nHFOV vs nCPAP: Effects on Gas Exchange for the Treatment of Neonates Recovering From RDS
Condition: Respiratory Distress Syndrome; Preterm Birth
MeSH terms: Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Premature Birth; Syndrome
Study type: Interventional

Summary: 
      The purpose of this study is to compare the effects of two different techniques of
      non-invasive ventilation (nCPAP and nHFOV) on gas exchange in preterm infants recovering from
      respiratory distress syndrome.
    

Detailed description: 
      Background - Extremely low birth weight (ELBW) infants usually develop respiratory distress
      syndrome (RDS), due to lung immaturity, surfactant deficiency and immature respiratory
      control mechanisms (1). Even though mechanical ventilation is frequently lifesaving,
      complications are common (2). Tracheal intubation and mechanical ventilation are associated
      with ventilator-induced lung injury (VILI) and airway inflammation, leading to
      bronchopulmonary dysplasia (BPD) (3). The mechanisms of this injury involve alveolar over
      distension, the presence of shear forces and the release of pro-inflammatory cytokines (6),
      moreover prolonged duration of intubation and mechanical ventilation is associated with an
      increased risk of death or survival with neurologic impairment (3). In an effort to reduce
      VILI and so BPD in premature infants, there has been a trend toward increased use of
      non-invasive forms of respiratory support: nasal continuous positive airway pressure (nCPAP),
      nasal intermittent positive-pressure ventilation (NIPPV), high-flow nasal cannula (HFNC),
      nasal high-frequency oscillatory ventilation (nasal-HFOV)(2, 1, 7).

      NCPAP is an alternative to intubation and a meta-analysis trials of early nasal CPAP versus
      intubation and ventilation showed that nasal CPAP reduces the risk of BPD. Nonetheless use of
      NCPAP in the delivery room may fail in ELBW, with 34 to 83% of such infants requiring
      subsequent intubation. Furthermore, post extubation support with nCPAP in these infants is
      associated with a 16-40% failure rate at 1 week (3, 4, 5, 9). NCPAP stabilized the surfactant
      deficient alveoli and improves oxygenation, but does not necessarily improve alveolar
      ventilation or partial pressure of carbon dioxide (pCO2) elimination (2, 8).

      Some Authors reported the use of nasal high-frequency ventilation (nHFOV) in 14 very low
      birth weight (VLBW) infants with respiratory failure, using nasopharyngeal tube (3) and they
      have shown that this technique can lower pCO2 (1).

      Other Authors investigated the efficacy of nasal HFOV applied on a single nasopharyngeal tube
      in an heterogeneous group of 21 infant with moderate respiratory insufficiency and they shown
      that was effective in reducing pCO2 (10).

      No randomized controlled trials have directly evaluated the efficacy of nasal HFOV versus
      nCPAP with use of nasal prongs/mask in ELBW. There is rationale and support for the idea that
      high-frequency oscillation using a nasal prongs may improve carbon dioxide elimination in
      infants and minimizing the need for intubation and mechanical ventilation. In premature
      infants, HFOV is believed to cause less lung injury than conventional ventilation. So the
      question can be whether the benefits of HFOV and non invasive (nasal) ventilation are
      synergistic.

      End-point - Our first end-point is that short-term application of nasal HFOV compared with
      nasal continuous airway pressure (nCPAP) in infants with persistent oxygen (O2) need
      recovering from RDS would improve CO2 removal. We also hypothesized that use of nHFOV can
      reduce the inspired fraction of O2 (FiO2) levels requiring to maintain normal percutaneous
      saturation of O2 (SpO2) levels .

      Design - Multi-center non-blinded, randomized, observational four period crossover study
      Setting/population Level III Neonatal Intensive Care Unit (NICU): very-low birth weight
      infants (< 1500 g) and/or gestational age < 32 weeks requiring nCPAP and oxygen while
      recovering from RDS.

      Methods - Infants requiring nasal CPAP (4-8 cm H2O) for > 24 hours prior to study enrolment,
      and FiO2 more than 0.21, will be randomized to either nCPAP or nHFOV delivered by Medin-CNO
      device. A crossover design with four 1 h treatment periods will be used such that each infant
      will receive both treatments twice. Oxygen saturation (SaO2), transcutaneous CO2 (tcCO2) and
      O2 (tcO2) and vital signs will be monitored continuously. Cardio-respiratory monitor
      recordings will be analyzed for apnoea, bradycardia and oxygen desaturations.

      Study - After written informed consent will be obtained, the patient will be placed in the
      supine position. A transcutaneous CO2 and O2 monitor as well as pneumocardiography sensors
      will be placed on the infant and monitored. The patient will be randomized by sealed envelope
      shuffle to a starting treatment mode of either nCPAP (4-8 cm H2O, with the same CPAP level
      used prior to entering into the study) or nHFOV with the following starting parameters: CPAP
      level: 4-8 cm H2O with the same CPAP level used prior to entering into the study; Flow: 7-10
      l/min (providing the desired CPAP level); Frequency: 10 Hz, Amplitude: 10, (eventually
      modified to obtain tcPCO2 values in the normal range (45-65 mmHg; 5.9-8.6 kPa). Short binasal
      prongs of right size will be always used. Prior to entering into the study all the patients
      will receive caffeine.

      All support will be delivered by the Medin-cno device. Research personnel will adjust the
      FiO2 to attain a targeted oxygen saturation of 87-94%. The patients will be maintained in the
      usual thermoneutral environment (incubator) throughout the study, and will receive the
      standard routine care by the primary care team.

      At study initiation, the infant will be started on the randomized starting mode of either
      nCPAP or nHFOV. The study will consist of four 1 h study blocks, alternating from the initial
      mode to the alternate mode twice. During the study neonates will be monitored continuously
      with a cardio-respiratory monitor, a pulse oximeter and a transcutaneous gas monitoring. All
      the data will be recorded continuously at 1-min intervals directly from the monitor and/or
      observed directly by an experienced neonatologist and manually recorded on a respiratory
      sheet. During each study block, the following data will be recorded: transcutaneous partial
      pressure of CO2 (tcPCO2), transcutaneous partial pressure of O2 (tcPO2), heart rate,
      respiratory rate, SaO2, Silverman score. Apnoeic episodes will be defined as absence of
      thoracic impedance change for a minimum of 20 s. Bradycardic episodes will be defined as
      persistent heart rate <80 beats per minute for a minimum of 10s. Significant desaturation
      episodes will be defined as persistent pulse oximetry values <80% for a minimum of 10s.
      Manual blood pressure will be taken with appropriate sized neonatal blood pressure cuff 30
      minutes after the beginning of each treatment block.

      Immediately after entering the study, at the beginning of the first study period, a
      transcutaneous monitoring of TcPCO2 and TcPO2 will be started and a capillary blood gas
      analysis (BGA) will be performed in order to test the reliability of the TcPCO2 data. A
      second capillary BGA will be performed at the end of second study period in both CPAP and
      nHFOV. Cerebral (cer-rSO2) and renal (ren-rSO2) tissue oxygenation will be measured by
      near-infrared spectroscopy (NIRS) as additional variable during the study period, based on
      the instrument's availability in each participating center.

      The study will be ended when the patient will complete the 4 h study or will be terminated
      early if the patient will develop any signs of intolerance during the study, including an
      increase of >50% in the number of episodes of apnea or bradycardia compared with the prestudy
      baseline noted 1 h preceding study entry, or increased supplemental FiO2 > 0.3 from pre-study
      baseline for at least 15 min (i.e. from 0.30 to 0.60). To allow for equilibration, we will
      group and analyze data points from the last 20 min of each treatment block.

      A sample size of 30 has been calculated to detect a mean difference of 3 mmHg tcCO2 based on
      a two-tailed p value of 0.05, power of 0.9 and a within-patient standard deviation (SD) of
      2.5 mmHg (2).

      Duration of study - To be defined, depending on the number of participating NICUs.

      Compliance to protocol - Compliance will be defined as full adherence to protocol. Compliance
      with the protocol will be ensured by a number of procedures as described below.

      Site set-up - Local principal investigators will participate to preparatory meetings in which
      details of study protocol, data collection and procedures will be accurately discussed. All
      centers will receive detailed written instruction on web based recording data, and, to solve
      possible difficulties, it will be possible to contact the Chief investigators. Moreover, it
      has been ascertained that the procedure is equally made in all participating centers.

      Data processing and monitoring - All study data will be

        1. Screened for out-of-range data, with cross-checks for conflicting data within and
           between data collection forms by a data manager.

        2. Referred back to relevant centre for clarification in the event of missing items or
           uncertainty.

      The Chief Investigator and trial statistician will review the results generated for logic and
      for patterns or problems. Outlier data will be investigated.

      Safety - Safety end-point measures will include incidence, severity, and causality of
      reported serious adverse effects (SAE), namely changes in occurrence of the expected common
      prematurity complications and clinical laboratory test assessments, and the development of
      unexpected SAEs in this high risk population. All SAEs will be followed until satisfactory
      resolution or until the investigator responsible for the care of the participant deems the
      event to be chronic or the patient to be stable. All expected and unexpected SAEs, whether or
      not they are attributable to the study intervention, will be reviewed by the local principal
      investigators to determine if there is reasonable suspected causal relationship to the
      intervention. If the relationship is reasonable SAEs will be reported to Chief Investigators
      who will report to Ethics Committee and inform all investigators to guaranty the safety of
      participants.
    

Intervention name(s): Medin-cno
Intervention type(s): Device
Intervention description(s): Medin-cno is a noninvasive ventilator. With this device we can practice either nCPAP and nHFOV ventilation.
Other intervention name(s): nHFOV; nCPAP
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: nCPAP; nHFOV; Preterm; RDS; CO2 Elimination