High Frequency Oscillatory Ventilation Combined With Intermittent Sigh Breaths: Effects on Blood Oxygenation and Stability of Oxygenation

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Brief Title

High Frequency Oscillatory Ventilation Combined With Intermittent Sigh Breaths: Effects on Blood Oxygenation and Stability of Oxygenation

Official Title

Does High Frequency Oscillatory Ventilation Combined With Intermittent Sigh Breaths Improve Oxygenation Compared to High Frequency Oscillatory Ventilation Without Sigh Breaths in Neonates?

Brief 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.
      This has however to our knowledge not been tested in a clinical trial using modern
      ventilators.

      Purpose, aims:

        -  To compare HFOV-sigh with HFOV-only and determine if there is a difference in
           oxygenation expressed as a/A-ratio and/or stability of oxygenation expressed as
           percentage time with oxygen saturation outside the reference range.

        -  To provide information on feasibility and treatment effect of HFOV-sigh to assist
           planning larger studies. We hypothesize that oxygenation is better during HFOV-sigh.

      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. Outcome will be calculated from normal clinical parameters
      including pulx-oximetry and transcutaneous monitoring of oxygen and carbon-dioxide partial
      pressures.
    

Detailed Description

      High frequency oscillatory ventilation (HFOV) has been used in neonatal respiratory care for
      more than three decades. HFOV provides effective gas exchange with minimal pressure
      fluctuation around a set mean airway pressure (MAP) functioning as a continuous distending
      pressure (CDP), and low tidal volume compared to conventional ventilation (CV). HFOV was
      therefore thought to be able to reduce the risk of bronchopulmonary dysplasia in ventilated
      preterm babies. 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 with respiratory distress
      syndrome (RDS). Consequently there are no absolute indications for HFOV in preterm babies and
      most neonatologists today use HFOV as a rescue mode when conventional ventilation is failing
      in the acute setting of RDS as well as in the baby with bronchopulmonary dysplasia.

      Maintaining adequate functional residual capacity (FRC) together with the fraction of
      inspired oxygen FiO2 are the main determinants of oxygenation. The larger the FRC, the larger
      is the volume of available oxygen in the alveoli for gas transport. Adequate oxygen
      saturation (SAT) of the blood in room air or an improvement in oxygen-saturation without
      changing the fraction of inspired oxygen can be seen as an indirect indicator of normal or
      normalized FRC, and most neonatologists use oxygenation as an indirect marker for lung volume
      during HFOV.

      The CDP or set-MAP is the main determinant of lung-aeration during HFOV. A too low MAP may
      cause non-homogenous aeration and atelectasis leading to atelectotrauma and redirection of
      airflow to more compliant alveoli leading to localized hyperinflation.

      Accordingly, early animal studies showed that recruitment and maintenance of FRC during HFOV
      could reduce lung injury. Lung recruitment was initially achieved by superimposing
      conventional ventilation (CV) breaths on top of HFOV with lower MAP than used today, either
      as recurrent sustained inflations lasting 15-20 seconds about every 20 minute, as
      intermittent sigh breaths (3-5 tidal breaths pr minute) delivered as normal conventional
      breaths or as conventional ventilation at normal rate combined with HFOV.

      Today most neonatologists perform this so-called "open lung" concept by adjusting the set-MAP
      using oxygenation as an indirect guide of lung recruitment. Different approaches are used
      explained by difficulties in direct bedside monitoring of FRC. Some initiate HFOV with MAP
      2-3 cm H2O above the MAP needed during conventional ventilation subsequently adjusting MAP
      until the fraction of inspired O2 (FiO2) <0.25-0.6 providing no signs of over inflation of
      the lungs on x-ray. Others go through a more complex step-wise increase in MAP till FiO2
      cannot be reduced further, and then gradually decrease MAP until FiO2 again needs to be
      increased to maintain a predefined SAT and then continues ventilations with a MAP set at 2 cm
      H2O above this point, thereby placing ventilation on the more compliant deflation limb of the
      pressure-volume relationship of the lung.

      During HFOV, MAP may be adjusted as mentioned above. Further increase in MAP may increase FRC
      by increased aeration and consequently improve oxygenation. Although recent clinical trials
      suggest this approach is safe, it could potentially lead to generalized hyperinflation and
      volutrauma in addition to interfering with systemic venous return and cardiac output
      especially if not combined with direct monitoring of lung volume which is currently not
      available in routine clinical care.

      Combining intermittent recruitment sigh breaths at a rate of 3-5 breaths/minute with HFOV
      could be an alternate way of assisting in maintaining or normalizing FRC during which MAP is
      only increased temporarily and intermittently. This could in theory lead to quicker weaning
      in MAP, less oxygen exposure and potentially reduced lung injury. A concern however could be,
      that the intermittent sigh breaths will lead to intermittent excessive pressures in distal
      airways and to excessive tidal volume and accordingly not be beneficial at all. Nevertheless
      the approach of combining HFOV and sigh breaths at a low rate seems to be encouraged by a
      number of neonatologist.

      It has however to our knowledge not yet been tested in a controlled human trial.

      A search on PubMed revealed no human or animal trials comparing HFOV combined with
      intermittent recruitment sigh-breaths at a low rate. Also no trials exploring this approach
      are currently registered on www.clinicaltrials.gov.

      To our knowledge so far only one human trial comparing HFVO with recruitment breaths at low
      rate has been registered but never published (Texas Infant Star Trial).

      Combining HFOV with conventional breaths has only been reported in a limited number of
      studies and only with focus on HFOV combined with CV at normal rate showing a possible
      benefit. Similar results have been reported when comparing High frequency Jet Ventilation
      (HFVJ) combined with CV at normal rate with HFVJ alone.

      Trial rationale:

      Combining intermittent recruitment sigh breaths at a low rate with HFOV could offer a further
      way of assisting in maintaining or normalizing FRC with only modest or no increase in MAP in
      alignment with the open lung concept.

      A concern however could be, that the intermittent sigh breaths will lead to intermittent
      increased pressures in distal airways and too large tidal volume and accordingly not be
      beneficial at all. Despite this, the approach of combining HFOV and sigh breaths seems to be
      encouraged by a number of neonatologist.

      It has however, to our knowledge not yet been tested in a controlled human trial. We
      therefore wish to conduct a controlled cross-over trial assessing the effect of HFOV combined
      with intermittent sigh breaths on oxygenation in ventilated neonates using oxygenation as an
      indirect indicator of lung recruitment.

      Objective and hypothesis:

      The objectives of this trial are to:

      • Compare HFOV combined with intermittent recruitment sigh breaths at a rate of 3/min
      (HFOV-sigh) with HFOV only (HFOV-only) and examine if:

        -  oxygenation expressed as a/A-ratio improves with HFOV-sigh

             -  a/A-ratio is a measure of oxygenation and calculated as

             -  a/A-ratio = paO2/(0,95*FiO2- PaCO2),

             -  paO2 and PaCO2 are measured on arterial blood if arterial access is in situ
                otherwise as transcutaneous values (see further down).

        -  stability of oxygenation improves with HFOV-sigh

           • expressed as a calculation of the percentage deviation of time spent outside the
           reference range for oxygen-saturation (SAT) for the given gestational age (AUC -
           area-under-the-curve) and comparing this with MAP and FiO2.

        -  Evaluate the possibility of setting up a larger randomized controlled trial We
           hypothesize that during HFOV-sigh the oxygenation will be improved as well at the
           stability of oxygenation with less time spent outside the reference range for SAT at an
           unchanged or lower FiO2

      Trial design:

      The trial is planned as a 4-period 2-treatment, double crossover clinical trial with each
      patient being its own control. Patients will be randomly assigned to receive HFOV-Sigh
      followed by HFOV-only or vice versa for four alternating 1-hours periods.
    


Study Type

Interventional


Primary Outcome

Delta-a/A-ratio

Secondary Outcome

 FiO2

Condition

Respiratory Distress Syndrome, Newborn

Intervention

HFOV combined with sigh breaths

Study Arms / Comparison Groups

 HFOV-sigh at start
Description:  Each patient will be exposed to either HFOV alone (HFOV-only) or HFOV combined with sigh breaths (HFOV-sigh), but in different order.
MAP=mean airway pressure.
DURING HFOV-SIGH:
Frequency 3 breaths/min
Ti = 1s
Peak inspiratory pressure (PIP) = 30 cm H2O
For patients already on HFOV-sigh at study start:
• MAP-set will be left unchanged at pre-trial settings.
For patients on HFOV-only at study start:
• During periods with superimposed sigh breaths, MAP-set will be reduced in accordance with a calculation of MAP aiming to keep average mean airway-pressure (MAP) unchanged. (MAP=(PIP*Tinsp+PEEP*Texp)/(Tinsp+Texp)
DURING HFOV-ONLY
For patients on HFOV-sigh at study start:
• During HFOV-only, the MAP-set will be increased in accordance with a calculation of MAP, aiming to keep average mean airway-pressure (MAP) unchanged.
For patients on HFOV-only at study start:
• MAP-set will be left unchanged at pre-trial settings.

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

Other

Estimated Enrollment

16

Start Date

August 2014

Completion Date

June 2018

Primary Completion Date

June 2018

Eligibility Criteria

        Inclusion Criteria:

          -  Infants at 24-36 weeks corrected gestational age

          -  Already ventilated with high frequency ventilation

          -  Requiring FiO2=21%-70% to maintain adequate oxygen saturation.

          -  Clinical stable

             o i.e. ventilated on current settings for more than just a few hours with stable but
             not necessarily normalized blood gases or transcutaneous values and oxygen
             requirement.

          -  Parent(s) or guardian able and willing to provide informed consent

        Exclusion Criteria:

          -  Major congenital cardiovascular or respiratory abnormalities.

          -  The attending neonatologist responsible for the baby considers one of the ventilation
             modes unsuitable for the infant.

          -  Poor skin integrity precluding use of transcutaneous monitoring.

          -  Lack of parental signed written informed consent.

          -  Parents under 18 years of age.
      

Gender

All

Ages

24 Weeks - 44 Weeks

Accepts Healthy Volunteers

No

Contacts

Christian Heiring, md, , 

Location Countries

Denmark

Location Countries

Denmark

Administrative Informations


NCT ID

NCT01959009

Organization ID

H-2-2012-167


Responsible Party

Principal Investigator

Study Sponsor

Rigshospitalet, Denmark


Study Sponsor

Christian Heiring, md, Principal Investigator, Rigshospitalet, Denmark


Verification Date

September 2017