Effect of Diaphragm Stimulation During Surgery

Mechanical Ventilation Complication Clinical Trial

Official title:

The Effect of Intermittent Hemidiaphragm Stimulation During Surgery on Mitochondrial Function, Single Fiber Contractile Force and Catabolic Pathways in Humans

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03303040
• Other study ID #: IRB201602186-N
• Secondary ID: R01AR072328
• Status: Active, not recruiting
• Phase: N/A
• Start date: February 14, 2018
• Est. completion date: October 6, 2023

Study information

• Verified date: June 2023
• Source: University of Florida
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 58
• Est. completion date: October 6, 2023
• Est. primary completion date: May 31, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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,

Related Conditions & MeSH terms

• Diaphragm Injury
• Mechanical Ventilation Complication

Intervention

Other:
• Electrical stimulation of hemidiaphragm
Electrical impulses

Locations

Country	Name	City	State
United States	University of Florida	Gainesville	Florida

Sponsors (4)

Lead Sponsor	Collaborator
University of Florida	National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), University of Arizona

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mitochondrial respiration	High-resolution respirometry will be used to assess mitochondrial respiration. It will be quantified as pmol oxygen/sec/mg wet weight.	Up to eight hours
Primary	Mitochondrial reactive oxygen species production	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.	Up to eight hours
Primary	Mitochondrial DNA mutation frequency	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.	Up to eight hours
Primary	Nuclear DNA mutation frequency	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.	Up to eight hours
Primary	Aconitase activity	In order to evaluate mitochondrial damage, actonitase activity will be measured spectrophotometrically. It will be quantified as units/mg protein.	Up to eight hours
Primary	Lipid peroxidation	Lipid peroxidation will be assessed by measuring 4-hydroxy-2-nonenal-modified proteins. It will be quantified as arbitrary optical density units.	Up to eight hours
Primary	Citrate cynthase activity	Changes in electron transport chain will be assessed by measuring citrate cynthase activity. It will be quantifed as nmol/mg protein/min.	Up to eight hours
Primary	Cytochrome c oxidase (COX) activity	Changes in electron transport chain will be assessed by measuring cytochrome c oxidase (COX) activity. It will be quantifed as Units/mcg protein.	Up to eight hours
Primary	Single diaphragm fiber, specific force	Single diaphragm fiber mechanical force properties will be measured. Specific force is quantified as kN/m^2.	Up to eight hours
Primary	Single diaphragm fiber, rate of tension redevelopment	Single diaphragm fiber mechanical force properties will be measured. The rate of tension redevelopment is quantified as s^(-1).	Up to eight hours
Primary	Single diaphragm fiber, maximum shortening velocity	Single diaphragm fiber mechanical force properties will be measured. The maximum shortening velocity is quantified as mm/s..	Up to eight hours
Primary	Titin size	Titin integrity will be assessed. A relative titin size will be quantified in nm.	Up to eight hours
Primary	Total titin to myosin heavy chain ratio	Titin integrity will be assessed. The total titin to myosin heavy chain ratio will be presented as a unitless value.	Up to eight hours
Primary	Titin exon composition	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.	Up to eight hours
Primary	Titin binding proteins	Titin binding proteins will be assessed and quantified via real-time polymerase chain reaction (qPCR). It will be presented as percent change in expression.	Up to eight hours
Primary	Calpain 1	Calpain 1 will be measured with Western Blot anaylsis and will be presented as percent difference in expression.	Up to eight hours
Primary	Calpain 2	Calpain 2 will be measured with Western Blot anaylsis and will be presented as percent difference in expression.	Up to eight hours
Primary	Calpain 3	Calpain 3 will be measured with Western Blot anaylsis and will be presented as percent difference in expression.	Up to eight hours
Primary	Caspase-3	Caspase-3 will be measured with Western Blot anaylsis and will be presented as percent difference in expression.	Up to eight hours
Primary	Caspase-9	Caspase-9 will be measured with Western Blot anaylsis and will be presented as percent difference in expression.	Up to eight hours
Primary	20S proteasome	20S proteasome will be measured with Western Blot anaylsis and will be presented as percent difference in expression.	Up to eight hours
Primary	26S proteasome	26S proteasome will be measured with Western Blot anaylsis and will be presented as percent difference in expression.	Up to eight hours
Primary	MurF1	MurF1 will be measured with Western Blot anaylsis and will be presented as percent difference in expression.	Up to eight hours
Primary	Atrogin 1	Atrogin 1 will be measured with Western Blot anaylsis and will be presented as percent difference in expression.	Up to eight hours
Primary	Foxo-3	Foxo-3 will be measured with Western Blot anaylsis and will be presented as percent difference in expression.	Up to eight hours
Primary	28SrRNA	28SrRNA will be measured with Western Blot anaylsis and will be presented as percent difference in expression.	Up to eight hours
Primary	18SrRNA	18SrRNA will be measured with Western Blot anaylsis and will be presented as percent difference in expression.	Up to eight hours
Primary	45S pre-rRNA	45S pre-rRNA will be measured with Western Blot anaylsis and will be presented as percent difference in expression.	Up to eight hours