A Randomized, Sham Controlled, Double-blinded, Multi-center Trial to Evaluate the Efficacy of the VentFree Respiratory Muscle Stimulator to Assist Ventilator Weaning in Critically Ill Patients

Mechanical ventilation is used as a life-saving intervention for conditions
such as acute respiratory failure, coma, and acute exacerbation of COPD.
Unfortunately, mechanical ventilation can also cause life-threatening
complications including barotrauma, ventilator associated pneumonia, muscle
atrophy and psychological conditions. The probability of survival decreases in
line with number of days of ventilator support. Hospital mortality is almost
double in those patients who take more than 7 days to wean from ventilator
support when compared to patients who require less. Furthermore, prolonged
periods in the ICU result in reduced functional status and increased mortality
up to one year after discharge.

In the US, the number of patients requiring mechanical ventilation for more
than four days (i.e. prolonged mechanical ventilation) is rising at a rate of
5.5% per year - a rate that is more than four times greater than the overall
increase in hospitalizations (1.2%). Patients who require prolonged mechanical
ventilation require more than double the resources needed than patients who
require short term mechanical ventilation (approximately $55,000 vs $22,000)
and are estimated to cost the US health care system $30 billion per year.
Accordingly, treatments aimed at reducing the duration of mechanical
ventilation have the potential to benefit patients, by reducing morbidity and
mortality and improving quality of life, and to benefit society, by reducing
ICU, inpatient and community health care costs.

After the pathology responsible for the institution of mechanical ventilation
has resolved and when patients are clinically stable, the current standard of
care is to conduct a weaning trial, consisting of a period of completely
unsupported breathing (e.g. T-tube trial) or a period of minimal ventilator
support (e.g. pressure support ventilation, or PSV). If the patient does well
during the weaning trial he/she can be considered for extubation; otherwise,
the patient is returned to the ventilator. When patients do not pass the first
weaning trial then either daily spontaneous breathing trials (SBT) or a gradual
reduction in PSV is implemented. The rationale of these strategies is to
recondition the respiratory muscles weakened during the preceding pre-weaning
period of mechanical ventilation. The duration of mechanical ventilation for
patients who do not pass the initial weaning trail can last between days and
months. In the most severe of cases, patients are never liberated from
mechanical ventilation. Therefore, novel interventions designed to reduce the
duration of mechanical ventilation are sorely needed.

Often, the initial clinical assessment to identify readiness to wean is
delayed, exposing patients to unnecessary discomfort of mechanical ventilation
and increased risk of ventilator-associated complications.

ICU acquired weakness is common among patients who receive mechanical
ventilation and primarily affects the respiratory and peripheral muscles. In
about 40% of patients, there is a rapid loss of diaphragm mass during the first
five days of mechanical ventilation, which results in a large reduction in its
force production. Similarly, approximately 30% of patients experience a rapid
loss of lateral abdominal muscle mass during the first week of mechanical
ventilation. As such, these patients experience considerable expiratory muscle
weakness.

Expiratory muscles play an important role in patients who have difficulty
weaning from mechanical ventilation. For example, maximum expiratory pressure
(MEP), the reference standard measure of expiratory muscle strength, is an
independent predictor of weaning success and delayed extubation. In addition,
an effective cough, which is dependent on expiratory muscle strength and
measured using cough peak flow (CPF), assists in the prediction of weaning
success, morbidity and mortality. Though the abdominal muscles are expiratory
muscles, their function also affects inspiration as they play an important role
in optimizing the neuromuscular coupling of the diaphragm, enhancing the
load-capacity balance of the muscle. Therefore, improvements in expiratory
muscle strength have the potential to reduce the duration of mechanical
ventilation and increase the probability of successful liberation from it.

Inspiratory muscle training using a threshold loading device is currently the
only available therapy that targets respiratory muscle atrophy in mechanically
ventilated patients. It has been shown to improve inspiratory muscle strength
and weaning success in patients who have otherwise failed to wean from
mechanical ventilation. Unfortunately, inspiratory muscle training depends on
patient motivation and cooperation. Therefore, this volitional technique is
often not suitable for use in the ICU, where patients are commonly sedated,
delirious, paralyzed, or cognitively impaired. Transvenous phrenic nerve pacing
is currently being studied as potential intervention for improving diaphragm
strength in difficult-to-wean patients (NCT03096639) and could be utilized in
sedated patients. Unfortunately, there are currently no available therapies
that target expiratory muscle atrophy in mechanically ventilated patients.

Neuromuscular electrical stimulation (NMES) applies small electrical pulses to
the motor nerves supplying a muscle to elicit a contraction. NMES of the
proximal muscles can preserve muscle mass and strength. When NMES is applied to
the abdominal wall muscles in synchrony with exhalation (so called abdominal
functional electrical stimulation [FES]), the effect on ventilation is like a
physiological contraction of the abdominal wall muscles. An important advantage
of using FES with critically ill patients is that it can be used to recruit the
abdominal wall muscles in the absence of patients* voluntary or automatic
recruitment of those muscles.

Previous studies have shown that abdominal FES can acutely improve respiratory
function and provide a training effect to the respiratory system. When used
over a period of time, the repeated application of abdominal FES results in a
lasting improvement in unassisted (i.e., without abdominal FES) forced vital
capacity (FVC), forced exhaled volume in one second (FEV1), peak expiratory
flow (PEF), and MEP. In a pilot study including 11 mechanically ventilated
patients with tetraplegia, a training program of abdominal FES increased tidal
volume and reduced weaning duration (compared with historical controls).

We propose to investigate FES of the abdominal wall muscles in synchrony with
the expiratory phase of breathing in patients requiring mechanical ventilation.
This intervention, also referred to as abdominal functional electrical
stimulation (or FES), was recently commercialized into a novel medical device
called the VentFree Respiratory Muscle Stimulator (Liberate Medical, LLC).

The primary objective of the trial is to determine whether abdominal FES
reduces the duration of invasive mechanical ventilation in critically ill adult
patients compared to a sham control.

The secondary objectives are to determine whether abdominal FES increases the
strength of the respiratory muscles, improves quality of life after discharge
and reduces reintubations, hospital acquired infections, hospital and ICU
length of stay and 90-day readmissions.

This is a randomized, sham controlled, double-blind multicenter global clinical
trial to evaluate exhalation synchronized abdominal FES in critically ill
invasively ventilated patients. Eligible participants will be randomized 1:1 to
the VentFree Respiratory Muscle Stimulator or a sham treatment. FES or sham
treatment will be applied as an adjunct to standard of care.

All participants will receive exhalation synchronized abdominal FES for 30
minutes twice per day, for a minimum of five days per week, for 28 days or
Intensive Care Unit (ICU) discharge, whichever comes first. In the VentFree
treatment group, FES will be applied with a frequency of 30 Hz and a pulse
width of 350 µs. The stimulation amplitude will be set to 90% of the
participant*s maximum tolerable level. The sham group will receive FES applied
with the same frequency and pulse width as the VentFree treatment group, but
with a stimulation amplitude set at 10 mA or less so that no muscle contraction
is seen.

Potential risks associated with VentFree Respiratory Muscle Stimulator include:
skin irritation, muscle soreness, temporary increase in the work of breathing,
electrical shock, ventilator asynchrony, respiratory muscle injury or fatigue,
and electrode burns. Potential risks to VentFree operators include electrical
shock.

Participants in the VentFree pilot studies experienced the following
non-serious adverse events that were possibly related to the intervention with
VentFree: increased MAP, increased respiratory rate and heart rate, decreased
oxygen saturation, and discomfort. Participant discomfort was additionally
reported twice in one patient and was considered to be definitely related to
VentFree. None of these adverse events resulted in injury to the participant.

As with all investigational medical devices, the long-term results of using the
VentFree Respiratory Muscle Stimulator are not known at the present time.

Exhalation synchronized abdominal stimulation could be a safe and effective
method of improving respiratory function in mechanically ventilated patients
and reducing mechanical ventilation duration and dependency. Previous research
has demonstrated the feasibility and safety of this intervention in the
critically ill patient. Furthermore, the patient will be monitored continuously
in a controlled ICU environment and FES will be performed by a researcher
experienced with this technique. Therefore, potential risks can be identified
early and anticipated upon early, if necessary. The burden to participation is
considered minimal especially since we are studying a potential treatment
effect and patients with contra-indications / high risks for FES will be
excluded from participation (see exclusion criteria).

Risks associated with participation in the clinical investigation include loss
of confidentiality. All protected health information will be secured to the
extent possible according to applicable law.

It is not anticipated that there will be any interactions with concomitant
medical treatments.