]
  70. 70. 
    Pun BT, Balas MC, Barnes-Daly MA et al. 2019. Caring for critically ill patients with the ABCDEF bundle: results of the ICU Liberation Collaborative in over 15,000 adults. Crit. Care Med. 47:13–14
    [Google Scholar]
  71. 71. 
    Foster J, Kelly M. 2013. A pilot study to test the feasibility of a nonpharmacologic intervention for the prevention of delirium in the medical intensive care unit. Clin. Nurse Spec. 27:5231–38
    [Google Scholar]
  72. 72. 
    Moon KJ, Lee SM. 2015. The effects of a tailored intensive care unit delirium prevention protocol: a randomized controlled trial. Int. J. Nurs. Stud. 52:91423–32
    [Google Scholar]
  73. 73. 
    Hanison J, Conway D. 2015. A multifaceted approach to prevention of delirium on intensive care. BMJ Qual. Improv. Rep. 4:1w4000
    [Google Scholar]
  74. 74. 
    Swan JT, Fitousis K, Hall JB, Todd SR, Turner KL 2012. Antipsychotic use and diagnosis of delirium in the intensive care unit. Crit. Care 16:3R84
    [Google Scholar]
  75. 75. 
    Jakob SM, Ruokonen E, Grounds RM et al. 2012. Dexmedetomidine versus midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials. JAMA 307:111151–60
    [Google Scholar]
  76. 76. 
    Burry L, Mehta S, Perreault MM et al. 2018. Antipsychotics for treatment of delirium in hospitalised non-ICU patients. Cochrane Database Syst. Rev. 6:CD005594
    [Google Scholar]
  77. 77. 
    Neufeld KJ, Yue J, Robinson TN, Inouye SK, Needham DM. 2016. Antipsychotic medication for prevention and treatment of delirium in hospitalized adults: a systematic review and meta-analysis. J. Am. Geriatr. Soc. 64:4705–14
    [Google Scholar]
  78. 78. 
    Hatta K, Kishi Y, Wada K et al. 2014. Preventive effects of ramelteon on delirium: a randomized placebo-controlled trial. JAMA Psychiatry 71:4397–403
    [Google Scholar]
  79. 79. 
    Hudetz JA, Iqbal Z, Gandhi SD et al. 2009. Ketamine attenuates post-operative cognitive dysfunction after cardiac surgery. Acta Anaesthesiol. Scand. 53:7864–72
    [Google Scholar]
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