Haemodynamic Changes With Different Noninvasive Respiratory Modes for Primary Respiratory Support in Preterm Neonates
Phase: NA
Conditions: Ventilation
Sponsor: Ain Shams University

 
 
 
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Protocol of a Thesis For Partial Fulfilment of MD Degree in Pediatrics 
 
Title: 
Haemodynamic changes with different Noninvasive respiratory 
modes for primary Respiratory Support in Preterm Neonates 
 
 
 
 
 
 
 
 
NCT number : 
Date : 17/9/2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Faculty of Medicine 
Ain Shams University 
2021 
 
 
 
 
 

 
 
 
MasterDegreeThesis/MFA/ISRO/FacultyOfMedicine/ASU 
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What is already known on this subject? AND What does this study add?  
The use of Noninvasive Respiratory Support (NRS) as primary and post 
extubation respiratory support in Neonatal Intensive Care Unit (NICU) has increased
in recent decades as a means to reduce ventilator-induced lung injury (Mukerji and
Dunn, 2016). 
The study evaluates the efficacy of Noninvasive High-Frequency Oscillatory
Ventilation (NHFOV) and High Velocity Nasal Insufflation (Hi-VNI Vapotherm) in
comparison to nasal CPAP as a primary noninvasive respiratory support  in preterm
infants. It also assesses echographic, cerebral blood flow and mesenteric blood flow 
changes during NHFOV and Hi-VNI Vapotherm in comparison to nasal CPAP. 
 
1. INTRODUCTION 
Respiratory distress is one of the most common causes of admission to NICU. 
Noninvasive ventilation (NIV) has significantly and positively altered the treatment 
outcomes and improved mortality rates of preterm infants with Respiratory Distress 
Syndrome (RDS) (Permal et al., 2019). 
NIV can reduce the adverse effects associated with intubation and mechanical 
ventilation, such as bronchopulmonary dysplasia(BPD), sepsis, and trauma to the upper 
airways. In the last 4 decades, nasal CPAP has been used to wean preterm infants off 
mechanical ventilation and as a primary mode of respiratory support for preterm infants 
with respiratory insufficiency (Mahmoud et al., 2011). 
Noninvasive high-frequency oscillatory ventilation (NHFOV) is a method of 
augmenting CPAP support in preterm infants, potentially combining the advantages 
of both invasive high-frequency oscillatory ventilation and CPAP (De Luca and 
Dell’Orto, 2016). 
Vapotherm 2000i® is a noninvasive high-flow respiratory support system used 
mainly in the treatment of type 1 respiratory failure. It uses a mixture of oxygen and 
air to deliver a set concentration via nasal cannula. The advantage of this system is 
the high humidity achieved using the integral heated water system. The system has 
been used in neonatal practice as a replacement for nasal CPAP (Price et al., 2008). 
Poor aeration of the lung leads to increased pulmonary vascular resistance and 
reduced blood flow. In contrast, overinflation of the lung causes compression of the 
vena cava, pulmonary vasculature, and heart. Low systemic blood flow and low 
superior vena cava (SVC) return are associated with increased morbidity in preterm 
infants. Therefore, the interaction between respiratory support and cardiac output 
(CO) is critically important (Beker et al.,2014). 
 
 
2. AIM/ OBJECTIVES 

 
 
 
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1. Primary aim is to evaluate the efficacy of NHFOV and Hi-VNI Vapotherm in 
comparison to nasal CPAP as a primary noninvasive respiratory support in 
preterm neonates through assessment of: 
• The need for invasive mechanical ventilation (IMV) during the first 72 hours 
after enrollment in one of the groups, days of hospitalization, days on 
noninvasive respiratory support, days on supplemental oxygen, mortality, 
severe retinopathy of prematurity(ROP), air leak syndromes, intraventricular 
hemorrhage(IVH), necrotizing enterocolitis(NEC), nasal trauma and BPD. 
2. Secondary aim is to assess haemodynamic changes during periods of non-invasive 
respiratory support including echocardiographic, cerebral blood flow and 
mesenteric blood flow changes. 
 
3. METHODOLOGY:  
1. Type of Study: Randomized controlled trial. 
2. Study Setting: NICU of Ain Shams University. Children hospital, Cairo, Egypt. 
3. Study Period: Two years , from September 2021 till September 2023.  
4. Study Population: Preterm neonates with RDS requiring noninvasive ventilation, the 
involved study group will be of matched gestational, postnatal age and sex. 
5. Inclusion Criteria: 
- Preterm neonates with gestational age ≤ 35 weeks with RDS  that need noninvasive 
ventilatory support primarily.  
6. Diagnosis of RDS is by clinical presentation, including signs of respiratory distress, 
ABGs showing hypoxemia and hypercapnia and chest x-ray showing diffuse 
atelectasis classically described as having a ground-glass appearance . (Hermansen 
and  Mahajan ,2015). 
7. The need for noninvasive ventilation in the following situations : 
- 
Preterm with mild to moderate respiratory distress, Silverman score <6 (Silverman 
and Anderson,1956). 
- 
Mild to moderate hypoxemia (Fio2 less than 50% to maintain SpO2 (90%-94%) 
- Mild to moderate respiratory acidosis (PaCO2<65mmHg with pH>7.20) 
- Apnea (not associated with bradycardia, not needing bag and mask ventilation) 
8. Exclusion Criteria: 
1. Patients with major upper or lower airway anomalies. 
2. Patients with significant congenital anomalies including cardiac, abdominal or 
respiratory.  
9. Sample size: 90 participants  
10. Sample size calculation:  
Sample size was calculated using One-way ANOVA F-test with significance 
level 0.05. Calculation according results from a previous study (Abdelhady et 
al.,2008) produced a sample size of 30 cases in each group. 
11. Sampling Method: 
     Preterms will be allocated randomly to one of 3 groups : 
o Group A: it will include 30 preterm neonates on NHFOV 

 
 
 
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o Group B: it will include 30 preterm neonates on Hi-VNI Vapotherm. 
o Group C: it will include30 preterm neonates on nasal CPAP  
12. Study Procedures:  
1. Detailed antenatal, natal and postnatal history. Gestational age will be estimated 
using the date of the last menstrual period and confirmed by the new Ballard 
scoring system (Ballard et al., 1991). 
2. Full clinical examination including: chest, cardiac, abdominal , neurological 
examination and  anthropometric measurements. 
3. Patients' ages, mean arterial blood pressure, urinary output, temperature , capillary 
refilling time and O2 saturation by pulse oximetry and according, Oxygen 
Saturation Index (OSI) will be calculated  as a noninvasive predictor of respiratory 
failure  (Muniraman et al., 2019).  
4. Daily inspection of infants’ nostrils to evaluate the presence of skin alterations, 
nasal injury score will be used (Khan et al., 2017). 
5. Surfactant if given with recording its timing and doses, Curosurf®; Chiesa 
pharmaceuticals, Parma, Italy. At a dose of 200 mg/kg will be administered via 
the INSURE method if an infant present with the following: 
o ≤30 weeks GA when FiO2 requirement >0.30 or >30 weeks GA when FiO2 
requirement >0.40. In the INSURE technique, surfactant is administered via 
an endotracheal tube and after a brief period of positive pressure ventilation, 
patients will be extubated to the assigned mode. (Zhu et al., 2018). 
6. Caffeine citrate; Chiesi Pharmaceuticals, Parma, Italy. Will be administered 
when infants present with significant apnea (defined as three or more episodes 
in 24 hrs or a single episode requiring resuscitation and bag and mask 
ventilation). The initial loading dose is 20 mg/kg, and the maintenance dose is 
5 mg/kg per day (Zhu et al., 2018). 
7. Assessment of feeding; method (parenteral or enteral) and detecting the type of 
milk, volume and duration to reach full enteral feeding together with recording 
presence of any feeding intolerance. 
8. Recording of patients' days of hospitalization, days on noninvasive respiratory 
support, days on supplemental oxygen, initial settings and modifications, 
inotropic support, sepsis, incidence of ROP, air leak syndromes, IVH, NEC, 
BPD (Jobe and Bancalari, 2001) and mortality. 
Candidates will be randomized into one of 3 groups :  
A. NHFOV group: NHFOV will be delivered by; SLE 6000 device, Wipro GE 
Healthcare Private Limited, Bengaluru, Karnataka. Amplitude range (20:35), 
frequency range (8-12)HZ, MAP range (6: 10) cmH2O and I:E ratio 1:1 may change 
to 1:2 in case of air trapping . 
B. Hi-VNI Vapotherm group:  
Hi-VNI 
Vapotherm 
will 
be 
delivered 
by; 
Vapotherm 
device,Vapotherm,INC,USA. The recommended starting flow rate is 4-6 L/min. To be 
titrated to clinical effect to maximum of 8 L/min as needed,with temperature 36-37°C 
and FiO2 titrated as needed to achieve target SpO2(90% to 94%) (Yoder et al.,2017). 

 
 
 
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C. Standard noninvasive mechanical ventilation group (CPAP):  
CPAP will be delivered by; MEDIN CNO device, medin Medical Innovations GmbH, 
Olching, Germany . Pressure ranging from 5 to 8 cm H2O,to maintain target oxygen 
saturation (SpO2) from 90% to 94%.  
We will define failure of non-invasive mode and need for invasive mechanical 
ventilation according to the following while on the maximum noninvasive 
settings : 
o Severe respiratory acidosis (PaCO2 ≥ 65 mmHg with pH ≤ 7.20), 
o Severe apnea and bradycardia (defined as recurrent apnea with >3 episodes 
per hour associated with heart rate <100/min or a single episode of apnea 
that requires bag and mask ventilation)  
o Hypoxemia (FiO2 >0.5 to maintain SpO2 90% to 94%) 
o Severe respiratory distress characterised by retractions, moaning sounds or 
nasal flaring (defined as Silverman score >6) (Silverman and 
Anderson,1956). 
o Pulmonary haemorrhage and Cardiopulmonary arrest needing chest 
compressions (Shi and De Luca, 2019). 
13. Laboratory investigations 
o Complete blood picture (CBC),C- reactive protein (CRP) and Venous blood 
gases, using a POC Siemens RAPID Point 500 blood gas system,Radiometer 
Medical ApS,Denmark (Allardet et al., 2017). 
14. Radiological investigation  
A. Chest X-ray with radiological assessment of grades of RDS. 
B. Echocardiography : Two dimensional Echocardiography will be done using 
Vivid 9,GE Ultrasonography machine (Norway) with 6 MHz transducer 
frequency.To assess any structural cardiac anomalies, the patency of ductus 
arteriosus, right ventricular output (RVO), left ventricular output (LVO), and 
superior vena cava (SVC) flow. 
C. Transcranial ultrasonography by; Samsong Medison Co ,Korea. Doppler 
applied to the major cerebral arteries to provide an estimate of cerebral blood 
flow . 
D. Assessment of pre-prandial superior mesenteric artery (SMA) velocity and 
volume of blood flow with Doppler sonography by; Samsong Medison Co 
,Korea. 
15. Statistical Analysis: Numerical data will be summarized using mean and standard 
deviations or medians and inter quartile ranges. Qualitative data will be presented 
as count and percentage, p-value <0.05 will be considered significant. 
16. Statistical Package: Statistical analysis will be performed with statistical package 
for social science (SPSS) 
17. Ethical Considerations: A written informed consent will be taken from the 
parents or legal guardians before enrolment, after fully explaining to them the 
nature of the study. The approval of the Research Ethics Committee at Ain Shams 
University will also be obtained. 
 

 
 
 
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