Clinical trial NCT03303040: Effect of Diaphragm Stimulation During Surgery
Official title: The Effect of Intermittent Hemidiaphragm Stimulation During Surgery on Mitochondrial Function, Single Fiber Contractile Force and Catabolic Pathways in Humans
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Mechanical Ventilation Complication
Diaphragm Injury
Keywords: Mechanical ventilation
Diaphragm weakness
Difficulty weaning from mechanical ventilation
Diaphragm stimulation
Lead sponsor: University of Florida
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: University of Arizona
name: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
First posted: 2017-10-05
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: PREVENTION

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.

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.

Eligibility 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,

Primary outcomes:
measure: Mitochondrial Respiration
timeFrame: Up to eight hours
measure: Aconitase Activity
timeFrame: Up to eight hours
measure: Lipid Peroxidation
timeFrame: Up to eight hours
measure: Citrate Cynthase Activity
timeFrame: Up to eight hours
measure: Single Diaphragm Fiber, Specific Force
timeFrame: Up to eight hours
measure: Single Diaphragm Fiber, Rate of Tension Redevelopment
timeFrame: Up to eight hours
measure: Calcium Sensitivity (pCa50)
timeFrame: Up to eight hours
measure: Difference in Total Titin to Myosin Heavy Chain Ratio
timeFrame: Up to eight hours
measure: Difference in Titin Exon Composition
timeFrame: Up to eight hours
measure: Difference in Titin Binding Protein Content
timeFrame: Up to eight hours
measure: Difference in Calpain 1 Protein Content
timeFrame: Up to eight hours
measure: Difference in Calpain 2 Protein Content
timeFrame: Up to eight hours
measure: Difference in Calpain 3 Protein Content
timeFrame: Up to eight hours
measure: Difference in Caspase-3 Protein Content
timeFrame: Up to eight hours
measure: Atrogin 1
timeFrame: Up to eight hours
Secondary outcomes:
Other outcomes:
measure: Mitochondrial Reactive Oxygen Species Production
timeFrame: Up to eight hours
measure: Cytochrome c Oxidase (COX) Activity
timeFrame: Up to eight hours
measure: Nuclear DNA Mutation Frequency
timeFrame: Up to eight hours
measure: Titin Size
timeFrame: Up to eight hours
measure: Caspase-9
timeFrame: Up to eight hours
measure: 20S Proteasome
timeFrame: Up to eight hours
measure: 26S Proteasome
timeFrame: Up to eight hours
measure: 28SrRNA
timeFrame: Up to eight hours
measure: 18SrRNA
timeFrame: Up to eight hours
measure: Foxo-3
timeFrame: Up to eight hours
measure: 45S Pre-rRNA
timeFrame: Up to eight hours
measure: Mitochondrial DNA Mutation Frequency
timeFrame: Up to eight hours
measure: MurF1
timeFrame: Up to eight hours
Locations:
city: Gainesville
country: United States
facility: University of Florida
state: Florida
Study officials:
affiliation: University of Florida
name: Anatole D Martin, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Florida
name: Thomas M Beaver, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Florida
name: Barbara Smith, PhD, PT
role: PRINCIPAL_INVESTIGATOR
References: