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

Sponsor

Centre Hospitalier Intercommunal Creteil (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05371886

Collaborator

(none)

180

Enrollment

Locations

Arm

Anticipated Duration (Months)

Patients Per Site

2.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Sedation Complication Mechanical Ventilation in Neonates	Other: Dose-effect relationship of morphine +/- midazolam administration	N/A

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 Design

Study Type:

Interventional

Anticipated Enrollment :

180 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention 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.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)

Primary Purpose:

Supportive Care

Official Title:

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

Anticipated Study Start Date :

Sep 1, 2022

Anticipated Primary Completion Date :

Dec 1, 2024

Anticipated Study Completion Date :

Dec 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Other: Dose-effect relationship of morphine +/- midazolam administration	Other: Dose-effect relationship of morphine +/- midazolam administration Dose-effect relationship of morphine +/- midazolam administration as continuous infusion in neonates undergoing mechanical ventilation through PKPD modelling

Arm

Intervention/Treatment

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

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

Dose-effect relationship of morphine +/- midazolam administration as continuous infusion in neonates undergoing mechanical ventilation through PKPD modelling

Outcome Measures

Primary Outcome Measures

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

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
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
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
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
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
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Hour to 4 Weeks

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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