Efficacy of a New Technique -"IN-REC-SUR-E"- in Preterm Neonates With RDS
Condition: Respiratory Distress Syndrome; Hyaline Membrane Disease
MeSH terms: Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Hyaline Membrane Disease; Syndrome
Study type: Interventional

Summary: 
      The primary hypothesis of this study is reduction in need of mechanical ventilation in the
      first 72 hours of life (excluding the transient tracheal intubation performed for surfactant
      administration and the mechanical ventilation for lung recruitment) in spontaneously
      breathing infants born at 24+0-27+6 weeks' gestation and failing nCPAP during the first 24
      hours of life who received an HFOV recruitment maneuver (IN-REC-SUR-E) compared to no
      recruitment maneuver (IN-SUR-E) just prior to surfactant administration followed by prompt
      extubation.
    

Detailed description: 
      EFFICACY OF A NEW TECHNIQUE -"IN-REC-SUR-E"- IN PRETERM NEONATES WITH RESPIRATORY DISTRESS
      SYNDROME DURING NON INVASIVE VENTILATION: A RANDOMIZED CONTROLLED TRIAL

      BACKGROUND The initial stabilization on Continuous Positive Airway Pressure (CPAP) and
      provision of rescue surfactant only when necessary is at least as beneficial and quite
      possibly preferred over the standard therapy of intubation of all infants at risk in the
      delivery room and subsequent support with mechanical ventilation (2-4). The percentage of
      CPAP failure in the newborns of 25-28 weeks' gestation is 45 % (30/66) in the Australian
      experience (5), higher than that reported by Ammari et al. (25 %) (6) and similar to that
      reported by De Jaegere et al. (50 %) (7) and in the COIN trial (46 %) (2). As a potential
      alternative, the INSURE (INtubate, SURfactant, Extubate) approach (8) is very attractive.
      Recently, several studies have investigated the effectiveness of the association between
      non-invasive ventilation and surfactant, administered by transient intubation (INSURE),
      showing that it is effective in preventing the need for mechanical ventilation. Although
      beneficial in clinical practice, the INSURE method cannot be universally applied to all
      preterm neonates with Respiratory Distress Syndrome (RDS) and is unsuccessful in a particular
      section of this population. The INSURE failure rate recently reported in preterm infants of
      different gestational age widely ranges from 19 % to 69 % (10, 11). Unfortunately, no
      randomized controlled trials have directly evaluated the efficacy of INSURE in extremely
      preterm neonates (<28 weeks gestation) (8). Nevertheless, the data of the "Sustained Lung
      Inflation (SLI) study" (14) recently conducted on infants with GA 25+0- 28+6 weeks showed
      that nasal CPAP failure and need for Mechanical Ventilation (MV) at 72 hours of life was 53 %
      in the SLI group and 65 % in the control group (only nasal CPAP). In this study surfactant
      was preferably administered with the INSURE approach at a Fraction of Inspired Oxygen (FiO2)
      threshold of 0.40 and then it could be reasonably argued that at least 50 % of 25-28 weeks'
      gestation infants, even if receiving a SLI maneuver and the INSURE treatment for CPAP
      failure, undergoes mechanical ventilation in the first 72 hours of life for unsuccessful
      INSURE. One of the possible mechanisms responsible for the unsuccessful INSURE, requiring
      subsequent re-intubation and mechanical ventilation is the inability of the preterm lung with
      RDS of achieving and maintaining an "optimal" Functional Residual Capacity (FRC).
      Prophylactic or early rescue surfactant administration before alveolar recruitment probably
      results in an uneven surfactant distribution to already open alveoli thus resulting in poor
      clinical response to the first surfactant treatment. We, therefore, seek to compare the
      application of a recruitment manoeuver - in High-Frequency Oscillatory Ventilation (HFOV)
      modality - just before the surfactant administration, followed by rapid extubation
      (INtubate-RECruited-SURfactant-Extubation: IN-REC-SUR-E) with INSURE alone in spontaneously
      breathing preterm infants requiring nasal CPAP as initial respiratory support and reaching
      pre-defined CPAP failure criteria, for evaluating its effectiveness in decreasing the need of
      MV and improving respiratory outcome.

      Study design This will be an unblinded multi-center randomized trial of IN-REC-SUR-E vs.
      IN-SUR-E in infants born at 24+0-27+6 weeks' gestation.

      Sample size The investigators hypothesized that a recruitment manoeuver (in HFOV modality)
      before surfactant administration might decrease of the need of subsequent mechanical
      ventilation during the first 72 hours of life from 50 % (2, 5, 7) to 30 %. The investigators
      calculated that 103 newborns must be enrolled in each group to detect this difference as
      statistically significant with 80 % power at 0.05 level.

      Randomisation Infants at each unit will be block (1st block: gestational age from 24+0 to
      25+6 weeks; 2nd block: gestational age from 26+0 to 27+6 weeks) randomly assigned to a
      treatment group using automatically generated sealed envelopes which will be prepared at
      Policlinico A. Gemelli Hospital in Rome and then distributed to participating centers.
      Permutated block randomization with 1:1 randomization between the two arms will be used.

      Blinding The study will not be blinded, and the staff performing the study also will take
      care of the infants later on. However, the decision to start mechanical ventilation will be
      made by clinicians other than the investigators and, moreover, parents, nurses involved in
      patient care and researchers assessing study end-points will be blinded to the nature of the
      study treatments. To minimize bias, strict criteria and definitions will be maintained during
      the trial.

      Management in the Delivery Room Positive pressure with a neonatal mask and a T-piece system
      (Neopuff Infant Resuscitator, Fisher and Paykel, Auckland, New Zealand) will be used to
      stabilize newborns after birth. All the neonates will receive one (or two) SLI manoeuver(s)
      (25 cmH2O for 10-15 seconds) (14) and will be transferred to the Neonatal Intensive Care Unit
      (NICU) in nasal CPAP (6 cmH2O). Infants will start mechanical ventilation in agreement with
      the American Academy of Paediatrics guidelines on neonatal resuscitation (16). In this latter
      case the babies will be excluded from the study (see exclusion criteria section, page 4).

      CPAP Failure Criteria In the NICU, nasal CPAP will be given through nasal prongs/mask using
      the standard method of the single centre (ventilator, flow-dependent system) with an initial
      pressure of 6 to 7 cmH2O, in all infants. CPAP failure is defined if they met any of the
      following criteria: FiO2 ≥ 0.30 on nasal CPAP (17) to maintain pulse oximetry (SpO2) 87-94
      %(18) for at least 30 minutes unless rapid clinical deterioration occurred, respiratory
      acidosis defined as pCO2 > 65 mmHg (8.5 kPa) and pH < 7.20 on arterial or capillary blood gas
      sample, apnea defined as >4 episodes of apnea per hour or >2 episodes of apnea per hour when
      ventilation with bag and mask will be required.

      HFOV Recruitment manoeuver Infants in the IN-REC-SUR-E group will undergo the following
      approach: after intubation, HFOV will be delivered with the ventilator available in each
      NICU. The following initial ventilator setting will be advocated: Continuous Distending
      Pressure (CDP): 8cmH2O; Frequency: 10-15 Hz; Delta P: 15 cmH2O or Amplitude 30 % eventually
      increased - chest to be "visibly vibrating "-; I:E 1:2. Delta P (or amplitude) first and/or
      frequency subsequently will be adjusted to achieve a Tidal Volume (VT) of 1,5-2 ml/kg and/or
      to maintain the transcutaneous partial carbon dioxide pressure (TcPCO2) between 40 and 60
      mmHg (5.3 and 8.0 kPa). The infants will be subjected to an open lung ventilation strategy
      aiming to recruit and stabilize the majority of collapsed alveoli/sacculi, using oxygenation
      as an indirect parameter for lung volume. Optimal recruitment is defined as adequate
      oxygenation using a FiO2 of 0.25 or less. Starting at 8 cmH2O, the CDP will be increased
      stepwise (2 cmH2O every 2-3 minutes) as long as SpO2 improves. The FiO2 will be reduced
      stepwise, keeping SpO2 within the target range (87-94 %). The recruitment procedure will be
      stopped if oxygenation no longer improves or if the FiO2 is equal to or less than 0.25. The
      corresponding CDP will be called the opening pressure (CDPO). Next, the CDP will be reduced
      stepwise (1-2 cmH2O every 2-3 minutes) until the SpO2 deteriorates (of at least 2-3 points).
      The corresponding CDP will be called the closing pressure (CDPC). After a second recruitment
      manoeuver at CDPO for 2 minutes, the optimal CDP (CDPOPT) will be set 2 cmH2O above the CDPC
      for at least 3 minutes (19). A chest radiograph at this point is advised.

      Surfactant Treatment

      Infants in the IN-REC-SUR-E arm will undergo the following approach: as soon as possible
      after the recruitment manoeuver (at CDPOPT) a dose of poractant alfa (Curosurf [Chiesi
      Farmaceutici, Parma, Italy]) of 200 mg/kg will be administered via a closed administration
      system in one-two aliquots (1-2 minutes). The tube position will be confirmed by
      auscultation. A temporary reduction of frequency may be necessary to increase the VT up to
      2.5 ml/kg for improving the surfactant spreading.

      Infants in the IN-SUR-E arm will undergo the following approach: after intubation, a dose of
      poractant alfa (Curosurf [Chiesi Farmaceutici, Parma, Italy]) of 200 mg/kg will be
      administered via a closed administration system in one-two aliquots (1-2 minutes). The tube
      position will be confirmed by auscultation. During surfactant administration, infants will be
      manually ventilated to facilitate surfactant distribution. If necessary, mechanical
      ventilation with a peak inspiratory pressure (PIP) of 20-22 cmH2O, a Positive End-Expiratory
      Pressure (PEEP) of 5-6 cmH2O and a respiratory rate of 30-40 breaths/min will be subsequently
      started to achieve a VT of 4-6 ml/kg and/or to maintain the transcutaneous partial carbon
      dioxide pressure (TcPCO2) between 40 and 60 mmHg (5.3 and 8.0 kPa).

      After surfactant administration, the babies of both groups will be extubated within 30
      minutes (if satisfactory respiratory drive is present) and will receive nasal CPAP (6-8
      cmH2O) (20). In case of insufficient respiratory drive, CDP (in the babies of IN-REC-SUR-E
      arm) or PIP (in the IN-SUR-E arm) will be reduced until spontaneous respiratory activity is
      restored. Maintaining a FiO2 < 0.30 to obtain SpO2 values in the desired range (87-94 %) will
      drive the eventual reduction in the level of CPAP in the following days. The decision as to
      whether to begin Bi-level Positive Airway Pressure (BiPAP) or nasal-Intermittent Mandatory
      Ventilation (N-IMV) to prevent the need for re-intubation in infants of both groups will be
      up to the neonatologist on duty, and will be considered in the final analysis.

      Infants of both groups can receive a subsequent dose of surfactant (100 mg/kg of poractant
      alfa) using the same method (INSURE or INRECSURE) if they meet the CPAP failure criteria
      again during the following 12 to 24 hours.

      Data collection All collected data can be obtained from the clinical records. They will be
      reported in electronic data sheets designed for this study.

      Statistical analysis The primary efficacy analysis will be conducted on an intention to treat
      basis. Clinical characteristics of infants in the "IN-REC-SUR-E" and "IN-SUR-E" groups will
      be described using mean values and standard deviation, median value and range, or rate and
      percentage. Univariate statistical analysis will be performed using the Student "t" test for
      parametric continuous variables, the Wilcoxon rank-sum test for non-parametric continuous
      variables, and Fisher's exact test for categorical variables. A p <0.05 will be considered
      statistically significant. Then, "IN-REC-SUR-E" treatment and clinical characteristics which
      are most likely associated with the need for mechanical ventilation (gestational age, birth
      weight, antenatal steroids, CRIB score) will be included in multiple logistic regression
      analysis to assess their independent role in predicting "IN-REC-SUR-E" success or failure.
      Effect estimates will be expressed as relative risk (RR) with profile likelihood-based 95 %
      confidence limits.

      An interim analysis is planned when 50 infants will be enrolled in each arm. Duration of
      study: 1 year

      QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES 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 are required to participate in preparatory meetings
      in which details of study protocol, data collection, "IN-REC-SUR-E" and "IN-SUR-E" procedures
      will be accurately discussed. All centers will receive detailed written instruction on web
      based data recording, and, to solve possible difficulties, it will be possible to contact the
      Clinical Trials Coordinating Center. Moreover, it has been ascertained that "IN-REC-SUR-E"
      procedure is followed similarly in all participating centers.
    

Intervention name(s): Poractant alfa, 200 mg/kg; Ventilator for High-frequency Oscillatory Ventilation (HFOV); Nasal Continuous Positive Airway Pressure (nCPAP)
Intervention type(s): Drug; Device; Device
Intervention description(s): Endotracheal Surfactant administration; This device will be used to perform an HFOV recruitment maneuver before surfactant administration; After surfactant administration, the babies will be extubated within 30 minutes and will receive nCPAP (6-8 cm H2O)
Other intervention name(s): Curosurf-Chiesi Farmaceutici, Parma, Italy
Intervention MeSH terms: Poractant alfa
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment