Birth Asphyxia
Conditions
Brief summary
The investigators will determine the maximum tolerable dose of sildenafil and establish the pharmacokinetic and pharmacodynamic profile of sildenafil in human asphyxiated neonates treated with hypothermia. They will use a 3+3 design to escalate the sildenafil dose up to 6 mg/kg/day (3mg/kg/dose q12h) in asphyxiated neonates demonstrating brain injury despite hypothermia treatment and assess whether we observe any beneficial effects of sildenafil on their brain and cardiopulmonary hemodynamics, without causing serious adverse events
Interventions
DRUGSildenafil Citrate
Cohort 1 of 3-6 neonates: 1st dose of 2mg/kg/dose, 2nd dose of 2.5 mg/kg/dose, and subsequent doses of 2.5mg/kg/dose q12h (= 5 mg/kg/day from dose #2) Cohort 2 of 3-6 neonates: 1st dose of 2mg/kg/dose, 2nd dose of 2.5 mg/kg/dose, 3rd dose of 3mg/kg/dose, and subsequent doses of 3mg/kg/dose q12h (= 6 mg/kg/day from dose #3) dose expansion phase in up to 5-15 asphyxiated neonates
Sponsors
McGill University Health Centre/Research Institute of the McGill University Health Centre
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
3+3 design to escalate the sildenafil dose up to 6 mg/kg/day (3mg/kg/dose q12h)
Eligibility
Sex/Gender
ALL
Age
0 Days to 2 Days
Healthy volunteers
No
Inclusion criteria
* Male and female neonates meeting the criteria for induced hypothermia: * Gestational age ≥ 36 weeks and birth weight ≥ 1800 g; * Evidence of fetal distress, i.e., history of an acute perinatal event, cord pH ≤ 7.0 or base deficit ≤ - 16 mEq/L; * Evidence of neonatal distress, such as an Apgar score ≤ 5 at 10 minutes, postnatal blood gas pH obtained within the first hour of life ≤ 7.0 or base deficit ≤ - 16 mEq/L, or a continued need for ventilation initiated at birth and continued for at least 10 minutes; * Evidence of moderate to severe neonatal encephalopathy by an abnormal neurological exam and/or an amplitude-integrated electroencephalogram (aEEG). * Evidence of brain injury on a brain magnetic resonance imaging (MRI) performed on day 2 of life.
Exclusion criteria
* Neonates with complex congenital heart disease * Neonates with cerebral malformations * Neonates with genetic syndrome * Neonates with intraventricular and/or intraparenchymal hemorrhage on MRI performed on day 2 of life
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Death | within first 10 days of life | Number of participants with death |
| Hypotension | within first 10 days of life | Number of participants with hypotension |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Peak Plasma Concentration (Cmax) | within first 10 days of life | Peak Plasma Concentration (Cmax) |
Countries
Canada
Outcome results
None listed