Mechanical Ventilation ComplicationNCT03303040
Effect of Diaphragm Stimulation During Surgery
A study testing Electrical stimulation of hemidiaphragm in people with Mechanical Ventilation Complication and Diaphragm Injury, run by University of Florida at 1 site in United States.
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. Read more about this study
- Who is it for?
- Ages 18 to 85 years
- Conditions the study is for
- Mechanical Ventilation Complication, Diaphragm Injury
- What is being tested?
- Electrical stimulation of hemidiaphragm
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 25 participants
- Where
- 1 siteUnited States
- Study dates
- 14 Feb 2018to 31 Dec 2023
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 85 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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)
Who cannot join
- 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);
Show all 10Show fewer
- 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,
Trial locations and contacts
1 site in 1 country.
About this study
Official title: 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.
Read the 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.
- Being tested
- Electrical stimulation of hemidiaphragm
- Keywords
- Mechanical ventilation, Diaphragm weakness, Difficulty weaning from mechanical ventilation, Diaphragm stimulation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Electrical stimulation of hemidiaphragmOther
Electrical impulses
| Study group | Role | What they receive |
|---|---|---|
| Stimulation | Experimental | Electrical stimulation of hemidiaphragm Receives: Other: Electrical stimulation of hemidiaphragm |
| Control | No intervention | No stimulation of hemidiaphragm |
What is being measured
The primary outcome is the main question the study is designed to answer.
Mitochondrial Respiration
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.
Measured: Up to eight hours
Aconitase Activity
In order to evaluate mitochondrial damage, actonitase activity will be measured spectrophotometrically. It will be quantified as units/mg protein.
Measured: Up to eight hours
Lipid Peroxidation
Lipid peroxidation will be assessed by measuring 4-hydroxy-2-nonenal-modified proteins. It will be quantified as arbitrary optical density units.
Measured: Up to eight hours
Citrate Cynthase Activity
Changes in electron transport chain will be assessed by measuring citrate cynthase activity. It will be quantified as nmol/mg protein/min.
Measured: Up to eight hours
Single Diaphragm Fiber, Specific Force
Specific force of single diaphragm fibers represents the force generated per unit area.
Measured: Up to eight hours
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).
Measured: Up to eight hours
Calcium Sensitivity (pCa50)
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.
Measured: Up to eight hours
Difference in Total Titin to Myosin Heavy Chain Ratio
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.
Measured: Up to eight hours
Difference in Titin Exon Composition
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.
Measured: Up to eight hours
Difference in Titin Binding Protein Content
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).
Measured: Up to eight hours
Difference in Calpain 1 Protein Content
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
Measured: Up to eight hours
Difference in Calpain 2 Protein Content
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.
Measured: Up to eight hours
Difference in Calpain 3 Protein Content
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.
Measured: Up to eight hours
Difference in Caspase-3 Protein Content
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.
Measured: Up to eight hours
Atrogin 1
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.
Measured: Up to eight hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Oct 2017
- Study start14 Feb 2018
- Primary completion31 May 2022
- Study completion31 Dec 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Mechanical Ventilation ComplicationStudies of the same condition, open and under way.
- More trials run by University of FloridaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Prevention
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- 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)
- Enrolment
- 25 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Florida
- Sponsor type
- University, hospital or other
- Collaborators
- National Institutes of Health (NIH), University of Arizona, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
- Responsible party
- Sponsor
- Investigators
- Anatole D Martin, PhD, Principal investigator, University of FloridaThomas M Beaver, MD, Principal investigator, University of FloridaBarbara Smith, PhD, PT, Principal investigator, University of Florida
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03303040
- Sponsor's protocol ID
- IRB201602186-N
- Other IDs
- R01AR072328
- Status last verified
- Jun 2024
- First submitted
- 26 Sep 2017
- Last updated
- 26 Jun 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 26 Jun 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effect of Intermittent Hemidiaphragm Stimulation During Surgery on Mitochondrial Function, Single Fiber Contractile Force and Catabolic Pathways in Humans
- ClinicalTrials.gov ID
- NCT03303040
- Acronym / sponsor ID
- IRB201602186-N
- Keywords
- Mechanical ventilation, Diaphragm weakness, Difficulty weaning from mechanical ventilation, Diaphragm stimulation
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 25 participants (actual)
- Lead sponsor
- University of FloridaUniversity, hospital or other
- Collaborators
- National Institutes of Health (NIH), University of Arizona, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
- Study start
- 14 Feb 2018 (actual)
- Primary completion
- 31 May 2022 (actual)
- Study completion
- 31 Dec 2023 (actual)
- First posted
- 5 Oct 2017 (actual)
- Results
- Posted 30 May 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Prevention
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- 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.
| Arm | Type | Receives |
|---|---|---|
| Stimulation | Experimental | Other: Electrical stimulation of hemidiaphragmElectrical stimulation of hemidiaphragm |
| Control | No intervention | –No stimulation of hemidiaphragm |
Who may qualify
- Ages
- 18 to 85 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- 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)
Key exclusion criteria (10 listed)
- 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);
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Electrical stimulation of hemidiaphragmElectrical impulses | Other | Stimulation |
Primary outcome
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.
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.
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.
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.
Single Diaphragm Fiber, Specific Force
Time frame: Up to eight hours
Specific force of single diaphragm fibers represents the force generated per unit area.
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).
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.
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.
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.
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).
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
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.
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.
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.
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.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Jun 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Anatole D Martin, PhD principal investigator
University of Florida
Thomas M Beaver, MD principal investigator
University of Florida
Barbara Smith, PhD, PT principal investigator
University of Florida
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Electrical stimulation of hemidiaphragm in people with Mechanical Ventilation Complication and Diaphragm Injury, run by University of Florida at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 26 Jun 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 30 May 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Mitochondrial Respiration (time frame: Up to eight hours). The study lists 15 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Jun 2024.