Sepsis Associated Encephalopathy (SAE) Biomarkers
| Status: | Recruiting |
|---|---|
| Conditions: | Hospital, Neurology, Psychiatric, Psychiatric |
| Therapuetic Areas: | Neurology, Psychiatry / Psychology, Other |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 6/10/2018 |
| Start Date: | June 1, 2017 |
| End Date: | April 2019 |
| Contact: | Sarah Gul, MD |
| Email: | sarah.shireen@ufl.edu |
| Phone: | 265068031463 |
Serum Biomarkers in Sepsis Associated Encephalopathy (SAE)
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.
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.
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.
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.
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
We found this trial at
1
site
University of Florida The University of Florida (UF) is a major, public, comprehensive, land-grant, research...
Click here to add this to my saved trials
