Functionality of Endogenous Biological Clock in Sepsis

NCT ID: NCT04063332

Last Updated: 2023-12-12

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 60 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2019-06-03
• Study Completion Date: 2024-06-30

Brief Summary

The aim of the current study is to demonstrate dysregulation of immune system΄s circadian rhythms as a consequence of sepsis, as well as marked malfunction of the central circadian clock in comparison with patients without sepsis , the presence of which burdens independently the final outcome and , hence, need to be addressed.

Detailed Description

Sepsis is number one cause of death within the critically ill patients ,with mortality that reaches a rate of 70%,while in case of the establishment of septic shock and multi organ failure it can rise up to 80%.Septic shock is the most common cause of death in the ICUs. It has been estimated that 25% of the total of septic patients will develop severe sepsis (sepsis and organ failure), while septic shock (sepsis and cardiovascular failure).

In order to call a biological rhythm circadian, the following 3 criteria must be satisfied:

1. Insistence on stable conditions, with endogenous period of about 24 hours.

2. Independence of ambient temperature, so that almost always progresses at the same rate (same frequency), independent of temperature.

3. This endogenous rhythm, of approximately 24 hours, can be synchronized in exactly 24 hours, influenced by environmental factors, such as light/dark cycles, social interactions, etc.

Many organic systems follow a circadian pattern, among others the immune system,on the grounds that peripheral blood lymphocytes own all the forementioned genes, whose coordinated expression with that particular periodicity results in the generation of maximum (peak) and minimum (nadir) of the number of circulating cells, their activity, the production and secretion of cytokines etc.This endogenous attitude is lost in case of sepsis, due to few or absent stimuli deriving from the central clock. As a result, an additional compounding factor comes up in the immune system ,which fails to fight the infectious agent and that inefficient immune response aggravates the circadian desynchronization , creating a vicious circle.

The direct evaluation of circadian rhythms' entails the examination of suprachiasmatic neurons' functionality, through biopsies from the examined patients ,which constitutes an ethically questionable ,practically expensive, time-consuming and quite demanding procedure. Thus, the estimation of actual circadian profile will take place indirectly, driven by a series of biomarkers, indicative of the functional status of the ''central biological clock'' found at the suprachiasmatic nucleus of CNS (melatonin, cortisol, core body temperature),as well as the ''peripheral clock'' placed at the immune system cells (Clock/ Bmal1 , Per/Cry genes' expression).

The purpose of this prospective, observational, case-control study is to investigate the discrepancy in levels of circadian biomarkers in patients suffering from sepsis in comparison with those coming from other ,non-septic patients in the same environment as well as deviation from healthy controls' values, and secondarily to assess the effect of septic syndrome in later development of endogenous clock that regulates daily life with regard to the quality of life that follows recovery.

Conditions

Circadian Rhythm Disorders; Sepsis

Keywords

circadian; sepsis; clock; melatonin

Study Design

• Observational Model Type: CASE_CONTROL
• Study Time Perspective: PROSPECTIVE

Study Groups

GROUP A

Absolutely healthy individuals without any comorbidities, working at the same environment with the rest of groups (doctors are excluded as belong to one of the special categories) patients with sepsis as defined by the Sepsis-3 classification criteria3

No interventions assigned to this group

GROUP B

Control patients without sepsis or infection and with the same exactly comorbidities (ideally ≤2 suffering organ systems) , i.e. identical Charlson score, identical mental status and age difference ≤ 5 years with group A

No interventions assigned to this group

GROUP C

Patients with sepsis as defined by the Sepsis-3 classification criteria3

No interventions assigned to this group

Eligibility Criteria

Inclusion Criteria

• Adults (age ≥18 years)
• Written informed consent
• Male or female gender
• Οne of the following cases:

• Healthy controls without comorbidities OR
• Patients without sepsis or infection , with identical Charlson Comorbidity Index and same mental status with the septic patients OR
• Patients with sepsis

Exclusion Criteria

• Failure to obtain written informed consent
• Age <18 years
• Pregnancy or breastfeeding
• Solid tumor or hematologic malignancy
• Asthma
• Neurodegenerative disease
• Traumatic brain injury
• Confirmed depression
• Autoimmune disorders
• Special categories following unfixed or varying routine schedules (e.g. travels overseas or even short distances, if frequent/jet lag/on-call duties/nightshifts with regard to doctors,security guards,singers)
• Per os or iv corticosteroids daily intake of dose at least
• Corticosteroid oral or intravenous intake of at least 0.4 mg/kg of equivalent prednisone daily over the last 15 days

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Hellenic Sepsis Study Group

OTHER

Sponsor Role: collaborator

University of Athens

OTHER

Sponsor Role: lead

Responsible Party

Evangelos J. Giamarellos-Bourboulis, M.D.

MD, PhD, Professor of Internal Medicine ,President-Elect: European Shock Society, Co-ordinator: Hellenic Sepsis Study Group

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Evangelos J Giamarellos-Bourboulis, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Athens

Locations

2nd Department of Intensive Care Medicine, Attikon University Hospital

Athens, Attica, Greece

Site Status: RECRUITING

4th Department of Internal Medicine, Attikon University Hospital

Athens, Attica, Greece

Site Status: RECRUITING

Countries

Greece

Central Contacts

Evangelos J Giamarellos-Bourboulis, MD, PhD

Role: CONTACT

Phone: +302107480662

Email: egiamarel@med.uoa.gr

Maria G Kalogridi, MD

Role: CONTACT

Phone: +302105831916

Email: mkalogr@med.uoa.gr

Facility Contacts

Apostolos Armaganidis, MD, PhD

Role: primary

Evangelos J Giamarellos-Bourboulis, MD, PhD

Role: primary

Maria G Kalogridi, MD

Role: backup

Other Identifiers

CLOCK

Identifier Type: -

Identifier Source: org_study_id