Breathing Pattern Variability in Preterm Infants: Effect of Non-invasive Neurally Adjusted Ventilatory Assist (NAVA-NIV) Versus Nasal Intermittent Positive Pressure Ventilation (PC-NIV), a Crossover Study
Conditions: Neonatal Respiratory Distress Syndrome, Prematurity
Sponsor: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

 
 
 
 
 
STUDY TITLE 
Breathing Pattern Variability in Preterm Infants: Effect of Non-invasive Neurally Adjusted 
Ventilatory Assist (NAVA-NIV) Versus Nasal Intermittent Positive Pressure Ventilation (PC-NIV), a 
Cross-Over Study. 
 
NCT number: not available yet. 
Date of the document, as submitted to local ethical committee: v1.1 of the 27th February 
2019 
Date of local ethical committee approval: 1st March 2019 
Date of translation in English: 29th May 2019 

STUDY OBJECTIVES 
Primary: To evaluate the effect of NAVA-NIV compared to Nasal Intermittent Positive Pressure 
Ventilation (PC-NIV) at the same of peak inspiratory pressure in terms of breath-by-breath variability 
of tidal breathing amplitude in preterm infants < 37+0 weeks+days post-menstrual age. 
Secondary: To evaluate the effect of NAVA-NIV compared to Nasal Intermittent Positive Pressure 
Ventilation (PC-NIV) at the same level of peak inspiratory pressure in terms of variability of the other 
breathing pattern parameters; lung mechanics; gas exchange; rate of apneic episodes; bradycardia 
and desaturations; respiratory asynchrony and comfort. 
STUDY DESIGN 
It will be a monocentric, randomized, cross-over trial. 
The setting will be the Neonatal Intensive Care Unit (NICU) of Fondazione IRCCS Cà Granda Ospedale 
Maggiore Policlinico, Milan, Italy, in collaboration with the Laboratorio di Tecnologie Biomediche – 
TBMLab, Dipartimento di Elettronica, Informazione e Bioingegneria – DEIB, Politecnico di Milano 
University, Milan, Italy. 
STUDY POPULATION 
Preterm infants born < 37 weeks of gestation, requiring non-invasive respiratory support 
INCLUSION CRITERIA 
• Preterm birth < 37 weeks of gestational age 
• Need of non-invasive respiratory support 
• Parental consent 
EXCLUSION CRITERIA 
• Major congenital abnormalities of the cardio-respiratory systems 
• Severe Respiratory Failure requiring intubation and mechanical ventilation at the time of the 
study; pH < 7.25 pCO2> 65 mmHg; pulmonary hypertension requiring pharmacological 
treatment (Nitric Oxide, Sildenafil) 
• Hypoxic-Ischaemic Encephalopathy, neurological disorders which may compromise the integrity 
of the neural transmission from the brain to the diaphragm 
• Contraindication to orogastric tube insertion (e.g. oesophageal atresia, gastric perforation...)  
• Haemodynamic instability requiring inotropic agents 
• Any condition that would expose the patient to undue risk as deemed by the attending physician 
STUDY INTERVENTION 
Preterm infants matching the inclusion criteria (listed elsewhere) will be enrolled in a cross-over 
trial of two modes of non-invasive respiratory support: nasal intermittent positive pressure 
ventilation (PC-NIV) and NAVA NIV (Sevo-n Neonatal Ventilator, Getinge, Solna, Sweden).  

In order to compare the two modes at the same level of PIP, a  20-minute registration of ventilator 
parameters during assistance on NAVA-NIV will allow calculating the mean PIP (peak inspiratory 
pressure).,.  
The ventilator settings other than PIP (i.e. FiO2, PEEP, IT, RR) will be based on the setting optimized 
by the attending physicians prior to the study entry.  
Infants will then receive a randomized sequence of 1-hour assistance by NAVA NIV and 1-hour 
assistance PC-NIV at the same level of PIP or vice-versa. 
FiO2 will be adjusted in order to maintain SpO2 88-93% in infants ≤ 32 weeks of postconceptional 
age, 90-95% in infants > 32 weeks of postconceptional age. 
Infants will receive respiratory support in a standardized supine position during the study period. 
RANDOMIZATION 
The randomization will be created by generating casual numbers by specific MatLab functions. 
Closed, opaque, sequentially numbered envelops will be then created by the collaborators from the 
department of Elettronica, Informazione e Bioingegneria – DEIB, Politecnico di Milano University. 
After enrolment, physicians will open the envelop containing the sequence of randomization. 
 
ENDPOINTS 
 
PRIMARY 
 
Breath-by-breath variability of tidal breathing amplitude. 
Tidal breathing amplitude will be recorded continuously via two, high resolution, small cameras 
placed inside the infant's incubator and skin (non-invasive) markers. Ventilator parameters (flow, 
pressure, volume and electrical diaphragmatic activity) will be recorded continuously during the 
study. Data will be analysed a posteriori applying parametric or non-parametric statistical tools 
depending on the results of normal distribution test and long term correlation properties will be 
studied by the DFA (Detrended Fluctuation Analysis) technique or similar. 
 
SECONDARY 
 
Breathing pattern variability (Tidal Volume, Respiratory Rate, Inspiratory Time, Duty Cycle) 
Ventilator parameters (flow, pressure, volume and the electrical diaphragmatic activity) will be 
recorded continuously during the study, chest and abdominal volume displacement will be detected 
by two high-resolution camera--based 3D depth sensors placed in the incubators. The variability of 
the breathing pattern will be then analyzed by the DFA technique. 
  
Lung mechanics (lung reactance and lung resistance) 
Lung mechanics will be measured by mean of the Forced Oscillation Technique (FOT) at the end of 
each step, by superimposing to the ventilator waveform an oscillatory pressure of small amplitude 
and high frequency (Fabian, Acutronic Medical Systems AG, Switzerland). Flow and pressure signals 
will be collected and respiratory mechanics will be evaluated by estimating offline the total 
respiratory system input impedance and expressed as reactance and resistance. 

Gas exchange 
Fraction on inspired oxygen (FiO2), SpO2 and trancutaneous pCO2 will be monitored continuously. 
Rate of apnoeas, desaturations, bradycardias 
Episodes of apnoea, desaturation, and bradycardia will be recorded over each study period 
Rate of patient-ventilator asynchronies 
Patient-ventilator asynchronies will be calculated by continuous recording of ventilator parameters 
(flow, pressure, volume and electrical diaphragmatic activity) and by continuous recording of 
abdominal and chest movements by high resolution cameras placed in the incubators and skin 
markers on abdomen and chest 
Patient's comfort 
Patient's comfort will be assessed by the attending nurse at the end of each step by means of the 
COMFORT scale at the end of each step. 
Number of caregiver interventions required 
The number of interventions required by the attending personnel during each step will be also 
recorded: for instance interventions to improve comfort, to adjust the ventilator interface, to 
optimize the efficacy of respiratory support, suctioning ... 
STUDY DURATION/TIME POINTS 
The first part of the study will be to determine the mean PIP during NAVA NIV over a 20-minute 
period, followed by the cross-over, made up of two steps lasting 1 hour each. At the end of each 
step, a 5-minute measurement by FOT will take place. Data will be assessed at the beginning of the 
study (t0), every 10 minutes during the first 30 minutes and every 5 minutes during the last 30 
minutes. 
STATISTICAL ANALYSIS 
The sample size of the study was calculated by G-power. 25 patients are needed for a two-tailed 
power > 0.80 with α=0.05, hypothesizing a normal distribution and an effect dimension of 0.59. The 
effect dimension was calculated considering a correlation among groups = 0.5 and tidal volume 
variations (used as a quantitative index for characterizing breathing amplitude variations) of 
newborn infants supported by nasal CPAP (0.79 ± 0.14) and after the application of nasal CPAP at 2 
cmH2O (0.71±0.13 )[ Zannin, Pediatr Pulmunology 2018]. 
Measured Variables and Data Analysis 
From the flow, pressure, volume and electrical diaphragmatic activity tracings, the breathing 
patterns will be measured (see above). The end-expiration will be identified by the two small, high 
resolution camera-based 3D sensors  and the skin markers. FIO2, SpO2, tc pCO2 will be also measured. 
At the end of each step lung resistance (Rrs) and reactance (Xrs) will be assessed by FOT. A dedicated 

operator will record the number of episodes of apnea, bradycardia and desaturation. Patient’s 
comfort will be assessed by the COMFORT scale. Mean (or median as appropriate) and SD (or IQR) 
will be calculated for all the parameters measured. Short-term variability will be determined by the 
variation coefficient (SD). Long-term correlation will be evaluated by the DFA technique. 
ANOVA or Friedman test for repeated measurements as appropriate according to data distribution 
will be used to verify differences in each of the parameters analysed, considering groups. 
 
ETHICS 
The present study will be conducted following the ICH/GCP International Conference of 
Harmonization/Good Clinical Practice rules and all the applicable regulations, including the 
declaration of Helsinki, June 1964, modified by the World Medical Association General Assembly in 
Seoul, 2008. 
The study protocol has been approved by the local Ethical Committee, Comitato Etico Milano di 
Area 2, on March 1st 2019. 
 
 

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