Feasibility and Impact of Volume Targeted Ventilation in the Delivery Room

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Brief Title

Feasibility and Impact of Volume Targeted Ventilation in the Delivery Room

Official Title

Feasibility and Impact of Volume Targeted Ventilation for Preterm Infants Born <32 Weeks Gestational Age With Need for Invasive Positive Pressure Ventilation in the Delivery Room in Reducing Neonatal Pulmonary Morbidities

Brief Summary

      Despite significant improvement in preterm infant survival, the incidence of bronchopulmonary
      dysplasia (BPD) in infants born < 28 weeks gestational age (GA) has been relatively stable at
      ~40%, with 10,000-15,000 new cases estimated annually. Delivery room (DR) management of
      preterm infants during the initial resuscitation has a significant impact on future
      development of BPD. Current DR practice as recommended by the Neonatal Resuscitation Program
      (NRP), focuses on providing positive pressure ventilation (PPV) for intubated infants based
      on pressure limited ventilation (PLV). But with rapidly changing pulmonary compliance during
      the early newborn period, PLV may lead to under or over inflation of the lungs and induce
      significant volutrauma, barotrauma and/or atelectotrauma, all of which are associated in the
      pathogenesis of BPD. No studies have specifically reported tidal volume (TV) provided in the
      DR in intubated infants with current PLV practices. Similarly, no study has evaluated the
      safety and efficacy of volume targeted ventilation (VTV) in the DR and its impact on BPD.

      With the proposed study, in Phase I, the investigators aim to demonstrate that measuring TV
      in intubated infants receiving PPV via PLV is feasible. The investigators also seek to
      demonstrate that with PLV, TV is highly variable in the first few hours of life, even with
      the same peak inspiratory pressures (PiP) due to rapidly changing pulmonary compliance. A
      successful Phase I will demonstrate that measuring TV is feasible in the DR, and with
      information on real time actual TV achieved during PPV, it is possible to target the TV for a
      goal TV by adjusting the PiP provided.

      Phase II will be a pilot randomized control trial to demonstrate feasibility of VTV compared
      to PLV. The investigators will also aim to understand the pulmonary mechanics and physiology
      during VTV. A successful Phase II will demonstrate VTV is feasible, is associated with stable
      TV, decreased peak inspiratory pressure and oxygen needs compared to PLV, and not associated
      with increased complications compared to PLV. It will thereby justify a larger randomized
      control trial with enough power to evaluate the efficacy of VTV in reducing BPD and other
      long term pulmonary morbidities for preterm infants.
    

Detailed Description

      BACKGROUND BPD continues to be one of the most common complications associated with preterm
      birth. A 2013 US study reported an increase in healthcare cost of $31,565 associated with
      BPD, after controlling for birth weight, gestational age, and socio-demographic
      characteristics during the initial neonatal intensive care unit (NICU) hospitalization
      itself. This economic burden starts from the initial NICU admission and persists through
      childhood and adulthood. A recent Spanish study published in 2013, reported that the
      healthcare related cost during the first 2 years of life of a preterm baby with BPD and no
      other major prematurity-related complications ranged between €45,049.81 and €118,760.43, in
      Spain, depending on birth weight and gestational age. If the baby required home oxygen
      therapy or developed pulmonary hypertension, this cost could further escalate to €181,742.43.
      With 10,000-15,000 new cases of BPD annually in USA alone, the economic impact of BPD is
      tremendous.

      The pathogenesis of BPD is multifactorial, with lung injury from mechanical ventilation,
      oxygen toxicity, and antenatal or postnatal infections, all leading to lung inflammation
      which play a key role in the development of BPD. Delivery room (DR) management of preterm
      infants during the initial resuscitation is critical, and can have a significant impact on
      development of BPD. Studies have demonstrated that DR respiratory management with invasive
      respiratory support and higher oxygen content is associated with increased risk of death
      and/or BPD compared to non-invasive ventilation and lower oxygen resuscitation, respectively.
      Preterm infants stabilized on continuous positive airway pressure (CPAP) with prudent
      titration of supplemental oxygen in the delivery room to achieve targeted oxygen saturations
      have demonstrated improved rates of BPD.

      CURRENT STANDARD OF PRACTICE Current DR practice for intubated preterm infants focuses on
      pressure limited ventilation using either a self-inflating bag or a T-piece resuscitator
      where the provider regulates the inflation pressure and inflation time, but not the tidal
      volume.

      As an infant transitions to extra uterine life, pulmonary compliance changes rapidly. Total
      pulmonary compliance is a composite of the lung and chest wall compliances. In preterm
      infants, the chest wall is composed primarily of cartilage rendering the chest wall highly
      compliant, and as a result, the neonatal lung is more prone to collapse. Preterm lungs
      additionally have reduced surfactant production which further decreases lung compliance. Upon
      initiation of positive pressure ventilation (PPV), the rapid fluid shift in the immediate
      newborn period can also result in swift changes in a newborn's pulmonary compliance.
      Provision of maternal antenatal steroids as well as surfactant replacement therapies can
      positively impact the preterm pulmonary outcomes. For these preterm infants, tidal volumes
      generated during PPV is directly proportional to the lung compliance as demonstrated by the
      formula: Cdyn=VT/(PiP-PEEP), where, VT = tidal volume; PIP=peak inspiratory pressure; and
      PEEP=positive end-expiratory pressure.

      Hence, with PLV the exact same pressure due to rapidly changing lung compliance may lead to
      under-inflation or over-inflation of the lungs.

      Once admitted in the NICU, providing VTV to preterm infants is standard practice in the
      investigators NICU, with inter-provider preference over volume versus pressure ventilation,
      with no true consensus. However, in the DR the practice continues to be utilizing PLV and
      with the proposed study, the investigators seek to provide physiologically more appropriate
      VTV to the preterm infants right from the birth in the DR.

      SIGNIFICANCE With rapidly changing lung compliance in the immediate neonatal transition
      phase, PLV can lead to significant variability in the delivered TV. Recent reports suggests
      that pressure limited resuscitation devices routinely used in the delivery room are capable
      of tripling the intended TV while providing PPV in a newborn manikin x. Large TV can lead to
      volutrauma, which is associated with adverse pulmonary outcomes. A study in preterm lambs
      showed as few as six large tidal volume breaths at birth can lead to acute lung injury and
      blunt the effect of subsequent surfactant treatment. Ventilation with large breaths may cause
      gross overexpansion of regions that are forced open, leaving major parts of the lung blocked
      by fluid and unexpanded, and such regional over distension can be expected to cause
      epithelial and microvascular injury and pulmonary edema. The resultant pulmonary edema may
      make the lung more susceptible to further volutrauma during conventional mechanical
      ventilation. Several animal studies have demonstrated that PPV with TV more than 8 mL/kg
      causes lung inflammation and lung injury. Additionally, animal and human studies have
      demonstrated that excessive TV delivery during PPV in the delivery room causes brain
      inflammation and injury. Likewise, recent meta-analysis data demonstrate infants ventilated
      using volume targeted ventilation (VTV) modes reduce rates of death or BPD, pneumothoraces,
      hypocarbia, severe cranial ultrasound pathologies and reduce the duration of ventilation
      compared with infants ventilated using PLV modes. The risk of lung injury is in all
      likelihood related to the magnitude of the volutrauma at birth, and therefore ventilation
      immediately after birth needs to be very gentle.

      Without information about TV in the DR and rapidly changing lung compliance, PLV may lead to
      volutrauma. But no study has specifically evaluated the ability to measure TV provided in
      intubated infants in the DR or aimed at performing VTV in the DR while assessing its
      potential role in reducing lung injury.

      INNOVATION With recent advances in technology and ability to measure small TV at the
      endotracheal tube (ET) level with the help of flow sensors, TV can be measured accurately at
      the ET tube level and volume targeted ventilation (VTV) becomes a possible alternative method
      of ventilating preterm infants. For the study, infants will have a flow sensor placed in
      series between the ETT and pressure generating device (T-piece resuscitator, self-inflating
      bag). The flow sensor will be connected to Respironics NM3 monitor (Philips Healthcare,
      Eindhoven, Netherlands) to measure the breath to breath TV. The flow sensor adds less than 1
      mL of airway dead space volume (Vd) for neonatal sensors (ETT size of 2.5-4 mm). Phase 1 of
      the study will look into the feasibility of measuring TV in preterm infants. As some of the
      smallest very low birth weight (VLBW) infants may weight as less as 500gm, goal TV range of
      4-6ml/kg will be equal to 2ml-3ml per breath. No study has specifically looked into the
      ability of measuring such small tidal volume, and hence this feasibility study is of prime
      importance.

      In Phase 2, by using the information of measured TV at the ETT level, the provider can
      quickly regulate the peak pressure delivered to the infant to achieve a goal TV of 4-6 ml/kg.
      The provider will be trained to increase or decrease the pressures, by following a strict
      protocol to ensure the TV remains at goal during neonatal resuscitation. As soon as the
      infant is stable, the infant will be transitioned to a ventilator with volume targeting
      capabilities. With stable lung expansion, infants receiving VTV will receive goal TV more
      consistently, will have reduced incidence of atelectotrauma, volutrauma and overall reduced
      lung injury with lesser long term pulmonary morbidities.

      With the proposed study, in Phase I, the investigators aim to demonstrate that measuring TV
      in the DR is feasible and is highly variable in the first few hours of life, even with the
      same peak inspiratory pressures due to rapidly changing pulmonary compliance. A successful
      Phase I will provide evidence that providing consistent VTV is possible in the DR by
      adjusting the PiP. In Phase II, the investigators aim to obtain pilot data assessing the
      feasibility of VTV in the DR, and attempt to understand the pulmonary mechanics and
      physiology during VTV. A successful pilot study will demonstrate that VTV is feasible; is
      associated with consistent delivered TV; lower PiP and oxygen needs for the patients; thereby
      justifying a larger randomized control trial to evaluate the efficacy of VTV in reducing BPD
      and long term pulmonary morbidities.
    


Study Type

Interventional


Primary Outcome

Timing of initiation of mechanical ventilation


Condition

Prematurity

Intervention

Volume Targeted Ventilation (VTV) using the Philips Respironics NM3 monitor

Study Arms / Comparison Groups

 Control Arm
Description:  Infant will receive pressure regulated breaths, 40-60 breaths/min, PiP of 20-24cm of water as recommended by 2017 Neonatal Resuscitation Program (NRP) guidelines. Reading of the TV will be blinded from the providers as in routine clinical situations

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Device

Estimated Enrollment

40

Start Date

July 11, 2019

Completion Date

December 31, 2020

Primary Completion Date

December 31, 2020

Eligibility Criteria

        Inclusion Criteria:

          -  Gestational age < 32 weeks of gestation

          -  Infant born at Baystate Medical Center

          -  Requiring intubation and positive pressure ventilation in the delivery room

          -  Parental Consent

        Exclusion Criteria:

          -  Maternal prolonged rupture of membrane > 2 weeks duration

          -  Known congenital or cardiac abnormalities or discovered in the immediate neonatal
             period.
      

Gender

All

Ages

N/A - 60 Minutes

Accepts Healthy Volunteers

No

Contacts

Ruben Vaidya, MD, 4137942400, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT03938532

Organization ID

BH-19-006


Responsible Party

Principal Investigator

Study Sponsor

Baystate Medical Center


Study Sponsor

Ruben Vaidya, MD, Principal Investigator, Baystate Medical Center


Verification Date

July 2019