Sepsis Associated Encephalopathy (SAE) Biomarkers

NCT03133208 | Active Not Recruiting

• 1 other identifier: IRB201700135
• Study Type: observational
• Target: 90
• Locations: 1 country
• Sites: 1

Brief Summary

Sepsis associated encephalopathy (SAE) is a poorly understood acute cerebral dysfunction that frequently appears in the setting of sepsis induced systemic inflammation. In fact, altered mentation is recognized as an independent predictor of death and poor outcomes in patients with sepsis. SAE may be manifested by a number of symptoms characterized by a change in baseline behavior, attention, alertness, cognition, or executive functioning. It occurs in the absence of direct Central Nervous System (CNS) infection, and the exact pathophysiology is of SAE is unknown, but theoretically seems to encompass a constellation of mechanisms such as impairment of the blood brain barrier (BBB), endothelial dysfunction, alteration in cerebral blood flow and neurotransmission, circulating inflammatory mediators, cellular hypoxia, and metabolic disturbances, that ultimately result in neuronal dysfunction and cell death. SAE is characterized by an altered mental status (AMS) that ranges from delirium to coma, and can lead to long-term cognitive impairment. SAE may appear early in the course of sepsis, and is often underestimated as an independent factor of mortality, yet the pathophysiology of SAE remains unknown, and there is a lack of specific investigations available to clinicians. Studies have evaluated biomarkers as prognostic tools. The Investigator propose to measure neuron specific enolase (NSE), S-100B, glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1 (UCH-L1), Tau protein, Copeptin, spectrin breakdown products (SBDP 145, SBDP150), αII-spectrin N-terminal fragment (SNTF), neurofilament light and heavy chains (NF-L, NF-H), myelin basic protein (MBP), secretoneurin (SN), and other peptide levels in the serum of sepsis patients who develop altered mental status, to evaluate the kinetics of said biomarkers for 72 hours. The Investigator will monitor the course of the patients' hospitalization to determine whether there are biomarker correlates with survival and outcomes, including neurologic impairment. Finally, this investigation may provide a mechanistic pathway that defines the development of AMS in septic patients.

Conditions

Sepsis; Altered Mental Status; Sepsis-Associated Delirium; Sepsis Associated Encephalopathy; Delirium, Sepsis Associated

Keywords

sepsis; sepsis associated encephalopathy; sepsis associated delirium; altered mental status

Outcome Measures

Primary Outcomes (2)

• Relationship between biomarkers and neurological outcome- Delirium

  Acute encephalopathy will be measured using the mental status assessment including the Delirium Triage Screen (DTS) Brief Confusion Assessment Method (bCAM). DTS-bCAM assessment is a flowchart that helps diagnose a patient who is altered.

  1 year

• Relationship between biomarkers and neurological outcome - Blessed

  Acute encephalopathy will be measured using the mental status assessment short blessed test (SBT). Sum Total (range 0-28) \[0-4 = normal cognition, 5-9 = questionable impairment, ≥ 10 = Impairment consistent with dementia\]

  1 year

Secondary Outcomes (4)

• Relationship between biomarkers and organ dysfunction

  1 year

• Relationship between biomarkers and overall survival

  7-day, 28-day, and 6-months mortality

• Degree of neurological impairment

  up to 2 weeks

• Degree of neurological impairment

  6 months after discharge

Study Arms (3)

Sepsis with AMS

Patients presenting to the ED with suspected sepsis who develop altered mental status

Procedure: Blood draws

Sepsis without AMS

Patients presenting to the ED with suspected sepsis without change in mental status

Procedure: Blood draws

Control

Patients presenting to the ED with no suspicion of systemic inflammation that need hospitalization (control category)

Procedure: Blood draws

Interventions

Blood draws PROCEDURE

Blood draws will be collected via venipuncture or IV at hours 0, 6, 12, 18, 24, 48, 72 (7 draws total). Each draw would be up to 20 mL of blood (but no less than 10 mL).

Control; Sepsis with AMS; Sepsis without AMS

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Patients who present to UF Health Shands emergency department with sepsis. The sepsis cohort will be further broken down into sub- cohorts: * Cohort 1: Patients who present with altered mental status * Cohort 2: Patients who do not present with altered mental status A control cohort (cohort 3) will include patients presenting to the ED with no suspicion of systemic inflammation that need hospitalization.

You may qualify if:

• Cohort 1:
• ≥ 18 years old
• Presented to the emergency department at Shands
• Has not donated blood within the last 8 weeks
• Willing to participate and follow up at 6 months after discharge from the hospital
• Not anemic or have any other hematological disorders that requires transfusions
• Meets two or more Systemic Inflammatory Response Syndrome (SIRS) criteria:
• Temperature \>38°C or \<36°C
• Heart rate (HR) \> 90bpm
• Respiratory rate (RR) \> 20bpm or partial pressures of carbon dioxide (PaCO2) \<32mm mercury (HG)
• White Blood Cell (WBC) \>12,000/µL or \< 4,000/µL or \>10% immature/ bands Clinical suspicion of sepsis (blood cultures ordered/ antibiotics started) Altered mental status Enrolled within 6 hours of ED presentation
• Cohort 2
• ≥ 18 years old
• Presented to the emergency department at Shands
• Has not donated blood within the last 8 weeks

You may not qualify if:

• Participating in another interventional, therapeutic study that may affect the results of this study
• Subject has neurodegenerative disease or other neurological disorder (dementia, Parkinson's disease, multiple sclerosis, seizure disorder, or brain tumours)
• History of neurosurgery within the last 30 days
• Acute brain injury within the last 30 days (ischemic/ haemorrhagic stroke, traumatic brain injury)
• Subject is anemic OR donated blood within the last 8 weeks OR has a hematological disorder that requires transfusions
• Subject has history of liver failure OR renal failure
• Pregnant or lactating female

Sponsors & Collaborators

• University of Florida: lead

Study Sites (1)

University of Florida

Gainesville, Florida, 32611, United States

Location

Related Publications (20)

• Chaudhry N, Duggal AK. Sepsis Associated Encephalopathy. Adv Med. 2014;2014:762320. doi: 10.1155/2014/762320. Epub 2014 Sep 30.

  PMID: 26556425 BACKGROUND

• Bello JH, Park M. Sepsis-associated encephalopathy as a differential diagnosis with motor deficit plus altered mental status. Clinics (Sao Paulo). 2007 Apr;62(2):199-202. doi: 10.1590/s1807-59322007000200017. No abstract available.

  PMID: 17505707 BACKGROUND

• Sprung CL, Peduzzi PN, Shatney CH, Schein RM, Wilson MF, Sheagren JN, Hinshaw LB. Impact of encephalopathy on mortality in the sepsis syndrome. The Veterans Administration Systemic Sepsis Cooperative Study Group. Crit Care Med. 1990 Aug;18(8):801-6. doi: 10.1097/00003246-199008000-00001.

  PMID: 2379391 BACKGROUND

• Shankar-Hari M, Rubenfeld GD. Understanding Long-Term Outcomes Following Sepsis: Implications and Challenges. Curr Infect Dis Rep. 2016 Nov;18(11):37. doi: 10.1007/s11908-016-0544-7.

  PMID: 27709504 BACKGROUND

• Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA. 2010 Oct 27;304(16):1787-94. doi: 10.1001/jama.2010.1553.

  PMID: 20978258 BACKGROUND

• Papadopoulos MC, Davies DC, Moss RF, Tighe D, Bennett ED. Pathophysiology of septic encephalopathy: a review. Crit Care Med. 2000 Aug;28(8):3019-24. doi: 10.1097/00003246-200008000-00057.

  PMID: 10966289 BACKGROUND

• Consales G, De Gaudio AR. Sepsis associated encephalopathy. Minerva Anestesiol. 2005 Jan-Feb;71(1-2):39-52. English, Italian.

  PMID: 15711505 BACKGROUND

• Jacob A, Brorson JR, Alexander JJ. Septic encephalopathy: inflammation in man and mouse. Neurochem Int. 2011 Mar;58(4):472-6. doi: 10.1016/j.neuint.2011.01.004. Epub 2011 Jan 8.

  PMID: 21219956 BACKGROUND

• Davies DC. Blood-brain barrier breakdown in septic encephalopathy and brain tumours. J Anat. 2002 Jun;200(6):639-46. doi: 10.1046/j.1469-7580.2002.00065.x.

  PMID: 12162731 BACKGROUND

• Polito A, Eischwald F, Maho AL, Polito A, Azabou E, Annane D, Chretien F, Stevens RD, Carlier R, Sharshar T. Pattern of brain injury in the acute setting of human septic shock. Crit Care. 2013 Sep 18;17(5):R204. doi: 10.1186/cc12899.

  PMID: 24047502 BACKGROUND

• Zhang QH, Sheng ZY, Yao YM. Septic encephalopathy: when cytokines interact with acetylcholine in the brain. Mil Med Res. 2014 Sep 1;1:20. doi: 10.1186/2054-9369-1-20. eCollection 2014.

  PMID: 25722876 BACKGROUND

• Szatmari S, Vegh T, Csomos A, Hallay J, Takacs I, Molnar C, Fulesdi B. Impaired cerebrovascular reactivity in sepsis-associated encephalopathy studied by acetazolamide test. Crit Care. 2010;14(2):R50. doi: 10.1186/cc8939. Epub 2010 Mar 31.

  PMID: 20356365 BACKGROUND

• Sharshar T, Annane D, de la Grandmaison GL, Brouland JP, Hopkinson NS, Francoise G. The neuropathology of septic shock. Brain Pathol. 2004 Jan;14(1):21-33. doi: 10.1111/j.1750-3639.2004.tb00494.x.

  PMID: 14997934 BACKGROUND

• Bozza FA, D'Avila JC, Ritter C, Sonneville R, Sharshar T, Dal-Pizzol F. Bioenergetics, mitochondrial dysfunction, and oxidative stress in the pathophysiology of septic encephalopathy. Shock. 2013 May;39 Suppl 1:10-6. doi: 10.1097/SHK.0b013e31828fade1.

  PMID: 23481496 BACKGROUND

• Hirota K. Involvement of hypoxia-inducible factors in the dysregulation of oxygen homeostasis in sepsis. Cardiovasc Hematol Disord Drug Targets. 2015;15(1):29-40. doi: 10.2174/1871529x15666150108115553.

  PMID: 25567333 BACKGROUND

• Shehabi Y, Riker RR, Bokesch PM, Wisemandle W, Shintani A, Ely EW; SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study Group. Delirium duration and mortality in lightly sedated, mechanically ventilated intensive care patients. Crit Care Med. 2010 Dec;38(12):2311-8. doi: 10.1097/CCM.0b013e3181f85759.

  PMID: 20838332 BACKGROUND

• Iacobone E, Bailly-Salin J, Polito A, Friedman D, Stevens RD, Sharshar T. Sepsis-associated encephalopathy and its differential diagnosis. Crit Care Med. 2009 Oct;37(10 Suppl):S331-6. doi: 10.1097/CCM.0b013e3181b6ed58.

  PMID: 20046118 BACKGROUND

• Sonneville R, Verdonk F, Rauturier C, Klein IF, Wolff M, Annane D, Chretien F, Sharshar T. Understanding brain dysfunction in sepsis. Ann Intensive Care. 2013 May 29;3(1):15. doi: 10.1186/2110-5820-3-15.

  PMID: 23718252 BACKGROUND

• Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992 Jun;101(6):1644-55. doi: 10.1378/chest.101.6.1644.

  PMID: 1303622 BACKGROUND

• Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL; International Surviving Sepsis Campaign Guidelines Committee; American Association of Critical-Care Nurses; American College of Chest Physicians; American College of Emergency Physicians; Canadian Critical Care Society; European Society of Clinical Microbiology and Infectious Diseases; European Society of Intensive Care Medicine; European Respiratory Society; International Sepsis Forum; Japanese Association for Acute Medicine; Japanese Society of Intensive Care Medicine; Society of Critical Care Medicine; Society of Hospital Medicine; Surgical Infection Society; World Federation of Societies of Intensive and Critical Care Medicine. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008 Jan;36(1):296-327. doi: 10.1097/01.CCM.0000298158.12101.41.

  PMID: 18158437 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

blood samples (serum).

MeSH Terms

Conditions

Sepsis; Sepsis-Associated Encephalopathy

Interventions

Blood Specimen Collection

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Marie-Carmelle Elie, MD

  University of Florida

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 10, 2017
• First Posted: April 28, 2017
• Study Start: June 1, 2017
• Primary Completion (Estimated): December 15, 2026
• Study Completion (Estimated): December 15, 2026
• Last Updated: October 28, 2025

Record last verified: 2025-10

Locations

US (1)