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Project 4B: Lower Extremity Strength Training in ICU Patients

Primary Purpose

Sepsis

Status

Completed

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

Muscle stimulation with Niveus medical stimulator

measurement of maximal isometric twitch strength

Muscle Biopsy

Muscle Biopsy Medication: Lidocaine

Muscle Biopsy Medication: Versed

Muscle Biopsy Medication: Fentanyl

Blood and Urine Sampling

ineffective muscle stimulation

About this trial

This is an interventional treatment trial for Sepsis focused on measuring chronic critical illness, strength training, exercise, sepsis, mechanical ventilation

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria

Presence in the surgery or trauma ICU,
age of ≥18 years,
received MV for 3 day and expected to survive ICU stay,
ability to obtain informed consent from patient or legally authorized representative,
approval of an ICU attending for patient to participate.

Exclusion criteria

Have an uncontrollable source of sepsis (e.g., irreversible disease state, unresectable dead bowel),
are receiving "comfort care" or have advanced care directives limiting resuscitative efforts,
have an implanted electronic device (pacemaker/defibrillator/insulin pump, etc.)
have known HIV infection with CD4 count < 200 cells/mm3,
are organ transplant recipients on immunosuppressive agent(s),
have a known pregnancy,
history of stroke with weakness,
Inability to walk without assistance prior to ICU admission (excluding the use of cane or walker)
lower-extremity amputations, rheumatic or severe osteoarthritis of any joint in the lower extremity,
Unrepaired hip fracture, unstable cervical spine or other bone diseases
arterial or venous insufficiency in the lower extremity,
have prior arrangements to be transferred to other facilities before 28 days of treatment,
have an unstable or "difficult airway" at 14 days of ICU care, predicted to last for more than 72 hours,
are on vasopressor or vasodilatory agents as a continuous infusion at more than a "renal dose,"
have severe cardiac dysrhythmias,
have acute coronary syndrome,
have pulmonary contraindications (pneumo/hemothorax, flail chest),
have persistent surgical problems in the post-operative period (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,
have 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), and
Allergic to lidocaine
High risk of bleeding secondary to organic conditions or medication
Any anatomical difficulty obtaining biopsy (such a being very overweight)
CPR on admission
Full dose anticoagulation therapy (ex. Heparin infusion, full anticoagulation dose enoxaparin, Coumadin/Warfarin/Jantoven/Marevan/Waran, and Argatroban).
Patient on antiplatelet therapy and medicine such as Plavix (also known as Clopidogrel, Clopilet, and Ceruvin), Aggrenox (also known as aspirin with Dipyridamol), Ticlid (also known as ticlopidine), Agrylin or Xagrid (also known as Anagrelide). Of note, aspirin is not an exclusion criteria, as long as that is the only anti-platelet medication the patient is receiving. In addition, other non steroidal anti-inflammatory agents-NSAIDS (Ibuprofen, Naproxen, Indomethicin or other anti-inflammatories) are not a contraindication to the muscle biopsy procedure and
any other factor in the investigators' judgment that would unnecessarily increase the risk to the patient.

Sites / Locations

UF Health Shands Hospital at the University of Florida

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

effective muscle stimulation group

ineffective muscle stimulation group

Arm Description

Subjects in this arm will be in the study for up to 28 days or until discharge from the ICU. They will receive lower extremity muscle stimulation with Niveus medical stimulator, multiple measurement of maximal isometric twitch strength, muscle biopsy with muscle biopsy medication fentanyl, muscle biopsy medication versed, muscle biopsy medication lidocaine, and blood and urine sampling.

Subjects assigned to this arm will be studied for up to 28 days or until discharge and will receive a sham muscle stimulation with Niveus medical stimulator, multiple measurement of maximal isometric twitch strength blood and urine samples, and a muscle biopsy sample with muscle biopsy medication fentanyl, muscle biopsy medication versed, and muscle biopsy medication lidocaine.

Outcomes

Primary Outcome Measures

Isometric muscle twitch force measured at the start of the study, approximately every seven days thereafter and final day of study.

Measurement of maximal isometric strength will be done by using a dynamometer.

Change in inflammatory markers on days 1, 7, 14, 21, and 28.

blood and urine will be tested for the markers of inflammation. The following will be tested: (IL)-1β, IL-6, IL-8, IL-10, IL-12, (TNF)α, (IFN)γ, (MCP)-1, (IP)10, (SDF)-1, (MIP)1α, (HMG)B1, procalcitonin, and (CRP).

Change in immunosuppressive markers on days 1, 7, 14, 21, and 28.

blood and urine will be tested for the markers of immunosuppression. The following will be tested: MDSC phenotype (HLA-DRlow)

Secondary Outcome Measures

Measurement of key proteins of mitochondrial function using immunohistochemistry and Western blotting

Quadriceps muscle samples will be obtained with percutaneous biopsies following training. Muscle fiber cross-sectional area, myosin heavy chain composition, and changes in atrophy-specific proteins will be assessed using immunohistochemistry and Western blotting, respectively. High-resolution respirometry on permeabilized muscle fibers will be used to measure changes in mitochondrial O2 consumption and muscle bioenergetics. In addition, we will measure key proteins of mitochondrial function and biogenesis.

Full Information

NCT ID

NCT02467023

First Posted

May 19, 2015

Last Updated

January 17, 2018

Sponsor

University of Florida

Collaborators

National Institutes of Health (NIH), National Institute of General Medical Sciences (NIGMS)

1. Study Identification

Unique Protocol Identification Number

NCT02467023

Brief Title

Project 4B: Lower Extremity Strength Training in ICU Patients

Official Title

Persistent Inflammation, Immunosuppression and Catabolism Syndrome (PICS): A New Horizon for Surgical Critical Care: Project 4B: Lower Extremity Strength Training in ICU Patients

Study Type

Interventional

2. Study Status

Record Verification Date

January 2018

Overall Recruitment Status

Completed

Study Start Date

September 2015 (undefined)

Primary Completion Date

July 7, 2016 (Actual)

Study Completion Date

July 15, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Florida

Collaborators

National Institutes of Health (NIH), National Institute of General Medical Sciences (NIGMS)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this research study is to see if electrical stimulation of the leg muscles will improve strength in patients receiving mechanical ventilation in the intensive care unit (ICU). ICU care frequently results in chronically critically ill (CCI) patients. Some CCI patients develop persistent inflammation/immunosuppression and catabolism syndrome (PICS), and they have morbid long-term outcomes. CCI patients with PICS often develop severe limb muscle atrophy, weakness and accelerated protein catabolism. Limb muscle dysfunction in PICS is due to many factors including sepsis/inflammation, proteolysis, apoptosis, and inactivity. Despite the seriousness of limb muscle weakness in CCI patients receiving mechanical ventilation, little is known about exercise strategies to treat this problem. There is limited knowledge about how strength training impacts inflammation and catabolism in CCI patients. In addition, an assessment of the effect of exercise on markers of inflammation and protein catabolism on muscle samples obtained with biopsy techniques and venous blood samples will be performed. This project will further understanding of how treating CCI-related muscle weakness with strength training cannot only improve muscle function, but also potentially blunt the inflammation and catabolism of PICS.

Detailed Description

As a participant in the study, the following will take place: Assignment to study groups: a random assignment will be done to one of two groups by a list generated by a computer program, much like flipping a coin. One group of subjects will be assigned to an effective muscle stimulation group and the second group will be assigned to a group that will receive ineffective stimulation (Control or Sham). Muscle stimulation will be performed with a Niveus medical stimulator on both quadriceps muscle groups for 30 minutes, five days per week. The stimulator will be individually adjusted in terms of intensity of stimulation to elicit a visible or palpable quadriceps muscle contraction. Four contractions per minute will be performed for a total of approximately 120 contractions per 30 minute treatment. Isometric Muscle strength testing: All subjects will undergo isometric muscle strength testing. Maximal isometric twitch strength will be measured by placing the subjects' dominant leg in a frame that will hold the knee at 60°. A cuff will be placed around the patient's ankle and will be connected to an electronic dynamometer with the cable. A magnetic nerve stimulator will be used over the body of the quadriceps muscle to stimulate the muscle.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Sepsis

Keywords

chronic critical illness, strength training, exercise, sepsis, mechanical ventilation

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

5 (Actual)

8. Arms, Groups, and Interventions

Arm Title

effective muscle stimulation group

Arm Type

Experimental

Arm Description

Arm Title

ineffective muscle stimulation group

Arm Type

Active Comparator

Arm Description

Intervention Type

Device

Intervention Name(s)

Muscle stimulation with Niveus medical stimulator

Intervention Description

Subjects will be treated five days per week, for 30 minutes each session. Muscle stimulation will be conducted for four seconds every 15 seconds, thus the subjects will undergo four stimulations per minute. Muscle stimulation will be adjusted until there is a visible or palpable bilateral quadriceps contraction.

Intervention Type

Device

Intervention Name(s)

measurement of maximal isometric twitch strength

Intervention Description

Quadriceps strength will be measured on the initial day of study approximately every seven days thereafter and on the final day of study participation. For this measurement, patients will remain supine in their bed and the dominant leg will be placed on a frame that will hold the knee at a 60° angle. A cuff will be placed around the ankle and connected to an electronic dynamometer that will record the force generated during the stimulation. The muscle will be stimulated to contract with magnetic stimulators placed over the body of the quadriceps muscle and stimulated at 100% of power output.

Intervention Type

Procedure

Intervention Name(s)

Muscle Biopsy

Intervention Description

This procedure will be done at the end of participation in the study.The biopsy will be performed with a sterile needle, which will be inserted through the skin. A skin incision (approximately 1/4" long) will be made in order to insert the needle. The biopsy procedure yields two small pieces of muscle tissue (200 mg total), each about half the size of the eraser on a pencil. After the biopsy is taken, the incision will be closed using a steri-strip bandage (no stitches are required), and a sterile dressing will be placed over the site to reduce the risk of bleeding.

Intervention Type

Drug

Intervention Name(s)

Muscle Biopsy Medication: Lidocaine

Other Intervention Name(s)

Lidocaine for biopsy

Intervention Description

Biopsy samples will be obtained under local anesthesia (up to 20 milliliters of 1% Lidocaine administered subcutaneously). Lidocaine, a drug to numb your pain will be injected into the skin and muscle tissue. The injection of the numbing medication will be slightly painful and is similar to receiving a shot into your arm for a vaccination. This medication numbs the skin and muscle so that you do not feel pain when the biopsy is obtained.

Intervention Type

Drug

Intervention Name(s)

Muscle Biopsy Medication: Versed

Other Intervention Name(s)

Versed for biopsy

Intervention Description

Prior to starting the muscle biopsy, you can receive a drug, Versed, to help you relax during the procedure. 1-2 milligrams of Versed will be administered intravenously (in the vein) through an existing peripheral or central intravenous catheter. This procedure drug is given as needed and can be repeated one time as needed.

Intervention Type

Drug

Intervention Name(s)

Muscle Biopsy Medication: Fentanyl

Other Intervention Name(s)

Fentanyl for biopsy

Intervention Description

Prior to starting the muscle biopsy, you can receive a drug, Fentanyl, to make you more comfortable during the procedure. 50-100 micrograms of Fentanyl will be administered intravenously (in the vein) through an existing peripheral or central intravenous catheter. This procedure drug is given as needed and can be repeated one time as needed.

Intervention Type

Other

Intervention Name(s)

Blood and Urine Sampling

Intervention Description

Blood and urine samples will be obtained and examined for markers inflammation and muscle catabolism. Sampling will occur at time of entry into study, and then once every 2-4 days and on the final day of participation or the last day of study (day 28). Peripheral blood will be collected from an existing venous line, or by venipuncture, if required. Urine will be collected from an existing catheter or if the patient is able to void on their own then we will provide a specimen cup. There will be no more than 14 ml of blood drawn at any given time point and a collection of 15 ml of urine at each time point.

Intervention Type

Device

Intervention Name(s)

ineffective muscle stimulation

Intervention Description

An investigator will perform range of motion on both legs, five days per week. The range of motion activity will include the investigator helping you bend and straighten each knee approximately 12 times. Rotation of the leg at the hip will also be performed by bending your knee and gently rotating your upper leg in a clockwise and counterclockwise motion. The range of motion will be performed on each leg and repeated five days per week.

Primary Outcome Measure Information:

Title

Isometric muscle twitch force measured at the start of the study, approximately every seven days thereafter and final day of study.

Description

Measurement of maximal isometric strength will be done by using a dynamometer.

Time Frame

Change from days 1, 7, 14, 21, and 28

Title

Change in inflammatory markers on days 1, 7, 14, 21, and 28.

Description

Time Frame

Change from days 1, 7, 14, 21, and 28

Title

Change in immunosuppressive markers on days 1, 7, 14, 21, and 28.

Description

blood and urine will be tested for the markers of immunosuppression. The following will be tested: MDSC phenotype (HLA-DRlow)

Time Frame

Change from days 1, 7, 14, 21, and 28

Secondary Outcome Measure Information:

Title

Measurement of key proteins of mitochondrial function using immunohistochemistry and Western blotting

Description

Time Frame

Measurement on day 28

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion criteria Presence in the surgery or trauma ICU, age of ≥18 years, received MV for 3 day and expected to survive ICU stay, ability to obtain informed consent from patient or legally authorized representative, approval of an ICU attending for patient to participate. Exclusion criteria Have an uncontrollable source of sepsis (e.g., irreversible disease state, unresectable dead bowel), are receiving "comfort care" or have advanced care directives limiting resuscitative efforts, have an implanted electronic device (pacemaker/defibrillator/insulin pump, etc.) have known HIV infection with CD4 count < 200 cells/mm3, are organ transplant recipients on immunosuppressive agent(s), have a known pregnancy, history of stroke with weakness, Inability to walk without assistance prior to ICU admission (excluding the use of cane or walker) lower-extremity amputations, rheumatic or severe osteoarthritis of any joint in the lower extremity, Unrepaired hip fracture, unstable cervical spine or other bone diseases arterial or venous insufficiency in the lower extremity, have prior arrangements to be transferred to other facilities before 28 days of treatment, have an unstable or "difficult airway" at 14 days of ICU care, predicted to last for more than 72 hours, are on vasopressor or vasodilatory agents as a continuous infusion at more than a "renal dose," have severe cardiac dysrhythmias, have acute coronary syndrome, have pulmonary contraindications (pneumo/hemothorax, flail chest), have persistent surgical problems in the post-operative period (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, have 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), and Allergic to lidocaine High risk of bleeding secondary to organic conditions or medication Any anatomical difficulty obtaining biopsy (such a being very overweight) CPR on admission Full dose anticoagulation therapy (ex. Heparin infusion, full anticoagulation dose enoxaparin, Coumadin/Warfarin/Jantoven/Marevan/Waran, and Argatroban). Patient on antiplatelet therapy and medicine such as Plavix (also known as Clopidogrel, Clopilet, and Ceruvin), Aggrenox (also known as aspirin with Dipyridamol), Ticlid (also known as ticlopidine), Agrylin or Xagrid (also known as Anagrelide). Of note, aspirin is not an exclusion criteria, as long as that is the only anti-platelet medication the patient is receiving. In addition, other non steroidal anti-inflammatory agents-NSAIDS (Ibuprofen, Naproxen, Indomethicin or other anti-inflammatories) are not a contraindication to the muscle biopsy procedure and any other factor in the investigators' judgment that would unnecessarily increase the risk to the patient.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Daniel Martin, PhD, PT

Organizational Affiliation

University of Florida

Official's Role

Principal Investigator

Facility Information:

Facility Name

UF Health Shands Hospital at the University of Florida

City

Gainesville

State/Province

Florida

ZIP/Postal Code

32610

Country

United States

12. IPD Sharing Statement

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Project 4B: Lower Extremity Strength Training in ICU Patients

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