Functionality of Endogenous Biological Clock in Sepsis

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.

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.

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