Sepsis Associated Encephalopathy (SAE) Biomarkers

  • STATUS
    Recruiting
  • End date
    Jun 9, 2022
  • participants needed
    90
  • sponsor
    University of Florida
Updated on 9 July 2021
antibiotic therapy
antibiotics
altered mental status
carbon dioxide
inflammatory response
delirium
systemic inflammatory response syndrome
blood culture

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), II-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.

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.

Details
Condition Septicemia, Sepsis and Septicemia, Altered Mental Status, Sepsis-Associated Delirium, Sepsis Associated Encephalopathy, Delirium, Sepsis Associated, Sepsis-Associated Delirium, Delirium, Sepsis Associated, Sepsis-Associated Delirium, Delirium, Sepsis Associated, Mental Impairment, Sepsis-Associated Delirium, Delirium, Sepsis Associated, Sepsis-Associated Delirium, Delirium, Sepsis Associated, systemic infection, systemic infections, sepsis, sepsis syndrome, Sepsis-Associated Delirium, Delirium, Sepsis Associated, Sepsis-Associated Delirium, Delirium, Sepsis Associated, Sepsis-Associated Delirium, Delirium, Sepsis Associated, Sepsis-Associated Delirium, Delirium, Sepsis Associated, Sepsis-Associated Delirium, Delirium, Sepsis Associated
Treatment Blood draws
Clinical Study IdentifierNCT03133208
SponsorUniversity of Florida
Last Modified on9 July 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Cohort 1
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 >38C or <36C
Heart rate (HR) > 90bpm
Respiratory rate (RR) > 20bpm or partial pressures of carbon dioxide (PaCO2) <32mm mercury (HG)
White Blood Cell (WBC) >12,000/L or < 4,000/L 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
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 >38C or <36C
HR > 90bpm
RR > 20bpm or PaCO 2 <32mmHG
WBC >12,000/L or < 4,000/L 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
Clear my responses

How to participate?

Step 1 Connect with a study center
What happens next?
  • You can expect the study team to contact you via email or phone in the next few days.
  • Sign up as volunteer to help accelerate the development of new treatments and to get notified about similar trials.

You are contacting

Investigator Avatar

Primary Contact

site

0/250

Additional screening procedures may be conducted by the study team before you can be confirmed eligible to participate.

Learn more

If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.

Learn more

Complete your scheduled study participation activities and then you are done. You may receive summary of study results if provided by the sponsor.

Learn more

Similar trials to consider

Loading...

Browse trials for

Not finding what you're looking for?

Every year hundreds of thousands of volunteers step forward to participate in research. Sign up as a volunteer and receive email notifications when clinical trials are posted in the medical category of interest to you.

Sign up as volunteer

user name

Added by • 

 • 

Private

Reply by • Private
Loading...

Lorem ipsum dolor sit amet consectetur, adipisicing elit. Ipsa vel nobis alias. Quae eveniet velit voluptate quo doloribus maxime et dicta in sequi, corporis quod. Ea, dolor eius? Dolore, vel!

  The passcode will expire in None.
Loading...

No annotations made yet

Add a private note
  • abc Select a piece of text from the left.
  • Add notes visible only to you.
  • Send it to people through a passcode protected link.
Add a private note