Longitudinal Evolution of Biomarkers of Dysautonomia and Inflammation During Sepsis in Children

Study Overview
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Brief Summary
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The Autonomic Nervous System (ANS) regulates the inflammatory response in real time, just as it controls heart rate and other vital functions. Many studies have investigated induced stimulation of the vagus nerve and its therapeutic effect in inhibiting TNFα (Tumor Necrosis Factor alpha) secretion, and therefore the risk of hypotension, septic shock, organ dysfunction during inflammation. While the anti-inflammatory effect of the autonomic nervous system on inflammation has been well studied, conversely, the effect of major inflammation on the balance of the autonomic nervous system is more difficult to understand. The inflammatory reflex could be overwhelmed and the regulatory centers of the brainstem dysregulated during situations of extreme inflammation.

Detailed Description
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The purpose of this study is to follow the short-term evolution of sympathetic and parasympathetic markers of dysautonomia in children hospitalized in intensive care units for severe sepsis, to characterize the evolution of the different autonomic indices according to the site of infection (meningitis, pulmonary infection, organ failure, bacteraemia) and types of pathogens (viral, bacterial, atypical germs) and correlating the evolution of the various inflammation biomarkers and cytokines with the degree of dysautonomia.

Official Title
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Longitudinal Evolution of Biomarkers of Dysautonomia and Inflammation During Sepsis in Children - An Observational Study

Conditions
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Sepsis, Autonomic Nervous System

Intervention / Treatment
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* Other: Ambulatory ECG
* Biological: Blood sample


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for cases group : Hospitalization in a pediatric intensive care unit. Presenting the sepsis criteria Patient affiliated or entitled to a social security scheme Holders of parental authority having received informed information about the study and having signed the consent form Exclusion Criteria for cases group : Parents or legal guardians who do not speak French Chronic or acute pathology that can alter autonomic balance (congenital heart disease, encephalopathy, neuropathy, acute pain, etc.) Recent general anesthesia less than 48 hours old. (inclusion may be made beyond 48 hours from the last general anesthesia if the inclusion criteria remain present) Taking treatments that can alter the ANS (β-blockers, etc.) or inflammation (NSAIDs, corticosteroids) Inclusion criteria for control group : Patient affiliated or entitled to a social security scheme Holders of parental authority having received informed information about the study and having signed the consent form Exclusion Criteria for control group : Parents or legal guardians who do not speak French Chronic or acute pathology that can alter autonomic balance (congenital heart disease, encephalopathy, neuropathy, acute pain, etc.) Recent general anesthesia less than 1 month. Taking treatments that can alter the ANS (β-blockers, etc.) or inflammation (NSAIDs, corticosteroids)

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Infant with sepsis (Case)<br>Patient hospitalized in the pediatric intensive care unit (ICU) for severe sepsis | Other: Ambulatory ECG<br>* 24h ECG monitoring<br>Biological: Blood sample<br>* The usual biological tests necessary for the management of the child and the addition of 1 tube of 2 ml<br>|
| Healthy child of the same sex and age (Control)<br>Healthy children will be matched to cases by age and gender | Other: Ambulatory ECG<br>* 24h ECG monitoring<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kinetic of the HF(High Frequency) index (ms2/Hz) of heart rate variability | Measure of the HF index of heart rate continuously at the patient's bed, during a quiet sleep phase at night, day by day for the entire duration of hospitalization in the ICU. | Through discharge from the ICU, an average of 15 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Global activity indices (SDNN (Standard deviation of the NN (R-R) intervals) evaluation | Measured continuously in quiet sleep at night, by temporal, geometric, frequency, fractal and entropy analysis | Through discharge from the ICU, an average of 15 days | 
| Plot (Poincaré plot)) evaluation | Measured continuously in quiet sleep at night, by temporal, geometric, frequency, fractal and entropy analysis | Through discharge from the ICU, an average of 15 days | 
| Parasympathetic indices (pNN50 (Percentage of successive RR intervals that differ by more than 50 ms) evaluation | Measured continuously in quiet sleep at night, by temporal, geometric, frequency, fractal and entropy analysis | Through discharge from the ICU, an average of 15 days | 
| Parasympathetic indices RMSSD (Root mean square of successive RR interval differences) evaluation | Measured continuously in quiet sleep at night, by temporal, geometric, frequency, fractal and entropy analysis | Through discharge from the ICU, an average of 15 days | 
| Parasympathetic indices HF (High Frequency) evaluation | Measured continuously in quiet sleep at night, by temporal, geometric, frequency, fractal and entropy analysis | Through discharge from the ICU, an average of 15 days | 
| Sympathetic indices (LF, LF/HF ratio) evaluation | Measured continuously in quiet sleep at night, by temporal, geometric, frequency, fractal and entropy analysis | Through discharge from the ICU, an average of 15 days | 
| Evolution of biological markers of inflammation: CRP (C-reactive protein) (mg/L) | Collection of blood sampling for analysis | Day : 1, at discharge from the ICU, an average of 90 days | 
| Evolution of biological markers of inflammation : Procalcitonin (ng/mL) | Collection of blood sampling for analysis | Day : 1, at discharge from the ICU, an average of 90 days | 
| Evolution of biological markers of inflammation : Leukocytes (G/L) | Collection of blood sampling for analysis | Day : 1, at discharge from the ICU, an average of 90 days | 
| Evolution of biological markers of inflammation : Ferritin (µg/L)s | Collection of blood sampling for analysis | Day : 1, at discharge from the ICU, an average of 90 days | 
| Evolution of biological markers of inflammation : Fibrinogen (g/L) | Collection of blood sampling for analysis | Day : 1, at discharge from the ICU, an average of 90 days | 
| Evolution of biological markers of inflammation : Platelets (G/L) | Collection of blood sampling for analysis | Day : 1, at discharge from the ICU, an average of 90 days | 
| Evolution of biological markers of inflammation : Triglycerides (g/L) | Collection of blood sampling for analysis | Day : 1, at discharge from the ICU, an average of 90 days | 
| Interferon alpha, interferon beta and interferon gamma. | Analysed by Luminex from blood sample (pg/mg) | Day : 1, at discharge from the ICU, an average of 90 days | 
| Tumor Necrosis Factor (TNF) | Analysed by Luminex from blood sample (pg/ml) | Day : 1, at discharge from the ICU, an average of 90 days | 
| Interleukines (IL1, IL2, IL3; IL4, IL5, IL6, IL7, IL8, IL9, IL10, IL11, IL12, IL13) | Analysed by Luminex from blood sample (pg/ml) | Day : 1, at discharge from the ICU, an average of 90 days | 
| Presence or absence of virus in blood | PCR (Polymerase chain reaction) multiplex | Day : 1, at discharge from the ICU, an average of 90 days | 
| Presence or absence of bacteria in blood | Blood cultures | Day : 1, at discharge from the ICU, an average of 90 days | 
| Presence or absence of bacteria in bone-marrow | Lumbar puncture | Day : 1, at discharge from the ICU, an average of 90 days | 
| Presence or absence of bacteria in urine | cytobacteriological examination of urine | Day : 1, at discharge from the ICU, an average of 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dysautonomia