Pharmacokinetics-pharmacodynamics of Morphine With or Without Midazolam Administered by Continuous Infusion in Neonatal Intensive Care

Study Overview
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Brief Summary
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This study aims to describe a dose-effect relationship of morphine alone and morphine and midazolam administered as continuous infusion in neonates hospitalized in Neonatal intensive care unit and undergoing mechanical ventilation, through PKPD modelling.

Detailed Description
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This study will include all neonates receiving a sedo-analgesia with continuous infusion of morphine alone or morphine and midazolam during mechanical ventilation in 3 French NICUs. Comfort and pain will be assessed by COMFORTneo pain scores and Newborn Infant Parasympathetic Evaluation Index. Morphine, midazolam and their metabolites' concentrations will be determined on samples taken during a planned blood test. Through PKPD modelling, the dose-concentration-effect relationships will be found and interindividual variability of these drugs in neonates and simulate doses needed to achieve comfort in neonates according to their individual characteristics (gestational age, post-natal age, weight etc.).

Official Title
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Pharmacokinetics-pharmacodynamics of Morphine With or Without Midazolam Administered by Continuous Infusion in Neonatal Intensive Care

Conditions
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Sedation Complication, Mechanical Ventilation in Neonates

Intervention / Treatment
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* Other: Dose-effect relationship of morphine +/- midazolam administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Neonates < 45 weeks of corrected gestational age Hospitalized in a Neonatal Intensive Care Unit Undergoing mechanical ventilation Patients that receive morphine alone or morphine and midazolam as continuous infusion Affiliated to a social security system Exclusion Criteria: Current weight < 600g Neonates under palliative care Therapeutic hypothermia for perinatal anoxia Neonates who underwent a surgical procedure during the past 72 hours Neonates receiving concomitantly a paralytic or another drug for sedation or analgesia other than morphine or midazolam (except for paracetamol/acetaminophen) Parents refusing that their child participate

Ages Eligible for Study
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Minimum Age: 1 Hour
Maximum Age: 4 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Intervention Model: Single Group Assignment
Interventional Model Description: The main objective is to estimate a dose-effect relationship of morphine +/- midazolam administration as continuous infusion in neonates undergoing mechanical ventilation through PKPD modelling.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Dose-effect relationship of morphine +/- midazolam administration<br> | Other: Dose-effect relationship of morphine +/- midazolam administration<br>* Dose-effect relationship of morphine +/- midazolam administration as continuous infusion in neonates undergoing mechanical ventilation through PKPD modelling<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effective dose for 50% of patients (ED50 ) of morphine in continuous infusion in neonates ventilated in the neonatal intensive care unit | To evaluate which dose is effective, cComfort will be assessed with COMFORTneo score (scale from 6 to 30 with decreasing score with increasing comfort). The dose-response relationship will be assessed with the correlation between a comfortable score (between 11 and 13) and the effective dose for 50% of patients (ED50), by PKPD modeling | From date of inclusion until the date of end of morphine +/- midazolam treatment, up to 20 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clearance (ml/min/kg) of morphine and midazolam | Morphine and midazolam serum levels (mg/L) will be used to describe clearance by PKPD | From date of inclusion until the date of end of morphine +/- midazolam treatment, up to 20 weeks | 
| Volume of distribution (L/kg) of morphine and midazolam | Morphine and midazolam serum levels (mg/L) will be used to describe volume of distribution by PKPD modeling | From date of inclusion until the date of end of morphine +/- midazolam treatment, up to 20 weeks | 
| Concentration of morphine | Morphine serum levels (mg/L) will be used to describe inter-individual variability by PKPD modeling | From date of inclusion until the date of end of morphine +/- midazolam treatment, up to 20 weeks | 
| Concentration of midazolam | midazolam serum levels (mg/L) will be used to describe inter-individual variability by PKPD modeling | From date of inclusion until the date of end of morphine +/- midazolam treatment, up to 20 weeks | 
| Doses of morphine and midazolam (µg/kg/h) | PKPD models will be used to simulate doses to determine optimal doses required according to gestational age, postnatal age, corrected age, weight and clinical context | From date of inclusion until the date of end of morphine +/- midazolam treatment, up to 20 weeks | 
| To assess pain responses by the Newborn Infant Parasympathetic Evaluation (NIPE) index | NIPE Index which provides an observer-independent, quantitative assessment of comfort and analgesia based on analysis of heart rate variability. The NIPE Index ranges from 0 to 100 with increasing index with increasing comfort | From date of inclusion until the date of end of morphine +/- midazolam treatment, up to 20 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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analgesia, morphine, midazolam, pharmacokinetics, pharmacodynamics, neonates