Project 4A: Inspiratory Muscle Training and Diaphragm Strength

NCT02367170 | Terminated Phase 1 Results DMC

• 2 other identifiers: IRB201400889-NGM111152
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

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).

Conditions

Sepsis

Keywords

respiratory dysfunction; chronic critical illness; diaphragm weakness; sepsis; ventilator dependance

Outcome Measures

Primary Outcomes (1)

• A Change in Diaphragm Strength From Baseline as an Effect of Inspiratory Muscle Strength Training (IMST) Intervention and Sham Patients

  In this randomized, interventional study, 24 CCI patients will be assigned to either a sham group or to receive IMST for up to 28 days. Evaluation of diaphragm/inspiratory muscle strength and muscle thickness will be made with three techniques: 1) non-volitional magnetic stimulation of the phrenic nerves, 2) noninvasive measurement of diaphragm thickness with ultrasound and 3) the standard, clinical method of measuring maximal inspiratory pressure (MIP). Investigators hypothesize that IMST will lead to improvements in all three measures. This study will provide information about possible effective respiratory muscle rehabilitation techniques that are likely to lead to reduced time patients will require mechanical ventilation and improved MIP and weaning outcome in long-term, failure to wean patients

  Day 1, Day 3, Day 5, Day 7, Day 9, Day 11, Day 13, Day 14, Day 15, Day 17, Day 19, Day 21, Day 23, Day 25, Day 28

Secondary Outcomes (2)

• A Change in the Results of the Biomarkers of Inflammation From Baseline

  Day 1, Day 3, Day 5, Day 7, Day 9, Day 11, Day 13, Day 15, Day 17, Day 19, Day 21

• A Change in the Urinary Excretion Markers of Muscle Catabolism From Baseline

  Day 1, Day 3, Day 5, Day 7, Day 9, Day 11, Day 13, Day 15, Day 17, Day 19, Day 21

Study Arms (2)

IMST Intervention group

EXPERIMENTAL

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%.

Procedure: Bilateral phrenic nerve stimulation and measurement of transdiaphragmatic pressure; Drug: Midazolam; Procedure: Volitional Measurement of Maximal Inspiratory Pressure (MIP); Device: Inspiratory Muscle Strength Training (IMST); Procedure: Diaphragm thickness measurement; Other: Blood and Urine samples

SHAM group

SHAM COMPARATOR

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.

Procedure: Bilateral phrenic nerve stimulation and measurement of transdiaphragmatic pressure; Drug: Midazolam; Procedure: Volitional Measurement of Maximal Inspiratory Pressure (MIP); Device: SHAM Inspiratory Muscle Strength Training (IMST); Procedure: Diaphragm thickness measurement; Other: Blood and Urine samples

Interventions

Bilateral phrenic nerve stimulation and measurement of transdiaphragmatic pressure 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.

IMST Intervention group; SHAM group

Midazolam 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.

Also known as: Versed

IMST Intervention group; SHAM group

Volitional Measurement of Maximal Inspiratory Pressure (MIP) 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.

IMST Intervention group; SHAM group

Inspiratory Muscle Strength Training (IMST) 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.

IMST Intervention group

SHAM Inspiratory Muscle Strength Training (IMST) 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.

SHAM group

Diaphragm thickness measurement 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.

IMST Intervention group; SHAM group

Blood and Urine samples 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).

IMST Intervention group; SHAM group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Florida: lead
• National Institute of General Medical Sciences (NIGMS): collaborator

Study Sites (1)

UF Health Shands Hospital at the University of Florida

Gainesville, Florida, 32610, United States

Location

MeSH Terms

Conditions

Sepsis; Dyspnea

Interventions

Midazolam; Blood Specimen Collection

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Respiration Disorders; Respiratory Tract Diseases; Signs and Symptoms, Respiratory; Signs and Symptoms

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Results Point of Contact

• Title: PhD in exercise physiology
• Organization: University of Florida

UFCT-gov@ufl.edu

352 2736105

Study Officials

• Daniel Martin, Ph.D., PT

  University of Florida

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 21, 2015
• First Posted: February 20, 2015
• Study Start: March 1, 2015
• Primary Completion: July 1, 2015
• Study Completion: July 1, 2015
• Last Updated: May 7, 2018
• Results First Posted: January 26, 2017

Record last verified: 2018-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)