Neuronal Damage In Delirium Study (NDID)

Delirium Severity, Subsyndromal Delirium, and Inflammation-associated Biomarkers in Mechanically Ventilated Patients With Sepsis

The purpose of this study is to evaluate associations between neuronal damage biomarkers (S100 calcium-binding protein beta [S-100β], neuron-specific enolase [NSE], ubiquitin carboxy-terminal hydrolase L1 [UCHL1], and brain-derived neurotropic factor [BDNF]) and delirium severity and subsyndromal delirium in a homogeneous population of mechanically ventilated patients with sepsis.

Study Overview

• Status: Completed
• Conditions: Delirium

Detailed Description

Due to high levels of inflammation, patients with sepsis are especially at risk of developing delirium, an organic state of confusion that affects over 80% of mechanically ventilated patients during their intensive care stay. A growing body of literature suggests that the severity of delirium symptoms may also have a significant impact on negative outcomes associated with delirium, including mortality, length of hospital stay, duration of mechanical ventilation, and functional and cognitive impairment. Similarly, recent literature suggests that patient outcomes may be worsened by a subthreshold severity level of delirium, known as subsyndromal delirium. Despite the urgent need to understand delirium and subsyndromal delirium etiology for better detection and management strategies, the multifactorial pathophysiology of delirium is still largely unknown. Clinical biomarker studies evaluating levels of S100 calcium-binding protein beta (S-100β), neuron-specific enolase (NSE), ubiquitin carboxy-terminal hydrolase L1 (UCHL1), and brain-derived neurotropic factor (BDNF) have suggested evidence for their role in delirium pathophysiology, but significant associations with delirium severity and subsyndromal delirium have not been reliably established. Evaluating the dose-response relationship of S-100β, NSE, UCHL1, and BDNF with delirium severity and subsyndromal delirium in a homogeneous population of mechanically ventilated patients with sepsis will provide novel insight on the etiological pathway of delirium. The investigators will evaluate effect modification and confounding by inflammation and blood-brain barrier permeability by measuring well-established biomarkers, interleukin-6 (IL-6) and E-selectin, respectively. Understanding the role of neuronal damage in delirium may be a promising avenue to develop better screening practices and neuroprotective management strategies that may reduce long-term cognitive and functional deficits associated with delirium.

• Study Type: Observational
• Enrollment (Actual): 10

Contacts and Locations

• Study Contact: Name: Karla D Krewulak, PhD; Phone Number: 4039448768; Email: kkrewula@ucalgary.ca

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T3A5E4
      • University of Calgary

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Mechanically ventilated patients with sepsis will be recruited from the largest adult ICU in Calgary, Alberta Foothills Medical Centre (FMC).

Description

Inclusion Criteria:

• Located in FMC ICU
• Able to consent or have a surrogate decision-maker able to consent
• Richmond Agitation and Sedation Scale Score ≥ -3
• Glasgow Coma Scale (GCS) score ≥ 9
• Able to communicate with the study team (English language, no hearing impairments)
• Expected to remain in the ICU longer than 24 hours
• Sequential Organ Failure Assessment (SOFA) score ≥2 (indicates sepsis based off of Sepsis 3 Guidelines)
• Invasively mechanically ventilated

Exclusion Criteria:

Neurological injury or neurodegenerative condition

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Delirium severity and subsyndromal delirium	The Confusion Assessment Method for the Intensive Care Unit 7 (CAM-ICU-7) will be completed once per day by a trained research assistant. The CAM-ICU-7 evaluates features and severity of delirium, including 1) acute onset or fluctuating course; 2) inattention; 3) disorganized thinking; and 4) altered level of consciousness. Features 1 and 2, and 3 or 4 must be present to indicate delirium. A non-zero score that does not meet the criteria of delirium indicates subsyndromal delirium. Feature 1 is scored dichotomous (0 or 1), while features 2, 3, and 4 are scored ranging between 0 and 2 (minimum 0, maximum 7). Higher scores indicate more severe delirium or subsyndromal delirium on delirium- or subsyndromal delirium-positive assessments.	Up to five days
Serum concentrations of serum S-100β, NSE, UCHL1, BDNF, E-selectin, and IL-6	A serum sample will be collected and processed for batched analysis on the first day of participant enrollment. Serum concentrations of target biomarkers will be quantified using Addressable Laser Bead Immunoassay (ALBIA), a high throughput immunosorbent assay that measures emissions from fluorescently labelled microbeads complexed with antigen-specific capture antibodies to yield a continuous measure of analyte concentration.	Once on the first day of enrollment

Collaborators and Investigators

• Sponsor: University of Calgary
• Collaborators: Alberta Health services
• Investigators: Principal Investigator: Kirsten M Fiest, PhD, University of Calgary

Publications and helpful links

Helpful Links

• Study description

Study record dates

Study Major Dates

• Study Start (Actual): July 30, 2018
• Primary Completion (Actual): May 1, 2019
• Study Completion (Actual): May 1, 2019

Study Registration Dates

• First Submitted: October 26, 2018
• First Submitted That Met QC Criteria: October 29, 2018
• First Posted (Actual): October 30, 2018

Study Record Updates

• Last Update Posted (Actual): December 20, 2023
• Last Update Submitted That Met QC Criteria: December 14, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Nervous System Diseases; Biomarkers; Pathophysiology; Confusion; Neurologic Manifestations; Mental Disorders; Delirium; Signs and Symptoms; Neurocognitive Disorders; Neurobehavioral Manifestations
• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Neurologic Manifestations; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Delirium
• Other Study ID Numbers: REB18-0409

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No