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NIV-NAVA Versus Nasal Continuous Positive Airway Pressure (nCPAP) or Non Synchronized NIPPV (Bio-NAVA)

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ClinicalTrials.gov Identifier: NCT02860325
Recruitment Status : Completed
First Posted : August 9, 2016
Last Update Posted : December 20, 2017
Sponsor:
Information provided by (Responsible Party):
Fermín García-Muñoz Rodrigo, Complejo Hospitalario Universitario Insular Materno Infantil

Tracking Information
First Submitted Date  ICMJE August 2, 2016
First Posted Date  ICMJE August 9, 2016
Last Update Posted Date December 20, 2017
Actual Study Start Date  ICMJE August 1, 2016
Actual Primary Completion Date November 30, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 8, 2016)
Survival without moderate or severe bronchopulmonary dysplasia (BPD) [ Time Frame: From admission to first discharge from hospital, assessed up to 1 year ]
Moderate or severe BPD: dependency on supplemental oxygen and/or ventilatory support at 36 weeks postmenstrual age (PMA) or at hospital discharge (what happens first).
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 19, 2017)
  • Blood level of cytokines: Tumor necrosis factor alpha (TNF-α), interleukin (IL) 1 beta (IL-1ß), IL-6, and IL-8. [ Time Frame: T-0: cord blood or immediately after admission; T-1: 48 to 72 h.; T-2: 5th to 7th day of life; and T-3: 28th day of life. ]
    Level of the different cytokines in blood
  • Total time of ventilatory support (in days) [ Time Frame: From admission to first discharge from hospital, assessed up to 1 year ]
    Number of days with invasive and/or non-invasive ventilatory support
  • Intervention failure [ Time Frame: From admission to first discharge from hospital, assessed up to 1 year ]
    Need for intubation
  • Total time of oxygen therapy (in days) [ Time Frame: From admission to first discharge from hospital, assessed up to 1 year ]
    Numer of days with supplementary oxygen
  • Length of stay (in days) [ Time Frame: From admission to first discharge from hospital, assessed up to 1 year ]
    Number of days in hospital until first discharge
Original Secondary Outcome Measures  ICMJE
 (submitted: August 8, 2016)
  • Blood level of cytokines: Tumor necrosis factor alpha (TNF-α), interleukin (IL) 1 beta (IL-1ß), IL-6, and IL-8. [ Time Frame: T-0: cord blood or immediately after admission; T-1: 48 to 72 h.; T-2: 5th to 7th day of life; and T-3: 28th day of life. ]
  • Total time of ventilatory support (in days) [ Time Frame: From admission to first discharge from hospital, assessed up to 1 year ]
  • Intervention failure [ Time Frame: From admission to first discharge from hospital, assessed up to 1 year ]
    Need for intubation
  • Total time of oxygen therapy (in days) [ Time Frame: From admission to first discharge from hospital, assessed up to 1 year ]
  • Length of stay (in days) [ Time Frame: From admission to first discharge from hospital, assessed up to 1 year ]
Current Other Pre-specified Outcome Measures
 (submitted: December 19, 2017)
  • Intraventricular haemorrhage (IVH) and grade [ Time Frame: From admission to first discharge from hospital, assessed up to 1 year ]
    According to Papile's classification
  • Periventricular leukomalacia (PVL) [ Time Frame: From admission to first discharge from hospital, assessed up to 1 year ]
    Cysts or hyperecogenicities for more tan 14 days
  • Retinopathy of Prematurity (ROP) stage and need for laser therapy [ Time Frame: From admission to first discharge from hospital, assessed up to 1 year ]
    Grade 3 or higher (International classification).
  • Necrotizing Enterocolitis (NEC) and stage [ Time Frame: From admission to first discharge from hospital, assessed up to 1 year ]
    Grade 2 or greater of Bell's classification
Original Other Pre-specified Outcome Measures
 (submitted: August 8, 2016)
  • Intraventricular haemorrhage (IVH) and grade [ Time Frame: From admission to first discharge from hospital, assessed up to 1 year ]
  • Periventricular leukomalacia (PVL) [ Time Frame: From admission to first discharge from hospital, assessed up to 1 year ]
  • Retinopathy of Prematurity (ROP) stage and need for laser therapy [ Time Frame: From admission to first discharge from hospital, assessed up to 1 year ]
  • Necrotizing Enterocolitis (NEC) and stage [ Time Frame: From admission to first discharge from hospital, assessed up to 1 year ]
 
Descriptive Information
Brief Title  ICMJE NIV-NAVA Versus Nasal Continuous Positive Airway Pressure (nCPAP) or Non Synchronized NIPPV
Official Title  ICMJE Non-invasive Neurally Adjusted Ventilatory Assist Versus nCPAP or Non Synchronized NIPPV in Preterm Infants Under 32 Weeks Gestational Age: A Randomized Clinical Trial
Brief Summary

Mechanical respiratory support of preterm neonates with respiratory distress syndrome (RDS) and/or apnoea of prematurity (AOP) might be associated with adverse effects due to positive pressure (barotrauma), excessive gas delivery (volutrauma) or inadequate volume (atelectrauma). Asynchrony between patient efforts and ventilator support increases patient discomfort, favouring "fighting" the machine, and increases the risk of air trapping and lung overdistension even in patients with non-invasive ventilation (NIV).

Recently, a new modality of synchronization has been available for pediatric and neonatal use: the neurally adjusted ventilatory assist (NAVA), which uses the diaphragmatic electrical activity (Edi) as a signal to start the rise in pressure of the ventilator, and to adjust the tidal volume and the inspiratory time (cycling off) to the patient needs, breath by breath.

The aims of this study are to know whether NIV-NAVA compared to unsynchronized modalities (nCPAP/nIPPV), in infants born < 32 weeks GA with respiratory distress syndrome or requiring prophylactic NIV (immaturity, apnoea) reduces systemic inflammation, measured by serum cytokines concentration, reduces the need for oxygen and respiratory support, and if it increases the probabilities of survival without bronchopulmonary dysplasia (BPD).

Detailed Description

Introduction. Mechanical respiratory support of preterm neonates with respiratory distress syndrome (RDS) and/or apnoea of prematurity (AOP) might be associated with adverse effects as a consequence of positive pressure use (barotrauma), excessive gas delivery (volutrauma) or inadequate volume (atelectrauma). All these factors could give rise to an increase in the alveolo-capillary membrane permeability, alveoli oedema, hyaline membrane formation and epithelial cells desquamation. These phenomena eventually could lead to activation of inflammatory mediators (biotrauma) with local and systemic noxious effects.

During assisted ventilation, the lack of synchrony between patient efforts and ventilator support increases patient discomfort, favouring "fighting" the machine, and increases the risk of air trapping and lung overdistension. Even in patients with non-invasive ventilation (NIV), uneasiness and respiratory distress would cause air hunger, developing intrapleural negative pressure with risk of lung overinflation despite using low airway positive pressures. The use of neuromuscular blockade in adults with acute respiratory distress syndrome (ARDS) has been associated with a decrease in serum cytokine levels and 90 days adjusted mortality.

NAVA uses the diaphragmatic electrical activity (Edi) as a signal to start the rise in pressure of the ventilator. Likewise, it allows automatic adjustment of peak inspiratory pressure (PIP) to the patient's effort, providing variable tidal volume according to his/her needs. Finally, the system allows the inspiratory cycling off with Edi decline (normally set at 70% of Edi Peak), that is, with diaphragmatic relaxation. NAVA has shown a faster response time and a better level of synchronization than traditional flow or pressure systems, achieving greater comfort levels in adults and paediatric patients. Some paediatric and neonatal studies have shown a reduction in PIP, without changes in mean airway pressure (MAP), and a reduction in oxygen requirement (FiO2). These changes were not associated with major complications (intraventricular haemorrhage, pneumothorax, or necrotizing enterocolitis).

A relevant target in neonatal ventilatory support is to minimize the aggression to the lungs and respiratory system using NIV whenever possible, and/or extubating patients as soon as possible. For this reason, profound sedation, analgesia, or neuromuscular blockade are rarely indicated in the newborn period. NAVA synchronization might improve patient comfort, preventing patient-ventilator fighting, and lung overinflation episodes (volutrauma), ultimately reducing biotrauma. To the knowledge of the investigators, studies evaluating this new ventilatory modality (NAVA) in the newborn period are still scarce, and its potential to reduce inflammation has not been tested.

Objectives.

To determine if NIV-NAVA compared to unsynchronized modalities (nCPAP/nIPPV), in infants born < 32 weeks GA with respiratory distress syndrome or requiring prophylactic NIV (immaturity, apnoea):

  1. Reduces systemic inflammation, measured by serum cytokines concentration.
  2. Reduces the need for oxygen and respiratory support.
  3. Increases the probabilities of survival without bronchopulmonary dysplasia (BPD).

Design. Single centre, prospective and controlled randomized clinical trial.

Setting. Tertiary Hospital with near 6000 births per year and a Neonatal Intensive Care Unit (NICU) with 15 beds and approximately 250 admissions per year.

Methods. Informed consent (IC) will be obtained before birth, during mothers' admission with threatened preterm labour. Once the IC is obtained and after the infant's birth, patients will be randomized by a random numbers table, kept in sealed envelops, to "Group A" (NAVA) or "Group B" (conventional strategies).

In all cases meeting inclusion criteria, a cord blood sample will be collected to determine the level of cytokines: Tumour necrosis factor alpha (TNF - α), interleukin (IL) 1 beta (IL-1ß), IL-6, and IL-8.

The decision to intubate in delivery room or to provide NIV will be carried out by the attending neonatologist at time of birth based on clinical criteria. In our unit, standard care is intubation and prophylactic surfactant administration in delivery room in neonates < 25 weeks GA, or older babies that did not received antenatal steroid and need intubation during resuscitation. Neonates 26 - 29 weeks GA with adequate respiratory effort are resuscitated and transferred to NICU with NIV (Neo-puff ®). Preterm babies > 29 weeks GA receive respiratory support (invasive or NIV) only when clinically indicated.

After admission to NICU, patients requiring invasive mechanical ventilation will be supported according to theirs needs and the criteria of the attending neonatologist. In our unit, modes with volume guarantee (VG) or volume control are currently used: Assist/Control+VG, Synchronized - Intermittent Mandatory Ventilation (S-IMV)+VG, and Pressure Regulated Volume Control (PRVC). After extubation and in patients supported non-invasively since the beginning, NIV will be provided according to randomization group:

Group A: With the ventilator SERVO-n (Maquet, Solna, Sweden), in NIV-NAVA mode. The ventilation parameters (PEEP, FiO2, NAVA level, etc.) will be established and adjusted by the attending clinician according to the patient's needs.

Group B: With the Infant Flow device (CareFusion) in nCPAP or non-synchronised Biphasic mode. The ventilation parameters (Flow, PEEP, FiO2, PIP level, etc.) will be established and adjusted by the attending clinician according to the patient's needs.

Surfactant (Curosurf ®, 100 mg/kg) will be administered according to clinical indications following the Unit's protocol. In general, if the patient did not receive it in delivery room, it is administered as soon as possible in the NICU when the patient needs FiO2 >0.3. Intubated patients will receive surfactant through a double lumen tube, and those with NIV by a minimally invasive method, or by the Insure (intubate, surfactant, and extubated) method.

Quantitative cytokine determination will be carried out simultaneously in all samples by X-MAP technology using the Bioplex cytometer (Biorad) which allows the simultaneous measure of multiple analytes.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Respiratory Distress Syndrome, Newborn
  • Apnea of Prematurity
Intervention  ICMJE
  • Device: NIV-NAVA
    Non-invasive ventilatory support by means of neurally adjusted ventilatory assist (SERVO-n, Maquet, Solna, Sweden)
  • Device: Conventional
    Non-invasive ventilatory support by means of nCPAP or non-synchronized nIPPV (Infant Flow, CareFusion)
Study Arms  ICMJE
  • Experimental: NIV-NAVA
    Patients allocated to non-invasive NAVA
    Intervention: Device: NIV-NAVA
  • Active Comparator: Conventional
    Patients allocated to nasal CPAP or non-synchronized nasal IPPV
    Intervention: Device: Conventional
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 15, 2017)
56
Original Estimated Enrollment  ICMJE
 (submitted: August 8, 2016)
60
Actual Study Completion Date  ICMJE December 2017
Actual Primary Completion Date November 30, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Newborns < 32 weeks GA with neonatal respiratory distress syndrome, diagnosed by clinical and radiological findings who need invasive or non-invasive mechanical ventilation.
  2. Newborns < 29 weeks of gestation (GA) with non-invasive mechanical ventilation at admission indicated as per protocol.
  3. Previous parent or legal guardian authorization (informed consent).

Exclusion Criteria:

  1. Major congenital malformation or chromosomal abnormality.
  2. Absence of informed consent.
  3. Outborn patients.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE Child, Adult, Older Adult
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Spain
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02860325
Other Study ID Numbers  ICMJE CEIC-CHUIMI-2014/761
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Fermín García-Muñoz Rodrigo, Complejo Hospitalario Universitario Insular Materno Infantil
Study Sponsor  ICMJE Complejo Hospitalario Universitario Insular Materno Infantil
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Fermín García-Muñoz Rodrigo, Ph.D Head of Neonatal Unit
PRS Account Complejo Hospitalario Universitario Insular Materno Infantil
Verification Date December 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP