High Frequency Oscillatory Ventilation Combined With Intermittent Sigh Breaths: Effects on Lung Volume Monitored by Electric Tomography Impedance.
Condition: Respiratory Distress Syndrome In Premature Infants; Bronchopulmonary Dysplasia; Ventilator-Induced Lung Injury; Functional Residual Capacity
MeSH terms: Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Lung Injury; Bronchopulmonary Dysplasia; Ventilator-Induced Lung Injury
Study type: Interventional

Summary: 
      Background Ventilator induced lung injury (VILI) remains a problem in neonatology. High
      frequency oscillatory ventilation (HFOV) provides effective gas exchange with minimal
      pressure fluctuation around a continuous distending pressure and therefore small tidal
      volume. Animal studies showed that recruitment and maintenance of functional residual
      capacity (FRC) during HFOV ("open lung concept") could reduce lung injury.

      "Open lung HFOV" is achieved by delivering a moderate high mean airway pressure (MAP) using
      oxygenation as a guide of lung recruitment. Some neonatologists suggest combining HFOV with
      recurrent sigh-breaths (HFOV-sigh) delivered as modified conventional ventilator-breaths at a
      rate of 3/min. The clinical observation is that HFOV-sigh leads to more stable oxygenation,
      quicker weaning and shorter ventilation. This may be related to improved lung recruitment.

      Electric Impedance Tomography (EIT) enables measurement and mapping of regional ventilation
      distribution and end-expiratory lung volume (EELV). EIT generates cross-sectional images of
      the subject based on measurement of surface electrical potentials resulting from an
      excitation with small electrical currents and has been shown to be a valid and safe tool in
      neonates.

      Purpose, aims:

        -  To compare HFOV-sigh with HFOV-only and determine if there is a difference in global and
           regional EELV (primary endpoints) and spatial distribution of ventilation measured by
           EIT

        -  To provide information on feasibility and treatment effect of HFOV-sigh to assist
           planning larger studies. We hypothesize that EELV during HFOV-sigh is higher, and that
           regional ventilation distribution is more homogenous.

      Methods:

      Infants at 24-36 weeks corrected gestational age already on HFOV are eligible. Patients will
      be randomly assigned to HFOV-sigh (3 breaths/min) followed by HFOV-only or vice versa for 4
      alternating 1-hours periods (2-treatment, double crossover design, each patient being its own
      control). During HFOV-sigh set-pressure will be reduced to keep MAP constant, otherwise HFOV
      will remain at pretrial settings.

      16 ECG-electrodes for EIT recording will be placed around the chest at study start. Each
      recording will last 180s, and will be done at baseline and at 30 and 50 minutes after each
      change in ventilator modus.

      Feasibility No information of EIT-measured EELV in babies on HFOV-sigh exists. This study is
      a pilot-trial.

      In a similar study-protocol of lung recruitment during HFOV-sigh using "a/A-ratio" as
      outcome, 16 patients was estimated to be sufficient to show an improvement by 25%. This
      assumption was based on clinical experience in a unit using HFOV-sigh routinely. As the
      present study examines the same intervention we assume that N=16 patients will be a
      sufficient sample size. We estimate to include this number in 6 months.
    

Detailed description: 
      Ventilator induced lung injury (VILI) is an important etiological factor in the pathogenesis
      of bronchopulmonary dysplasia (BPD), defined as need for respiratory support or supplemental
      oxygen at 36 weeks post-conceptual age. Despite advances in antenatal and neonatal care,
      50-80% of very-low-birth-weight infants will be ventilated during their neonatal admission.
      Accordingly, further development of neonatal ventilation strategies with specific emphasis on
      lung-protective ventilation remains an important research field. Volutrauma and
      atelectotrauma caused by excessive tidal volume and insufficient lung recruitment
      respectively rather than barotrauma are today considered as the most important factors for
      VILI. High frequency oscillatory ventilation (HFOV) provides effective gas exchange with
      minimal pressure fluctuation around a continuous distending pressure and therefore small
      tidal volume and is in theory more lung protective. However results from randomized
      controlled trials comparing HFOV with conventional ventilation have been conflicting and
      meta-analyses have not shown clear evidence that HFOV is safer or more effective than
      conventional ventilation neither when used as initial strategy nor as rescue strategy in
      preterm babies. Accordingly HFOV still has no absolute indication and is mostly used as a
      rescue treatment. Early animal studies showed that recruitment and maintenance of functional
      residual capacity (FRC) during HFOV ("open lung concept") could reduce lung injury. Because
      of fear of barotrauma, lung recruitment was initially achieved by superimposing conventional
      ventilation (CV) breaths on top of HFOV with much lower mean airway pressure (MAP) than what
      is used today. Today most neonatologists provide "open lung HFOV" by delivering a higher MAP
      using oxygenation as an indirect guide of lung recruitment. In some units a clinical praxis
      has evolved combining HFOV (using "modern" high MAP) with recurrent sigh-breaths (HFOV-sigh)
      delivered as modified conventional inflations at a rate of 3/min. The clinical observation
      is, that when compared to standard HFOV, HFOV-sigh leads to more stable oxygenation, quicker
      weaning in FiO2 and MAP, and shorter ventilation. This approach seems to be encouraged by a
      number of neonatologist.

      Electric Impedance Tomography (EIT) enables measurement and mapping of regional ventilation
      distribution, end-expiratory lung volume (EELV) and other respiratory physiological
      parameters. EIT generates cross-sectional images of the studied subject based on the
      measurement of surface electrical potentials resulting from an excitation with known small
      electrical currents (5 mAmp and 50 kHz). Both the voltage measurements and current injections
      take place between pairs of conventional self-adhesive surface electrodes of a 16-electrode
      array attached on the chest circumference. Electrical impedance tomography scans are
      generated from the collected potential differences and the known excitation currents using
      weighted back-projection in a 32x32 pixel matrix. Each pixel of the scan shows the
      instantaneous local impedance. EIT has been shown to be a valid and safe tool in neonates to
      monitor changes in global and regional lung ventilation and EELV.

      Combining HFOV with conventional breaths has only been reported in a limited number of
      studies and only with focus on HFOV combined with conventional breaths at normal rate showing
      a possible benefit. Similar results have been reported when comparing High frequency Jet
      Ventilation (HFVJ) combined with conventional breaths at normal rate with HFVJ alone. To our
      knowledge only one human trial comparing standard HFOV with HFOV combined with recruitment
      breaths at low rate has been registered but never published (Texas Infant Star Trial).

      The clinical observation is that oxygenation during HFOV-sigh seems to be improved which is
      considered to be an indirect sign of improved lung volume. However no clinical studies
      estimating lung volume during HFOV-sigh exist to confirm or dispute this, which is the main
      reason we propose this study.

      Ideally, during HFOV the MAP should be set at a level at which lung volume is optimal.
      However in some situations the cardiovascular status of the patient does not allow the MAP to
      be increased to this level, in which case combining HFOV with sigh-breaths at a lower MAP
      could be an alternative way of optimizing lung volume.

      The purpose of this study is to investigate the effect of HFOV-sigh compared with HFOV-only
      on EIT derived measurements of EELV and regional ventilation distribution and other
      respiratory physiological parameters such as heart rate and respiratory rate.

      Research question:

      In ventilated newborn infants, does combining high frequency oscillatory ventilation (HFOV)
      with intermittent sigh breaths result in increased end-expiratory lung volume (EELV) and more
      homogenous distribution of ventilation when compared to standard HFOV without sigh-breaths.
      Lung volume and distribution of ventilation will be monitored by electric impedance
      tomography (EIT).

      Hypothesis and Aims of project:

      Primary hypothesis of the study is that end-expiratory lung volume (EELV) during HFOV
      combined with sigh-breaths (HFOV-sigh) is relatively higher than EELV during HFOV without
      HFOV (HFOV-only), and that regional distribution of ventilation will be more homogenous
      indicating a more homogenous lung-recruitment. The following specific aims of this study will
      address these hypotheses:

        -  To determine if there is a significant difference in global and regional EELV measured
           by EIT between HFOV-sigh and HFOV-only

        -  To determine if there is a significant difference in spatial distribution of ventilation
           and timing of ventilation between HFOV-sigh and HFOV-only using specific EIT derived
           calculation

        -  To determine if there is a significant difference in other respiratory variables, such
           as heart rate (HR), oxygen saturation (SpO2) and spontaneous breathing rate between
           HFOV-sigh and HFOV-only

        -  To provide information on feasibility and data on treatment effect of HFOV-sigh to
           assist in planning a larger study.
    

Intervention name(s): HFOV combined with sigh breaths
Intervention type(s): Other
Intervention description(s): It is planned only to investigate infants already ventilated on the HFOV-modus on high frequency oscillators, where the HFOV modus can be superimposed on conventional modes of ventilation. This gives the opportunity to combine HFOV with intermittent sigh breaths with a pre-set frequency and pre-set peak inspiratory pressure (PIP) and thus comparing HFOV combined with sigh breaths (HFOV-sigh) with conventional HFOV (HFOV-only).
All included participants will be exposed to the two different ventilator strategies tested in this trial, albeit in alternating and different order.
Each patient will serve, as it's own control. The trial will involve four alternating 1-hours periods allowing a sufficient "wash-out" period, as it has been shown that alveolar recruitment and derecruitment may take up to 25 min after changes to ventilator pressures At study start the patients will randomly be assigned to either starting with HFOV-only or HFOV-sigh
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Respiratory Distress Syndrome In Premature Infants; Bronchopulmonary Dysplasia; Ventilator-Induced Lung Injury; Functional Residual Capacity; Electric impedance tomography