Sepsis Associated Encephalopathy (SAE) Biomarkers

Sponsor

University of Florida (Other)

Overall Status

Recruiting

CT.gov ID

NCT03133208

Collaborator

(none)

Enrollment

Location

Anticipated Duration (Months)

1.5

Patients Per Site Per Month

Study Details

Study Description

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	Phase
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.

Study Design

Study Type:

Observational

Anticipated Enrollment :

90 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

Serum Biomarkers in Sepsis Associated Encephalopathy (SAE)

Actual Study Start Date :

Jun 1, 2017

Anticipated Primary Completion Date :

Aug 1, 2022

Anticipated Study Completion Date :

Aug 1, 2022

Arms and Interventions

Arm	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).

Arm

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).

Outcome Measures

Primary Outcome Measures

Relationship between biomarkers and neurological outcome- Delirium [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.
Relationship between biomarkers and neurological outcome - Blessed [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

Relationship between biomarkers and organ dysfunction [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.
Relationship between biomarkers and overall survival [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.
Degree of neurological impairment [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
Degree of neurological impairment [6 months after discharge]
Cognitive Failure Questionnaire (CFQ) sum of 25 questions, range 0-100 assessing Forgetfulness, Distractibility, and False Triggering

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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