<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/NCT03240263</url>
  </required_header>
  <id_info>
    <org_study_id>S60516</org_study_id>
    <nct_id>NCT03240263</nct_id>
  </id_info>
  <brief_title>Inspiratory Muscle Training in Difficult to Wean Patients</brief_title>
  <official_title>Inspiratory Muscle Training in Difficult to Wean Patients: a Randomised Controlled Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>KU Leuven</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>KU Leuven</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Prolonged mechanical ventilation secondary to weaning failure demands a significant amount of&#xD;
      intensive care unit (ICU) resources, thus increasing the economic burden of public healthcare&#xD;
      costs. One of the proposed mechanisms accounting for weaning failure is the concept that&#xD;
      excessive work of breathing for weak respiratory muscles during the liberation from&#xD;
      mechanical ventilation compromises cerebral blood flow, thereby predisposing the brain to&#xD;
      dysfunction. Restriction in brain perfusion could have an adverse impact on the function of&#xD;
      the respiratory muscles by impairing the output of the respiratory centre thus promoting&#xD;
      respiratory muscle fatigue, leading to weaning failure. Inspiratory muscle training (IMT) has&#xD;
      been shown to improve the functional capacity of the inspiratory muscles in patients with&#xD;
      respiratory muscle weakness whilst has been recently proposed as a possible additional&#xD;
      component of weaning strategies. Therefore, this project aims to identify both a mechanism&#xD;
      that might be linked to prolong ICU length of stay and that at the same time might be&#xD;
      amenable to treatment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      1. Introduction.&#xD;
&#xD;
      Weaning covers the entire process of liberating the patient from mechanical ventilation (MV)&#xD;
      support and the endotracheal tube or tracheostomy. For the majority of&#xD;
      mechanically-ventilated patients spontaneous breathing (weaning) can be successfully&#xD;
      accomplished quickly and easily, however, this is not the case for 15-30% of ventilated&#xD;
      patients. The most common factors leading to weaning failure are i) respiratory muscle&#xD;
      fatigue ii) hypercapnia iii) dyspnoea and iv) anxiety. Along these lines, a proposed a&#xD;
      mechanism that may contribute to weaning failure namely the ''stealing effect'' theory. More&#xD;
      specifically, the ''stealing effect'' theory hypothesizes that during the weaning process the&#xD;
      energy demand of the respiratory muscles can increase to such an extent that respiratory&#xD;
      muscles may deprive oxygen and blood of other tissues such as the brain. In fact, at least&#xD;
      for the brain, the decrease in blood and oxygen delivery could theoretically predispose this&#xD;
      organ to dysfunction. Restriction in oxygen delivery to the brain could have an adverse&#xD;
      impact on the function of the respiratory muscles per se by impairing the output of the&#xD;
      respiratory centre and of neuromuscular competence of the ventilatory pump, rendering the&#xD;
      ventilatory pump incapable of inflating the lungs thus exaggerating respiratory muscle&#xD;
      fatigue and leading to weaning failure. Inspiratory muscle training (ΙΜΤ) is a&#xD;
      non-pharmacological and cost-effective treatment which has been shown to improve the&#xD;
      functional capacity of the inspiratory muscles in patients with respiratory muscle weakness&#xD;
      whilst has been recently proposed as a possible additional component of weaning strategies.&#xD;
      Implementation of an IMT program may decrease the energy demands of inspiratory muscles by&#xD;
      improving inspiratory muscles breathing efficiency on the one hand and by optimizing the&#xD;
      respiratory muscle oxygen utilization on the other hand. Enhancement in muscle strength and&#xD;
      contractile function, as well as oxidative capacity in response to IMT that have been&#xD;
      documented in patients with chronic lung diseases in response to IMT, may increase the oxygen&#xD;
      utilization by the inspiratory muscles thus decreasing the demand of blood flow and oxygen in&#xD;
      favour of the cerebral cortex.&#xD;
&#xD;
      The aims of the project are:&#xD;
&#xD;
        1. To investigate whether the inspiratory muscles steal blood and oxygen from the cerebral&#xD;
           cortex (''stealing effect'').&#xD;
&#xD;
        2. To investigate the effect of the ''stealing effect'' theory on weaning outcomes.&#xD;
&#xD;
        3. To evaluate the effects of IMT using a recently developed TFRL device on weaning&#xD;
           outcomes and on the ''stealing effect'' in difficult to wean patients in the ICU&#xD;
           compared to a sham low-intensity endurance training group.&#xD;
&#xD;
      2. Primary methodologies&#xD;
&#xD;
      Patients with difficult weaning will be included according to inclusion criteria. In&#xD;
      addition, a group of &quot;simple weaning&quot; defined as patients who succeed in the first weaning&#xD;
      trial will be used as a control group for addressing the 1st and 2nd objective of the study.&#xD;
      Simple weaning patients, difficult to wean, and prolonged weaning patients will be classified&#xD;
      according to criteria that have been proposed in the recent WIND study. Specifically,&#xD;
      patients will be classified in group 1 (i.e., simple weaning patients-weaning successfully&#xD;
      achieved at first weaning attempt resulting in successful extubation within 1 day. Patients&#xD;
      will be included if classified in group 2 (i.e., difficult to wean - weaning successfully&#xD;
      achieved after more than 1 day but in less than 1 week after the first separation attempt&#xD;
      (successful separation or death) or group 3 (i.e., prolonged weaning - weaning still not&#xD;
      terminated 7 days after the first separation attempt by success or death). After being&#xD;
      informed about the study written informed consent will be obtained from all patients if awake&#xD;
      and adequate or from a family member if unconscious. In order to address the 3rd objective of&#xD;
      the study patients will then be randomized in one of the two groups: IMT group or endurance&#xD;
      training (SHAM) group. Block randomization will be performed stratifying on two factors:&#xD;
      score on the APACHE II and the presence of COPD. Envelopes will be prepared and sealed (80&#xD;
      for the treatment group and 80 for endurance training group). Piles of envelopes will be&#xD;
      separated in APACHE&lt;18, APACHE&gt;18, non-COPD or COPD and its combinations (20 for each&#xD;
      condition) considering 10 IMT envelopes and 10 endurance training envelopes for each pile.&#xD;
&#xD;
      2.1. Regional blood flow, oxygen delivery and oxygen availability measurements by NIRS-ICG&#xD;
      derived BFI.&#xD;
&#xD;
      Inspiratory and cerebral cortex blood flow index (BFI) will simultaneously be measured by&#xD;
      near-infrared spectroscopy (NIRS) in combination with injections of the tracer indocyanine&#xD;
      green dye (ICG). ICG that is widely used as hemodynamic tracer elicits an absorption peak at&#xD;
      805 nm and, following intravenous infusion, is restricted to the intravascular compartment by&#xD;
      &gt;95% binding to plasma proteins. NIRS-ICG derived BFI as relative measurement of local&#xD;
      perfusion in respiratory and peripheral muscles and cerebral cortex will be calculated by&#xD;
      dividing the muscle ICG peak concentration (assessed by NIRS-ICG curve) by the rise time from&#xD;
      10 to 90% of peak. To measure inspiratory muscles and cerebral cortex ICG concentrations,&#xD;
      four sets of NIRS optodes will be transcutaneously positioned as follows: for the brain over&#xD;
      the prefrontal cortex area (at an adequate distance to avoid interference with the midline&#xD;
      sinus), on the scalene muscles and on the upper rectus abdominis. An additional probe (4th)&#xD;
      will be placed on a non-working muscle group (i.e., thenar eminence) which will be used as a&#xD;
      control measurement spot. Skeletal muscle and cerebral tissue oxygen delivery will be&#xD;
      calculated by multiplying BFI to arterial oxygen content; the latter will be calculated by&#xD;
      arterial and venous blood gas samples. Inspiratory and thebar muscle and cerebral cortex&#xD;
      oxygen saturation (Stio2,%) -a noninvasive index of local tissue oxygen availability which&#xD;
      reflects the balance between oxygen supply and utilization- will be recorded continuously by&#xD;
      NIRS.&#xD;
&#xD;
      2.2 Hemodynamic status&#xD;
&#xD;
      Cardiac output will be assessed continuously by pulse contour analyses using a sensor&#xD;
      (Pulsioflex Monitor, Pulsion Medical Systems SE) connected to an existing arterial catheter32&#xD;
      (see online supplement). The calculation of cardiac output is performed beat-by-beat by&#xD;
      simply multiplying the stroke volume that is calculated by arterial pressure waveform&#xD;
      analysis with the recorded heart rate. Pulse contour analyses method has been validated&#xD;
      against cardiac output calculations using gold-standard methods. The results show that this&#xD;
      method can provide a clinically acceptable cardiac output trend assessment in hemodynamically&#xD;
      stable ICU patients. Cardiac output and heart rate data will be averaged over 60 seconds&#xD;
      during each BFI determination.&#xD;
&#xD;
      2.3. Inspiratory muscle training program&#xD;
&#xD;
      Both groups (i.e., IMT group or endurance training (SHAM) group) will participate in usual&#xD;
      care training interventions aimed at improving respiratory muscle endurance such as&#xD;
      spontaneous breathing trials (SBT) performed with pressure support ventilation (PSV),&#xD;
      continuous positive airway pressure (CPAP), T-tube as well as early mobilization. After&#xD;
      inclusion and randomization patients in both groups will start the training with the TFRL&#xD;
      device (POWERBREATHE KH2, HaB International Ltd, UK). Before and after every session,&#xD;
      respiratory rate, heart rate, oxygen hemoglobin saturation and blood pressure will be&#xD;
      recorded. Sessions will consist of 4 sets of minimum 6 and maximum 10 breathes per set with&#xD;
      resting periods of at least 2 minutes where the patient will be placed in a sitting position&#xD;
      (45 degrees), aspirated if necessary, and the cuff will be inflated to prevent air leakage.&#xD;
      Patients will be instructed to achieve full inspiration and expiration at every breath and to&#xD;
      perform a fast and forceful inspiration. Instructions and encouragements during the sessions&#xD;
      are standardized. A feedback screen on the computer will be available for patients on the IMT&#xD;
      group to show patients' performance during the training (BreatheLink Software, HaB&#xD;
      International Ltd, UK). The training session will be interrupted if patient reports symptoms&#xD;
      of dyspnea, anxiety or coughing, discomfort or when the transcutaneous oxygen desaturation&#xD;
      falls below 85%. The training load in the strength training group will be adjusted to&#xD;
      maintain the highest tolerable intensity throughout the course of the study until weaning of&#xD;
      MV. Patients in the endurance training group will perform the same regimen of training&#xD;
      without adjustments of the training resistance (&lt;10%MIP). After the sessions Borg-scale&#xD;
      scores on perceived breathing effort and dyspnea will be recorded. Experienced&#xD;
      physiotherapists will perform the sessions in all groups.Training will last for 28 days or&#xD;
      until the patient is successfully weaned from MV. Patients still in MV after 28 days of IMT&#xD;
      will be considered failure to wean. MIP and VC will be measured weekly to follow lung&#xD;
      function progression and adequate resistance of training.&#xD;
&#xD;
      3. Statistical Analysis plan&#xD;
&#xD;
      3.1. Statistical analysis plan for the 1st and 2nd objective of the study&#xD;
&#xD;
      For the sample size calculation of this study, we used the change in cerebral cortex BFI from&#xD;
      MV to the SBT between SBT success and SBT failure patients. An expected effect size [Cohens&#xD;
      d] of 0.467 was calculated from the mean difference of cerebral cortex BFI (i.e., 6.70 nM/s)&#xD;
      and the corresponding pooled standard deviation (i.e., 14.0 nM/s), from a previous study that&#xD;
      investigated interhemispheric differences in cerebral cortex BFI in critically ill patients.&#xD;
      Accordingly, using this effect size, the critical sample size is calculated to be 20 SBT&#xD;
      failure patients on the basis of using an ANOVA as the statistical analysis method.&#xD;
      Anticipating that approximately only 1 out of 5 patients (20% rate)1 is expected to fail the&#xD;
      SBT, an estimated number of (i.e., 20*5=100) patients in total is considered to be included&#xD;
      in order to identify the 20 weaning failure patients. Continuous variables will be presented&#xD;
      as mean values with standard deviations if normally distributed or as a median with an&#xD;
      interquartile range if not. Categorical values will be presented as numbers and proportion.&#xD;
      For comparisons between SBT success or failure group, continuous variables will be compared&#xD;
      using Student t-test or Mann Whitney U test based on the distribution of the variables.&#xD;
      Categorical values will be compared using Chi-square or Fisher's exact test, as appropriate.&#xD;
      Two-way analysis of variance (ANOVA) will be applied to examine the interaction amongst&#xD;
      respiratory, hemodynamic, blood gases and peripheral circulation and oxygenation responses&#xD;
      and different time points (i.e., T1-T4, see Table 1) between SBT success and SBT failure&#xD;
      group. One-way ANOVA with repeated measures will be used for the comparison of the different&#xD;
      time measurements (i.e., T1-T4, see Table 1) for each group. Independent association between&#xD;
      changes in cerebral cortex BFI from MV to different time measurements during SBT and SBT&#xD;
      outcomes (failure, success) will be explored by logistic regression analysis. Further&#xD;
      exploration of independent associations between SBT outcomes (failure, success) and all&#xD;
      respiratory, hemodynamic, blood gases and peripheral circulation and oxygenation variables&#xD;
      will be also explored by logistic regression analysis. Finally, multiple logistic regression&#xD;
      analysis including all significant independent predictors (after checking them for&#xD;
      collinearity) will be performed to identify determinants of SBT outcomes. Data will be&#xD;
      analyzed using the SPSS Software (Chicago, IL, USA). Statistical significance will be defined&#xD;
      as p&lt;0.05. Additionally, analogous analyses will be performed for weaning outcomes (failure,&#xD;
      success).&#xD;
&#xD;
      3.2. Statistical analysis plan for the 3rd objective of the study&#xD;
&#xD;
      The sample size calculation for the effectiveness of IMT (IMT group versus endurance training&#xD;
      group) on weaning outcome is based on a previous literature review that evaluated the effects&#xD;
      of IMT in difficult to wean patients. According to the proportions of weaning success&#xD;
      observed in this meta-analysis, 78% in the IMT group and 50% in the control group, and&#xD;
      assuming [a]- and [β]-risks of 5% and 20%, a sample of 45 patients should be included in the&#xD;
      IMT group and 45 in the endurance training group. For data analysis, regarding the first&#xD;
      objective of this study - comparison between IMT group x endurance training group -&#xD;
      chi-square test will be used to compare weaning success between groups and independent sample&#xD;
      t-test (or correspondent non-parametric test) will be used to compare weaning duration&#xD;
      between groups. Other continuous variables will also be evaluated by the same tests.&#xD;
      Comparisons of within-patient breathing pattern characteristics will be evaluated by t-tests&#xD;
      for paired measures or Wilcoxon signed-rank test will be performed according to the normality&#xD;
      of sample distribution. Statistical significance will be set at p&lt;0.05.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">September 1, 2017</start_date>
  <completion_date type="Anticipated">October 2023</completion_date>
  <primary_completion_date type="Anticipated">August 2023</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Weaning Success</measure>
    <time_frame>Maximal duration of IMT treatment: 28 days</time_frame>
    <description>Successful separation attempt without reintubation or reconnection to the MV</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Inspiratory muscles and cerebral cortex blood flow index ([BFI] measured in nanomoles per second, [minimum and maximum scores 0 to 100 nanomoles per second])</measure>
    <time_frame>Maximal duration of IMT treatment: 28 days</time_frame>
    <description>Measured with Near Infrared Spectroscopy</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Inspiratory muscles and cerebral cortex fractional oxygen availability (StiO2% measured as a percentage [minimum and maximum scores 0 to 100 %])</measure>
    <time_frame>Maximal duration of IMT treatment: 28 days</time_frame>
    <description>Measured with Near Infrared Spectroscopy</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Length of stay in the ICU</measure>
    <time_frame>Maximal duration of IMT treatment: 28 days</time_frame>
    <description>(days)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of mechanical ventilation</measure>
    <time_frame>Maximal duration of IMT treatment: 28 days</time_frame>
    <description>days since patient was connected to mechanical ventilator</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>rapid shallow breathing index after 2 hours of successful SBT</measure>
    <time_frame>Maximal duration of IMT treatment: 28 days</time_frame>
    <description>(Breaths/minute/liters)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Vital Capacity</measure>
    <time_frame>Maximal duration of IMT treatment: 28 days</time_frame>
    <description>(L)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>MIP</measure>
    <time_frame>Maximal duration of IMT treatment: 28 days</time_frame>
    <description>(cmH2O)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ventilator-free days</measure>
    <time_frame>Maximal duration of IMT treatment: 28 days</time_frame>
    <description>days free from the mechanical ventilation</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">94</enrollment>
  <condition>Weaning Failure</condition>
  <arm_group>
    <arm_group_label>Inspiratory muscle training</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>High intensity inspiratory muscle training</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sham endurance training</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>Sham inspiratory muscle training at low intensity</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Inspiratory Muscle Training</intervention_name>
    <description>Supervised daily sessions of training including 4 sets of 6-10 breaths using a tapared flow resistive load device*. Resistance adjusted to the highest tolerable load.&#xD;
*Electronic Variable Flow Resistive Loading IMT Device/ POWERbreathe®KH1, HaB International Ltd., Southam, UK</description>
    <arm_group_label>Inspiratory muscle training</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Endurance training</intervention_name>
    <description>Supervised daily sessions of training including 4 sets of 6-10 breaths using a tapared flow resistive load device*. Low training resistance adjusted to &lt;10% maximal inspiratory pressure.&#xD;
*Electronic Variable Flow Resistive Loading IMT Device/ POWERbreathe®KH1, HaB International Ltd., Southam, UK</description>
    <arm_group_label>Sham endurance training</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Difficult and prolonged weaning patients&#xD;
&#xD;
          -  Simple weaning patients&#xD;
&#xD;
          -  Adequate oxygenation&#xD;
&#xD;
          -  Febrile temperature &lt; 38ºC&#xD;
&#xD;
          -  Hemodynamic stability&#xD;
&#xD;
          -  Stable blood pressure&#xD;
&#xD;
          -  No or minimal pressors&#xD;
&#xD;
          -  No myocardial ischemia&#xD;
&#xD;
          -  Adequate hemoglobin and mentation&#xD;
&#xD;
          -  Resolution of disease acute phase&#xD;
&#xD;
          -  Able to follow simple verbal commands related to IMT&#xD;
&#xD;
          -  Mechanically ventilated via a tracheostomy or endotracheal tube&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pre-existing neuromuscular disease&#xD;
&#xD;
          -  Agitation&#xD;
&#xD;
          -  Hemodynamically instable (arrhythmia, decompensated heart failure, coronary&#xD;
             insufficiency)&#xD;
&#xD;
          -  Hemoptysis&#xD;
&#xD;
          -  Diaphoresis&#xD;
&#xD;
          -  Spinal cord injury above T8&#xD;
&#xD;
          -  Use of any type of home MV support prior to hospitalization&#xD;
&#xD;
          -  Skeletal pathology that impairs chest wall movements&#xD;
&#xD;
          -  Poor general prognosis or fatal outcome&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Rik Gosselink, PT, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>KU Leuven</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Daniel Langer, PT, PhD</last_name>
    <phone>032-16-330192</phone>
    <email>daniel.langer@faber.kuleuven.be</email>
  </overall_contact>
  <location>
    <facility>
      <name>University Hospital Leuven</name>
      <address>
        <city>Leuven</city>
        <zip>3000</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Daniel Langer, PT,PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Rik Gosselink, PT, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Universitair Medisch Centra Amsterdam</name>
      <address>
        <city>Amsterdam</city>
        <state>North Holland</state>
        <zip>1105</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Erna Alberts, Researchcoordinator</last_name>
      <phone>0204443824</phone>
      <email>Erna.Alberts@vumc.nl</email>
    </contact>
    <investigator>
      <last_name>Leo Heunks, Full professor</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Belgium</country>
    <country>Netherlands</country>
  </location_countries>
  <link>
    <url>https://www.uzleuven.be/nl/ethische-commissie/onderzoek</url>
    <description>Institutional Review Board</description>
  </link>
  <reference>
    <citation>Vassilakopoulos T, Zakynthinos S, Roussos Ch. Respiratory muscles and weaning failure. Eur Respir J. 1996 Nov;9(11):2383-400. doi: 10.1183/09031936.96.09112383.</citation>
    <PMID>8947090</PMID>
  </reference>
  <reference>
    <citation>Gosselink R, Langer D. Recovery from ICU-acquired weakness; do not forget the respiratory muscles! Thorax. 2016 Sep;71(9):779-80. doi: 10.1136/thoraxjnl-2016-208835. Epub 2016 Jul 21. No abstract available.</citation>
    <PMID>27444580</PMID>
  </reference>
  <reference>
    <citation>Hermans G, Van den Berghe G. Clinical review: intensive care unit acquired weakness. Crit Care. 2015 Aug 5;19(1):274. doi: 10.1186/s13054-015-0993-7.</citation>
    <PMID>26242743</PMID>
  </reference>
  <reference>
    <citation>Langer D, Charususin N, Jacome C, Hoffman M, McConnell A, Decramer M, Gosselink R. Efficacy of a Novel Method for Inspiratory Muscle Training in People With Chronic Obstructive Pulmonary Disease. Phys Ther. 2015 Sep;95(9):1264-73. doi: 10.2522/ptj.20140245. Epub 2015 Apr 9.</citation>
    <PMID>25858974</PMID>
  </reference>
  <reference>
    <citation>Louvaris Z, Vogiatzis I. Respiratory muscle blood flow measured by Near-Infrared Spectroscopy (NIRS) by indocyanine green dye. In: Aliverti A PA, ed. Mechanics of breathing. Italy: Springler-Verlag, 169-178, 2014.</citation>
  </reference>
  <reference>
    <citation>Vogiatzis I, Louvaris Z, Habazettl H, Andrianopoulos V, Wagner H, Roussos C, Wagner PD, Zakynthinos S. Cerebral cortex oxygen delivery and exercise limitation in patients with COPD. Eur Respir J. 2013 Feb;41(2):295-301. doi: 10.1183/09031936.00016312. Epub 2012 May 3.</citation>
    <PMID>22556019</PMID>
  </reference>
  <reference>
    <citation>Boushel R, Langberg H, Olesen J, Gonzales-Alonzo J, Bulow J, Kjaer M. Monitoring tissue oxygen availability with near infrared spectroscopy (NIRS) in health and disease. Scand J Med Sci Sports. 2001 Aug;11(4):213-22. doi: 10.1034/j.1600-0838.2001.110404.x.</citation>
    <PMID>11476426</PMID>
  </reference>
  <reference>
    <citation>CHERRICK GR, STEIN SW, LEEVY CM, DAVIDSON CS. Indocyanine green: observations on its physical properties, plasma decay, and hepatic extraction. J Clin Invest. 1960 Apr;39(4):592-600. doi: 10.1172/JCI104072. No abstract available.</citation>
    <PMID>13809697</PMID>
  </reference>
  <reference>
    <citation>Riley RL. The work of breathing and its relation to respiratory acidosis. Annals of Internal Medicine 41:172-176, 1954</citation>
  </reference>
  <reference>
    <citation>Hermans G, Agten A, Testelmans D, Decramer M, Gayan-Ramirez G. Increased duration of mechanical ventilation is associated with decreased diaphragmatic force: a prospective observational study. Crit Care. 2010;14(4):R127. doi: 10.1186/cc9094. Epub 2010 Jul 1.</citation>
    <PMID>20594319</PMID>
  </reference>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>August 2, 2017</study_first_submitted>
  <study_first_submitted_qc>August 2, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 7, 2017</study_first_posted>
  <last_update_submitted>February 7, 2023</last_update_submitted>
  <last_update_submitted_qc>February 7, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 8, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>KU Leuven</investigator_affiliation>
    <investigator_full_name>Daniel Langer</investigator_full_name>
    <investigator_title>PT, PhD</investigator_title>
  </responsible_party>
  <keyword>Difficult to wean patients</keyword>
  <keyword>ICU aquired muscle weakness</keyword>
  <keyword>Cerebral perfusion</keyword>
  <keyword>Respiratroy muscles</keyword>
  <keyword>IMT</keyword>
  <keyword>Cerebral oxygenation</keyword>
  <keyword>Weaning outcomes</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/NCT03240263
org study id: S60516
nct id: NCT03240263
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
Prolonged mechanical ventilation secondary to weaning failure demands a significant amount of
      intensive care unit (ICU) resources, thus increasing the economic burden of public healthcare
      costs. One of the proposed mechanisms accounting for weaning failure is the concept that
      excessive work of breathing for weak respiratory muscles during the liberation from
      mechanical ventilation compromises cerebral blood flow, thereby predisposing the brain to
      dysfunction. Restriction in brain perfusion could have an adverse impact on the function of
      the respiratory muscles by impairing the output of the respiratory centre thus promoting
      respiratory muscle fatigue, leading to weaning failure. Inspiratory muscle training (IMT) has
      been shown to improve the functional capacity of the inspiratory muscles in patients with
      respiratory muscle weakness whilst has been recently proposed as a possible additional
      component of weaning strategies. Therefore, this project aims to identify both a mechanism
      that might be linked to prolong ICU length of stay and that at the same time might be
      amenable to treatment.
1. Introduction.

      Weaning covers the entire process of liberating the patient from mechanical ventilation (MV)
      support and the endotracheal tube or tracheostomy. For the majority of
      mechanically-ventilated patients spontaneous breathing (weaning) can be successfully
      accomplished quickly and easily, however, this is not the case for 15-30% of ventilated
      patients. The most common factors leading to weaning failure are i) respiratory muscle
      fatigue ii) hypercapnia iii) dyspnoea and iv) anxiety. Along these lines, a proposed a
      mechanism that may contribute to weaning failure namely the ''stealing effect'' theory. More
      specifically, the ''stealing effect'' theory hypothesizes that during the weaning process the
      energy demand of the respiratory muscles can increase to such an extent that respiratory
      muscles may deprive oxygen and blood of other tissues such as the brain. In fact, at least
      for the brain, the decrease in blood and oxygen delivery could theoretically predispose this
      organ to dysfunction. Restriction in oxygen delivery to the brain could have an adverse
      impact on the function of the respiratory muscles per se by impairing the output of the
      respiratory centre and of neuromuscular competence of the ventilatory pump, rendering the
      ventilatory pump incapable of inflating the lungs thus exaggerating respiratory muscle
      fatigue and leading to weaning failure. Inspiratory muscle training (ΙΜΤ) is a
      non-pharmacological and cost-effective treatment which has been shown to improve the
      functional capacity of the inspiratory muscles in patients with respiratory muscle weakness
      whilst has been recently proposed as a possible additional component of weaning strategies.
      Implementation of an IMT program may decrease the energy demands of inspiratory muscles by
      improving inspiratory muscles breathing efficiency on the one hand and by optimizing the
      respiratory muscle oxygen utilization on the other hand. Enhancement in muscle strength and
      contractile function, as well as oxidative capacity in response to IMT that have been
      documented in patients with chronic lung diseases in response to IMT, may increase the oxygen
      utilization by the inspiratory muscles thus decreasing the demand of blood flow and oxygen in
      favour of the cerebral cortex.

      The aims of the project are:

        1. To investigate whether the inspiratory muscles steal blood and oxygen from the cerebral
           cortex (''stealing effect'').

        2. To investigate the effect of the ''stealing effect'' theory on weaning outcomes.

        3. To evaluate the effects of IMT using a recently developed TFRL device on weaning
           outcomes and on the ''stealing effect'' in difficult to wean patients in the ICU
           compared to a sham low-intensity endurance training group.

      2. Primary methodologies

      Patients with difficult weaning will be included according to inclusion criteria. In
      addition, a group of "simple weaning" defined as patients who succeed in the first weaning
      trial will be used as a control group for addressing the 1st and 2nd objective of the study.
      Simple weaning patients, difficult to wean, and prolonged weaning patients will be classified
      according to criteria that have been proposed in the recent WIND study. Specifically,
      patients will be classified in group 1 (i.e., simple weaning patients-weaning successfully
      achieved at first weaning attempt resulting in successful extubation within 1 day. Patients
      will be included if classified in group 2 (i.e., difficult to wean - weaning successfully
      achieved after more than 1 day but in less than 1 week after the first separation attempt
      (successful separation or death) or group 3 (i.e., prolonged weaning - weaning still not
      terminated 7 days after the first separation attempt by success or death). After being
      informed about the study written informed consent will be obtained from all patients if awake
      and adequate or from a family member if unconscious. In order to address the 3rd objective of
      the study patients will then be randomized in one of the two groups: IMT group or endurance
      training (SHAM) group. Block randomization will be performed stratifying on two factors:
      score on the APACHE II and the presence of COPD. Envelopes will be prepared and sealed (80
      for the treatment group and 80 for endurance training group). Piles of envelopes will be
      separated in APACHE<18, APACHE>18, non-COPD or COPD and its combinations (20 for each
      condition) considering 10 IMT envelopes and 10 endurance training envelopes for each pile.

      2.1. Regional blood flow, oxygen delivery and oxygen availability measurements by NIRS-ICG
      derived BFI.

      Inspiratory and cerebral cortex blood flow index (BFI) will simultaneously be measured by
      near-infrared spectroscopy (NIRS) in combination with injections of the tracer indocyanine
      green dye (ICG). ICG that is widely used as hemodynamic tracer elicits an absorption peak at
      805 nm and, following intravenous infusion, is restricted to the intravascular compartment by
      >95% binding to plasma proteins. NIRS-ICG derived BFI as relative measurement of local
      perfusion in respiratory and peripheral muscles and cerebral cortex will be calculated by
      dividing the muscle ICG peak concentration (assessed by NIRS-ICG curve) by the rise time from
      10 to 90% of peak. To measure inspiratory muscles and cerebral cortex ICG concentrations,
      four sets of NIRS optodes will be transcutaneously positioned as follows: for the brain over
      the prefrontal cortex area (at an adequate distance to avoid interference with the midline
      sinus), on the scalene muscles and on the upper rectus abdominis. An additional probe (4th)
      will be placed on a non-working muscle group (i.e., thenar eminence) which will be used as a
      control measurement spot. Skeletal muscle and cerebral tissue oxygen delivery will be
      calculated by multiplying BFI to arterial oxygen content; the latter will be calculated by
      arterial and venous blood gas samples. Inspiratory and thebar muscle and cerebral cortex
      oxygen saturation (Stio2,%) -a noninvasive index of local tissue oxygen availability which
      reflects the balance between oxygen supply and utilization- will be recorded continuously by
      NIRS.

      2.2 Hemodynamic status

      Cardiac output will be assessed continuously by pulse contour analyses using a sensor
      (Pulsioflex Monitor, Pulsion Medical Systems SE) connected to an existing arterial catheter32
      (see online supplement). The calculation of cardiac output is performed beat-by-beat by
      simply multiplying the stroke volume that is calculated by arterial pressure waveform
      analysis with the recorded heart rate. Pulse contour analyses method has been validated
      against cardiac output calculations using gold-standard methods. The results show that this
      method can provide a clinically acceptable cardiac output trend assessment in hemodynamically
      stable ICU patients. Cardiac output and heart rate data will be averaged over 60 seconds
      during each BFI determination.

      2.3. Inspiratory muscle training program

      Both groups (i.e., IMT group or endurance training (SHAM) group) will participate in usual
      care training interventions aimed at improving respiratory muscle endurance such as
      spontaneous breathing trials (SBT) performed with pressure support ventilation (PSV),
      continuous positive airway pressure (CPAP), T-tube as well as early mobilization. After
      inclusion and randomization patients in both groups will start the training with the TFRL
      device (POWERBREATHE KH2, HaB International Ltd, UK). Before and after every session,
      respiratory rate, heart rate, oxygen hemoglobin saturation and blood pressure will be
      recorded. Sessions will consist of 4 sets of minimum 6 and maximum 10 breathes per set with
      resting periods of at least 2 minutes where the patient will be placed in a sitting position
      (45 degrees), aspirated if necessary, and the cuff will be inflated to prevent air leakage.
      Patients will be instructed to achieve full inspiration and expiration at every breath and to
      perform a fast and forceful inspiration. Instructions and encouragements during the sessions
      are standardized. A feedback screen on the computer will be available for patients on the IMT
      group to show patients' performance during the training (BreatheLink Software, HaB
      International Ltd, UK). The training session will be interrupted if patient reports symptoms
      of dyspnea, anxiety or coughing, discomfort or when the transcutaneous oxygen desaturation
      falls below 85%. The training load in the strength training group will be adjusted to
      maintain the highest tolerable intensity throughout the course of the study until weaning of
      MV. Patients in the endurance training group will perform the same regimen of training
      without adjustments of the training resistance (<10%MIP). After the sessions Borg-scale
      scores on perceived breathing effort and dyspnea will be recorded. Experienced
      physiotherapists will perform the sessions in all groups.Training will last for 28 days or
      until the patient is successfully weaned from MV. Patients still in MV after 28 days of IMT
      will be considered failure to wean. MIP and VC will be measured weekly to follow lung
      function progression and adequate resistance of training.

      3. Statistical Analysis plan

      3.1. Statistical analysis plan for the 1st and 2nd objective of the study

      For the sample size calculation of this study, we used the change in cerebral cortex BFI from
      MV to the SBT between SBT success and SBT failure patients. An expected effect size [Cohens
      d] of 0.467 was calculated from the mean difference of cerebral cortex BFI (i.e., 6.70 nM/s)
      and the corresponding pooled standard deviation (i.e., 14.0 nM/s), from a previous study that
      investigated interhemispheric differences in cerebral cortex BFI in critically ill patients.
      Accordingly, using this effect size, the critical sample size is calculated to be 20 SBT
      failure patients on the basis of using an ANOVA as the statistical analysis method.
      Anticipating that approximately only 1 out of 5 patients (20% rate)1 is expected to fail the
      SBT, an estimated number of (i.e., 20*5=100) patients in total is considered to be included
      in order to identify the 20 weaning failure patients. Continuous variables will be presented
      as mean values with standard deviations if normally distributed or as a median with an
      interquartile range if not. Categorical values will be presented as numbers and proportion.
      For comparisons between SBT success or failure group, continuous variables will be compared
      using Student t-test or Mann Whitney U test based on the distribution of the variables.
      Categorical values will be compared using Chi-square or Fisher's exact test, as appropriate.
      Two-way analysis of variance (ANOVA) will be applied to examine the interaction amongst
      respiratory, hemodynamic, blood gases and peripheral circulation and oxygenation responses
      and different time points (i.e., T1-T4, see Table 1) between SBT success and SBT failure
      group. One-way ANOVA with repeated measures will be used for the comparison of the different
      time measurements (i.e., T1-T4, see Table 1) for each group. Independent association between
      changes in cerebral cortex BFI from MV to different time measurements during SBT and SBT
      outcomes (failure, success) will be explored by logistic regression analysis. Further
      exploration of independent associations between SBT outcomes (failure, success) and all
      respiratory, hemodynamic, blood gases and peripheral circulation and oxygenation variables
      will be also explored by logistic regression analysis. Finally, multiple logistic regression
      analysis including all significant independent predictors (after checking them for
      collinearity) will be performed to identify determinants of SBT outcomes. Data will be
      analyzed using the SPSS Software (Chicago, IL, USA). Statistical significance will be defined
      as p<0.05. Additionally, analogous analyses will be performed for weaning outcomes (failure,
      success).

      3.2. Statistical analysis plan for the 3rd objective of the study

      The sample size calculation for the effectiveness of IMT (IMT group versus endurance training
      group) on weaning outcome is based on a previous literature review that evaluated the effects
      of IMT in difficult to wean patients. According to the proportions of weaning success
      observed in this meta-analysis, 78% in the IMT group and 50% in the control group, and
      assuming [a]- and [β]-risks of 5% and 20%, a sample of 45 patients should be included in the
      IMT group and 45 in the endurance training group. For data analysis, regarding the first
      objective of this study - comparison between IMT group x endurance training group -
      chi-square test will be used to compare weaning success between groups and independent sample
      t-test (or correspondent non-parametric test) will be used to compare weaning duration
      between groups. Other continuous variables will also be evaluated by the same tests.
      Comparisons of within-patient breathing pattern characteristics will be evaluated by t-tests
      for paired measures or Wilcoxon signed-rank test will be performed according to the normality
      of sample distribution. Statistical significance will be set at p<0.05.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Outcomes Assessor)
measure: Weaning Success
time frame: Maximal duration of IMT treatment: 28 days
description: Successful separation attempt without reintubation or reconnection to the MV
measure: Inspiratory muscles and cerebral cortex blood flow index ([BFI] measured in nanomoles per second, [minimum and maximum scores 0 to 100 nanomoles per second])
time frame: Maximal duration of IMT treatment: 28 days
description: Measured with Near Infrared Spectroscopy
measure: Inspiratory muscles and cerebral cortex fractional oxygen availability (StiO2% measured as a percentage [minimum and maximum scores 0 to 100 %])
time frame: Maximal duration of IMT treatment: 28 days
description: Measured with Near Infrared Spectroscopy
measure: Length of stay in the ICU
time frame: Maximal duration of IMT treatment: 28 days
description: (days)
measure: Duration of mechanical ventilation
time frame: Maximal duration of IMT treatment: 28 days
description: days since patient was connected to mechanical ventilator
measure: rapid shallow breathing index after 2 hours of successful SBT
time frame: Maximal duration of IMT treatment: 28 days
description: (Breaths/minute/liters)
measure: Vital Capacity
time frame: Maximal duration of IMT treatment: 28 days
description: (L)
measure: MIP
time frame: Maximal duration of IMT treatment: 28 days
description: (cmH2O)
measure: ventilator-free days
time frame: Maximal duration of IMT treatment: 28 days
description: days free from the mechanical ventilation
arm group label: Inspiratory muscle training
arm group type: Experimental
description: High intensity inspiratory muscle training
arm group label: Sham endurance training
arm group type: Sham Comparator
description: Sham inspiratory muscle training at low intensity
intervention type: Procedure
intervention name: Inspiratory Muscle Training
description: Supervised daily sessions of training including 4 sets of 6-10 breaths using a tapared flow resistive load device*. Resistance adjusted to the highest tolerable load.
*Electronic Variable Flow Resistive Loading IMT Device/ POWERbreathe®KH1, HaB International Ltd., Southam, UK
arm group label: Inspiratory muscle training
intervention type: Procedure
intervention name: Endurance training
description: Supervised daily sessions of training including 4 sets of 6-10 breaths using a tapared flow resistive load device*. Low training resistance adjusted to <10% maximal inspiratory pressure.
*Electronic Variable Flow Resistive Loading IMT Device/ POWERbreathe®KH1, HaB International Ltd., Southam, UK
arm group label: Sham endurance training
criteria: 
gender: All
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: No
last name: Rik Gosselink, PT, PhD
role: Principal Investigator
affiliation: KU Leuven
last name: Daniel Langer, PT, PhD
phone: 032-16-330192
email: daniel.langer@faber.kuleuven.be
facility: 
status: Recruiting
investigator: 
investigator: 
facility: 
status: Not yet recruiting
contact: 
investigator: 
country: Belgium
country: Netherlands
url: https://www.uzleuven.be/nl/ethische-commissie/onderzoek
description: Institutional Review Board
citation: Vassilakopoulos T, Zakynthinos S, Roussos Ch. Respiratory muscles and weaning failure. Eur Respir J. 1996 Nov;9(11):2383-400. doi: 10.1183/09031936.96.09112383.
PMID: 8947090
citation: Gosselink R, Langer D. Recovery from ICU-acquired weakness; do not forget the respiratory muscles! Thorax. 2016 Sep;71(9):779-80. doi: 10.1136/thoraxjnl-2016-208835. Epub 2016 Jul 21. No abstract available.
PMID: 27444580
citation: Hermans G, Van den Berghe G. Clinical review: intensive care unit acquired weakness. Crit Care. 2015 Aug 5;19(1):274. doi: 10.1186/s13054-015-0993-7.
PMID: 26242743
citation: Langer D, Charususin N, Jacome C, Hoffman M, McConnell A, Decramer M, Gosselink R. Efficacy of a Novel Method for Inspiratory Muscle Training in People With Chronic Obstructive Pulmonary Disease. Phys Ther. 2015 Sep;95(9):1264-73. doi: 10.2522/ptj.20140245. Epub 2015 Apr 9.
PMID: 25858974
citation: Louvaris Z, Vogiatzis I. Respiratory muscle blood flow measured by Near-Infrared Spectroscopy (NIRS) by indocyanine green dye. In: Aliverti A PA, ed. Mechanics of breathing. Italy: Springler-Verlag, 169-178, 2014.
citation: Vogiatzis I, Louvaris Z, Habazettl H, Andrianopoulos V, Wagner H, Roussos C, Wagner PD, Zakynthinos S. Cerebral cortex oxygen delivery and exercise limitation in patients with COPD. Eur Respir J. 2013 Feb;41(2):295-301. doi: 10.1183/09031936.00016312. Epub 2012 May 3.
PMID: 22556019
citation: Boushel R, Langberg H, Olesen J, Gonzales-Alonzo J, Bulow J, Kjaer M. Monitoring tissue oxygen availability with near infrared spectroscopy (NIRS) in health and disease. Scand J Med Sci Sports. 2001 Aug;11(4):213-22. doi: 10.1034/j.1600-0838.2001.110404.x.
PMID: 11476426
citation: CHERRICK GR, STEIN SW, LEEVY CM, DAVIDSON CS. Indocyanine green: observations on its physical properties, plasma decay, and hepatic extraction. J Clin Invest. 1960 Apr;39(4):592-600. doi: 10.1172/JCI104072. No abstract available.
PMID: 13809697
citation: Riley RL. The work of breathing and its relation to respiratory acidosis. Annals of Internal Medicine 41:172-176, 1954
citation: Hermans G, Agten A, Testelmans D, Decramer M, Gayan-Ramirez G. Increased duration of mechanical ventilation is associated with decreased diaphragmatic force: a prospective observational study. Crit Care. 2010;14(4):R127. doi: 10.1186/cc9094. Epub 2010 Jul 1.
PMID: 20594319
responsible party type: Principal Investigator
investigator affiliation: KU Leuven
investigator full name: Daniel Langer
investigator title: PT, PhD
mesh term: Respiratory Aspiration