ESTABLISH: Early Sepsis TrAnslational BioLogy InformaticS in Humans

Sponsor
Lawson Health Research Institute (Other)
Overall Status
Not yet recruiting
CT.gov ID
NCT05591924
Collaborator
London Health Sciences Centre (Other), Western University, Canada (Other), Western University (Other)
1,000
1
131.9
7.6

Study Details

Study Description

Brief Summary

Sepsis is the most common diagnosis in patients admitted to the Intensive Care Unit (ICU). Sepsis happens when the immune system fails to stop the spread of infection. Recognizing sepsis early is challenging because sepsis is a collection of symptoms that are present in many other conditions that are not specific to infection. It is difficult to make a correct diagnosis and begin early treatments and as a consequence, many patients require admission to the ICU to support their injured organs. There are no specific therapies for sepsis and approximately 1 in 2 patients in the ICU with the most severe form of sepsis will not survive.

The purpose of this observational study is to identify early patient biologic factors that contribute to sepsis. This will help to diagnose sepsis earlier, identify who could benefit most from specific therapies, and could lead to the discovery of new treatments for sepsis.

Condition or Disease Intervention/Treatment Phase
  • Procedure: Phelebotomy
  • Procedure: Broncheoalveolar Lavage

Detailed Description

Background:

Sepsis is the most common diagnosis in patients admitted to the ICU. Uncontrolled local infection that results in disseminated changes in the immune system is the key driver of this syndrome. Sepsis is associated with tremendous heterogeneity in patient predisposing risk factors, mechanisms of acute insult contributing to infection, presenting symptoms, response to therapies, as well as short and long-term outcomes. Since the first standardization of sepsis definitions 30 years ago, significant insight into biological mechanisms contributing to sepsis has been made. However, there are many important unanswered questions that prevent accurate diagnosis, treatment, and prognosis of patients presenting to the ICU with early sepsis.

Of the many gaps about the biology of sepsis that remain unanswered, the following are particularly important: (1) what constitutes immune system dysregulation; (2) how the immune system response depends on interaction with the infecting pathogens; and (3) what are biologic traits that distinguish other diagnoses that mimic this syndrome. To address these questions and to improve our understanding this complex and heterogenous syndrome, a multifaceted and collaborative approach is needed. This study will investigate the biology of early sepsis in critically ill patients by developing a longitudinal prospective observational cohort called Early Sepsis TrAnslational BioLogy InformaticS in Humans (ESTABLISH).

Specific objectives:

Objective 1: To study biologic mechanisms of immune system regulation during early sepsis. The three main questions that will be addressed include: (1) how immune function at the time of admission and over the course of the ICU stay is related to clinical complications; (2) how anatomic compartmentalization of immune responses is associated with clinical complications; (3) how immune responses in different anatomic locations contribute to endothelial cell injury

Objective 2: To characterize the host-pathogen interaction during early sepsis. The main question that will be addressed include: (1) how the microbial composition at the time of ICU admission affects the immune response; (2) how the change in host-pathogen interactions over time influence clinical complications.

Objective 3: To identify biologic traits that distinguish patients with early sepsis from other critically ill patients. The main questions that will be addressed include: (1) are biological trains unique to sepsis or are they shared by other clinical diagnoses that mimic sepsis?; (2) can accurately prognosticate clinically important short and long-term patient outcomes?; (3) are biologic traits associated with differential responses to therapies?

Methods:

The ESTABLISH cohort will enroll patients within 48 hours of ICU admission who presented to the emergency department within 72 hours of ICU admission. Patients will be enrolled with deferred consent to enable the earliest possible collection of biological specimen. The biological specimen will include anticoagulated blood, a PAX gene tube, and a bronchioalveolar lavage fluid (BALF) sample (in mechanically ventilated patients, when bronchoscopy is clinically indicated) collected at the time of ICU admission (Day 0), and on 4 subsequent timepoints during the ICU admission (Days 1,3,7,14).

Data generated during ESTABLISH will be analyzed in batches on an ongoing, regular basis and will be objective-specific. Batch sample preparation and data analysis will minimize biological assay and methodological heterogeneity. Objective 1 and 2 data will be analyzed after enrollment of the first 50 patients, and every 50 patients after this. Objective 3 data will be analyzed after enrollment of the first 200 patients and every 200 patients after this.

Study Design

Study Type:
Observational [Patient Registry]
Anticipated Enrollment :
1000 participants
Observational Model:
Cohort
Time Perspective:
Prospective
Official Title:
Prospective Observational Study of Biology of Critical Illness
Anticipated Study Start Date :
Jan 3, 2023
Anticipated Primary Completion Date :
Jan 3, 2033
Anticipated Study Completion Date :
Dec 30, 2033

Arms and Interventions

Arm Intervention/Treatment
ESTABLISH

Adults over 18 years of age admitted to the ICU within 48 hours and whose presentation to the Emergency Department was within 72h of ICU admission, and whose ICU admission was for suspected infection on the basis of administration of 1 or more antimicrobial agent(s) before or at the time of ICU admission OR collection of a microbiological specimen at any time from presentation to ER to ICU admission.

Procedure: Phelebotomy
Collection of 10mL of heparin anticoagulated blood, 10mL of EDTA anticoagulated blood, and 3mL of blood in a PAX gene tube

Procedure: Broncheoalveolar Lavage
Bronchioalveolar lavage fluid (BALF) samples will be obtained from participants who are mechanically ventilated, and a bronchoscopy is indicated as part of routine clinical care. The BALF will be collected by a qualified ICU physician using standard clinical practice. Briefly, patients will receive appropriate sedation and analgesia, a flexible video-bronchoscope will be inserted into the patient's airway, and bronchial segments will be identified. The bronchoscope will be wedged in the most appropriate lung segment and 40-100mL of sterile normal saline (NS) as clinically indicated, will be injected into the bronchoscope port with using a 50mL syringe. Next, the instilled NS (i.e.: lavage fluid) will be collected in a sterile container using gentle suction. The BALF will then be partitioned and sent to clinical laboratories, and the remaining BALF (10-20mL) will be used in the ESTABLISH research study.

Healthy Controls

Adults over 18 years of age with no infectious symptoms, interaction with the health care system, or antimicrobial use in the past 14 days and no history of immunosuppression.

Procedure: Phelebotomy
Collection of 10mL of heparin anticoagulated blood, 10mL of EDTA anticoagulated blood, and 3mL of blood in a PAX gene tube

Outcome Measures

Primary Outcome Measures

  1. Risk of developing nosocomial infections during ICU admission [Assessed daily until discharge from ICU, through study completion, an average of 1 year]

    Development of any of the following: Ventilator Associated Pneumonia, Central Line Infections, Clostridium difficile-Associated Diarrhea, Blood stream infections

  2. Severity of illness measured by APACHE score [At the time of ICU admission]

    APACHE

  3. Severity of illness measured by SOFA score [At the time of ICU admission]

    SOFA

  4. Severity of illness measured by MODS score [At the time of ICU admission]

    MODS

  5. Change in severity of illness measured by APACHE score [From the time of ICU admission, assessed daily until death or discharge from ICU, up to 12 months]

    APACHE

  6. Change in severity of illness measured by SOFA score [From the time of ICU admission, assessed daily until death or discharge from ICU, up to 12 months]

    SOFA

  7. Change in severity of illness measured by MODS score [From the time of ICU admission, assessed daily until death or discharge from ICU, up to 12 months]

    MODS

  8. Hospital disposition [Determined at the time of discharge from the hospital, through study completion, an average of 1 year]

    Survival, death

Secondary Outcome Measures

  1. Neurocognitive dysfunction [1, 6, and 12 months after ICU discharge]

    Cambridge Brain Sciences (CBS) web-based neurocognitive battery

  2. Physiological outcomes [0, 24, 48, and 72 hours after ICU admission]

    Ultrasound-identified volume responsiveness

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
Yes
Inclusion Criteria:
  • Age ≥18 years old

  • ≤48h since ICU admission

  • Suspected infection defined as either:

  1. Administration of ≥1 antimicrobial agent(s) before or at the time of ICU admission OR

  2. Collection of a microbiological specimen (blood culture, sputum culture, viral nasal swab, urine culture) at any time from presentation to ER to ICU admission

  • ICU admission from:
  1. The emergency department (ER), operating room (OR), or interventional radiology (IR) without prior hospital ward admission

  2. Hospital ward if <72h from the time of ER presentation at the time of ICU admission

  3. Transfer from an outside hospital for a higher level of care within 72h of ER presentation at that hospital

Exclusion Criteria:
  • Age <18 years old for >72h

  • 48h since ICU admission

  • No administration of antimicrobial agent OR no microbial specimen collected from any site at or before ICU admission

  • Admission from a hospital ward in patients >72h after the presentation to the ER

  • Transfer from a peripheral hospital where the admission occurred >72h before transfer to the LHSC ICU

Contacts and Locations

Locations

Site City State Country Postal Code
1 Aleks Leligdowicz London Ontario Canada N6A 3K7

Sponsors and Collaborators

  • Lawson Health Research Institute
  • London Health Sciences Centre
  • Western University, Canada
  • Western University

Investigators

  • Principal Investigator: Aleks Leligdowicz, MD PhD, Western University

Study Documents (Full-Text)

None provided.

More Information

Publications

Responsible Party:
Aleks Leligdowicz, Clinician Scientist, Lawson Health Research Institute
ClinicalTrials.gov Identifier:
NCT05591924
Other Study ID Numbers:
  • 12145
First Posted:
Oct 24, 2022
Last Update Posted:
Oct 27, 2022
Last Verified:
Oct 1, 2022
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Studies a U.S. FDA-regulated Drug Product:
No
Studies a U.S. FDA-regulated Device Product:
No
Additional relevant MeSH terms:

Study Results

No Results Posted as of Oct 27, 2022