<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03289936</url>
  </required_header>
  <id_info>
    <org_study_id>SyncNIV</org_study_id>
    <nct_id>NCT03289936</nct_id>
  </id_info>
  <brief_title>Short Term Effects of Synchronized vs. Non-synchronized NIPPV in Preterm Infants.</brief_title>
  <acronym>SyncNIV</acronym>
  <official_title>Short Term Effects of Synchronized vs. Non-synchronized NIPPV in Preterm Infants: Study Protocol for an Unmasked Randomized Crossover Trial.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Turin, Italy</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Turin, Italy</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Comparing the cardio-respiratory adaptation and differences to non invasive ventilation&#xD;
      techniques, nasal intermittent positive pressure ventilation (NIPPV) non synchronized vs&#xD;
      synchronized (SNIPPV) in preterm newborns (gestational age at birth &lt; 32 weeks) at their&#xD;
      first approach to non invasive ventilation as first intention (soon after birth) or after&#xD;
      extubation.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Respiratory problems are one of the major issues to deal with in preterm newborns.&#xD;
&#xD;
      Because of the immaturity of respiratory mechanisms and structures, the use of supporting&#xD;
      devices is often necessary. These include both conventional mechanical ventilation (MV)&#xD;
      techniques, which require the use of an endotracheal tube, as well as non-invasive&#xD;
      ventilation (NIV) techniques that use softer ventilator-patient interfaces. Increasing&#xD;
      attention is payed to the latter ones as less aggressive and associated with better outcomes&#xD;
      both in terms of mortality and short and long-term complications, such as bronchopulmonary&#xD;
      dysplasia (BPD).&#xD;
&#xD;
      Nasal intermittent positive pressure ventilation (NIPPV) is a NIV technique in which newborn&#xD;
      airways are kept open between two pressure levels: peak inspiratory pressure (PIP) and&#xD;
      positive end expiratory pressure (PEEP). The frequency and duration of each phase are defined&#xD;
      by setting the inspiratory and expiratory times or the ventilation rate.&#xD;
&#xD;
      This technique has already shown its superiority in terms of reduced duration of MV, reduced&#xD;
      necessity of intubation, decreased failure of extubating and reduced prevalence of BPD if&#xD;
      compared with non-invasive techniques based on continuous pressure support, such as&#xD;
      continuous positive airway pressure (CPAP). Recent meta-analyses of studies where NIPPV has&#xD;
      been used as an alternative to CPAP following extubation show that it reduces need for&#xD;
      re-ventilation and air leaks but without any reduction in BPD: there is insufficient evidence&#xD;
      to recommend NIPPV as primary mode of respiratory support in the delivery room.&#xD;
&#xD;
      It should be specified that the ventilation rate on NIPPV does not reflect the real&#xD;
      respiratory rate (RR) of the newborn, as the ventilator supplies the PIP regardless of&#xD;
      newborn respiratory efforts. To reproduce a more physiological and gentle ventilation new&#xD;
      devices able to detect newborn respiratory efforts and consequently supply a PIP have been&#xD;
      developed to synchronize the ventilation rate with RR of the newborn.&#xD;
&#xD;
      The devices used for synchronization can identify newborn respiratory effort by detecting&#xD;
      variation in flow or pressure. While in MV the exact beginning of inspiration can be detected&#xD;
      through a continuous monitoring of pressure or through the precise interception of&#xD;
      inspiratory and expiratory flow some difficulties occur in NIV where, as a consequence of the&#xD;
      impossibility to detect expiratory flow, the moment of the exact beginning of spontaneous&#xD;
      inspiration is hard to identify.&#xD;
&#xD;
      Recently, a new type of NIV ventilator equipped with a pressure sensor has been put on the&#xD;
      market. The software of this ventilator is able to calculate the flow according to the&#xD;
      pressure variations of the circuit and to capture the flow variations induced by spontaneous&#xD;
      breathing allowing a synchronization of the flow with the patient's respiratory acts.&#xD;
&#xD;
      The use of a synchronized NIV technique would allow a more physiological respiratory support,&#xD;
      reducing respiratory fatigue and improving newborn compliance. Despite these premises, the&#xD;
      diffusion of synchronized NIPPV in neonatal intensive care units (NICUs) and works on its&#xD;
      efficacy are limited.&#xD;
&#xD;
      Some authors have already demonstrated the benefits of using a synchronized NIV technique in&#xD;
      terms of extubating success rate, BPD prevalence and mortality and neurocognitive&#xD;
      development. Synchronized NIPPV (SNIPPV) seems more effective than NIPPV and NCPAP in&#xD;
      reducing need for intubation in respiratory distress syndrome (RDS), in improving the success&#xD;
      of extubation and in treating apnea of prematurity, with a reassuring absence of relevant&#xD;
      side effects. Synchronised NIPPV delivered through a ventilator can reduce extubation failure&#xD;
      but may not confer long-term advantages such as reduction in BPD. Other reported advantageous&#xD;
      aspects of SNIPPV include improved thoraco-abdominal synchrony, reduced work of breathing&#xD;
      (WOB) and reduced need of intubation.&#xD;
&#xD;
      It has already been shown that SNIPPV is more effective than NIPPV and CPAP in reducing the&#xD;
      number of desaturations and apnoea in preterm infants undergoing CPAP treatment for&#xD;
      prematurity apnoea. However, the effectiveness of SNIPPV compared to NIPPV in preterm infants&#xD;
      with respiratory distress is still not completely clear.&#xD;
&#xD;
      Our study protocol was designed to evaluate the short-term effects of SNIPPV vs NIPPV on the&#xD;
      major cardio-respiratory variables, trying to identify the best ventilation modality for&#xD;
      preterm newborns at their first approach to NIV ventilation support, on the bases of&#xD;
      cardio-respiratory events reduction and fraction of inspired oxygen (FiO2) request.&#xD;
&#xD;
      NUMBER OF PATIENTS The number of patients to be enrolled is calculated based on a predicted&#xD;
      difference of 30% in cardio-respiratory events between the two ventilation modalities.&#xD;
      Assuming a mean of 5 and a SD of 1.5 events/hour (based on available literature data), the&#xD;
      number of patients to be enrolled is 30, to obtain an 80% power and a significance threshold&#xD;
      of 0.05.&#xD;
&#xD;
      STUDY DESIGN The decision to use a NIV support is based on clinical evaluation. At starting&#xD;
      of NIV, eligible patients will be allocated to one of the two arms (NIPPV or SNIPPV) by block&#xD;
      randomization. A custom software will be used to obtain a casual sequence to randomize&#xD;
      patients in both arms, creating a balance between patients needing NIV as first intention or&#xD;
      after extubating.&#xD;
&#xD;
      After 2 hours of stabilization (stabilization phase) in NIV, enrolled patients will be&#xD;
      alternatively ventilated with 2 different techniques for 2 time frame of 4 hours each.&#xD;
&#xD;
      In case of needing surfactant, the stabilization phase will be 4 hours after its&#xD;
      administration.&#xD;
&#xD;
      Infants will be kept supine throughout the study. During the whole study duration (including&#xD;
      stabilization phase) all patients will be continuously monitored with a multiparametric&#xD;
      monitor, recording also data from the ventilator. The first hour of each NIPPV/SNIPPV phase&#xD;
      will be considered as wash-out phase and named &quot;adaptation phase&quot;: data recorded during this&#xD;
      phase are excluded from the analysis. Milk meals will be administered during the adaptation&#xD;
      phase.&#xD;
&#xD;
      Pain and compliance scales will be filled in by nurses every 60 minutes. EGA values will be&#xD;
      recorded at the end of the stabilization phase, at the end of Phase A (first NIV modality)&#xD;
      and Phase B (second NIV modality).&#xD;
&#xD;
      Patients will considered drop out of the study in case of:&#xD;
&#xD;
        1. NIV failure criteria: FiO2 &gt; 40%, pH &lt; 7.2, pCO2 &gt; 65mmHg, ≥ 3 episodes of desaturations&#xD;
           (transcutaneous O2 saturation (SatO2 TC) &lt; 80%) per hour, ≥ 3 episodes of apnea (&gt; 20 s)&#xD;
           and/or bradycardia (heart rate (HR) &lt; 80 beats per minute (bpm)) per hour, Silverman&#xD;
           score &gt;6. Necrotizing enterocolitis, bowel perforation, and hemodynamic instability as&#xD;
           indications of NIV failure&#xD;
&#xD;
        2. Air leak syndrome (i.e. pneumothorax)&#xD;
&#xD;
        3. Needing of invasive procedures during the study&#xD;
&#xD;
        4. Needing of surfactant during the study&#xD;
&#xD;
        5. Development of hemodynamic instability or surgical problems during the study&#xD;
&#xD;
        6. Death Data obtained from dropouts (patients who drop out of the study) will be analyzed&#xD;
           separately.&#xD;
&#xD;
      After 8 hours of study, each patient will be ventilated with the best NIV modality according&#xD;
      to clinical data and cardio-respiratory parameters observed during the study.&#xD;
&#xD;
      MONITORING Nurse staff will continuously monitor patients to avoid biases due to device wrong&#xD;
      positioning&#xD;
&#xD;
      DATA&#xD;
&#xD;
      For each patient enrolled the following variables will be collected:&#xD;
&#xD;
        -  ANAMNESTIC VARIABLES:&#xD;
&#xD;
        -  Gestational age at birth&#xD;
&#xD;
        -  Birth weight&#xD;
&#xD;
        -  Delivery type&#xD;
&#xD;
        -  APGAR at 1/5 minutes (and 10 minutes if available)&#xD;
&#xD;
        -  Presence of intrauterine growth restriction&#xD;
&#xD;
        -  Maternal administration of magnesium sulphate&#xD;
&#xD;
        -  Steroid prenatal prophylaxis (number of doses)&#xD;
&#xD;
        -  Intrapartum antibiotic prophylaxis (if indicated)&#xD;
&#xD;
        -  Presence of intraamniotic infection and administration of intrapartum antibiotic therapy&#xD;
&#xD;
        -  CLINICAL VARIABLES&#xD;
&#xD;
        -  Surfactant administration (time and number of doses)&#xD;
&#xD;
        -  Type and duration of MV previously administered (if any)&#xD;
&#xD;
        -  Type and duration of NIV previously administered (if any)&#xD;
&#xD;
        -  Corrected GA at enrolling&#xD;
&#xD;
        -  Caffeine doses administered (if any)&#xD;
&#xD;
        -  Neonatal Pain Scale score&#xD;
&#xD;
        -  CARDIO-RESPIRATORY VARIABLES&#xD;
&#xD;
        -  FiO2 to maintain SatO2 TC 90-94% (as weighted mean)&#xD;
&#xD;
        -  NIV failure and endotracheal intubation&#xD;
&#xD;
        -  Number of cardiorespiratory events, defined as episodes of apnea lasting more than 20&#xD;
           seconds or over 5 seconds if followed by desaturation or bradycardia and/or episodes of&#xD;
           desaturation with blood oxygen saturation below 80% for 4 sec. or more and/or episodes&#xD;
           of bradycardia with heart rate below 80 bpm&#xD;
&#xD;
        -  OTHER POLYGRAPH VARIABLES (continuous monitoring)&#xD;
&#xD;
        -  Heart rate&#xD;
&#xD;
        -  Respiratory rate&#xD;
&#xD;
        -  SatO2 TC&#xD;
&#xD;
        -  Thoracic impedance&#xD;
&#xD;
        -  From ventilator: trigger, pressure, flow&#xD;
&#xD;
        -  Pressure in ventilator circuit&#xD;
&#xD;
        -  LABORATORISTIC VARIABLES&#xD;
&#xD;
        -  EGA values at the end of stabilization phase, Phase A and Phase B&#xD;
&#xD;
      RESULTS INTERPRETATION The main result will be the difference in cardio-respiratory events&#xD;
      during SNIPPV versus NIPPV.&#xD;
&#xD;
      Tolerance to each of the two NIV modalities will be evaluated by evaluating the number of&#xD;
      failure episodes and of cardio-respiratory events and analysing the scores for individual&#xD;
      compliance and pain. The individual need for oxygen under the two modalities of NIV will be&#xD;
      evaluated as a known risk factor for premature retinopathy and various other complications.&#xD;
&#xD;
      STATISTICAL ANLYSES Descriptive variables will be analyzed in function of their distribution.&#xD;
      T student test or Mann Whitney U test in case of continuous variables (if normally or not&#xD;
      normally distributed respectively) and chi-squared or fisher test for qualitative ones. All&#xD;
      test will be two-sided with a significance threshold of 0.05.&#xD;
&#xD;
      EXPECTED RESULTS Identifying the best NIV modality for preterm newborns at their first&#xD;
      approach to NIV ventilation support, on the bases of cardio-respiratory events reduction and&#xD;
      fraction of inspired oxygen (FiO2) request.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">November 16, 2020</start_date>
  <completion_date type="Anticipated">March 31, 2023</completion_date>
  <primary_completion_date type="Anticipated">March 31, 2023</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Frequency of episodes of desaturation</measure>
    <time_frame>3 hours of NIPPV vs 3 hours SNIPPV</time_frame>
    <description>Desaturation is defined as a blood oxygen saturation below 80% for 4 sec. or more</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of cardiorespiratory events</measure>
    <time_frame>3 hours of NIPPV vs 3 hours SNIPPV</time_frame>
    <description>Cardiorespiratory events are defined as:&#xD;
Hypoxic episodes (SatO2 TC &lt; 80% for at least 4 seconds)&#xD;
Apneas episodes (absence of breath for at least 20 sec or at least 5 sec if followed by desaturation or bradycardia)&#xD;
Bradycardia episodes (heart rate &lt;80 bpm)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>O2 needing during SNIPPV vs NIPPV monitoring to maintain SatO2 TC between 90 and 94%</measure>
    <time_frame>3 hours of NIPPV vs 3 hours SNIPPV</time_frame>
    <description>FiO2 weighted mean necessity</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Newborn pain score evaluation during SNIPPV vs NIPPV monitoring.</measure>
    <time_frame>3 hours of NIPPV vs 3 hours SNIPPV</time_frame>
    <description>Neonatal Pain Scale Score</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Synchronization index</measure>
    <time_frame>3 hours of NIPPV vs 3 hours SNIPPV</time_frame>
    <description>Percentage of spontaneous breaths supported by ventilator</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient-ventilator concordance</measure>
    <time_frame>3 hours of NIPPV vs 3 hours SNIPPV</time_frame>
    <description>Time between the onset of the patient's inspiratory effort and mechanical inflation in synchronized ventilation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Thoracoabdominal asynchrony</measure>
    <time_frame>3 hours of NIPPV vs 3 hours SNIPPV</time_frame>
    <description>Phase difference between thoracic and abdominal impedance</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">30</enrollment>
  <condition>Newborn Respiratory Distress</condition>
  <condition>Preterm Infant</condition>
  <arm_group>
    <arm_group_label>Start ventilation with NIPPV</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Alternatively vented with NIPPV and SNIPPV</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Start ventilation with SNIPPV</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Alternatively vented with SNIPPV and NIPPV</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>NIPPV</intervention_name>
    <description>Non invasive ventilation technique in which PIP and PEEP administration is not synchronized with newborn's respiratory efforts</description>
    <arm_group_label>Start ventilation with NIPPV</arm_group_label>
    <arm_group_label>Start ventilation with SNIPPV</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>SNIPPV</intervention_name>
    <description>Non invasive ventilation technique in which PIP and PEEP administration is synchronized with newborn's respiratory efforts through an algorithm based on flow detection</description>
    <arm_group_label>Start ventilation with NIPPV</arm_group_label>
    <arm_group_label>Start ventilation with SNIPPV</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Gestational age at birth &lt;32 weeks&#xD;
&#xD;
          -  First approach to NIV ventilation (primary or after extubation)&#xD;
&#xD;
          -  Parent's informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Neurological (including IVH &gt; 2° grade) or surgical diseases&#xD;
&#xD;
          -  Sepsis (clinical or laboratory confirmed)&#xD;
&#xD;
          -  Chromosomal or genetic abnormalities&#xD;
&#xD;
          -  Major malformations and congenital anomalies&#xD;
&#xD;
          -  Cardiac problems (including hemodynamically significant PDA)&#xD;
&#xD;
          -  Contraindication to NIV (i.e. nasal trauma and gastrointestinal surgery within the&#xD;
             previous 7 days).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>32 Weeks</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Francesco Cresi, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Città della Salute e della Scienza - Ospedale S.Anna - University of Turin</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Enrico Bertino, Prof</last_name>
    <phone>+39 11 3135775</phone>
    <email>enrico.bertino@unito.it</email>
  </overall_contact>
  <location>
    <facility>
      <name>Ospedale S.Anna di Torino</name>
      <address>
        <city>Torino</city>
        <state>(to)</state>
        <zip>10126</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Francesco Cresi, MD, PhD</last_name>
      <phone>+39113135781</phone>
      <email>francesco.cresi@unito.it</email>
    </contact>
    <investigator>
      <last_name>Francesco Cresi, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Federica Chiale, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Silvia Borgione, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Elena Maggiora, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Maria Chiara Ariotti, MSN, RN</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Mattia Ferroglio, Dr</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <reference>
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  </reference>
  <reference>
    <citation>Aghai ZH, Saslow JG, Nakhla T, Milcarek B, Hart J, Lawrysh-Plunkett R, Stahl G, Habib RH, Pyon KH. Synchronized nasal intermittent positive pressure ventilation (SNIPPV) decreases work of breathing (WOB) in premature infants with respiratory distress syndrome (RDS) compared to nasal continuous positive airway pressure (NCPAP). Pediatr Pulmonol. 2006 Sep;41(9):875-81. doi: 10.1002/ppul.20461.</citation>
    <PMID>16850439</PMID>
  </reference>
  <reference>
    <citation>Huang L, Mendler MR, Waitz M, Schmid M, Hassan MA, Hummler HD. Effects of Synchronization during Noninvasive Intermittent Mandatory Ventilation in Preterm Infants with Respiratory Distress Syndrome Immediately after Extubation. Neonatology. 2015;108(2):108-14. doi: 10.1159/000431074. Epub 2015 Jun 17.</citation>
    <PMID>26107742</PMID>
  </reference>
  <reference>
    <citation>Bhandari V. Noninvasive respiratory support in the preterm infant. Clin Perinatol. 2012 Sep;39(3):497-511. doi: 10.1016/j.clp.2012.06.008.</citation>
    <PMID>22954265</PMID>
  </reference>
  <reference>
    <citation>Gizzi C, Papoff P, Giordano I, Massenzi L, Barbara CS, Campelli M, Panetta V, Agostino R, Moretti C. Flow-synchronized nasal intermittent positive pressure ventilation for infants &lt;32 weeks' gestation with respiratory distress syndrome. Crit Care Res Pract. 2012;2012:301818. doi: 10.1155/2012/301818. Epub 2012 Nov 27.</citation>
    <PMID>23227317</PMID>
  </reference>
  <verification_date>August 2022</verification_date>
  <study_first_submitted>September 18, 2017</study_first_submitted>
  <study_first_submitted_qc>September 18, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 21, 2017</study_first_posted>
  <last_update_submitted>August 22, 2022</last_update_submitted>
  <last_update_submitted_qc>August 22, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">August 23, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Turin, Italy</investigator_affiliation>
    <investigator_full_name>Francesco Cresi, MD, PhD</investigator_full_name>
    <investigator_title>MD, PhD</investigator_title>
  </responsible_party>
  <keyword>preterm</keyword>
  <keyword>ventilation</keyword>
  <keyword>nasal intermittent positive pressure ventilation</keyword>
  <keyword>synchronization</keyword>
  <keyword>cardio-respiratory events</keyword>
  <keyword>newborn</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hyaline Membrane Disease</mesh_term>
    <mesh_term>Premature Birth</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03289936
org study id: SyncNIV
nct id: NCT03289936
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Comparing the cardio-respiratory adaptation and differences to non invasive ventilation
      techniques, nasal intermittent positive pressure ventilation (NIPPV) non synchronized vs
      synchronized (SNIPPV) in preterm newborns (gestational age at birth < 32 weeks) at their
      first approach to non invasive ventilation as first intention (soon after birth) or after
      extubation.
Respiratory problems are one of the major issues to deal with in preterm newborns.

      Because of the immaturity of respiratory mechanisms and structures, the use of supporting
      devices is often necessary. These include both conventional mechanical ventilation (MV)
      techniques, which require the use of an endotracheal tube, as well as non-invasive
      ventilation (NIV) techniques that use softer ventilator-patient interfaces. Increasing
      attention is payed to the latter ones as less aggressive and associated with better outcomes
      both in terms of mortality and short and long-term complications, such as bronchopulmonary
      dysplasia (BPD).

      Nasal intermittent positive pressure ventilation (NIPPV) is a NIV technique in which newborn
      airways are kept open between two pressure levels: peak inspiratory pressure (PIP) and
      positive end expiratory pressure (PEEP). The frequency and duration of each phase are defined
      by setting the inspiratory and expiratory times or the ventilation rate.

      This technique has already shown its superiority in terms of reduced duration of MV, reduced
      necessity of intubation, decreased failure of extubating and reduced prevalence of BPD if
      compared with non-invasive techniques based on continuous pressure support, such as
      continuous positive airway pressure (CPAP). Recent meta-analyses of studies where NIPPV has
      been used as an alternative to CPAP following extubation show that it reduces need for
      re-ventilation and air leaks but without any reduction in BPD: there is insufficient evidence
      to recommend NIPPV as primary mode of respiratory support in the delivery room.

      It should be specified that the ventilation rate on NIPPV does not reflect the real
      respiratory rate (RR) of the newborn, as the ventilator supplies the PIP regardless of
      newborn respiratory efforts. To reproduce a more physiological and gentle ventilation new
      devices able to detect newborn respiratory efforts and consequently supply a PIP have been
      developed to synchronize the ventilation rate with RR of the newborn.

      The devices used for synchronization can identify newborn respiratory effort by detecting
      variation in flow or pressure. While in MV the exact beginning of inspiration can be detected
      through a continuous monitoring of pressure or through the precise interception of
      inspiratory and expiratory flow some difficulties occur in NIV where, as a consequence of the
      impossibility to detect expiratory flow, the moment of the exact beginning of spontaneous
      inspiration is hard to identify.

      Recently, a new type of NIV ventilator equipped with a pressure sensor has been put on the
      market. The software of this ventilator is able to calculate the flow according to the
      pressure variations of the circuit and to capture the flow variations induced by spontaneous
      breathing allowing a synchronization of the flow with the patient's respiratory acts.

      The use of a synchronized NIV technique would allow a more physiological respiratory support,
      reducing respiratory fatigue and improving newborn compliance. Despite these premises, the
      diffusion of synchronized NIPPV in neonatal intensive care units (NICUs) and works on its
      efficacy are limited.

      Some authors have already demonstrated the benefits of using a synchronized NIV technique in
      terms of extubating success rate, BPD prevalence and mortality and neurocognitive
      development. Synchronized NIPPV (SNIPPV) seems more effective than NIPPV and NCPAP in
      reducing need for intubation in respiratory distress syndrome (RDS), in improving the success
      of extubation and in treating apnea of prematurity, with a reassuring absence of relevant
      side effects. Synchronised NIPPV delivered through a ventilator can reduce extubation failure
      but may not confer long-term advantages such as reduction in BPD. Other reported advantageous
      aspects of SNIPPV include improved thoraco-abdominal synchrony, reduced work of breathing
      (WOB) and reduced need of intubation.

      It has already been shown that SNIPPV is more effective than NIPPV and CPAP in reducing the
      number of desaturations and apnoea in preterm infants undergoing CPAP treatment for
      prematurity apnoea. However, the effectiveness of SNIPPV compared to NIPPV in preterm infants
      with respiratory distress is still not completely clear.

      Our study protocol was designed to evaluate the short-term effects of SNIPPV vs NIPPV on the
      major cardio-respiratory variables, trying to identify the best ventilation modality for
      preterm newborns at their first approach to NIV ventilation support, on the bases of
      cardio-respiratory events reduction and fraction of inspired oxygen (FiO2) request.

      NUMBER OF PATIENTS The number of patients to be enrolled is calculated based on a predicted
      difference of 30% in cardio-respiratory events between the two ventilation modalities.
      Assuming a mean of 5 and a SD of 1.5 events/hour (based on available literature data), the
      number of patients to be enrolled is 30, to obtain an 80% power and a significance threshold
      of 0.05.

      STUDY DESIGN The decision to use a NIV support is based on clinical evaluation. At starting
      of NIV, eligible patients will be allocated to one of the two arms (NIPPV or SNIPPV) by block
      randomization. A custom software will be used to obtain a casual sequence to randomize
      patients in both arms, creating a balance between patients needing NIV as first intention or
      after extubating.

      After 2 hours of stabilization (stabilization phase) in NIV, enrolled patients will be
      alternatively ventilated with 2 different techniques for 2 time frame of 4 hours each.

      In case of needing surfactant, the stabilization phase will be 4 hours after its
      administration.

      Infants will be kept supine throughout the study. During the whole study duration (including
      stabilization phase) all patients will be continuously monitored with a multiparametric
      monitor, recording also data from the ventilator. The first hour of each NIPPV/SNIPPV phase
      will be considered as wash-out phase and named "adaptation phase": data recorded during this
      phase are excluded from the analysis. Milk meals will be administered during the adaptation
      phase.

      Pain and compliance scales will be filled in by nurses every 60 minutes. EGA values will be
      recorded at the end of the stabilization phase, at the end of Phase A (first NIV modality)
      and Phase B (second NIV modality).

      Patients will considered drop out of the study in case of:

        1. NIV failure criteria: FiO2 > 40%, pH < 7.2, pCO2 > 65mmHg, ≥ 3 episodes of desaturations
           (transcutaneous O2 saturation (SatO2 TC) < 80%) per hour, ≥ 3 episodes of apnea (> 20 s)
           and/or bradycardia (heart rate (HR) < 80 beats per minute (bpm)) per hour, Silverman
           score >6. Necrotizing enterocolitis, bowel perforation, and hemodynamic instability as
           indications of NIV failure

        2. Air leak syndrome (i.e. pneumothorax)

        3. Needing of invasive procedures during the study

        4. Needing of surfactant during the study

        5. Development of hemodynamic instability or surgical problems during the study

        6. Death Data obtained from dropouts (patients who drop out of the study) will be analyzed
           separately.

      After 8 hours of study, each patient will be ventilated with the best NIV modality according
      to clinical data and cardio-respiratory parameters observed during the study.

      MONITORING Nurse staff will continuously monitor patients to avoid biases due to device wrong
      positioning

      DATA

      For each patient enrolled the following variables will be collected:

        -  ANAMNESTIC VARIABLES:

        -  Gestational age at birth

        -  Birth weight

        -  Delivery type

        -  APGAR at 1/5 minutes (and 10 minutes if available)

        -  Presence of intrauterine growth restriction

        -  Maternal administration of magnesium sulphate

        -  Steroid prenatal prophylaxis (number of doses)

        -  Intrapartum antibiotic prophylaxis (if indicated)

        -  Presence of intraamniotic infection and administration of intrapartum antibiotic therapy

        -  CLINICAL VARIABLES

        -  Surfactant administration (time and number of doses)

        -  Type and duration of MV previously administered (if any)

        -  Type and duration of NIV previously administered (if any)

        -  Corrected GA at enrolling

        -  Caffeine doses administered (if any)

        -  Neonatal Pain Scale score

        -  CARDIO-RESPIRATORY VARIABLES

        -  FiO2 to maintain SatO2 TC 90-94% (as weighted mean)

        -  NIV failure and endotracheal intubation

        -  Number of cardiorespiratory events, defined as episodes of apnea lasting more than 20
           seconds or over 5 seconds if followed by desaturation or bradycardia and/or episodes of
           desaturation with blood oxygen saturation below 80% for 4 sec. or more and/or episodes
           of bradycardia with heart rate below 80 bpm

        -  OTHER POLYGRAPH VARIABLES (continuous monitoring)

        -  Heart rate

        -  Respiratory rate

        -  SatO2 TC

        -  Thoracic impedance

        -  From ventilator: trigger, pressure, flow

        -  Pressure in ventilator circuit

        -  LABORATORISTIC VARIABLES

        -  EGA values at the end of stabilization phase, Phase A and Phase B

      RESULTS INTERPRETATION The main result will be the difference in cardio-respiratory events
      during SNIPPV versus NIPPV.

      Tolerance to each of the two NIV modalities will be evaluated by evaluating the number of
      failure episodes and of cardio-respiratory events and analysing the scores for individual
      compliance and pain. The individual need for oxygen under the two modalities of NIV will be
      evaluated as a known risk factor for premature retinopathy and various other complications.

      STATISTICAL ANLYSES Descriptive variables will be analyzed in function of their distribution.
      T student test or Mann Whitney U test in case of continuous variables (if normally or not
      normally distributed respectively) and chi-squared or fisher test for qualitative ones. All
      test will be two-sided with a significance threshold of 0.05.

      EXPECTED RESULTS Identifying the best NIV modality for preterm newborns at their first
      approach to NIV ventilation support, on the bases of cardio-respiratory events reduction and
      fraction of inspired oxygen (FiO2) request.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Double (Participant, Outcomes Assessor)
measure: Frequency of episodes of desaturation
time frame: 3 hours of NIPPV vs 3 hours SNIPPV
description: Desaturation is defined as a blood oxygen saturation below 80% for 4 sec. or more
measure: Number of cardiorespiratory events
time frame: 3 hours of NIPPV vs 3 hours SNIPPV
description: Cardiorespiratory events are defined as:
Hypoxic episodes (SatO2 TC < 80% for at least 4 seconds)
Apneas episodes (absence of breath for at least 20 sec or at least 5 sec if followed by desaturation or bradycardia)
Bradycardia episodes (heart rate <80 bpm)
measure: O2 needing during SNIPPV vs NIPPV monitoring to maintain SatO2 TC between 90 and 94%
time frame: 3 hours of NIPPV vs 3 hours SNIPPV
description: FiO2 weighted mean necessity
measure: Newborn pain score evaluation during SNIPPV vs NIPPV monitoring.
time frame: 3 hours of NIPPV vs 3 hours SNIPPV
description: Neonatal Pain Scale Score
measure: Synchronization index
time frame: 3 hours of NIPPV vs 3 hours SNIPPV
description: Percentage of spontaneous breaths supported by ventilator
measure: Patient-ventilator concordance
time frame: 3 hours of NIPPV vs 3 hours SNIPPV
description: Time between the onset of the patient's inspiratory effort and mechanical inflation in synchronized ventilation
measure: Thoracoabdominal asynchrony
time frame: 3 hours of NIPPV vs 3 hours SNIPPV
description: Phase difference between thoracic and abdominal impedance
arm group label: Start ventilation with NIPPV
arm group type: Experimental
description: Alternatively vented with NIPPV and SNIPPV
arm group label: Start ventilation with SNIPPV
arm group type: Experimental
description: Alternatively vented with SNIPPV and NIPPV
intervention type: Device
intervention name: NIPPV
description: Non invasive ventilation technique in which PIP and PEEP administration is not synchronized with newborn's respiratory efforts
arm group label: Start ventilation with NIPPV
arm group label: Start ventilation with SNIPPV
intervention type: Device
intervention name: SNIPPV
description: Non invasive ventilation technique in which PIP and PEEP administration is synchronized with newborn's respiratory efforts through an algorithm based on flow detection
arm group label: Start ventilation with NIPPV
arm group label: Start ventilation with SNIPPV
criteria: 
gender: All
minimum age: N/A
maximum age: 32 Weeks
healthy volunteers: No
last name: Francesco Cresi, PhD
role: Principal Investigator
affiliation: Città della Salute e della Scienza - Ospedale S.Anna - University of Turin
last name: Enrico Bertino, Prof
phone: +39 11 3135775
email: enrico.bertino@unito.it
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
country: Italy
citation: Moretti C, Giannini L, Fassi C, Gizzi C, Papoff P, Colarizi P. Nasal flow-synchronized intermittent positive pressure ventilation to facilitate weaning in very low-birthweight infants: unmasked randomized controlled trial. Pediatr Int. 2008 Feb;50(1):85-91. doi: 10.1111/j.1442-200X.2007.02525.x.
PMID: 18279212
citation: Gizzi C, Montecchia F, Panetta V, Castellano C, Mariani C, Campelli M, Papoff P, Moretti C, Agostino R. Is synchronised NIPPV more effective than NIPPV and NCPAP in treating apnoea of prematurity (AOP)? A randomised cross-over trial. Arch Dis Child Fetal Neonatal Ed. 2015 Jan;100(1):F17-23. doi: 10.1136/archdischild-2013-305892. Epub 2014 Oct 15.
PMID: 25318667
citation: Sweet DG, Carnielli V, Greisen G, Hallman M, Ozek E, Te Pas A, Plavka R, Roehr CC, Saugstad OD, Simeoni U, Speer CP, Vento M, Visser GHA, Halliday HL. European Consensus Guidelines on the Management of Respiratory Distress Syndrome - 2019 Update. Neonatology. 2019;115(4):432-450. doi: 10.1159/000499361. Epub 2019 Apr 11.
PMID: 30974433
citation: Cummings JJ, Polin RA; Committee on Fetus and Newborn, American Academy of Pediatrics. Noninvasive Respiratory Support. Pediatrics. 2016 Jan;137(1). doi: 10.1542/peds.2015-3758. Epub 2015 Dec 29.
PMID: 26715607
citation: Isayama T, Iwami H, McDonald S, Beyene J. Association of Noninvasive Ventilation Strategies With Mortality and Bronchopulmonary Dysplasia Among Preterm Infants: A Systematic Review and Meta-analysis. JAMA. 2016 Aug 9;316(6):611-24. doi: 10.1001/jama.2016.10708. Erratum In: JAMA. 2016 Sep 13;316(10):1116.
PMID: 27532916
citation: Owen LS, Manley BJ. Nasal intermittent positive pressure ventilation in preterm infants: Equipment, evidence, and synchronization. Semin Fetal Neonatal Med. 2016 Jun;21(3):146-53. doi: 10.1016/j.siny.2016.01.003. Epub 2016 Feb 26.
PMID: 26922562
citation: Permall DL, Pasha AB, Chen XQ. Current insights in non-invasive ventilation for the treatment of neonatal respiratory disease. Ital J Pediatr. 2019 Aug 19;45(1):105. doi: 10.1186/s13052-019-0707-x.
PMID: 31426828
citation: Ferguson KN, Roberts CT, Manley BJ, Davis PG. Interventions to Improve Rates of Successful Extubation in Preterm Infants: A Systematic Review and Meta-analysis. JAMA Pediatr. 2017 Feb 1;171(2):165-174. doi: 10.1001/jamapediatrics.2016.3015.
PMID: 27918754
citation: Lemyre B, Davis PG, De Paoli AG, Kirpalani H. Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for preterm neonates after extubation. Cochrane Database Syst Rev. 2017 Feb 1;2(2):CD003212. doi: 10.1002/14651858.CD003212.pub3.
PMID: 28146296
citation: Moretti C, Gizzi C, Montecchia F, Barbara CS, Midulla F, Sanchez-Luna M, Papoff P. Synchronized Nasal Intermittent Positive Pressure Ventilation of the Newborn: Technical Issues and Clinical Results. Neonatology. 2016;109(4):359-65. doi: 10.1159/000444898. Epub 2016 Jun 3.
PMID: 27251453
citation: Charles E, Hunt KA, Rafferty GF, Peacock JL, Greenough A. Work of breathing during HHHFNC and synchronised NIPPV following extubation. Eur J Pediatr. 2019 Jan;178(1):105-110. doi: 10.1007/s00431-018-3254-3. Epub 2018 Oct 30.
PMID: 30374754
citation: Salvo V, Lista G, Lupo E, Ricotti A, Zimmermann LJ, Gavilanes AW, Barberi I, Colivicchi M, Temporini F, Gazzolo D. Noninvasive ventilation strategies for early treatment of RDS in preterm infants: an RCT. Pediatrics. 2015 Mar;135(3):444-51. doi: 10.1542/peds.2014-0895. Epub 2015 Feb 9.
PMID: 25667244
citation: Manley BJ, Doyle LW, Owen LS, Davis PG. Extubating Extremely Preterm Infants: Predictors of Success and Outcomes following Failure. J Pediatr. 2016 Jun;173:45-9. doi: 10.1016/j.jpeds.2016.02.016. Epub 2016 Mar 5.
PMID: 26960919
citation: Alexiou S, Panitch HB. Physiology of non-invasive respiratory support. Semin Fetal Neonatal Med. 2016 Jun;21(3):174-80. doi: 10.1016/j.siny.2016.02.007. Epub 2016 Feb 28.
PMID: 26923501
citation: Li W, Long C, Zhangxue H, Jinning Z, Shifang T, Juan M, Renjun L, Yuan S. Nasal intermittent positive pressure ventilation versus nasal continuous positive airway pressure for preterm infants with respiratory distress syndrome: a meta-analysis and up-date. Pediatr Pulmonol. 2015 Apr;50(4):402-9. doi: 10.1002/ppul.23130. Epub 2014 Nov 21.
PMID: 25418007
citation: Handoka NM, Azzam M, Gobarah A. Predictors of early synchronized non-invasive ventilation failure for infants < 32 weeks of gestational age with respiratory distress syndrome. Arch Med Sci. 2019 May;15(3):680-687. doi: 10.5114/aoms.2019.83040. Epub 2019 Feb 18.
PMID: 31110534
citation: Aghai ZH, Saslow JG, Nakhla T, Milcarek B, Hart J, Lawrysh-Plunkett R, Stahl G, Habib RH, Pyon KH. Synchronized nasal intermittent positive pressure ventilation (SNIPPV) decreases work of breathing (WOB) in premature infants with respiratory distress syndrome (RDS) compared to nasal continuous positive airway pressure (NCPAP). Pediatr Pulmonol. 2006 Sep;41(9):875-81. doi: 10.1002/ppul.20461.
PMID: 16850439
citation: Huang L, Mendler MR, Waitz M, Schmid M, Hassan MA, Hummler HD. Effects of Synchronization during Noninvasive Intermittent Mandatory Ventilation in Preterm Infants with Respiratory Distress Syndrome Immediately after Extubation. Neonatology. 2015;108(2):108-14. doi: 10.1159/000431074. Epub 2015 Jun 17.
PMID: 26107742
citation: Bhandari V. Noninvasive respiratory support in the preterm infant. Clin Perinatol. 2012 Sep;39(3):497-511. doi: 10.1016/j.clp.2012.06.008.
PMID: 22954265
citation: Gizzi C, Papoff P, Giordano I, Massenzi L, Barbara CS, Campelli M, Panetta V, Agostino R, Moretti C. Flow-synchronized nasal intermittent positive pressure ventilation for infants <32 weeks' gestation with respiratory distress syndrome. Crit Care Res Pract. 2012;2012:301818. doi: 10.1155/2012/301818. Epub 2012 Nov 27.
PMID: 23227317
responsible party type: Principal Investigator
investigator affiliation: University of Turin, Italy
investigator full name: Francesco Cresi, MD, PhD
investigator title: MD, PhD
mesh term: Hyaline Membrane Disease
mesh term: Premature Birth