Sepsis Associated Encephalopathy (SAE) Biomarkers

NCT ID: NCT03133208

Last Updated: 2025-10-28

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Total Enrollment: 90 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2017-06-01
• Study Completion Date: 2026-12-15

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.

Detailed Description

Sepsis associated encephalopathy (SAE) is a common neurological complication of sepsis that is often associated with worse prognosis, yet remains poorly understood. It occurs in the absence of direct brain infection or other types of disease-associated encephalopathy such as hepatic or renal encephalopathy, and is a result of systemic inflammation (1). Clinically, a diagnosis of SAE is made when there is an impaired mental state in the presence of an extracranial infection. Clinical features of SAE include change in mental status (altered mental status/ AMS), disturbances in mental processes, agitation, disorientation, impaired attention, hypersomnolence, delirium or coma. SAE may be an early sign of sepsis that is manifested prior to overt evidence of other organ failures (2), and is an independent prognosticator of morbidity and mortality (3). Moreover, sepsis survivors can suffer from long-term cognitive impairments that impact their quality of life.

The pathophysiology of SAE is a complex constellation of proposed mechanisms that include direct insult to brain tissue from circulating inflammatory mediators that are overexpressed in sepsis, disturbances in metabolic pathways, cellular hypoxia, disruption of the BBB integrity, alterations in neurotransmission, impairment of regulation of the brain perfusion. The consequence of this combination of neuroinflammatory and ischemic processes is neuronal degeneration and cell death (apoptosis).

It is difficult to diagnose SAE early, as sepsis is often a diagnosis of exclusion and can be occult in presentation. For example, emergency physicians may conduct diagnostic studies to evaluate for stroke, metabolic disturbance (i.e. hyponatremia, hypoglycemia, vitamin deficiency, medication reaction), toxicity, seizure or other acute neurologic condition. In addition, severe sepsis patients may be intubated and are often sedated, which poses a challenge to conducting a neurological assessment of their mental status. There may be changes in electroencephalography (EEG), somatosensory-evoked potentials (SSEP), or neuroimaging but these tests lack specificity and SAE remains a diagnosis of exclusion.

Injured neurons release neuron specific proteins that diffuse across the disrupted BBB into the blood and could have diagnostic relevance in diagnosing SAE. Neuron specific enolase (NSE) and S100 beta (S100B) are biomarkers currently used in the setting of SAE and have been studied clinically. There is a lack of human studies on other proteins such as GFAP, co-peptin, Tau, neurofilament light/ heavy chain, UCH-L1, SBDP, MBP, and secretoneurin that have been proposed as potential biomarkers of neurological outcome for other causes of acute brain dysfunction such as traumatic brain injury (TBI) and hypoxic ischemic encephalopathies (HIE) and could potentially serve as candidate biomarkers to diagnose SAE.

Most studies lack a control cohort. The Investigator intends to sample sepsis patients that present to the emergency department but do not develop altered mental status within our study as well.

The Investigator therefore propose a prospective, observational study in which the study team will perform blood biomarker analysis from time of enrollment up to study day 3. This would be done by drawing blood at (0-30mins), and additional blood draws at hours 6, 12, 18, 24, 48, 72. The Investigator will then determine whether biomarker levels correlate with neurologic assessment in the Emergency Department (ED), degree of overall organ dysfunction, survival to hospital admission, survival to hospital discharge, and functional neurologic outcome at discharge and at 6 months.

Conditions

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

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

Sepsis with AMS

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

Blood draws

Intervention Type: 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).

Sepsis without AMS

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

Blood draws

Intervention Type: 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

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

Blood draws

Intervention Type: 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).

Interventions

Blood draws

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).

Intervention Type: PROCEDURE

Eligibility Criteria

Inclusion Criteria

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
• 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 SIRS criteria:

• Temperature >38°C or <36°C
• HR > 90bpm
• RR > 20bpm or PaCO 2 <32mmHG
• WBC >12,000/µL or < 4,000/µL or >10% immature/ bands Clinical suspicion of sepsis (blood cultures ordered/ antibiotics started) No altered mental status Enrolled within 6 hours of ED presentation

Cohort 3 (control)

• Does not meet SIRS criteria
• No clinical suspicion of sepsis (no cultures/ antibiotics ordered)
• Not altered
• Patient has admission orders

Exclusion Criteria

• 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Florida

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Marie-Carmelle Elie, MD

Role: PRINCIPAL_INVESTIGATOR

University of Florida

Locations

University of Florida

Gainesville, Florida, United States

Countries

United States

References

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

Reference Type: BACKGROUND

PMID: 26556425 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 17505707 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 2379391 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 27709504 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 20978258 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 10966289 (View on PubMed)

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

Reference Type: BACKGROUND

PMID: 15711505 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 21219956 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 12162731 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 24047502 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 25722876 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 20356365 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 14997934 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 23481496 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 25567333 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 20838332 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 20046118 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 23718252 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 1303622 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 18158437 (View on PubMed)

Other Identifiers

IRB201700135

Identifier Type: -

Identifier Source: org_study_id