Multimodal Approach to the Ontogenesis of Nociception in Very Preterm and Term Infants

Study Overview
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Brief Summary
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The management of pain related to venipuncture remains insufficient in very preterm infants (VPI. The separation between the mother (father) and her(his) child can aggravate the short-term painful experience of the newborn. Accurate diagnosis and treatment of pain is necessary to preserve the well-being and brain development of VPI. A better understanding of the development of pain pathways and the cortical integration of nociceptive messages is essential to reach this goal.

Official Title
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Multimodal Approach to the Ontogenesis of Nociception in Very Preterm and Term Infants

Conditions
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Procedural Pain, Pre-Term, Venipuncture

Intervention / Treatment
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* Behavioral: Maternal vocal contact


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Experimental group: VPIs of gestational age less than or equal to 33 weeks on the day of birth and hospitalized in the neonatal intermediate care unit or the neonatal intensive care unit of the Neonatal department of the Hautepierre Hospital (Strasbourg University Hospital) Control group: Healthy full-term babies (> 37 weeks gestational age) hospitalized in the maternity ward of Strasbourg University Hospital Consent obtained from both parents Subject affiliated to a social health insurance plan. Exclusion Criteria: - Any malformation known before inclusion Cerebral lesions discovered on cerebral ultrasound performed as part of the standard management of newborns (Intra-Ventricular Hemorrhages of grade III or IV of the Papile classification, Periventricular Leucomalacia) Unstable clinical status according to the investigator's judgment Expected transfer of the child to another hospital before the term of 40 weeks PMAs.
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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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Very preterm infant<br>Preterm infant below 33 weeks of GA | Behavioral: Maternal vocal contact<br>* Two consecutive venipuncture (order randomly balanced) within a short period of time will be realized with and without the presence of the mother talking/singing to her VPI infant. In this intervention group, the mother will be supported to talk or to sing to her infants during before and during the venipuncture.<br>|
| Active Comparator: Full term neonate<br>Term neonate from a gestational age of 37 weeks. | Behavioral: Maternal vocal contact<br>* Two consecutive venipuncture (order randomly balanced) within a short period of time will be realized with and without the presence of the mother talking/singing to her VPI infant. In this intervention group, the mother will be supported to talk or to sing to her infants during before and during the venipuncture.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The cortical hemodynamic response profile | The measurements will be performed using receiver and transmitter optodes to measure the variations of oxy and deoxyhemoglobin in the cerebral cortex below the optodes. The optodes will be placed in the primary and secondary somatosensory areas, and in other cortical areas (nociceptive pathway and control areas) using the EEG 10-20 classification. The data set will be collected over a basal period, a stimulation period and a post-stimulation period. Response patterns will be analyzed by mixed models and compared in VPIs in the different APM groups and with term neonates. A typical response associates an increase in oxyhemoglobin (Hb02) with a concomitant stability or decrease in deoxyhemoglobin (HHb). | During a venipuncture (needed for the standard care of the infants) and realized around 30 (+/- 2) weeks PMAs in VPI | 
| The cortical hemodynamic response profile | The measurements will be performed using receiver and transmitter optodes to measure the variations of oxy and deoxyhemoglobin in the cerebral cortex below the optodes. The optodes will be placed in the primary and secondary somatosensory areas, and in other cortical areas (nociceptive pathway and control areas) using the EEG 10-20 classification. The data set will be collected over a basal period, a stimulation period and a post-stimulation period. Response patterns will be analyzed by mixed models and compared in VPIs in the different APM groups and with term neonates. A typical response associates an increase in oxyhemoglobin (Hb02) with a concomitant stability or decrease in deoxyhemoglobin (HHb). | During a venipuncture at 34 (+/-2) weeks PMAs in VPI | 
| The cortical hemodynamic response profile | The measurements will be performed using receiver and transmitter optodes to measure the variations of oxy and deoxyhemoglobin in the cerebral cortex below the optodes. The optodes will be placed in the primary and secondary somatosensory areas, and in other cortical areas (nociceptive pathway and control areas) using the EEG 10-20 classification. The data set will be collected over a basal period, a stimulation period and a post-stimulation period. Response patterns will be analyzed by mixed models and compared in VPIs in the different APM groups and with term neonates. A typical response associates an increase in oxyhemoglobin (Hb02) with a concomitant stability or decrease in deoxyhemoglobin (HHb). | During a venipuncture at 40 (+/-2) weeks PMAs in VPI | 
| The cortical hemodynamic response profile | The measurements will be performed using receiver and transmitter optodes to measure the variations of oxy and deoxyhemoglobin in the cerebral cortex below the optodes. The optodes will be placed in the primary and secondary somatosensory areas, and in other cortical areas (nociceptive pathway and control areas) using the EEG 10-20 classification. The data set will be collected over a basal period, a stimulation period and a post-stimulation period. Response patterns will be analyzed by mixed models and compared in VPIs in the different APM groups and with term neonates. A typical response associates an increase in oxyhemoglobin (Hb02) with a concomitant stability or decrease in deoxyhemoglobin (HHb). | During a venipuncture at 2 to 3 days of life in term neonates | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of the hemodynamic response profiles and salivary oxytocin levels | Comparison of the hemodynamic response profiles and salivary oxytocin levels during 2 consecutive venipunctures, without and with the addition of the maternal voice as a supplementary non-pharmacological pain strategies | During a venipuncture (needed for the standard care of the infants) and realized around 30 (+/- 2) weeks PMAs in VPI | 
| Comparison of the hemodynamic response profiles and salivary oxytocin levels | Comparison of the hemodynamic response profiles and salivary oxytocin levels during 2 consecutive venipunctures, without and with the addition of the maternal voice as a supplementary non-pharmacological pain strategies | During a venipuncture at 34 (+/-2) weeks PMAs in VPI | 
| Comparison of the hemodynamic response profiles and salivary oxytocin levels | Comparison of the hemodynamic response profiles and salivary oxytocin levels during 2 consecutive venipunctures, without and with the addition of the maternal voice as a supplementary non-pharmacological pain strategies | During a venipuncture at 40 (+/-2) weeks PMAs in VPI | 
| Comparison of the hemodynamic response profiles and salivary oxytocin levels | Comparison of the hemodynamic response profiles and salivary oxytocin levels during 2 consecutive venipunctures, without and with the addition of the maternal voice as a supplementary non-pharmacological pain strategies | During a venipuncture at 2 to 3 days of life in term neonates | 
| Analysis of the impact on the responses of maternal separation | Analysis of the impact on the responses of maternal separation determined by the absence of early skin-to-skin contact (in the VPI < 3 days of life and in the term newborn < 2 hours of life). | During a venipuncture (needed for the standard care of the infants) and realized around 30 (+/- 2) weeks PMAs in VPI | 
| Analysis of the impact on the responses of maternal separation | Analysis of the impact on the responses of maternal separation determined by the absence of early skin-to-skin contact (in the VPI < 3 days of life and in the term newborn < 2 hours of life). | During a venipuncture at 34 (+/-2) weeks PMAs in VPI | 
| Analysis of the impact on the responses of maternal separation | Analysis of the impact on the responses of maternal separation determined by the absence of early skin-to-skin contact (in the VPI < 3 days of life and in the term newborn < 2 hours of life). | During a venipuncture at 40 (+/-2) weeks PMAs in VPI | 
| Analysis of the impact on the responses of maternal separation | Analysis of the impact on the responses of maternal separation determined by the absence of early skin-to-skin contact (in the VPI < 3 days of life and in the term newborn < 2 hours of life). | During a venipuncture at 2 to 3 days of life in term neonates | 
| Comparison of the response profiles according to the sex | Comparison of the response profiles obtained in females and males | During a venipuncture (needed for the standard care of the infants) and realized around 30 (+/- 2) weeks PMAs in VPI | 
| Comparison of the response profiles according to the sex | Comparison of the response profiles obtained in females and males | During a venipuncture at 34 (+/-2) weeks PMAs in VPI | 
| Comparison of the response profiles according to the sex | Comparison of the response profiles obtained in females and males | During a venipuncture at 40 (+/-2) weeks PMAs in VPI | 
| Comparison of the response profiles according to the sex | Comparison of the response profiles obtained in females and males | During a venipuncture at 2 to 3 days of life in term neonates | 
| Comparison of conduction velocities of small caliber nociceptive fibers | Comparison of conduction velocities of small caliber nociceptive fibers measured by evoked potentials, in response to non-painful cold stimulation in the VPIs of different APMs groups. | During a venipuncture (needed for the standard care of the infants) and realized around 30 (+/- 2) weeks PMAs in VPI | 
| Comparison of conduction velocities of small caliber nociceptive fibers | Comparison of conduction velocities of small caliber nociceptive fibers measured by evoked potentials, in response to non-painful cold stimulation in the VPIs of different APMs groups. | During a venipuncture at 34 (+/-2) weeks PMAs in VPI | 
| Comparison of conduction velocities of small caliber nociceptive fibers | Comparison of conduction velocities of small caliber nociceptive fibers measured by evoked potentials, in response to non-painful cold stimulation in the VPIs of different APMs groups. | During a venipuncture at 40 (+/-2) weeks PMAs in VPI | 
| Comparison of conduction velocities of small caliber nociceptive fibers | Comparison of conduction velocities of small caliber nociceptive fibers measured by evoked potentials, in response to non-painful cold stimulation in the VPIs of different APMs groups. | During a venipuncture at 2 to 3 days of life in term neonates | 
| Correlational analyses by APM group | Correlational analyses, by APM group, between the different pain indicators in response to stimulation | During a venipuncture (needed for the standard care of the infants) and realized around 30 (+/- 2) weeks PMAs in VPI | 
| Correlational analyses by APM group | Correlational analyses, by APM group, between the different pain indicators in response to stimulation | During a venipuncture at 34 (+/-2) weeks PMAs in VPI | 
| Correlational analyses by APM group | Correlational analyses, by APM group, between the different pain indicators in response to stimulation | During a venipuncture at 40 (+/-2) weeks PMAs in VPI | 
| Correlational analyses by APM group | Correlational analyses, by APM group, between the different pain indicators in response to stimulation | During a venipuncture at 2 to 3 days of life in term neonates | 
| Facial pain behavior | Facial pain behavior with the Neonatal Facial Coding System | During a venipuncture (needed for the standard care of the infants) and realized around 30 (+/- 2) weeks PMAs in VPI | 
| Facial pain behavior | Facial pain behavior with the Neonatal Facial Coding System | During a venipuncture at 34 (+/-2) weeks PMAs in VPI | 
| Facial pain behavior | Facial pain behavior with the Neonatal Facial Coding System | During a venipuncture at 40 (+/-2) weeks PMAs in VPI | 
| Facial pain behavior | Facial pain behavior with the Neonatal Facial Coding System | During a venipuncture at 2 to 3 days of life in term neonates | 
| Pain index | Pain index assessing the sympathetic and parasympathetic system | During a venipuncture (needed for the standard care of the infants) and realized around 30 (+/- 2) weeks PMAs in VPI | 
| Pain index | Pain index assessing the sympathetic and parasympathetic system | During a venipuncture at 34 (+/-2) weeks PMAs in VPI | 
| Pain index | Pain index assessing the sympathetic and parasympathetic system | During a venipuncture at 40 (+/-2) weeks PMAs in VPI | 
| Pain index | Pain index assessing the sympathetic and parasympathetic system | During a venipuncture at 2 to 3 days of life in term neonates | 
| Cortical evoked potentials | Cortical evoked potentials in Cz according to EEG 10:20 classification | During a venipuncture (needed for the standard care of the infants) and realized around 30 (+/- 2) weeks PMAs in VPI | 
| Cortical evoked potentials | Cortical evoked potentials in Cz according to EEG 10:20 classification | During a venipuncture at 34 (+/-2) weeks PMAs in VPI | 
| Cortical evoked potentials | Cortical evoked potentials in Cz according to EEG 10:20 classification | During a venipuncture at 40 (+/-2) weeks PMAs in VPI | 
| Cortical evoked potentials | Cortical evoked potentials in Cz according to EEG 10:20 classification | During a venipuncture at 2 to 3 days of life in term neonates | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Very preterm infants, Development of nociception, Cortical hemodynamic responses, Pain indicators, Gender, Maternal voice, Oxytocin