Double blind randomized controlled study on the benefit-risk profile of in the treatment of at term or late preterm newborn infants with severe respiratory disorders and pulmonary hypertension

INTERVENTION: Trade Name: REVATIO Pharmaceutical Form: Oral solution INN or Proposed INN: Sildenafil Concentration unit: mg/kg milligram(s)/kilogram Concentration type: equal Concentration number: 1‐ Pharmaceutical form of the placebo: Oral solution Route of administration of the placebo: Gastroenteral use CONDITION: treatment of at term or late preterm newborn infants with severe respiratory disorders and pulmonary hypertension ; Level: PT Classification code 10037400 INCLUSION CRITERIA: neonates ≥34 weeks of gestational age hospitalized in neonatal intensive care units (NICU) within the first week of life with acute respiratory failure of any origin, who require mechanical ventilation, either conventional (tidal) or high frequency oscillatory (HFOV), with an OI ≥10 and echocardiographic evidence of PH. Are the trial subjects under 18? yes Number of subjects for this age range: F.1.2 Adults (18‐64 years) no F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range PRIMARY OUTCOME: Main Objective: The study primary aim is to assess whether the use of sildenafil in term or late preterm (≥34 weeks) neonates with severe hypoxemia associated with persistent pulmonary hypertension (PH) improves oxygenation and decreases right ventricular pressure without increasing the incidence of side effects such as systemic arterial hypotension. Primary end point(s): a) ≥10 units OI reduction after treatment onset. OI will be determined at inclusion (time point 0), then every 6 hours, within 30? from the following S/P dose (time points 1 to 7), then 6 hours after the last dose (time point 8), then, lastly, 24 hours after (time point 9), through arterial blood sampling for PaO2 measurement, mean airway pressure (MAP) and FiO2 readings. Considering a maximum of 0.5 mL per sample, the total amount of blood drawn will be 5 mL for each subject.; b) PP reduction. PP will be evaluated by echocardiography through doppler tricuspid regurgitation flow velocity if present, or through intra‐ventricular septum configuration (flattened or left‐bowed septum). PP will be evaluated at time point 0, then every 24 hours for 3 measurements (thus, the last evaluation will be performed 24 hours after last S/P administration, and will match the last OI determination).; c) Systemic arterial hypotension. Arterial blood pressure will be measured non‐invasively and expressed in mm Hg; it will be recorded at time point 0, then every 2 hours until 24 hours after the last S/P dose, thus matching the last OI/PP determination. Arterial hypotension will be defined as a mean arterial blood pressure <2 SD the average value for birth weight [8].; d) Other potential side effects will be noted through routine cardio‐respiratory monitoring and clinical observation, such as gastro‐intestinal intolerance (abdominal distension, clear or bile‐stained aspirates), decreased urine output, vasomotor skin reactions. Secondary Objective: Secondary objective are: in‐hospital mortality and incidence of long‐term outcomes (neurosensorial, auxological and respiratory impairments) not higher than those observed without the administration of sildenafil or following the use of iNO.; The evaluation of some process indicators will be also performed, such as duration of mechanical ventilation, frequency of administration and dosage of inotropic drugs, amount and duration of iNO if used, hospitalization lenght. We expect these indicators to be reduced in sildenafil‐treated infants, compared to non‐treated ones.