Clinical trial NCT06603766
Conditions: Magnesium Sulfate - PPHN
Keywords: PPHN magnesium sulfate Neonates
Sponsor: Benha University
Start date: 2021-10-01; Completion date: 2023-09-28
Enrollment: 40 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
we conducted this study to compare between effect of nebulized and intravenous magnesium sulfate (MgSO₄) for better treatment of persistent pulmonary hypertension of neonates with less side effects.

Detailed description:
Persistent pulmonary hypertension of the newborn (PPHN) is a serious syndrome characterized by sustained fetal elevation of pulmonary vascular resistance (PVR) at birth. The syndrome is seen in two of 1000 live-born infants and is associated with anormal or low systemic vascular resistance. Pulmonary hypertension is defined as a mean pulmonary artery pressure greater than 25 mmHg at rest and \> 30 mmHg during exercise. PPHN-targeted therapy is used for infants with PPHN who fail to respond to general cardiopulmonary supportive care. Oxygen and inhaled Nitric Oxide (iNO) are the only well-studied pulmonary vasodilators in neonates with PPHN. Magnesium is a potent vasodilator and hence has the potential to reduce the high pulmonary arterial pressures as it's able to dilate constricted muscles in the pulmonary arteries. However, its action is not specific and when given via an intravenous infusion, it will act on other muscles in the body including other arteries. Excessive magnesium causes hypotonia, hypotension, and cardiorespiratory failure. However, no studies have demonstrated long-term benefit. Delivering magnesium sulfate by nebulization may enhance effectiveness and minimizes systemic adverse effects.

Arms: arm 1: NebMag group (n=20) was administered nebulized isotonic magnesium (64 mg/mL). For nebulization, an isotonic MgSO₄ solution (64 mg/mL) was formulated by diluting a 10% intravenous preparation of MgSO₄ heptahydrate with sterile distilled water. 4 mL aliquots of the isotonic MgSO₄ solution (containing 256 mg of MgSO₄) were administered every 15 minutes through the jet nebulizer connected to the ventilator during the 24 hour study period. arm 2: IVMag group (n=20) received intravenous magnesium. For intravenous administration, a 10% MgSO₄ solution was prepared by diluting a 50% intravenous formulation of MgSO₄ heptahydrate with 5% glucose and administrated in a loading dose of 2 mL/kg over 30 minutes (equivalent to 200 mg/kg of MgSO₄), followed by a continuous infusion at a rate of 0.5 mL/kg/h (equivalent to 50 mg/kg/h of MgSO₄) over the 24 hour study period.
Interventions: intervention 1: IV Magnesium Sulfate intervention 2: Inhalational magnesium sulfate
Intervention descriptions: intervention 1: MgSO₄'s mechanism in PPHN includes activating cellular processes, modulating membrane excitability, and acting as a physiological calcium antagonist. It exerts sedative, muscle relaxant, and bronchodilatory properties, while concurrently inducing a state of alkalosis. intervention 2: It gives us the same mechanism of action as IV MgSO4 with less side effects.

Protocol documents:
Prot_SAP_000.pdf: 
Dear Dr., 
This enclosed our Study Protocol with Statistical analysis  
plan (SAP) . 
 
 
Official title:  
Comparative study between nebuliezed and  
intravenous magnesium sulfate for  
treatment of persistant pulmonary  
hypertension in neonates  
 
 
NCT number: NCT06603766  
 
 
Document updated date: 4/2/2025 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Study Protocol with SAP 
 
After obtaining approval from the medical ethical committee of 
Benha University Hospital. 
This study was conducted in Benha University Hospitals at Neonatal 
Intensive Care Unit (NICU) on neonates who were admitted for PPHN 
after delivery. An informed consent was obtained from parents after 
explaining the procedure. 
Community design and sampling:  
A non-randomized controlled trial on neonates who met inclusion 
criteria. It was carried on 40 mechanically ventilated neonates with severe 
PPHN who was divided into two groups: 
(A) Nebulized magnasium (NebMag) group (n= 20): received nebulized 
isotonic magnesium (64 mg/mL) and intravenous placebo. 
(B) Intravenous magnesium (IVMag) group (n= 20): received intravenous 
magnesium and nebulized placebo.  
The study time frame was 24h. 
Duration of the study: 
The study was conducted for two years from October 2021 to septmber 
2023.  
 
 


Ethical consideration: 
- The whole study design was approved by the local ethics committee, 
Faculty of Medicine, Benha University (Approval Number: 39-9-
204). 
- Confidentiality and personal privacy were respected in all levels of the 
study. 
- Guardians felt free to withdraw from the study at any time without any 
consequences. 
- Collected data was not and will not be used for any other purpose. 
Inclusion criteria: 
1) Newborns with documented PPHN as confirmed by ECHO. 
2) Neonates born at ≥ 35 weeks’ gestation with a birth weight of 2.5–4 kg  
3) Neonates have to be connected to mechanical ventilation with an 
oxygenation index (OI) > 30 on two occasions at least 15 minutes 
apart.  
4) The ECHO had to show a predominant right-to-left or bidirectional 
shunt (through ductus arteriosus and/or foramen ovale) and/or 
tricuspid regurgitant jet with a pressure gradient ≥ 2/3 of the 
systemic systolic blood pressure. 
 
 
 


Exclusion criteria: 
1) Infants of mothers who received magnesium sulfate within 48h before 
labor. 
2) Congenital heart diseases other than PDA and patent foramen ovale. 
3) Major congenital anomalies, including congenital diaphragmatic hernia 
and lung hypoplasia. 
4) Prior need for cardiopulmonary resuscitation. 
5) Mean arterial blood pressure (MABP) < 35 mmHg despite therapy 
with volume infusions and vasoactive inotropes. 
6) Impaired kidney function; and prior administration of pulmonary 
vasodilators or prior administration of surfactant. 
Methods of the study: 
Patients included in the study were subjected to the following: 
Complete history taking: Full antenatal and postnatal histories. 
were obtained from all cases including: 
 Demographic data (gestional age, sex, mode of delivery, birth weight). 
 Associated condition (asphyxia, infection, polycythemia). 
Clinical examination: 
Full clinical examination: including general examination included vital 
signs, anthropmetric measurements, APGAR score in the 1st and 5th 
minutes (7).  


systematic examination including chest and abdominal examination with 
emphasize on the cardiac examination including the apex site,1st, and 2nd 
heart sounds and manifestations of heart failure (tachycardia, tachypnea 
and enlarged liver), musculoskeletal and central nervous system 
examination.    
Radiological investigation 
 Chest X-ray 
 ECG: The ECG may provide suggestive or supportive evidence of 
pulmonary hypertension by demonstrating RV hypertrophy and 
strain, and right atrial dilatation 
 ECHO: measures pulmonary artery pressure, low ventricular output and 
low ejection fraction and fraction shortening. 
Laboratory analysis 
  Pulse oximeter monitoring in the four limbs:  
 Blood pressure monitoring in the four limbs. 
 Serial arterial blood gases: Post ductal arterial blood samples were 
drawn before (baseline) and 6, 12, and 24 h following study drug 
administration for gas analysis PH, PaO2, PaCO2, HCO3). 
 Ventilatory parameters were recorded from ventilator (PIP, PEEP, 
MAP, fiO2, rate/min). 
 serum magnesium level was measured before and 12 h following study 
drug administration. 
 


The protocol of administration of magnesium sulfate: 
 For intravenous administration a magnesium sulfate 10% solution was 
prepared by diluting an intravenous form of magnesium sulfate 
heptahydrate 50% with glucose 5%. Pharmacy designed 60mL 
aliquots of magnesium sulfate 10% and similar aliquots of glucose 
5% as a placebo was prepared. Study participants received either 
active drug or placebo through an intravenous line a loading dose of 
2 mL/kg over 30 min (equivalent to magnesium sulfate 200 mg/kg in 
case of the active drug), followed by a continuous infusion at a rate 
of 0.5 mL/kg/h (equivalent to magnesium sulfate 50 mg/kg/h in case 
of the active drug) for the 24 h study duration. 
 For nebulization, an isotonic solution of magnesium sulfate (64 mg/mL) 
was prepared by diluting an intravenous form of magnesium sulfate 
heptahydrate 10% with distilled sterile water, 4-ml aliquots of 
isotonic magnesium sulfate (256 mg) and similar aliquots of isotonic 
saline as a placebo was designed. a 4-mL aliquot of active drug or 
placebo was loaded every 15 min to the jet nebulizer of ventilator. 
 The primary outcome in this study has been the change in 
oxygenation index (OI) from baseline to 12 and 24 h following study 
drug administration. OI: monitoring the oxygenation trend helps to guide 
when a baby might need to be referred for ECMO. It is a useful guide to 
monitor regularly in babies with PPHN. 
OI: Mean Airway Pressure x FiO2 x 100 ÷PaO2 (in Pka) x 7.5 
OI was preferred as it considers both oxygenation status and 
ventilatory support, over merely reporting individual values of SpO2, 
PaO2, FiO2, and ventilatory parameters. 


Note: When you are calculating OI, be aware of which units of 
measurement you use for the PaO2 – kPa or mmHg (kPa x 7.5 converts to 
the equivalent PaO2 in mmHg). 
FiO2 is the inspired fraction (e.g. 21% = 0.21, 100% =1.0) 
 
 The secondary outcomes have been the changes in (a) mean arterial 
pressure and VIS from baseline to 6, 12, and 24 h following study drug 
administration and (b) serum magnesium level from baseline to 12 h after 
study drug administration. 
Statistical analysis 
The data were coded, entered and processed on computer using 
SPSS (version 24). The results were represented in tabular and 
diagrammatic forms then interpreted. Mean, standard deviation, range, 
frequency, and percentage were use as descriptive statistics. The 
following tests were done:  Chi-Square test Χ² was used to test the 
association variables for categorical data. Student's t-test was used to 
assess the statistical significance of the difference between two 
population means in a study involving independent samples, with normal 
distribution. The accepted level of significance was 0.05. P value >0.05 
is non-significant, P<0.05 is significant (*)