Project 4A: Inspiratory Muscle Training and Diaphragm Strength

Phase 1

Terminated

Conditions: Sepsis

Interventions: 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)
Device: SHAM Inspiratory Muscle Strength Training (IMST)
Procedure: Diaphragm thickness measurement
Other: Blood and Urine samples

Registration Number: NCT02367170

Lead Sponsor: University of Florida

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 1

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
IMST Intervention group	Inspiratory Muscle Strength Training (IMST)	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%.
IMST Intervention group	Bilateral phrenic nerve stimulation and measurement of transdiaphragmatic pressure	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%.
IMST Intervention group	Volitional Measurement of Maximal Inspiratory Pressure (MIP)	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%.
SHAM group	Volitional Measurement of Maximal Inspiratory Pressure (MIP)	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.
IMST Intervention group	Blood and Urine samples	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%.
SHAM group	Diaphragm thickness measurement	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.
SHAM group	Blood and Urine samples	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.
IMST Intervention group	Diaphragm thickness measurement	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%.
SHAM group	Bilateral phrenic nerve stimulation and measurement of transdiaphragmatic pressure	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.
SHAM group	SHAM Inspiratory Muscle Strength Training (IMST)	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.
IMST Intervention group	Midazolam	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%.
SHAM group	Midazolam	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.

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
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	Investigators will determine the effects of IMST on biomarkers of inflammation in patients with CCI. Investigators hypothesize that exercise will decrease markers of inflammation compared to the SHAM condition.
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	Investigators will determine the effects of IMST on urinary excretion markers of muscle catabolism in patients with CCI. Investigators hypothesize that exercise will decrease urinary markers of catabolism compared to the SHAM condition.