Effect of Melatonin on Pulmonary Hypertension in Full Term Neonates

Neonates fulfilling the inclusion criteria will be divided into 2 groups:

1. Intervention group(26 Neonates) will receive iNO and melatonin
2. iNO

• iNO will be initiated at 20 ppm.
• The expected clinical response will be improved oxygenation and cardio-respiratory stability in the first 30 minutes after initiation of iNO therapy.
• If there is no clinical response, the iNO dose will be increased to up to 40 ppm.
• If after 30 minutes there is no clinical response, iNO will be discontinued.
• After clinical response iNO may be weaned by 50% every 4hours provided the oxygenation index remains at ≤10, pre-ductal SpO2 does not decrease by ≥5%, and/or FiO2 does not increase by ≥10%
• When a dose of 5 ppm has been reached, iNO may be decreased by steps of 1 ppm (every 30 minutes to 2 h) until discontinuation, provided the infant remains well oxygenated at <60% FiO2
• Oxygen saturation index (OSI) replaces PaO2 with oxygen saturation as measured by pulse oximetry (SpO2) in the OI equation and is calculated as OSI = MAP × FIO2 × 100 / SpO2

1. Melatonin will be given by nasogastric tube at a dose (3 mg/kg) divided every 8 hours till the end of iNO therapy
2. Control group (26 Neonates) gestational age and weight matched to the intervention group and will receive only iNO with the same previous dose and manner.

In case of failure of either group, patient will receive rescue treatment as milrinone at a dose 0.375 µg/kg/min to a maximum 0.750 µg/kg/min intravenous infusion

Study Tools : All of the following data will be obtained:

1. Full history taking: antenatal, natal and postnatal history.
2. Gestational age and anthropometric measurements.
3. Diagnosis of the patient and cause of pulmonary hypertension.
4. Full clinical examination: including general, cardiopulmonary, abdominal, and neurological examination.
5. Physiological parameters with special emphasis on heart rate, respiratory rate, oxygen saturation, blood pressure and fraction of inspired oxygen (FiO2) which will all be measured at baseline (just before iNO administration) and at pre-specified intervals (15, 30, 45, and 60 min) after iNO then every 3hours through the course of study.
6. Management in NICU:
7. Respiratory support type, mode of ventilation, duration, settings at the time of administration and throughout the course of study.
8. Cardiac supports: type, dose and duration.
9. Antibiotics: type and duration.
10. Feeding: type (artificial or breast feeding), route and volume.
11. Effectiveness of iNO will be assessed using oxygen saturation and fio2.
12. ECHO: It will be done before starting therapy, after 24 hours and after completing the treatment
13. Estimation of pulmonary artery pressure will be assessed by measuring tricuspid valve regurgitation peak velocity, pulmonary regurgitation peak velocity, transductal right-to-left flow peak velocity, and interventricular septum (IVS) configuration.
14. Right ventricular function will be assessed by measuring tricuspid annular plane systolic excursion (TAPSE). Left ventricular function will be analyzed by ejection fraction (EF biplane Simpson).
15. Assessment of the direction and peak flow velocity of transductal blood flow will indicate the relation between pulmonary and systemic pressures
16. Transcranial ultrasound (TCUS): Will be done to measure the resistive index of middle cerebral artery before starting therapy and after 72hrs.
17. Amplitude EEG: will be applied once diagnosed and throughout the course of the study. Double channel aEEG will be applied using 4 electrodes (C3 C4 P3 P4) electrodes and interpretation will be done by Burdjalov score
18. Serum S100B will be measured 24 hours after diagnosis and starting the treatment with cut off value (≥ 0.10 µg/L) indicating neuronal damage
19. Monitoring of complications:
20. Monitoring signs of bleeding as epistaxis, hematemesis and bleeding from umbilical stump.
21. Laboratory monitoring of bleeding by bleeding profile (PT, PTT, INR) and CBC according to NICU protocol.
22. Methaemoglobin level: will be measured before starting treatment to exclude congenital methemoglobinemia which is >2% as seen in venous blood gases and throughout the study daily
23. NO2 level will be measured continuously by NO generator device