Clinical trial NCT03001089: Impact of the Administration of Fludrocortisone in Very Premature Infants
Official title: Impact of the Administration of Fludrocortisone on Fluid and Electrolyte Balance in Very Premature Infants: Pilot Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Partial Mineralocorticoid Deficiency
Keywords: Neonatology
Endocrinology
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2016-12-22
Enrollment: 66
Sex: ALL
Minimum age (years): 26
Maximum age (years): 32
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Water and electrolytic homeostasis is remarkably controlled by the mineralocorticoid pathway (renin-angiotensin-aldosterone system acting on the renal tubule). However, the neonatal period in humans is characterized by a reduced ability of the kidney to ensure normal functions of urine concentration and maintenance of sodium and water balance. This renal functional immaturity, is associated in the very premature infants (VPT) (born \<32 weeks of amenorrhea (SA)) to an immaturity of the adrenal responsible for a default of aldosterone biosynthesis . This relative aldosterone deficiency induces difficulties for VPT to adapt to extra-uterine life when maintaining a positive sodium balance is essential for postnatal growth. The improvement of perinatal care (antenatal corticosteroids maturation, ventilation techniques and use of surfactant) have increased the survival of these children . Nevertheless, extreme prematurity (less than 32 weeks), which concerns nearly 2% of live births in France, remains associated with neurodevelopmental sequelae in nearly 40% of children at 5 years .

Secondary hydroelectrolytic disorders with transient mineralocorticoid adrenal insufficiency is probably one of the factors responsible of these neurological deleterious outcomes as well as the occurrence of other complications (bronchopulmonary dysplasia, enterocolitis necrotizing) of extreme prematurity. Indeed, aside from the administration of antenatal steroids to induce maturation, the prevention of postnatal dehydration reduces the risk of intracranial hemorrhage in that population. However, high fluid intake are associated with an increased incidence of patent ductus arteriosus, of bronchopulmonary dysplasia and necrotizing enterocolitis. This necessitates the evaluation of preventive measures to avoid such fluid and electrolyte imbalances by a pharmacological approach based on mineralocorticoid administration in very premature infants, due to the relative aldosterone deficiency identified in this population.

Detailed description: Extreme prematurity affects about 2% of births per year in France and is subject to a significant morbidity and mortality. It is likely that the fluid and electrolyte imbalances associated with mineralocorticoid adrenal insufficiency transient observed in this population of vulnerable newborns contribute to the occurrence of complications that will influence the prognosis medium and long term these children. The expected impact of our pilot study is a direct benefit to the patient, with reduced kidney soda losses from the 3rd day of life and throughout the first week of life (assessed by a non-invasive method: urine collection to compress and measurement of urinary Na / creatinine). This physiological approach (substitution of the deficient hormone) allow better control of sodium and water balance. This could limit a number of common complications of extreme prematurity, occurring in the first weeks of life, such as patent ductus arteriosus, intra-ventricular hemorrhage and bronchopulmonary dysplasia.

The administration of glucocorticoids during the postnatal period (with action both glucocorticoid and mineralocorticoid) enables a reduction in the incidence of bronchopulmonary dysplasia severe. However, such treatment is associated with an increased incidence of neurodevelopmental effects related to activation of the glucocorticoid pathway. Using a specific mineralocorticoid agonist should preserve the beneficial effects without the adverse effects observed. The results of this pilot study will in a second time to consider a clinical trial Phase III national or international evaluating the significant reduction of these complications after substitution by Fludrocortisone the first week of life in the great premature. These results should have a major medical and economic impact. Indeed, neonatal morbidity indicators (intraventricular hemorrhage, patent ductus arteriosus, bronchopulmonary dysplasia and enterocolitis necrotizing) are associated with the subsequent development of neurodevelopmental sequelae (cerebral palsy and / or cognitive impairment) at the age of two and five years.

Eligibility criteria: Inclusion Criteria:

* Very premature newborns defined by a gestational age \<32 and ≥ 26 gestational weeks
* Eutrophic: birth weight between the 10th and 90th percentile of the French reference curves
* Absence of malformations or chromosomal abnormality identified
* Lack of adrenal, pituitary or gonadal diseases diagnosed prior birth
* Lack of participation in another research protocol
* "Inborn": born and hospitalized in the four neonatology departments participating in the study
* Informed consent of the holders of parental authority

Exclusion criteria:

* Maternal treatment prior to pregnancy: systemic or inhaled corticosteroids, hormone therapy for adrenal or pituitary insufficiency, antihypertensive treatment (calcium channel blockers, beta blockers, angiotensin)
* Lack or incomplete treatment of antenatal glucocorticoids (betamethasone)

Primary outcomes:
measure: Urinary sodium loss evaluated by the urinary ratio Na / creatinine
timeFrame: day 3 (when urinary sodium losses are at their highest in very premature infants)
Secondary outcomes:
measure: Urinary sodium loss evaluated by the urinary ratio Na / creatinine
timeFrame: day1, day5, day8, day10 and day15
measure: urinary sodium and potassium concentrations
timeFrame: day1,day3, day5, day8, day10 and day15
measure: plasma sodium and potassium concentrations
timeFrame: day1, day3, day8 et day15
measure: plasma renin concentrations
timeFrame: day1, day3, day8 et day15
measure: Number of blood tests
timeFrame: day1,day3, day5, day8, day10 and day15
measure: Neonatal complications
timeFrame: up to 36 post-conceptional weeks (PCW)
measure: Patent ductus arteriosus (diagnosed by ultrasound)
timeFrame: Between day2 and day5 and between day7 and day15
measure: Presence of intraventricular hemorrhage (diagnosed by ultrasound)
timeFrame: between day2 and day5, and between day7 and day15, and at the age of 36 PCW
measure: Oxygen inspired fraction (FiO2)
timeFrame: At Day 28 and 36 PCW
measure: Blood pressure
timeFrame: From day1 to day8, at day10, at day15, at one month, three month, six month, twelve month and at 36 PCW
measure: urinary dosage of aldosterone and cortisol
timeFrame: At one month, three month, six month and twelve month.
measure: urinary index (Aldosterone/Nau)
timeFrame: day3, day8 and day15
measure: number of days of invasive and non invasive ventilation
timeFrame: At Day 28 and 36 PCW
measure: weight newborns
timeFrame: from day1 to day 8, at day 10 and day 15and at 36 PCW
Other outcomes:
Locations:
city: Paris
country: France
facility: Hôpital Robert Debré
Study officials:
affiliation: APHP
name: Martinerie Laetitia, PHD
role: PRINCIPAL_INVESTIGATOR
References: