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Trial record 1 of 1 for:    NCT03303040
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Effect of Diaphragm Stimulation During Surgery

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03303040
Recruitment Status : Active, not recruiting
First Posted : October 5, 2017
Last Update Posted : June 30, 2022
Sponsor:
Collaborators:
National Institutes of Health (NIH)
University of Arizona
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Information provided by (Responsible Party):
University of Florida

Brief Summary:

During major surgical procedures general anesthesia is used to make the patient unconscious. General anesthesia insures that the patient is unaware of any pain caused by surgery. General anesthesia also prevents the patient from moving to prevent any potential surgical error. At the same time general anesthesia makes it impossible for the patient to breathe. To help the patient breathe a breathing tube is placed into the patient's airway and connected to the mechanical ventilator. A mechanical ventilator is an artificial breathing pump, which delivers gas into a patient's airways.

The purpose of this research study is to determine if brief periods of diaphragm stimulation can prevent diaphragm problems caused by the use of mechanical ventilators and surgery. To answer this question the changes in the genes responsible for maintaining diaphragm function will be studied. A gene is the code present in each cell in your body and controls the behavior of that cell. In addition, the changes in the contractile properties of muscle fibers will be studied. The results from this study may help develop new treatments to prevent diaphragm weakness resulting from mechanical ventilation use.


Condition or disease Intervention/treatment Phase
Mechanical Ventilation Complication Diaphragm Injury Other: Electrical stimulation of hemidiaphragm Not Applicable

Detailed Description:

Although mechanical ventilation (MV) is life-sustaining, it comes with a cost. MV dramatically reduces diaphragm contractility, induces ventilator-induced diaphragm dysfunction (VIDD) and sometimes leads to weaning failure. VIDD includes reduced mitochondrial respiration and increased oxidative stress, muscle fiber damage and decreased diaphragm force production.

In animal models, intermittent diaphragm contraction during MV support attenuates VIDD. However, there are only limited data addressing this problem in humans. Here, the study team propose to directly test the hypothesis that intermittent electrical stimulation (ES) of the human hemidiaphragm during prolonged cardiac surgeries with MV support prevents/attenuates VIDD in the active hemidiaphragm. Mitochondrial function is central to energy metabolism and skeletal muscle function in a chronically active muscle, such as the diaphragm. Although abnormal mitochondrial function is thought to precipitate VIDD in animal models, limited data are available concerning mitochondrial contributions to VIDD in humans. Of even greater importance, there are no interventions available to attenuate these defects in humans. Here, the study team will test the impact of an innovative experimental treatment, intermittent electrical stimulation (ES) of the hemidiaphragm during prolonged surgeries with MV, on mitochondrial function, single fiber contractile properties and catabolic muscle pathways in human diaphragm. Using a within-subjects experimental design, muscle samples from a stimulated hemidiaphragms will be compared with samples from the unstimulated hemidiaphragm. The study team will investigate mitochondrial dysfunction and oxidative stress during prolonged CTS/MV, and the potential of ES to attenuate or prevent VIDD. Next, the study team will investigate the effects of ES on single fiber contractile properties and Titin integrity. Finally, the study team will study the effect of ES on proteolytic pathways (caspase, calpain and ubiquitin-proteasome) and ribosomal RNA markers of decreased protein synthesis implicated in VIDD.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 58 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This is a within subjects design. One side of each subject's diaphragm will be stimulated. The other side of the subject's diaphragm will not be stimulated and will therefore serve as the control. Biopsies will be taken from both sides and compared.
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: The Effect of Intermittent Hemidiaphragm Stimulation During Surgery on Mitochondrial Function, Single Fiber Contractile Force and Catabolic Pathways in Humans
Actual Study Start Date : February 14, 2018
Actual Primary Completion Date : May 31, 2022
Estimated Study Completion Date : April 6, 2023

Arm Intervention/treatment
Experimental: Stimulation
Electrical stimulation of hemidiaphragm
Other: Electrical stimulation of hemidiaphragm
Electrical impulses

No Intervention: Control
No stimulation of hemidiaphragm



Primary Outcome Measures :
  1. Mitochondrial respiration [ Time Frame: Up to eight hours ]
    High-resolution respirometry will be used to assess mitochondrial respiration. It will be quantified as pmol oxygen/sec/mg wet weight.

  2. Mitochondrial reactive oxygen species production [ Time Frame: Up to eight hours ]
    Mitochondrial reactive oxygen species (ROS) production will be assessed using an in situ approach to measure hydrogen peroxide production in permeabilized diaphragm skeletal muscle fiber bundles. It will be quantified as pmol/min/mg dry weight.

  3. Mitochondrial DNA mutation frequency [ Time Frame: Up to eight hours ]
    Long-Amplicon quantitative PCR will be used to measure the frequency of mitochondrial DNA mutations. It will be quantified as number of lesions/10 kilobases.

  4. Nuclear DNA mutation frequency [ Time Frame: Up to eight hours ]
    Long-Amplicon quantitative PCR will be used to measure the frequency of nuclear DNA mutations. It will be quantified as number of lesions/10 kilobases.

  5. Aconitase activity [ Time Frame: Up to eight hours ]
    In order to evaluate mitochondrial damage, actonitase activity will be measured spectrophotometrically. It will be quantified as units/mg protein.

  6. Lipid peroxidation [ Time Frame: Up to eight hours ]
    Lipid peroxidation will be assessed by measuring 4-hydroxy-2-nonenal-modified proteins. It will be quantified as arbitrary optical density units.

  7. Citrate cynthase activity [ Time Frame: Up to eight hours ]
    Changes in electron transport chain will be assessed by measuring citrate cynthase activity. It will be quantifed as nmol/mg protein/min.

  8. Cytochrome c oxidase (COX) activity [ Time Frame: Up to eight hours ]
    Changes in electron transport chain will be assessed by measuring cytochrome c oxidase (COX) activity. It will be quantifed as Units/mcg protein.

  9. Single diaphragm fiber, specific force [ Time Frame: Up to eight hours ]
    Single diaphragm fiber mechanical force properties will be measured. Specific force is quantified as kN/m^2.

  10. Single diaphragm fiber, rate of tension redevelopment [ Time Frame: Up to eight hours ]
    Single diaphragm fiber mechanical force properties will be measured. The rate of tension redevelopment is quantified as s^(-1).

  11. Single diaphragm fiber, maximum shortening velocity [ Time Frame: Up to eight hours ]
    Single diaphragm fiber mechanical force properties will be measured. The maximum shortening velocity is quantified as mm/s..

  12. Titin size [ Time Frame: Up to eight hours ]
    Titin integrity will be assessed. A relative titin size will be quantified in nm.

  13. Total titin to myosin heavy chain ratio [ Time Frame: Up to eight hours ]
    Titin integrity will be assessed. The total titin to myosin heavy chain ratio will be presented as a unitless value.

  14. Titin exon composition [ Time Frame: Up to eight hours ]

    The composition of titin exons will be assessed and quantified via real-time polymerase chain reaction (qPCR). It will be presented as percent change in expression.

    as a percent change in expression.


  15. Titin binding proteins [ Time Frame: Up to eight hours ]
    Titin binding proteins will be assessed and quantified via real-time polymerase chain reaction (qPCR). It will be presented as percent change in expression.

  16. Calpain 1 [ Time Frame: Up to eight hours ]
    Calpain 1 will be measured with Western Blot anaylsis and will be presented as percent difference in expression.

  17. Calpain 2 [ Time Frame: Up to eight hours ]
    Calpain 2 will be measured with Western Blot anaylsis and will be presented as percent difference in expression.

  18. Calpain 3 [ Time Frame: Up to eight hours ]
    Calpain 3 will be measured with Western Blot anaylsis and will be presented as percent difference in expression.

  19. Caspase-3 [ Time Frame: Up to eight hours ]
    Caspase-3 will be measured with Western Blot anaylsis and will be presented as percent difference in expression.

  20. Caspase-9 [ Time Frame: Up to eight hours ]
    Caspase-9 will be measured with Western Blot anaylsis and will be presented as percent difference in expression.

  21. 20S proteasome [ Time Frame: Up to eight hours ]
    20S proteasome will be measured with Western Blot anaylsis and will be presented as percent difference in expression.

  22. 26S proteasome [ Time Frame: Up to eight hours ]
    26S proteasome will be measured with Western Blot anaylsis and will be presented as percent difference in expression.

  23. MurF1 [ Time Frame: Up to eight hours ]
    MurF1 will be measured with Western Blot anaylsis and will be presented as percent difference in expression.

  24. Atrogin 1 [ Time Frame: Up to eight hours ]
    Atrogin 1 will be measured with Western Blot anaylsis and will be presented as percent difference in expression.

  25. Foxo-3 [ Time Frame: Up to eight hours ]
    Foxo-3 will be measured with Western Blot anaylsis and will be presented as percent difference in expression.

  26. 28SrRNA [ Time Frame: Up to eight hours ]
    28SrRNA will be measured with Western Blot anaylsis and will be presented as percent difference in expression.

  27. 18SrRNA [ Time Frame: Up to eight hours ]
    18SrRNA will be measured with Western Blot anaylsis and will be presented as percent difference in expression.

  28. 45S pre-rRNA [ Time Frame: Up to eight hours ]
    45S pre-rRNA will be measured with Western Blot anaylsis and will be presented as percent difference in expression.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Gender Based Eligibility:   Yes
Gender Eligibility Description:   12 females and 12 males (based on gender identity) will be recruited for the study
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients undergoing complex, elective prolonged surgeries, usually lasting 5-8 hours or longer, including lung transplants (e.g. valveoplasty, coronary artery bypass and/or aortic repairs)

Exclusion Criteria:

  • history of prior surgery to the diaphragm or pleura;
  • a diagnosis of COPD will be determined from a clinical history consistent with chronic bronchitis and/or emphysema, a long history of cigarette smoking, and pulmonary function tests consistent with irreversible airflow obstruction (FEV1 < 40% predicted, according to European Respiratory Society criteria [will not apply to transplant patients]
  • a diagnosis of chronic heart failure (NYHA class IV)
  • clinical diagnosis of other lung disease (cystic fibrosis, bronchiectasis, lung cancer; etc.) [will not apply to transplant patients]
  • renal insufficiency (serum creatinine > 1.6 mg/dl);
  • severe hepatic disease (any liver function tests > 1.5 times the upper limit of normal);
  • undernourishment (body mass index < 20 kg/m2),
  • chronic uncontrolled or poorly controlled metabolic diseases (e.g., diabetes, hypo- or hyperthyroidism)
  • orthopedic diseases, suspected paraneoplastic or myopathic syndromes,
  • if in the surgeons' judgment the patients' clinical status warrants, diaphragm stimulation will be stopped and biopsies will not be obtained,

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03303040


Locations
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United States, Florida
University of Florida
Gainesville, Florida, United States, 32610
Sponsors and Collaborators
University of Florida
National Institutes of Health (NIH)
University of Arizona
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Investigators
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Principal Investigator: Anatole D Martin, PhD University of Florida
Principal Investigator: Thomas M Beaver, MD University of Florida
Principal Investigator: Barbara Smith, PhD, PT University of Florida
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Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT03303040    
Other Study ID Numbers: IRB201602186-N
R01AR072328 ( U.S. NIH Grant/Contract )
First Posted: October 5, 2017    Key Record Dates
Last Update Posted: June 30, 2022
Last Verified: June 2022

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of Florida:
Mechanical ventilation
Diaphragm weakness
Difficulty weaning from mechanical ventilation
Diaphragm stimulation