Impact of the Administration of Fludrocortisone in Very Premature Infants
Condition: Partial Mineralocorticoid Deficiency
MeSH terms: Hypoaldosteronism
Study type: Interventional
Phase: Phase 2

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.
    

Intervention name(s): Oral Fludrocortisone (enteral); Placebo Oral Tablet
Intervention type(s): Drug; Drug
Intervention description(s): Oral Fludrocortisone (enteral) at a dose of 10 mcg 2 times daily (every 12 hours) for 8 days from day 1 (first administration between H24 and H30, and then every 12 hours) until day 8.; oral placebo (enteral) at a dose of 10 mcg 2 times daily (every 12 hours) for 8 days from day 1 (first administration between H24 and H30, and then every 12 hours) until day 8.
Intervention MeSH terms: Fludrocortisone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Neonatology; Endocrinology