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

Not Applicable

Recruiting

• Conditions: Sedation Complication; Mechanical Ventilation in Neonates
• Interventions: Other: Dose-effect relationship of morphine +/- midazolam administration

• Registration Number: NCT05371886
• Lead Sponsor: Centre Hospitalier Intercommunal Creteil

Brief Summary

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

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.).

Study Timeline

• Study First Submitted: 2022-01-31
• Study First Submitted QC: 2022-05-10
• Study First Posted: 2022-05-12
• Study Start: 2023-04-01
• Primary Completion: 2023-07-01
• Status Verified: 2024-03
• Last Update Submitted: 2024-03-26
• Last Update Posted: 2024-03-27
• Study Completion: 2025-07-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 180

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Dose-effect relationship of morphine +/- midazolam administration	Dose-effect relationship of morphine +/- midazolam administration	-

Primary Outcome Measures

Name	Time	Method
Effective dose for 50% of patients (ED50 ) of morphine in continuous infusion in neonates ventilated in the neonatal intensive care unit	From date of inclusion until the date of end of morphine +/- midazolam treatment, up to 20 weeks	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

Secondary Outcome Measures

Name	Time	Method
Concentration of morphine	From date of inclusion until the date of end of morphine +/- midazolam treatment, up to 20 weeks	Morphine serum levels (mg/L) will be used to describe inter-individual variability by PKPD modeling
Volume of distribution (L/kg) of morphine and midazolam	From date of inclusion until the date of end of morphine +/- midazolam treatment, up to 20 weeks	Morphine and midazolam serum levels (mg/L) will be used to describe volume of distribution by PKPD modeling
Doses of morphine and midazolam (µg/kg/h)	From date of inclusion until the date of end of morphine +/- midazolam treatment, up to 20 weeks	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
Clearance (ml/min/kg) of morphine and midazolam	From date of inclusion until the date of end of morphine +/- midazolam treatment, up to 20 weeks	Morphine and midazolam serum levels (mg/L) will be used to describe clearance by PKPD
Concentration of midazolam	From date of inclusion until the date of end of morphine +/- midazolam treatment, up to 20 weeks	midazolam serum levels (mg/L) will be used to describe inter-individual variability by PKPD modeling
To assess pain responses by the Newborn Infant Parasympathetic Evaluation (NIPE) index	From date of inclusion until the date of end of morphine +/- midazolam treatment, up to 20 weeks	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

Trial Locations

Locations (5)

CHRU Morvan; 🇫🇷 Brest, France

CH SUD Francilien; 🇫🇷 Corbeil-Essonnes, France

CHI Créteil; 🇫🇷 Créteil, France

CHU Lille; 🇫🇷 Lille, France

CHU Tours; 🇫🇷 Tours, France