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Sepsis Associated Encephalopathy (SAE) Biomarkers

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ClinicalTrials.gov Identifier: NCT03133208
Recruitment Status : Recruiting
First Posted : April 28, 2017
Last Update Posted : May 8, 2020
Sponsor:
Information provided by (Responsible Party):
University of Florida

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.

Condition or disease Intervention/treatment
Sepsis Altered Mental Status Sepsis-Associated Delirium Sepsis Associated Encephalopathy Delirium, Sepsis Associated Procedure: Blood draws

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.

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Study Type : Observational
Estimated Enrollment : 90 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Serum Biomarkers in Sepsis Associated Encephalopathy (SAE)
Actual Study Start Date : June 1, 2017
Estimated Primary Completion Date : April 18, 2021
Estimated Study Completion Date : April 18, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Delirium Sepsis

Group/Cohort Intervention/treatment
Sepsis with AMS
Patients presenting to the ED with suspected sepsis who develop altered mental status
Procedure: 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).

Sepsis without AMS
Patients presenting to the ED with suspected sepsis without change in mental status
Procedure: 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).

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




Primary Outcome Measures :
  1. Relationship between biomarkers and neurological outcome- Delirium [ Time Frame: 1 year ]
    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.

  2. Relationship between biomarkers and neurological outcome - Blessed [ Time Frame: 1 year ]
    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]


Secondary Outcome Measures :
  1. Relationship between biomarkers and organ dysfunction [ Time Frame: 1 year ]
    Organ dysfunction will be assessed using Sequential Organ Failure Assessment (SOFA) methodology, a mortality assessment tool that monitors the dynamics of cardiovascular, respiratory, neurological, renal, hepatic, and hematological organ function.

  2. Relationship between biomarkers and overall survival [ Time Frame: 7-day, 28-day, and 6-months mortality ]
    Date of death will be recorded for all patients who died during the study period. Rate of survival will be assessed.

  3. Degree of neurological impairment [ Time Frame: up to 2 weeks ]
    assessed using the Cerebral Performance Category (CPC) scoring [CPC 1: A return to normal cerebral function and normal living, CPC 2: Cerebral disability but sufficient function for independent activities of daily living, CPC 3: Severe disability, limited cognition, inability to carry out independent existence, CPC 4: Coma, CPC 5: Brain death

  4. Degree of neurological impairment [ Time Frame: 6 months after discharge ]
    Cognitive Failure Questionnaire (CFQ) sum of 25 questions, range 0-100 assessing Forgetfulness, Distractibility, and False Triggering


Biospecimen Retention:   Samples With DNA
blood samples (serum).


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
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 (all cohorts):

  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03133208


Contacts
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Contact: Sarah Gul, MD 265068031463 sarah.shireen@ufl.edu

Locations
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United States, Florida
University of Florida Recruiting
Gainesville, Florida, United States, 32611
Sponsors and Collaborators
University of Florida
Investigators
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Principal Investigator: Marie-Carmelle Elie, MD University of Florida
Publications:
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. Erratum in: Crit Care Med. 2008 Apr;36(4):1394-6.

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Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT03133208    
Other Study ID Numbers: IRB201700135
First Posted: April 28, 2017    Key Record Dates
Last Update Posted: May 8, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of Florida:
sepsis
sepsis associated encephalopathy
sepsis associated delirium
altered mental status
Additional relevant MeSH terms:
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Sepsis
Toxemia
Delirium
Brain Diseases
Sepsis-Associated Encephalopathy
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Confusion
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Neurocognitive Disorders
Mental Disorders
Central Nervous System Diseases