Project 4A: Inspiratory Muscle Training and Diaphragm Strength

NCT ID: NCT02367170

Last Updated: 2018-05-07

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 1 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-03-31
• Study Completion Date: 2015-07-31

Brief Summary

Investigators will assess the effect of exercise on markers of inflammation and protein catabolism. This research study will further our understanding of how treating Chronic Critical illness (CCI) - related respiratory muscle weakness with strength training can not only improve muscle function, but also potentially blunt the inflammation and catabolism of Peristent Inflammation/Immunosuppression and Catabolism (PICS).

Detailed Description

In this research study, investigators will assign study participants to two groups: high intensity inspiratory muscle training and low intensity inspiratory muscle training group. This research study will last up to 28 days in 24 mechanically ventilated patients with CCI. The goal is to determine if the research participants can respond to a training program by improving weaning outcomes from the ventilator. This will be determined by measurement of breathing muscle strength with magnetic stimulation, measurement of diaphragm thickness with ultrasound, inspiratory muscle training, and blood and urine samples.

Conditions

Sepsis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: SINGLE

Study Groups

IMST Intervention group

IMST will be conducted 5 days per week by study staff using a threshold inspiratory muscle training device (Respironics model 735). Prior to training, the tracheal cuff pressure is assessed to ensure no air leakage and appropriate inflation. The IMST training takes approximately 15 minutes to complete. To perform IMST, FiO2 is increased for 2 minutes prior to each training bout to maintain oxygen saturation more than 92%.

Group Type: EXPERIMENTAL

Bilateral phrenic nerve stimulation and measurement of transdiaphragmatic pressure

Intervention Type: PROCEDURE

Pressure changes are recorded. The phrenic nerves are stimulated with bilateral magnetic stimulators over the neck. Measurements will be performed on day 1, every 7 days after and on last day of participation. The FiO2 will be increased (at least 20%) for at least 2 min. prior to measurement to maintain oxygen saturation \>92%. Prior to activating the stimulator, the artificial airway will be occluded with a pneumatic valve to create a quasi-isometric diaphragm contraction. The airway will be occluded for 3 seconds or less for each stimulation. The procedure will be repeated up to a maximum of 5 times per testing day.

Midazolam

Intervention Type: DRUG

In the event a subject shows signs of distress during the Bilateral phrenic nerve stimulation and measurement of transdiaphragmatic pressures, a dose of Midazolam is available. IV (in the vein) dose from 0.5 mg to 2 mg.

Volitional Measurement of Maximal Inspiratory Pressure (MIP)

Intervention Type: PROCEDURE

MIP is tested on all subjects on day 1, every 7 days after and on the last day of participation. To measure MIP, a subject will be suctioned, disconnected from the ventilator, and instructed to take a few spontaneous breaths. A 1-way exhalation valve connected to a NICO respiratory monitor will be placed on the ET/tracheotomy tube. The subject will be instructed to inhale and exhale as forcefully as possible for 20 seconds, followed by at least 2 minutes of rest on full mechanical ventilation support. MIP trials will be repeated 3 times, and the greatest negative pressure recorded with a NICO respiratory monitor connected to a laptop computer, which will digitize airway pressure, flow and volume signals at 100Hz. This allows for analysis of the individual pressure waves, facilitating pre-post comparisons of MIP at specific time points during inspiration.

Inspiratory Muscle Strength Training (IMST)

Intervention Type: DEVICE

Occurs 5 days/wk using threshold IMST device-Respironics model 735. Prior to training, cuff pressure is assessed, FiO2 increased for 2 min. to keep O2 sats ≥92%. The ventilator circuit is disconnected, IMST device is attached to endotracheal or tracheotomy tube and subject is instructed to exhale then forcefully inhale for 10 breaths. The initial setting of device is set to -5cmH2O, subject must generate a negative inspiratory pressure more negative than -5cmH2O to open spring-loaded valve and receive inspiratory airflow. Pressure setting is made more negative/difficult to open by 2-5cm every few breaths until a setting is found where the patient has difficulty fully opening valve, resulting in valve flutter noise. Training pressure is then made more positive /easier by 2-4cm of H2O, so subject can fully open valve, and 4 sets of 6-10 breaths are completed. Training pressures advanced as rapidly as possible, provided the patient is able to open the valve without"valve flutter"noise.

Diaphragm thickness measurement

Intervention Type: PROCEDURE

Ultrasound will be used to obtain measurements of the thickness of the right hemidiaphragm. Ultrasonography of the diaphragm will be performed upon enrollment, every 2-4 days during hospitalization and as long as the patient is hospitalized or up to 28 days of participation.

Blood and Urine samples

Intervention Type: OTHER

Peripheral blood and urine samples will be collected once upon study entry day (+/- 2 days), once every 2-4 days and once on final day of study participation (+/- 2days).

SHAM group

SHAM training will also be conducted five days per week with an identical training device that has been modified by removing the valve leaflet, which essentially removes all inspiratory loading by the device. The modified SHAM device makes a whistling sound during inspiration, which enhances the sham effect. For SHAM treatment, supplemental oxygen FiO2 will be increased for two minute prior to each bout.

Group Type: SHAM_COMPARATOR

Bilateral phrenic nerve stimulation and measurement of transdiaphragmatic pressure

Intervention Type: PROCEDURE

Pressure changes are recorded. The phrenic nerves are stimulated with bilateral magnetic stimulators over the neck. Measurements will be performed on day 1, every 7 days after and on last day of participation. The FiO2 will be increased (at least 20%) for at least 2 min. prior to measurement to maintain oxygen saturation \>92%. Prior to activating the stimulator, the artificial airway will be occluded with a pneumatic valve to create a quasi-isometric diaphragm contraction. The airway will be occluded for 3 seconds or less for each stimulation. The procedure will be repeated up to a maximum of 5 times per testing day.

Midazolam

Intervention Type: DRUG

In the event a subject shows signs of distress during the Bilateral phrenic nerve stimulation and measurement of transdiaphragmatic pressures, a dose of Midazolam is available. IV (in the vein) dose from 0.5 mg to 2 mg.

Volitional Measurement of Maximal Inspiratory Pressure (MIP)

Intervention Type: PROCEDURE

MIP is tested on all subjects on day 1, every 7 days after and on the last day of participation. To measure MIP, a subject will be suctioned, disconnected from the ventilator, and instructed to take a few spontaneous breaths. A 1-way exhalation valve connected to a NICO respiratory monitor will be placed on the ET/tracheotomy tube. The subject will be instructed to inhale and exhale as forcefully as possible for 20 seconds, followed by at least 2 minutes of rest on full mechanical ventilation support. MIP trials will be repeated 3 times, and the greatest negative pressure recorded with a NICO respiratory monitor connected to a laptop computer, which will digitize airway pressure, flow and volume signals at 100Hz. This allows for analysis of the individual pressure waves, facilitating pre-post comparisons of MIP at specific time points during inspiration.

SHAM Inspiratory Muscle Strength Training (IMST)

Intervention Type: DEVICE

Training will also be conducted 5 days/wk with an identical IMST device that has been modified by removing the valve leaflet, which essentially removes all inspiratory loading by the device. The modified SHAM IMST device makes a whistling sound during inspiration, which enhances the sham effect. For SHAM treatment, supplemental oxygen FiO2 will be increased for two minute prior to each bout. The ventilator will be disconnected and a SHAM device will be attached to the endotracheal or tracheostomy tube. The subject will be instructed to take 6-10 breaths with a normal tidal volume through the SHAM device and will be reconnected to the ventilator for a 2-minute rest period. The process will be repeated 3 more times for a total of 4 sets of 6-10 breaths.

Diaphragm thickness measurement

Intervention Type: PROCEDURE

Ultrasound will be used to obtain measurements of the thickness of the right hemidiaphragm. Ultrasonography of the diaphragm will be performed upon enrollment, every 2-4 days during hospitalization and as long as the patient is hospitalized or up to 28 days of participation.

Blood and Urine samples

Intervention Type: OTHER

Peripheral blood and urine samples will be collected once upon study entry day (+/- 2 days), once every 2-4 days and once on final day of study participation (+/- 2days).

Interventions

Bilateral phrenic nerve stimulation and measurement of transdiaphragmatic pressure

Pressure changes are recorded. The phrenic nerves are stimulated with bilateral magnetic stimulators over the neck. Measurements will be performed on day 1, every 7 days after and on last day of participation. The FiO2 will be increased (at least 20%) for at least 2 min. prior to measurement to maintain oxygen saturation \>92%. Prior to activating the stimulator, the artificial airway will be occluded with a pneumatic valve to create a quasi-isometric diaphragm contraction. The airway will be occluded for 3 seconds or less for each stimulation. The procedure will be repeated up to a maximum of 5 times per testing day.

Intervention Type: PROCEDURE

Midazolam

In the event a subject shows signs of distress during the Bilateral phrenic nerve stimulation and measurement of transdiaphragmatic pressures, a dose of Midazolam is available. IV (in the vein) dose from 0.5 mg to 2 mg.

Intervention Type: DRUG

Volitional Measurement of Maximal Inspiratory Pressure (MIP)

MIP is tested on all subjects on day 1, every 7 days after and on the last day of participation. To measure MIP, a subject will be suctioned, disconnected from the ventilator, and instructed to take a few spontaneous breaths. A 1-way exhalation valve connected to a NICO respiratory monitor will be placed on the ET/tracheotomy tube. The subject will be instructed to inhale and exhale as forcefully as possible for 20 seconds, followed by at least 2 minutes of rest on full mechanical ventilation support. MIP trials will be repeated 3 times, and the greatest negative pressure recorded with a NICO respiratory monitor connected to a laptop computer, which will digitize airway pressure, flow and volume signals at 100Hz. This allows for analysis of the individual pressure waves, facilitating pre-post comparisons of MIP at specific time points during inspiration.

Intervention Type: PROCEDURE

Inspiratory Muscle Strength Training (IMST)

Occurs 5 days/wk using threshold IMST device-Respironics model 735. Prior to training, cuff pressure is assessed, FiO2 increased for 2 min. to keep O2 sats ≥92%. The ventilator circuit is disconnected, IMST device is attached to endotracheal or tracheotomy tube and subject is instructed to exhale then forcefully inhale for 10 breaths. The initial setting of device is set to -5cmH2O, subject must generate a negative inspiratory pressure more negative than -5cmH2O to open spring-loaded valve and receive inspiratory airflow. Pressure setting is made more negative/difficult to open by 2-5cm every few breaths until a setting is found where the patient has difficulty fully opening valve, resulting in valve flutter noise. Training pressure is then made more positive /easier by 2-4cm of H2O, so subject can fully open valve, and 4 sets of 6-10 breaths are completed. Training pressures advanced as rapidly as possible, provided the patient is able to open the valve without"valve flutter"noise.

Intervention Type: DEVICE

SHAM Inspiratory Muscle Strength Training (IMST)

Training will also be conducted 5 days/wk with an identical IMST device that has been modified by removing the valve leaflet, which essentially removes all inspiratory loading by the device. The modified SHAM IMST device makes a whistling sound during inspiration, which enhances the sham effect. For SHAM treatment, supplemental oxygen FiO2 will be increased for two minute prior to each bout. The ventilator will be disconnected and a SHAM device will be attached to the endotracheal or tracheostomy tube. The subject will be instructed to take 6-10 breaths with a normal tidal volume through the SHAM device and will be reconnected to the ventilator for a 2-minute rest period. The process will be repeated 3 more times for a total of 4 sets of 6-10 breaths.

Intervention Type: DEVICE

Diaphragm thickness measurement

Ultrasound will be used to obtain measurements of the thickness of the right hemidiaphragm. Ultrasonography of the diaphragm will be performed upon enrollment, every 2-4 days during hospitalization and as long as the patient is hospitalized or up to 28 days of participation.

Intervention Type: PROCEDURE

Blood and Urine samples

Peripheral blood and urine samples will be collected once upon study entry day (+/- 2 days), once every 2-4 days and once on final day of study participation (+/- 2days).

Intervention Type: OTHER

Other Intervention Names

Versed

Eligibility Criteria

Inclusion Criteria

• presence in the surgical or trauma ICU
• age of ≥18 years
• received mechanical ventilation (MV) for 3 days and expected to survive ICU stay
• ability to obtain informed consent from patient or proxy

Exclusion Criteria

• Inability to speak and understand English
• Uncontrollable source of sepsis with imminent death (e.g., irreversible disease state, unresectable dead bowel)
• Receiving "comfort care only" or have advanced care directives limiting resuscitative efforts
• Known HIV infection with CD4 count < 200 cells/mm
• Organ transplant recipients on immunosuppressive agent(s),
• Known pregnancy
• Unable to follow simple, one-step commands, such as "breathe in as hard as you can!"
• Prior arrangements to be transferred to other facilities before 28 days of treatment
• Contraindications to being disconnected from MV for sham or inspiratory muscle strength training treatment
• Unstable or "difficult airway" at 3 days of ICU care defined by ICU protocol, predicted to last for more than 72 hours
• Ongoing use of vasopressor or vasodilatatory agents for unstable blood pressure. (beyond minimal intermittent amount or "renal perfusion dose,"
• Severe cardiac dysrhythmias
• Esophageal varices or recent esophageal or gastric surgery,
• Upper-airway issues that would be aggravated by inserting esophageal pressure transducers
• Unstable neck/cervical anatomy that might be adversely impacted by bilateral magnetic stimulation of phrenic nerves at the neck
• Acute coronary syndrome
• Pulmonary contraindications (pneumon/hemothorax not drained, flail chest)
• Cardiac pacemakers and/or implanted defibrillator or other implanted electronic devices interfering with magnetic stimulation
• Implanted metal in the chest, neck or head, making magnetic stimulation contraindicated (dental fillings are permitted)
• Postoperative severe surgical problems interfering with the respiratory training (serious postoperative bleeding, wound dehiscence, etc.) - when and if these problems resolve and the patient meets other entry criteria, they will be eligible to be recruited for participation
• Active neuromuscular diseases that would prevent or interfere with responding to strength training (e.g. amyotrophic lateral sclerosis, multiple sclerosis, myasthenia gravis, polymyositis, muscular dystrophy or other dystrophies and myopathies)
• Any other factor that in the investigators' opinions would prevent response to training or create an unsafe condition for the patient.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of General Medical Sciences (NIGMS)

NIH

Sponsor Role: collaborator

University of Florida

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Daniel Martin, Ph.D., PT

Role: PRINCIPAL_INVESTIGATOR

University of Florida

Locations

UF Health Shands Hospital at the University of Florida

Gainesville, Florida, United States

Countries

United States

Other Identifiers

GM111152

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

IRB201400889-N

Identifier Type: -

Identifier Source: org_study_id