Clinical trial NCT06878703: Efficacy of Dexmedetomidine Versus Midazolam Sedation on Extubation Time in Mechanically Ventilated Preterm Infants
Official title: Efficacy of Dexmedetomidine Versus Midazolam Sedation on Extubation Time in Mechanically Ventilated Preterm Infants: a Randomized Controlled Multicenter Trial - DEXPRE
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: PreTerm Neonate
Sedation for Invasive Mechanical Ventilation
Very Preterm Neonates with Sedation for Invasive Mechanical Ventilation
Keywords: Mechanical ventilation
Sedative agent
Sedation-analgesia
Midazolam
Extubation
Very preterm neonate
Dexmedetomidine
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Dr DATA
First posted: 2025-03-17
Enrollment: 380
Sex: ALL
Maximum age (years): 32
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

Brief summary: Very preterm neonates (born before 32 weeks' gestation) often require invasive mechanical ventilation (IMV) to manage respiratory insufficiency. In France, around 8,250 infants are born annually at \<32 weeks, with an estimated 5,000 needing IMV. Although non-invasive support such as continuous positive airway pressure (CPAP) has become more common, a substantial proportion of these neonates still transition to IMV within the first few days of life. To reduce lung injury and the incidence of bronchopulmonary dysplasia (BPD), a key strategy in neonatal intensive care involves limiting the duration of IMV and promoting earlier extubation.

However, effective sedation and analgesia are essential for preterm infants subjected to intubation and mechanical ventilation. Traditionally, neonatologists combine a sedative (frequently midazolam) with an opioid (morphine, fentanyl, or sufentanil). Although these agents control pain and distress, they may cause respiratory depression, complicate weaning, and potentially contribute to adverse long-term outcomes. Midazolam, one of the few sedatives authorized for use in neonates, can improve comfort and sedation scores, but concerns persist about hypotension, altered cerebral perfusion, and a possible link to intraventricular hemorrhage (IVH). Moreover, combining benzodiazepines and opioids can prolong ventilation, increase the risk of complications, and impede timely extubation.

Rationale for Dexmedetomidine (DEX) Dexmedetomidine (DEX) is a highly selective α2-adrenergic agonist that offers sedative, anxiolytic, and analgesic properties with relatively minimal respiratory depression. Unlike certain other sedatives, DEX induces a state akin to natural sleep, allowing for easier arousal and potentially better respiratory drive. Animal studies suggest that DEX might be neuroprotective, reducing inflammation, oxidative stress, and apoptotic processes that can be detrimental to the developing brain. These features make DEX a promising alternative to the commonly used benzodiazepine-opioid regimens in very preterm neonates, who remain especially vulnerable to adverse drug effects.

Minimizing Invasive Mechanical Ventilation Reducing the time on IMV is crucial for preventing ventilator-induced lung injury and decreasing the likelihood of BPD. Early extubation is a central goal in this population, but sedation-related respiratory depression can thwart successful weaning and lead to reintubation. By preserving spontaneous breathing more effectively than midazolam or high-dose opioids, DEX may help neonates maintain adequate ventilation as they transition to non-invasive support. Furthermore, DEX's analgesic action could reduce the need for opioids, thereby mitigating withdrawal risks and other opioid-related complications such as feeding intolerance and extended hospital stays.

Objective of the DEXPRE Trial The objective of the DEXPRE trial is to compare the efficacy of dexmedetomidine-based sedation with that of midazolam-based sedation in very preterm neonates requiring IMV. Specifically, investigators aim to determine whether DEX can facilitate more rapid extubation and better overall respiratory outcomes compared to midazolam. By systematically evaluating sedation quality, respiratory stability, and potential side effects, the trial seeks to generate evidence that will guide future sedation protocols in neonatal intensive care units.

Detailed description: Hypothesis : the use of dexmedetomidine (DEX), 0.05 to 0.2 μg/kg/h, for very preterm neonates (\<32 weeks' gestation, WG), requiring prolonged sedation throughout the period of invasive mechanical ventilation (IMV) (usually after intubation and until extubation), may improve weaning, and thus reduce extubation time in neonatal intensive care units.

Population of study participants : Very preterm neonate (gestational age at birth \< 32 WG) with corrected gestational age \<45 WG).

In the experimental group, neonates will receive dexmedetomidine via continuous intravenous infusion, starting with a 0.05 μg/kg loading dose over 30 minutes, followed by a maintenance dose ranging from 0.05 to 0.2 μg/kg per hour.

In the control group, neonates will receive midazolam via continuous intravenous infusion, starting with a 10 μg/kg loading dose over 30 minutes, followed by a maintenance dose ranging from 10 to 40 μg/kg per hour.

To achieve the randomization of 292 patients, an estimated enrollment of about 380 participants is anticipated, resulting in an allocation of 146 patients per study arm.

During the inclusion visit, after verifying the inclusion and exclusion criteria, an investigator will inform the parents of eligible neonates. If the neonate requires invasive mechanical ventilation and meets the randomization criteria, the investigator will proceed with the randomization.

According to the allocation arm, the nurse in charge of the patient will be able to prepare the experimental treatment using the kit provided by the hospital pharmacy.

The experimental treatment will start with a 30-minute loading dose, followed by a maintenance dose. The infusion rate will be adjusted according to medical prescriptions to achieve the desired sedation level, ranging from 0.1 mL/hr to 0.4 mL/hr. This treatment can be administered via any venous line, either peripheral or central.

Vital signs will be regularly recorded at 5, 10, 30, and 60 minutes, then at 2, 3, 6, and 12 hours after the start of treatment. Following this, recordings will be taken every 12 hours until the treatment ends.

Pain scores will be recorded 30 and 60 minutes after the initiation of treatment, and then every 3 hours, following standard practice.

On the day of extubation, routine data recording will include the timing and duration of experimental treatment and opioid interruptions, the extubation time, vital signs before and after treatment discontinuation, and any adverse events.

The final study visit will occur when the child reaches 2 years of corrected age +/- 2 months. At this visit, weight, height, head circumference, cerebral palsy status, age of walking acquisition, and the Ages \& Stages Questionnaire (ASQ) score will be recorded.

Eligibility criteria: Inclusion Criteria:

* Patient admitted in NICU (intubated or not yet),
* Gestational age at birth \< 32 weeks of gestation (WG),
* Corrected gestational age \<45 weeks postmenstrual age Written or electronic informed consent signed by both parents.

Randomization Criteria :

* Indication for sedation in the context of invasive mechanical ventilation,
* Patient intubated or not yet,
* Elective sedation (acceptable delay between the decision to sedate and the administration of the sedative agent),
* Presence or plan of a venous access,
* No medical contraindication related to the administration of dexmedetomidine or midazolam,
* No previous use of dexmedetomidine or midazolam within 48 hours, except for the sedation procedure for intubation,
* No concomitant use of curare agent,
* No clonidine treatment,
* No previous extubation within 7 days,
* No hemodynamic instability
* No palliative care,

Exclusion Criteria:

* Patient admitted in NICU (intubated or not yet),
* Gestational age at birth \< 32 weeks of gestation (WG),
* Corrected gestational age \<45 weeks postmenstrual age Written or electronic informed consent signed by both parents.

Primary outcomes:
measure: Time, measured in minutes, is evaluated from the discontinuation of the experimental treatment (either dexmedetomidine-based or midazolam-based sedation) to extubation.
timeFrame: from the discontinuation of the experimental treatment to extubation (48 maximum)
Secondary outcomes:
measure: Administration of Opioid Agents During Sedation with Dexmedetomidine or Midazolam in Neonatal Intensive Care.
timeFrame: from the start of treatment (dexmedetomidine or midazolam) until extubation (16 days maximum)
measure: Quality of sedation
timeFrame: Before sedation, then every 30 min after sedation initiation, then every 3 hours after the initial 60 min, and up to 14 days
measure: Extubation failure 24 hours after extubation
timeFrame: In 24 hours after extubation
measure: Withdrawal syndrome (Finnegan score >8).
timeFrame: 6 hours, within 7 days after extubation.
measure: Hemodynamic and respiratory adverse effects between inclusion and 84 hours after treatment discontinuation,
timeFrame: From start of the sedation until 84 h after the sedative is stopped (maximum 18 days)
measure: In hospital morbi mortality.
timeFrame: the period of hospitalization and within the limit of 24 months
Other outcomes:
measure: Exploratory outcome: Duration (in hours) of invasive mechanical ventilation from intubation to extubation
timeFrame: From intubation to extubation
measure: Exploratory outcome: Length of stay in the NICU
timeFrame: Within the limit of 24 months
measure: Exploratory outcome: : Short-term clinical outcomes
timeFrame: at 36 Week of Gestation
measure: Exploratory outcome: 2 years neurodevelopment
timeFrame: At 2 years
Locations:
city: Paris
country: France
facility: Hospital Armand Trousseau, APHP Service : Department of Neonatology
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Clément CHOLLAT, Doctor
role: PRINCIPAL_INVESTIGATOR
References: