Effect of Diaphragm Stimulation During Surgery

June 13, 2024 updated by: University of Florida

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

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
25

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Florida
      • Gainesville, Florida, United States, 32610
        • University of Florida

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 85 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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,

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Stimulation
Electrical stimulation of hemidiaphragm
Other: Electrical stimulation of hemidiaphragm
Electrical impulses
No Intervention: Control
No stimulation of hemidiaphragm

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Mitochondrial Respiration
Time Frame: Up to eight hours
High-resolution respirometry will be used to assess mitochondrial respiration of permeablilized diaphragm bundles. Addition of substrate medium to the Oroboros O2K respirometry instrument enables quantification of leak respiration and peak uncoupled respiration, expressed as pmol oxygen/sec/mg wet weight.
Up to eight hours
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.
Up to eight hours
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.
Up to eight hours
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 quantified as nmol/mg protein/min.
Up to eight hours
Single Diaphragm Fiber, Specific Force
Time Frame: Up to eight hours
Specific force of single diaphragm fibers represents the force generated per unit area.
Up to eight hours
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).
Up to eight hours
Calcium Sensitivity (pCa50)
Time Frame: Up to eight hours
The pCa50 value is the logarithmic scale of pCa (sensitivity of Ca+2) at which half-maximal force generation was obtained. The pCa value is calculated as the -log10[Ca (nm)]; the pCa50 is the -log10[Ca (nm)] at which half-maximal force is generated.
Up to eight hours
Difference in Total Titin to Myosin Heavy Chain Ratio
Time Frame: Up to eight hours
The quantities of total titin protein and myosin heavy chain protein content in homogenized diaphragm fiber specimens were measured and then calculated as a ratio of total titin to myosin heavy chain content (unitless value). The statistical approach was selected apriori as the difference of the ratio between the stimulated and unstimulated sides.
Up to eight hours
Difference in Titin Binding Protein Content
Time Frame: Up to eight hours
The content of titin binding proteins will be quantified via Western blot. It will be normalized to a reference protein (GAPDH) and presented as optical intensity (AU).
Up to eight hours
Difference in Calpain 1 Protein Content
Time Frame: Up to eight hours
Calpain 1 (mu-calpain) will be measured with Western Blot analysis and will be presented as percent of total intensity in stimulated and unstimulated hemidiaphragms
Up to eight hours
Difference in Calpain 2 Protein Content
Time Frame: Up to eight hours
Calpain 2 will be measured with automated, capillary-based immunoassay using a Jess System, normalized to total protein, and will be presented as an area of corrected peak (AU) in stimulated and unstimulated hemidiaphragms.
Up to eight hours
Difference in Calpain 3 Protein Content
Time Frame: Up to eight hours
Calpain 3 will be measured with Western Blot analysis and will be presented as a ratio of cleaved to total calpain 3 (unitless value) in stimulated and unstimulated hemidiaphragms.
Up to eight hours
Difference in Caspase-3 Protein Content
Time Frame: Up to eight hours
Caspase-3 will be measured with Western Blot analysis, normalized to total protein loaded in each lane, and will be presented as an area of corrected peak (AU) in stimulated and unstimulated hemidiaphragm muscle fibers.
Up to eight hours
Atrogin 1
Time Frame: Up to eight hours
Atrogin 1 will be measured with Jess protein immunoassay analysis, normalized to total protein, and will be presented as the corrected peak area (AU) in stimulated and unstimulated hemidiaphragm muscle fibers.
Up to eight hours
Difference in 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). The N2A and tT2 will be calculated as a percentage of total titin.
Up to eight hours

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
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.
Up to eight hours
MurF1
Time Frame: Up to eight hours
MurF1 will be measured with Western Blot anaylsis and will be presented as percent difference in expression.
Up to eight hours
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.
Up to eight hours
28SrRNA
Time Frame: Up to eight hours
28SrRNA will be measured with Western Blot anaylsis and will be presented as percent difference in expression.
Up to eight hours
18SrRNA
Time Frame: Up to eight hours
18SrRNA will be measured with Western Blot anaylsis and will be presented as percent difference in expression.
Up to eight hours
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.
Up to eight hours
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.
Up to eight hours
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.
Up to eight hours
Titin Size
Time Frame: Up to eight hours
Titin integrity will be assessed. A relative titin size will be quantified in nm.
Up to eight hours
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.
Up to eight hours
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.
Up to eight hours
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.
Up to eight hours
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.
Up to eight hours

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University of Florida

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
National Institutes of Health (NIH)
University of Arizona

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • 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

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
February 14, 2018

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
May 31, 2022

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 31, 2023

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
September 26, 2017

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
October 4, 2017

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
October 5, 2017

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
June 26, 2024

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 13, 2024

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
June 1, 2024

More Information

Terms related to this study

Keywords

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • IRB201602186-N
  • R01AR072328 (U.S. NIH Grant/Contract)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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