Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT01959009 |
| Other study ID # |
H-2-2012-167 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
August 2014 |
| Est. completion date |
June 2022 |
Study information
| Verified date |
October 2020 |
| Source |
Rigshospitalet, Denmark |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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.
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.
