<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04423614</url>
  </required_header>
  <id_info>
    <org_study_id>IRB202001038</org_study_id>
    <secondary_id>OCR35362</secondary_id>
    <nct_id>NCT04423614</nct_id>
  </id_info>
  <brief_title>Preoperative Inspiratory Muscle Training</brief_title>
  <official_title>Telehealth-Delivered Preoperative Inspiratory Muscle Training: An Innovative Solution to Conserve Scarce ICU Resources</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Florida</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Florida</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      In light of the corona virus pandemic (COVID-19), there is critical need to conserve scarce&#xD;
      mechanical ventilation (MV) resources. This study evaluates an intervention in non-infected&#xD;
      cardiac patients as a means to assist with minimizing MV and ICU length of stay (LOS). Pre-op&#xD;
      inspiratory muscle training (IMT) has been shown to decrease pulmonary complications, MV&#xD;
      dependence, and ICU LOS following thoracic surgery. The investigators aim to determine the&#xD;
      mechanism of remodeling in diaphragms of adults who undergo pre-op IMT.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Highly active muscles such as the diaphragm are particularly sensitive to both disuse and&#xD;
      training. For example, diaphragm fibers of controlled mechanically ventilated young adults&#xD;
      atrophy by more than 50% within 36 hours of complete inactivity, and mechanical ventilation&#xD;
      (MV) initiates signaling pathways within the first several hours of inactivity that promote&#xD;
      progressive diaphragmatic fiber dysfunction. The investigators have shown that widespread&#xD;
      atrophy signaling begins in the operating room during cardiac surgery, after only a few hours&#xD;
      of MV. In addition to this fiber atrophy, MV leads to significant declines in the strength of&#xD;
      the diaphragm, which can lengthen the time it takes to wean from MV. The clinical occurrence&#xD;
      of early onset, progressive contractile dysfunction is defined as ventilator-induced&#xD;
      diaphragmatic dysfunction (VIDD). VIDD is regarded as a primary contributor to difficulties&#xD;
      with weaning from MV.&#xD;
&#xD;
      Conversely, the investigators have shown that IMT increases the pressure-generating capacity&#xD;
      of the diaphragm and inspiratory synergist muscles, and facilitates weaning in patients with&#xD;
      VIDD. Preoperative IMT for as little as 1-2 weeks reportedly increases inspiratory muscle&#xD;
      strength. IMT prior to cardiothoracic surgery has been shown to reduce post-operative&#xD;
      pulmonary complications such as atelectasis, pneumonia, or delayed ventilator weaning.&#xD;
      Additionally, strength gains associated with preoperative IMT are associated with shorter ICU&#xD;
      and hospital lengths of stay, which may potentially offer a cost benefit.&#xD;
&#xD;
      Unfortunately, very little is understood about the neuromuscular adaptations and signaling&#xD;
      mechanisms that contribute to these IMT clinical advantages. A particularly novel aspect of&#xD;
      this project is it will be the first study of the mechanisms that contribute to diaphragm&#xD;
      strengthening. A greater understanding of these mechanisms may help future investigators to&#xD;
      develop more efficient exercise prescriptions to offset MV use in cases such as surgery, and&#xD;
      it may help identify molecules and exercise that could protect the diaphragms of individuals&#xD;
      who cannot exercise in advance, as in the case of acute infections that compromise breathing.&#xD;
&#xD;
      The overall objective of this study is to investigate diaphragm neuromuscular remodeling&#xD;
      associated with pre-operative, telehealth delivered IMT, compared with relaxation breathing&#xD;
      training (RLX). Guided RLX exercises have been shown to improve post-operative pain&#xD;
      perception and modestly lower systolic blood pressure in hypertensives but are not thought to&#xD;
      significantly alter diaphragm strength.&#xD;
&#xD;
      Forty adult volunteers will receive either IMT (n=20) or RLX training (n=20) for 2-4 weeks&#xD;
      prior to elective cardiothoracic surgery and undergo breathing performance tests before and&#xD;
      after the training period. A full thickness biopsy (approximately 6mm x 20 mm) from the right&#xD;
      ventral costal diaphragm will be acquired as soon as the diaphragm is exposed during surgery.&#xD;
      Additionally, a biopsy from the pectoralis major will be obtained and used as a non-exercised&#xD;
      control muscle. Histological and RNA sequencing analyses will be performed to examine the&#xD;
      mechanisms that contribute to neuromuscular adaptations to training.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Study staff were busy with other projects and unable to devote time to this study&#xD;
  </why_stopped>
  <start_date type="Anticipated">December 2021</start_date>
  <completion_date type="Actual">January 5, 2022</completion_date>
  <primary_completion_date type="Actual">January 5, 2022</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Subjects will be randomized into one of two arms. In Arm 1, subjects will perform pre-operative inspiratory muscle training. In Arm 2, subjects will perform pre-operative relaxation breathing. A diaphragm biopsy will be taken during surgery for both arms and the tissue will be compared. In addition, a biopsy of the pectoralis major will be obtained from each subject and serve as a non-exercised control which will compared to the subject's diaphragm muscle biopsy (which participated in the intervention).</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Maximal inspiratory pressure</measure>
    <time_frame>Post breathing exercise sessions (up to 4 weeks)</time_frame>
    <description>Maximal inspiratory pressure will be quantified in cm of water pressure.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Muscle fiber cross-sectional area and fiber type proportion.</measure>
    <time_frame>Intra-operatively</time_frame>
    <description>Histology will be used to determine fiber type and cross-sectional area using primary antibodies for laminin and type-specific myosin heavy chain, followed by a triple immunofluorescence-conjugated secondary antibody labeling technique.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Peak expiratory flow</measure>
    <time_frame>Post breathing exercise sessions (up to 4 weeks)</time_frame>
    <description>Spirometry will be used to measure peak expiratory flow during a voluntary cough maneuver. It will be quantified in liters per second.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to extubation</measure>
    <time_frame>Up to discharge from ICU</time_frame>
    <description>Time to extubation will be measured as hours of post-operative mechanical ventilation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Length of ICU stay</measure>
    <time_frame>Up to 1 month</time_frame>
    <description>Length of ICU stay will be measured as hours spent in ICU after surgery.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Length of hospital stay</measure>
    <time_frame>Up to 1 month</time_frame>
    <description>Length of hospital stay will be measured as hours spent in hospital after surgery.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neuromuscular junction morphology</measure>
    <time_frame>Intra-operatively</time_frame>
    <description>Histology will be used to assess neuromuscular junction number and morphology using immunofluorescent-labeled antibodies for synaptophysin and alpha bungarotoxin. Neuromuscular junction image stacks will be visualized with confocal microscopy and morphology classified according to endplate area and area fractions of fragmented junctions, acetylcholine receptor-occupied endplate area, synaptophysin-occupied endplates, and abandoned endplates.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Muscle differential gene expression</measure>
    <time_frame>Intra-operatively</time_frame>
    <description>RNA isolation will be performed using Tri Reagent and chloroform based manual method. RNA will be quantified and RNA-Seq will be used to assess gene expression.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Physical Function</measure>
    <time_frame>Post breathing exercise sessions (up to 4 weeks)</time_frame>
    <description>Physical function will be assessed with the Patient Reported Outcomes Measurement Information System Physical Function questionnaire. Each answer corresponds to a number between 1 and 5.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Dyspnoea</measure>
    <time_frame>Post breathing exercise sessions (up to 4 weeks)</time_frame>
    <description>Dyspnoea will be assessed with the Dyspnoea 12 Questionnaire. Responses range from None to Severe.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Mechanical Ventilation Complication</condition>
  <arm_group>
    <arm_group_label>Inspiratory Muscle Training (IMT)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Pre-operative inspiratory muscle training</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Relaxation Breathing (RLX)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Relaxation breathing exercises</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Inspiratory Muscle Training</intervention_name>
    <description>Inspiratory muscle training exercises, performed 5 times a week for 2-4 weeks prior to cardiac surgery.</description>
    <arm_group_label>Inspiratory Muscle Training (IMT)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Relaxation Breathing</intervention_name>
    <description>Relaxation breathing exercises, performed 5 times a week for 2-4 weeks prior to cardiac surgery.</description>
    <arm_group_label>Relaxation Breathing (RLX)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Cardiac surgery candidate&#xD;
&#xD;
          -  Ability to complete pre-operative breathing exercises&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Surgery is scheduled in less than 2 weeks&#xD;
&#xD;
          -  New York Heart Association Class III or IV Cardiac Disease&#xD;
&#xD;
          -  History of hemiparesis&#xD;
&#xD;
          -  History of spinal cord injury&#xD;
&#xD;
          -  History of progressive neuromuscular disease that may interfere with the ability to&#xD;
             complete study interventions&#xD;
&#xD;
          -  Previous cardiothoracic surgery within the last 12 weeks&#xD;
&#xD;
          -  History of pneumonectomy&#xD;
&#xD;
          -  History of lung surgery&#xD;
&#xD;
          -  History of skeletal pathology (e.g. scoliosis) that may interfere with chest wall&#xD;
             movements&#xD;
&#xD;
          -  Routine usage of muscle relaxants, immunosuppressants, or corticosteroid medications&#xD;
             within the past 30 days&#xD;
&#xD;
          -  Forced expiratory volume 1 less than 40% of age-predicted value&#xD;
&#xD;
          -  Presence of active malignancy&#xD;
&#xD;
          -  Presence of any organ dysfunction that may limit ability to participate in seated&#xD;
             respiratory exercises&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>55 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Barbara Smith, PhD, PT</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Florida</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Thomas Beaver, MD, MPH</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Florida</affiliation>
  </overall_official>
  <removed_countries>
    <country>United States</country>
  </removed_countries>
  <verification_date>January 2022</verification_date>
  <study_first_submitted>June 2, 2020</study_first_submitted>
  <study_first_submitted_qc>June 8, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 9, 2020</study_first_posted>
  <last_update_submitted>January 10, 2022</last_update_submitted>
  <last_update_submitted_qc>January 10, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">January 21, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Mechanical ventilation</keyword>
  <keyword>Inspiratory muscle training</keyword>
  <keyword>Difficulty weaning from mechanical ventilation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Respiratory Aspiration</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04423614
org study id: IRB202001038
secondary id: OCR35362
nct id: NCT04423614
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
In light of the corona virus pandemic (COVID-19), there is critical need to conserve scarce
      mechanical ventilation (MV) resources. This study evaluates an intervention in non-infected
      cardiac patients as a means to assist with minimizing MV and ICU length of stay (LOS). Pre-op
      inspiratory muscle training (IMT) has been shown to decrease pulmonary complications, MV
      dependence, and ICU LOS following thoracic surgery. The investigators aim to determine the
      mechanism of remodeling in diaphragms of adults who undergo pre-op IMT.
Highly active muscles such as the diaphragm are particularly sensitive to both disuse and
      training. For example, diaphragm fibers of controlled mechanically ventilated young adults
      atrophy by more than 50% within 36 hours of complete inactivity, and mechanical ventilation
      (MV) initiates signaling pathways within the first several hours of inactivity that promote
      progressive diaphragmatic fiber dysfunction. The investigators have shown that widespread
      atrophy signaling begins in the operating room during cardiac surgery, after only a few hours
      of MV. In addition to this fiber atrophy, MV leads to significant declines in the strength of
      the diaphragm, which can lengthen the time it takes to wean from MV. The clinical occurrence
      of early onset, progressive contractile dysfunction is defined as ventilator-induced
      diaphragmatic dysfunction (VIDD). VIDD is regarded as a primary contributor to difficulties
      with weaning from MV.

      Conversely, the investigators have shown that IMT increases the pressure-generating capacity
      of the diaphragm and inspiratory synergist muscles, and facilitates weaning in patients with
      VIDD. Preoperative IMT for as little as 1-2 weeks reportedly increases inspiratory muscle
      strength. IMT prior to cardiothoracic surgery has been shown to reduce post-operative
      pulmonary complications such as atelectasis, pneumonia, or delayed ventilator weaning.
      Additionally, strength gains associated with preoperative IMT are associated with shorter ICU
      and hospital lengths of stay, which may potentially offer a cost benefit.

      Unfortunately, very little is understood about the neuromuscular adaptations and signaling
      mechanisms that contribute to these IMT clinical advantages. A particularly novel aspect of
      this project is it will be the first study of the mechanisms that contribute to diaphragm
      strengthening. A greater understanding of these mechanisms may help future investigators to
      develop more efficient exercise prescriptions to offset MV use in cases such as surgery, and
      it may help identify molecules and exercise that could protect the diaphragms of individuals
      who cannot exercise in advance, as in the case of acute infections that compromise breathing.

      The overall objective of this study is to investigate diaphragm neuromuscular remodeling
      associated with pre-operative, telehealth delivered IMT, compared with relaxation breathing
      training (RLX). Guided RLX exercises have been shown to improve post-operative pain
      perception and modestly lower systolic blood pressure in hypertensives but are not thought to
      significantly alter diaphragm strength.

      Forty adult volunteers will receive either IMT (n=20) or RLX training (n=20) for 2-4 weeks
      prior to elective cardiothoracic surgery and undergo breathing performance tests before and
      after the training period. A full thickness biopsy (approximately 6mm x 20 mm) from the right
      ventral costal diaphragm will be acquired as soon as the diaphragm is exposed during surgery.
      Additionally, a biopsy from the pectoralis major will be obtained and used as a non-exercised
      control muscle. Histological and RNA sequencing analyses will be performed to examine the
      mechanisms that contribute to neuromuscular adaptations to training.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Subjects will be randomized into one of two arms. In Arm 1, subjects will perform pre-operative inspiratory muscle training. In Arm 2, subjects will perform pre-operative relaxation breathing. A diaphragm biopsy will be taken during surgery for both arms and the tissue will be compared. In addition, a biopsy of the pectoralis major will be obtained from each subject and serve as a non-exercised control which will compared to the subject's diaphragm muscle biopsy (which participated in the intervention).
primary purpose: Prevention
masking: None (Open Label)
measure: Maximal inspiratory pressure
time frame: Post breathing exercise sessions (up to 4 weeks)
description: Maximal inspiratory pressure will be quantified in cm of water pressure.
measure: Muscle fiber cross-sectional area and fiber type proportion.
time frame: Intra-operatively
description: Histology will be used to determine fiber type and cross-sectional area using primary antibodies for laminin and type-specific myosin heavy chain, followed by a triple immunofluorescence-conjugated secondary antibody labeling technique.
measure: Peak expiratory flow
time frame: Post breathing exercise sessions (up to 4 weeks)
description: Spirometry will be used to measure peak expiratory flow during a voluntary cough maneuver. It will be quantified in liters per second.
measure: Time to extubation
time frame: Up to discharge from ICU
description: Time to extubation will be measured as hours of post-operative mechanical ventilation.
measure: Length of ICU stay
time frame: Up to 1 month
description: Length of ICU stay will be measured as hours spent in ICU after surgery.
measure: Length of hospital stay
time frame: Up to 1 month
description: Length of hospital stay will be measured as hours spent in hospital after surgery.
measure: Neuromuscular junction morphology
time frame: Intra-operatively
description: Histology will be used to assess neuromuscular junction number and morphology using immunofluorescent-labeled antibodies for synaptophysin and alpha bungarotoxin. Neuromuscular junction image stacks will be visualized with confocal microscopy and morphology classified according to endplate area and area fractions of fragmented junctions, acetylcholine receptor-occupied endplate area, synaptophysin-occupied endplates, and abandoned endplates.
measure: Muscle differential gene expression
time frame: Intra-operatively
description: RNA isolation will be performed using Tri Reagent and chloroform based manual method. RNA will be quantified and RNA-Seq will be used to assess gene expression.
measure: Physical Function
time frame: Post breathing exercise sessions (up to 4 weeks)
description: Physical function will be assessed with the Patient Reported Outcomes Measurement Information System Physical Function questionnaire. Each answer corresponds to a number between 1 and 5.
measure: Dyspnoea
time frame: Post breathing exercise sessions (up to 4 weeks)
description: Dyspnoea will be assessed with the Dyspnoea 12 Questionnaire. Responses range from None to Severe.
arm group label: Inspiratory Muscle Training (IMT)
arm group type: Experimental
description: Pre-operative inspiratory muscle training
arm group label: Relaxation Breathing (RLX)
arm group type: Experimental
description: Relaxation breathing exercises
intervention type: Other
intervention name: Inspiratory Muscle Training
description: Inspiratory muscle training exercises, performed 5 times a week for 2-4 weeks prior to cardiac surgery.
arm group label: Inspiratory Muscle Training (IMT)
intervention type: Other
intervention name: Relaxation Breathing
description: Relaxation breathing exercises, performed 5 times a week for 2-4 weeks prior to cardiac surgery.
arm group label: Relaxation Breathing (RLX)
criteria: 
gender: All
minimum age: 55 Years
maximum age: 80 Years
healthy volunteers: No
last name: Barbara Smith, PhD, PT
role: Principal Investigator
affiliation: University of Florida
last name: Thomas Beaver, MD, MPH
role: Principal Investigator
affiliation: University of Florida
country: United States
responsible party type: Sponsor
mesh term: Respiratory Aspiration