Sepsis-associated encephalopathy and ICU delirium

Katarzyna Kotfis



Introduction: Sepsis-associated encephalopathy is an acute dysfunction of the central nervous system (CNS) that arises as a consequence of generalized systemic infection, yet without brain infection.

The aim of this review is to introduce septic encephalopathy as a disease, with all of the epidemiology data, diagnostic opportunities, pathophysiology and possible treatment.

Sepsis-associated encephalopathy is a medical condition characterized by a broad spectrum of disturbances of consciousness, from delirium to coma, with possible seizures or focal neurological signs. Many pathophysiological mechanisms lie at the basis of septic encephalopathy, including inflammation or dysfunction of cerebral perfusion. Another important mechanism includes interactions between inflammatory cytokines and acetylcholine that lead to abnormal cholinergic transmission and neuronal death. Moreover, interaction between acetylcholine and inflammatory cytokines may induce immunosuppression.

Sepsis-associated encephalopathy diagnosis is strictly clinical, based on neurological examination and the exclusion of other causes, because there are no definite biochemical tests or radiological studies specific for this disease. The use of ICU delirium screening tools, such as CAM-ICU (Confusion Assessment Method for the Intensive Care Unit) enables earlier detection of brain dysfunction. Neuroimaging studies (computed tomography, magnetic resonance imaging), as well as electroencephalograhy may be helpful in the assessment of the severity of dysfunction.

The most important element is early diagnosis of sepsis, especially with the use of the QuickSOFA scale, and early initiation of multidirectional treatment according to Surviving Sepsis Campaign guidelines: early source identification and source control, initiation of optimal antibiotic therapy, adequate fluid therapy and supportive treatment for major organs. In order to prevent CNS dysfunction in the ICU, deep sedation and benzodiazepines should be avoided and dexmedetomidine and propofol introduced instead. Pharmacological treatment of ICU delirium is based on the use of typical (haloperidol) and atypical (i.e. quetiapine) antipsychotics. Non-pharmacological methods include early mobilization, ensuring day and night cycles, the minimalization of noctural factors (light, sounds, interventions), and family engagement.

Conclusion: Sepsis-associated encephalopathy is a serious illness associated with severe consequences, including increased mortality, long-term cognitive dysfunction, and immunosuppression. The co-dependence between septic encephalopathy and the immune system should be underlined in the approach towards sepsis treatment.


sepsis associated encephalopathy; sepsis; ICU delirium; CAM-ICU; cognitive dysfunction

Full Text:

PDF (Język Polski)


Ebersoldt M, Sharshar T, Annane D. Sepsis-associated delirium. Intensive Care Med 2007;33:941-50.

Kumar G, Kumar N, Taneja A, Kaleekal T, Tarima S, McGinley E, et al. Milwaukee Initiative in Critical Care Outcomes Research (MICCOR) Group of Investigators. Nationwide trends of severe sepsis in the 21st century (2000–2007). Chest 2011;140(5):1223-31. doi: 10.1378/chest.11-0352.

Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA 2010;304:1787-94.

Gofton TE, Young GB. Sepsis-associated encephalopathy. Nat Rev Neurol 2012;8(10):557-66. doi: 10.1038/nrneurol.2012.183.

Salluh JI, Soares M, Teles JM, Ceraso D, Raimondi N, Nava VS, et al. Delirium Epidemiology in Critical Care Study Group. Delirium epidemiology in critical care (DECCA): an international study. Crit Care 2010;14(6):R210. doi: 10.1186/cc9333.

Zhang LN, Wang XT, Ai YH, Guo QL, Huang L, Liu ZY, et al. Epidemiological features and risk factors of sepsis-associated encephalopathy in intensivecare unit patients: 2008–2011. Chin Med J (Engl) 2012;125:828-31.

Mikkelsen ME, Christie JD, Lanken PN, Biester RC, Thompson BT, Bellamy SL, et al. The adult respiratory distress syndrome cognitive outcomes study: long-term neuropsychological function in survivors of acute lung injury. Am J Respir Crit Care Med 2012;185:1307-15.

Pandharipande PP, Girard TD, Jackson JC, Morandi A, Thompson JL, Pun BT, et al. BRAIN-ICU Study Investigators. Long-term cognitive impairment after critical illness. N Engl J Med 2013;369:1306-16. doi: 10.1056/NEJMoa1301372.

Ehlenbach WJ, Hough CL, Crane PK, Haneuse SJ, Carson SS, Curtis JR, et al. Association between acute care and critical illness hospitalization and cognitive function in older adults. JAMA 2010;303:763-70.

Griffin WS. Neuroinflammatory cytokine signaling and Alzheimer’s disease. N Engl J Med 2013;368:770-1.

Munster BC, Aronica E, Zwinderman AH, Eikelenboom P, Cunningham C, Rooij SE. Neuroinflammation in delirium: a postmortem case–control study. Rejuvenation Res 2011;14(6):615-22. doi: 10.1089/rej.2011.1185.

Murray C, Sanderson DJ, Barkus C, Deacon RM, Rawlins JN, Bannerman DM, et al. Systemic inflammation induces acute working memory deficits in the primed brain: relevance for delirium. Neurobiol Aging 2012;33:603-16.e603.

Luitse MJ, van Asch CJ, Klijn CJ. Deep coma and diffuse white matter abnormalities caused by sepsis-associated encephalopathy. Lancet 2013;381:2222.

Gofton TE, Young GB. Sepsis-associated encephalopathy. Nat Rev Neurol 2012;8(10):557-66. doi:10.1038/nrneurol.2012.183.

Young GB, Bolton CF, Austin TW, Archibald YM, Gonder J, Wells GA. The encephalopathy associated with septic illness. Clin Invest Med 1990;13:297-304.

van den Boogaard M, Kox M, Quinn KL, van Achterberg T, van der Hoeven JG, Schoonhoven L, et al. Biomarkers associated with delirium in critically ill patients and their relation with long-term subjective cognitive dysfunction; indications for different pathways governing delirium in inflamed and noninflamed patients. Crit Care 2011;15:R297.

Nguyen DN, Spapen H, Su F, Schiettecatte J, Shi L, Hachimi-Idrissi S, et al. Elevated serum levels of S-100beta protein and neuron-specific enolase are associated with brain injury in patients with severe sepsis and septic shock. Crit Care Med 2006;34:1967-74.

Fioretto JR, Martin JG, Kurokawa CS, Carpi MF, Bonatto RC, Ricchetti SM, et al. Interleukin-6 and procalcitonin in children with sepsis and septic shock. Cytokine 2008;43:160-4.

Field RH, Gossen A, Cunningham C. Prior pathology in the basal forebrain cholinergic system predisposes to inflammation-induced working memory deficits: reconciling inflammatory and cholinergic hypotheses of delirium. J Neurosci 2012;32:6288-94.

Martin BJ, Buth KJ, Arora RC, Baskett RJ. Delirium as a predictor of sepsis in post-coronary artery bypass grafting patients: a retrospective cohort study. Crit Care 2010;14:R171.

Girard TD, Jackson JC, Pandharipande PP, Pun BT, Thompson JL, Shintani AK, et al. Delirium as a predictor of long-term cognitive impairment in survivors of critical illness. Crit Care Med 2010;38:1513-20.

Gunther ML, Morandi A, Krauskopf E, Pandharipande P, Girard TD, Jackson JC, et al. VISIONS Investigation, VISualizing Icu SurvivOrs Neuroradiological Sequelae. The association between brain volumes, delirium duration, and cognitive outcomes in intensive care unit survivors: the VISIONS cohort magnetic resonance imaging study. Crit Care Med 2012;40(7):2022-32. doi: 10.1097/CCM.0b013e318250acc0.

Boomer JS, To K, Chang KC, Takasu O, Osborne DF, Walton AH, et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA 2011;306:2594-605.

Hotchkiss RS, Coopersmith CM, McDunn JE, Ferguson TA. The sepsis seesaw: tilting toward immunosuppression. Nat Med 2009;15:496-7.

Woiciechowsky C, Schoning B, Daberkow N, Asche K, Stoltenburg G, Lanksch WR, et al. Brain-IL-1beta induces local inflammation but systemic anti-inflammatory response through stimulation of both hypothalamic-pituitary-adrenal axis and sympathetic nervous system. Brain Res 1999;816:563-71.

Sundar SK, Cierpial MA, Kilts C, Ritchie JC, Weiss JM. Brain IL-1-induced immunosuppression occurs through activation of both pituitary-adrenal axis and sympathetic nervous system by corticotropin-releasing factor. J Neurosci 1990;10:3701-6.

Dungan KM, Braithwaite SS, Preiser JC. Stress hyperglycaemia. Lancet 2009;373:1798-807.

Sharshar T, Blanchard A, Paillard M, Raphael JC, Gajdos P, Annane D. Circulating vasopressin levels in septic shock. Crit Care Med 2003;31:1752-8.

Zhang X, Zhang G, Zhang H, Karin M, Bai H, Cai D. Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell 2008;135:61-73.

Kavanagh BP, McCowen KC. Clinical practice. Glycemic control in the ICU. N Engl J Med 2010;363:2540-6.

Hotta N, Ichiyama T, Shiraishi M, Takekawa T, Matsubara T, Furukawa S. Nuclear factor-kappaB activation in peripheral blood mononuclear cells in children with sepsis. Crit Care Med 2007;35:2395-401.

Hoorn EJ, Betjes MG, Weigel J, Zietse R. Hypernatraemia in critically ill patients: too little water and too much salt. Nephrol Dial Transplant 2008;23:1562-8.

Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Djillali A, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016;315(8):801-10.

Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013;41(2):580-637.

Sakr Y, Rubatto Birri PN, Kotfis K, Nanchal R, Shah B, Kluge S, et al. Intensive Care Over Nations Investigators. Higher fluid balance increases the risk of death from sepsis: results from a large international audit. Crit Care Med 2017;45(3):386-94. doi: 10.1097/CCM.0000000000002189.


Copyright (c) 2018 Katarzyna Kotfis

License URL: