Invasive Ventilation, Infant Pain, Infant Discomfort, Infant Neurodevelopment, Neonatal Respiratory Failure
Conditions
Keywords
Neonatology, Invasive mechanical ventilation, Analgesia, Dexmedetomidine, Neurodevelopment, Opioids, Pain, Withdrawal syndrome
Brief summary
Despite the increasing use of non-invasive ventilation, a large majority of premature neonates still receive invasive ventilation during their NICU (neonatal intensive care unit) stay. Invasive ventilation is a unanimous source of discomfort and pain. As opposed to the adult and pediatric population, routine use of opioids or midazolam is not recommended in ventilated neonates. Although opioids are the most frequently prescribed analgosedative drugs in ventilated premature neonates, their use is controversial because of the risk of respiratory depression - which can prolong invasive ventilation- and concerns on long-term neurodevelopment. Dexmedetomidine, a selective alpha-2- adrenergic agonist routinely used in the adult ICU (intensive care unit), provides light sedation and some analgesia with no or little respiratory-depression effect. It also has neuroprotective properties after pediatric cardiac surgery and in neonatal animal models. Dexmedetomidine is thus a promising candidate drug in ventilated premature neonates that might reduce the duration of mechanical ventilation and preserve neurodevelopment in this vulnerable population. The investigators hypothesize that the use of dexmedetomidine in ventilated premature neonates could decrease the need for opioids, facilitate extubation and thereby preserve long-term neurodevelopmental outcome.
Interventions
Intravenous administration for maximum 20 days
DRUGGlucose 5% Injectable Solution
Intravenous administration for maximum 20 days
Sponsors
Centre Hospitalier Intercommunal Creteil
Pr Xavier DURRMEYER
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Use of similar vials and labels for the 2 allocation arms. Masking of the result of randomization (arm description) in the eCRF. Only the treatment unit number will appear on the eCRF for administration.
Intervention model description
Double blind, multicenter, randomized, placebo-controlled trial
Eligibility
Sex/Gender
ALL
Age
No minimum to 10 Weeks
Healthy volunteers
No
Inclusion criteria
Above mentioned age limits (0 -10 weeks) apply to postnatal age. Inclusion criteria apply to gestational age at birth and postmenstrual age (in weeks). Inclusion Criteria: * Neonates with a gestational age at birth \< 32 weeks of gestation and corrected gestational age \< 32 weeks postmenstrual age * Invasively ventilated with an expected or effective duration of ventilation \> 24 hours at inclusion * Under mechanical ventilation since less than 72 hours at inclusion * With parental consent * Affiliated to or benefiting from a social security system
Exclusion criteria
* Previous inclusion in this trial * Participation in another trial including analgesics or sedatives * Ongoing palliative care * Administration of dexmedetomidine or another alpha-2 agonist in the 96 previous hours * Hemodynamic compromise defined as any of: poor perfusion (increased capillary refill time, oliguria); hypotension defined as a mean blood pressure in mm Hg \< postmenstrual age in weeks; ongoing inotropic treatment with dopamine or dobutamine ≥ 5 µg/kg/min, or any other inotropic drug at any dose, or need for more than one volume expansion (20 ml/kg) in the 6 previous hours * Pulmonary hypertension requiring pharmacological treatment * Heart rate \<100 bpm * Hepatic impairment defined as alanine aminotransferase level \> 2 x normal upper limit * Known contra-indications to dexmedetomidine: hypersensitivity, atrioventricular block, acute cerebrovascular event * Hypersensitivity to the active substance or to any of the excipients contained in the medicine
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose of Opioids used | From the start of the investigational drug to the cessation of any opioid or of the investigational drug for at least 24 hours, whichever comes last | Cumulative dose of opioids (morphine, sufentanil, fentanyl) converted to equivalent morphine dose in µg/kg using fixed equipotency ratios based on national prescriptions habits, administered during the studied period defined as the time between the start of the investigational drug and the cessation of any opioid or of the investigational drug for at least 24 hours, whichever comes last. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of time (hours) spent within an excessive/appropriate/ insufficient comfort/analgesia state based on the COMFORTneo scale | From the start of the investigational drug to the cessation of any opioid or of the investigational drug for at least 24 hours, whichever comes last | Scores of COMFORTneo scale : * excessive: score \<11 * appropriate: score between 11 to 13 * insufficient : score \>13 |
| Duration of invasive ventilation in hours | From inclusion to first planned extubation or unplanned extubation lasting at least 24 hours | — |
| Number of days with opioids and/or benzodiazepines | From the start of the investigational drug to the cessation of any opioid or of the investigational drug for at least 24 hours, whichever comes last | — |
| Cumulative dose of midazolam or other benzodiazepines | From the start of the investigational drug to the cessation of any opioid or of the investigational drug for at least 24 hours, whichever comes last | — |
| Number of days with paracetamol use | From the start of the investigational drug to the cessation of any opioid or of the investigational drug for at least 24 hours, whichever comes last | — |
| Frequency of muscle blocker use to improve ventilation | From the start of the investigational drug to the cessation of any opioid or of the investigational drug for at least 24 hours, whichever comes last | Number of patients receiving muscle bocker |
| Rate of extubation failure | Within 7 days after the first planned extubation | Number of reintubation within 7 days after the first planned extubation |
| Rate of unplanned extubation | From the start of the investigational drug to the cessation of any opioid or of the investigational drug for at least 24 hours, whichever comes last | — |
| Age at full enteral feeding in postmenstrual age (weeks) | From inclusion to hospital discharge, assessed up to 24 weeks | To respond to the secondary objective : frequency of opioid-related adverse effects |
| Frequency of urinary retention episodes | From the start of the investigational drug to the cessation of any opioid or of the investigational drug for at least 24 hours, whichever comes last | To respond to the secondary objective : frequency of opioid-related adverse effects |
| Finnegan neonatal withdrawal scale or any other validated withdrawal scale | Within 7 days of the first planned extubation or unplanned extubation lasting at least 24 hours | To respond to the secondary objective : frequency of opioid-related adverse effects |
| Number of Bradycardia episodes | From the start of the investigational drug to the cessation of any opioid or of the investigational drug for at least 24 hours, whichever comes last | Heart rate \< 100/min for 5 consecutive minutes |
| Number of hypotension episodes | From the start of the investigational drug to the cessation of any opioid or of the investigational drug for at least 24 hours, whichever comes last | Mean arterial blood pressure in mmHg \< postmenstrual age in weeks. |
| Frequency of anti-hypotensive treatments use | From the start of the investigational drug to the cessation of any opioid or of the investigational drug for at least 24 hours, whichever comes last | Volume expansion (at least 10 ml/kg), dopamine, dobutamine, epinephrine, norepinephrine, milrinone or hydrocortisone for hemodynamic support. |
| Number of In-hospital deaths | At 36 weeks postmenstrual age | — |
| Total duration of invasive ventilation | From the start of the investigational drug to hospital discharge or death, whichever comes first, assessed up to 24 weeks | Number of days |
| Total duration of non-invasive ventilation | From the start of the investigational drug to hospital discharge or death, whichever comes first, assessed up to 24 weeks | Number of days |
| Total duration of NICU stays | From the start of the investigational drug to hospital discharge or death, whichever comes first, assessed up to 24 weeks | Number of days |
| Total duration Hospital stay | From the start of investigational drug to hospital discharge or death, whichever comes first, assessed up to 24 weeks | Number of days |
| Number of patients presenting high-grade intraventricular hemorrhage Grade 3 and 4 | From the start of investigational drug to hospital discharge or death, whichever comes first, assessed up to 24 weeks | To respond secondary objective of neonatal morbidities |
| Number of patients presenting periventricular leukomalacia | From the start of investigational drug to hospital discharge or death, whichever comes first, assessed up to 24 weeks | To respond secondary objective of severe neonatal morbidities |
| Number of patients presenting secondary sepsis | From the start of investigational drug to hospital discharge or death, whichever comes first, assessed up to 24 weeks | To respond secondary objective of severe neonatal morbidities |
| Number of patientsTreated for patent ductus arteriosus | From the start of investigational drug to hospital discharge or death, whichever comes first, assessed up to 24 weeks | To respond secondary objective of severe neonatal morbidities |
| Number of patients presenting bronchopulmonary dysplasia | At 36 weeks postmenstrual age | To respond secondary objective of severe neonatal morbidities |
| Number of patients presenting necrotizing enterocolitis | From the start of investigational drug to hospital discharge or death, whichever comes first, assessed up to 24 weeks | To respond secondary objective of severe neonatal morbidities |
| Number of patients presenting isolated intestinal perforation | From the start of investigational drug to hospital discharge or death, whichever comes first, assessed up to 24 weeks | To respond secondary objective of severe neonatal morbidities |
| Number of patients presenting treated retinopathy of prematurity | From the start of investigational drug to hospital discharge or death, whichever comes first, assessed up to 24 weeks | To respond secondary objective of severe neonatal morbidities |
| Long-term neurodevelopment using tests validated in French : Parent Report of Children's Abilities-Revised (PARCA-R) | At 2 years corrected age +/- 2 months | Higher scores indicate improved neurodevelopment |
| Long-term neurodevelopment using tests validated in French : BMT-i (Batterie Modulable de Tests informatisée, or "computerized Adaptable Test Battery") | At age 6 years +/- 2 months | Higher scores indicate improved neurodevelopment |
Countries
France
Contacts
CONTACTXavier DURRMEYER, MD, PhD
CONTACTManon TAUZIN, MD
Outcome results
None listed