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NCT Number: NCT05371886

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

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.

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Key information

Conditions

Sedation Complication Agnosia Mechanical Ventilation in Neonates Nervous System Diseases Neurobehavioral Manifestations Neurologic Manifestations Pathological Conditions, Signs and Symptoms Perceptual Disorders Signs and Symptoms

Age range

20 week–45 week

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

CHRU Morvan, Brest, France

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About this study

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.).

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Dose-effect relationship of morphine +/- midazolam administration

Other

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

Primary outcomes

  1. Effective dose for 50% of patients (ED50 ) of morphine in continuous infusion in neonates ventilated in the neonatal intensive care unit

    Time frame: 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 outcomes

  1. Clearance (ml/min/kg) of morphine and midazolam

    Time frame: 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

  2. Volume of distribution (L/kg) of morphine and midazolam

    Time frame: 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

  3. Concentration of morphine

    Time frame: 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

  4. Concentration of midazolam

    Time frame: 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

  5. Doses of morphine and midazolam (µg/kg/h)

    Time frame: 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

  6. To assess pain responses by the Newborn Infant Parasympathetic Evaluation (NIPE) index

    Time frame: 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

Study contacts

Contact information is provided by the study sponsor or research team.

Manon TAUZIN, MD

CONTACT

[email protected]

01 45 17 50 00 ext. 9479

Sponsors and collaborators

Lead sponsor

Centre Hospitalier Intercommunal Creteil

Other

Registry information

Important dates

Study start
2023
Primary completion
2023
Study completion
2027
First posted
May 12, 2022
Registry last updated
Nov 17, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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