<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/NCT03244891</url>
  </required_header>
  <id_info>
    <org_study_id>HRV2017_Healthy</org_study_id>
    <nct_id>NCT03244891</nct_id>
  </id_info>
  <brief_title>Autonomic Challenges From Mild Hypovolemia and Mechanical Ventilation</brief_title>
  <official_title>Effects of Low Central Volume and Intermittent Positive Pressure Ventilation on the Heart Rate Variability</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>ASST Fatebenefratelli Sacco</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>ASST Fatebenefratelli Sacco</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>
      Heart Rate Variability (HRV) analysis has been studied in the critically ill patients&#xD;
      although it is affected by several uncontrolled variables in the clinical conditions. The aim&#xD;
      of this trial is to measure the effects of mildly reduced central volume and cyclic variation&#xD;
      of intrathoracic pressure on the variables frequently used to describe the HRV.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Twelve healthy volunteers will be studied. Mild hypovolemia will be induced by 12 hours&#xD;
      fasting from food and drinks. At 8.30 AM the study protocol will start. The studied subjects&#xD;
      will lie calm supine in a ICU bed able to provide passive head up and head down tilt. They&#xD;
      will be connected to a Siemens SC9000 monitor showing their ECG waves and to a Nexfin (BMEYE)&#xD;
      monitor for continuous noninvasive blood pressure (NBP) assessment. Both waves (ECG and NBP)&#xD;
      will be recorded on a laptop PC through analogic/digital input/output converter (PowerLab&#xD;
      8/35, ADinstruments). The studied subjects will undergo to a sequence of (1) spontaneous&#xD;
      breathing at 10 degrees head up, (2) spontaneous breathing at 7 degrees head down, (3)&#xD;
      noninvasive ventilation at 10 degrees head up, and (4) noninvasive ventilation at 7 degrees&#xD;
      head down. The sequence 1-2-3-4 will be randomized. After this four phases, a fluid challenge&#xD;
      of ringer acetate 15ml*kg will be intravenously administered and the a sequence 1-2-3-4 will&#xD;
      be repeated after a new randomization. Noninvasive ventilation will be provided with a facial&#xD;
      mask with ventilatory setting: Psupp 8 cmH2O, PEEP 5 cmH2O, FiO2 0.28. Psupp will be&#xD;
      decreased by 2 cmH2O steps if the inspiratory tidal volume will be &gt;10ml*kg. During both&#xD;
      spontaneous breathing and noninvasive ventilation the subjects will breathe following a&#xD;
      metronome at 18bpm.&#xD;
&#xD;
      HRV analysis will be conducted following the recommendation of the Task Force of the European&#xD;
      Society of Cardiology and the North American Society of Pacing and Electrophysiology (see&#xD;
      reference).&#xD;
&#xD;
      Furthermore, the healthy volunteers will be studied by trans-thoracic ultrasound assessment&#xD;
      with a Philips EPIQ7 sonographer, during each study phase.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 15, 2019</start_date>
  <completion_date type="Actual">July 30, 2019</completion_date>
  <primary_completion_date type="Actual">July 30, 2019</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Effects of increasing central blood volume on heart rate variability</measure>
    <time_frame>10 mins each step</time_frame>
    <description>The studied subjects will undergo to increase of central blood volume in two steps:&#xD;
passive head down tilt at -7 degrees&#xD;
intravenous infusion of ringer acetate of 15ml*kg body weight</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Effect of cyclic intrathoracic pressure oscillations on heart rate variability</measure>
    <time_frame>10 min each step</time_frame>
    <description>The studied subject will undergo to two ventilatory modes:&#xD;
spontaneous breathing at 18 breaths per min&#xD;
positive pressure ventilation via face mask</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Effects of increasing central blood volume and of cyclic intrathoracic pressure oscillations on echographic cardiac function variables</measure>
    <time_frame>10 mins each step</time_frame>
    <description>At each step cardiac functionality assessment will be done by transthoracic echocardiography</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">12</enrollment>
  <condition>Autonomic Nervous System Imbalance</condition>
  <condition>Hypovolemia</condition>
  <condition>Positive-Pressure Respiration</condition>
  <arm_group>
    <arm_group_label>Studied subjects</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Each subject will be studied during two sequential phases:&#xD;
before fluid challenge&#xD;
after fluid challenge&#xD;
During each phase, the subjects will be studied at:&#xD;
baseline - spontaneously breathing&#xD;
head down position - spontaneously breathing&#xD;
baseline - positive pressure ventilation&#xD;
head down position - positive pressure ventilation The sequence a-b-c-d will be randomized for each subject and for each phase</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Increase of central volume</intervention_name>
    <description>Mild hypovolemia will be induced in healthy volunteers by 12 hours fasting. Three conditions will be considered for the analysis, each of them both during spontaneous breathing and positive pressure ventilation:&#xD;
baseline&#xD;
after fluid shift induced by passive head down position at 15 degrees&#xD;
after fluid challenge with Ringer acetate 15ml*kg in head down position&#xD;
A total of six steps will be considered for the analysis</description>
    <arm_group_label>Studied subjects</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Ventilation mode</intervention_name>
    <description>Each previous step will be done in two respiratory conditions:&#xD;
spontaneous breathing&#xD;
noninvasive ventilation via facial mask in pressure support mode at 8 cmH2O above positive end expiratory pressure of 5 cmH2O, inspiratory fraction of oxygen of 0.25 In both conditions respiratory rate will be set at 18 breaths per min following a metronome</description>
    <arm_group_label>Studied subjects</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  healthy volunteers&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  history of cardiac, metabolic, respiratory, renal, neurological or hematologic disease&#xD;
             of any kind&#xD;
&#xD;
          -  chronically assuming drugs of any kind&#xD;
&#xD;
          -  non sinus cardiac rhythm&#xD;
&#xD;
          -  ectopic beats &gt;5% of all cardiac beats&#xD;
&#xD;
          -  claustrophobia or unable to tolerate noninvasive ventilation via facial mask&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>35 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>ASST Fatebenefratelli Sacco, Luigi Sacco Hospital</name>
      <address>
        <city>Milan</city>
        <zip>20157</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <reference>
    <citation>Guyton JE, Arthur C. The Autonomic Nervous System and The Adrenal Medulla, in Textbook of Medical Physiology, 12th ed., Saunders Elsevier, Ed. Philadelphia, 2011, pp. 738-739</citation>
  </reference>
  <reference>
    <citation>Akselrod S, Gordon D, Ubel FA, Shannon DC, Berger AC, Cohen RJ. Power spectrum analysis of heart rate fluctuation: a quantitative probe of beat-to-beat cardiovascular control. Science. 1981 Jul 10;213(4504):220-2. doi: 10.1126/science.6166045.</citation>
    <PMID>6166045</PMID>
  </reference>
  <reference>
    <citation>Ferrario M, Moissl U, Garzotto F, Cruz DN, Tetta C, Signorini MG, Ronco C, Grassmann A, Cerutti S, Guzzetti S. The forgotten role of central volume in low frequency oscillations of heart rate variability. PLoS One. 2015 Mar 20;10(3):e0120167. doi: 10.1371/journal.pone.0120167. eCollection 2015.</citation>
    <PMID>25793464</PMID>
  </reference>
  <reference>
    <citation>Galletly DC, Larsen PD. Relationship between cardioventilatory coupling and respiratory sinus arrhythmia. Br J Anaesth. 1998 Feb;80(2):164-8. doi: 10.1093/bja/80.2.164.</citation>
    <PMID>9602579</PMID>
  </reference>
  <reference>
    <citation>Monnet X, Rienzo M, Osman D, Anguel N, Richard C, Pinsky MR, Teboul JL. Passive leg raising predicts fluid responsiveness in the critically ill. Crit Care Med. 2006 May;34(5):1402-7. doi: 10.1097/01.CCM.0000215453.11735.06.</citation>
    <PMID>16540963</PMID>
  </reference>
  <reference>
    <citation>Heart rate variability: standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Circulation. 1996 Mar 1;93(5):1043-65. No abstract available.</citation>
    <PMID>8598068</PMID>
  </reference>
  <verification_date>October 2019</verification_date>
  <study_first_submitted>August 5, 2017</study_first_submitted>
  <study_first_submitted_qc>August 5, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 10, 2017</study_first_posted>
  <last_update_submitted>October 10, 2019</last_update_submitted>
  <last_update_submitted_qc>October 10, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">October 14, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>ASST Fatebenefratelli Sacco</investigator_affiliation>
    <investigator_full_name>Riccardo Colombo</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypovolemia</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03244891
org study id: HRV2017_Healthy
nct id: NCT03244891
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Heart Rate Variability (HRV) analysis has been studied in the critically ill patients
      although it is affected by several uncontrolled variables in the clinical conditions. The aim
      of this trial is to measure the effects of mildly reduced central volume and cyclic variation
      of intrathoracic pressure on the variables frequently used to describe the HRV.
Twelve healthy volunteers will be studied. Mild hypovolemia will be induced by 12 hours
      fasting from food and drinks. At 8.30 AM the study protocol will start. The studied subjects
      will lie calm supine in a ICU bed able to provide passive head up and head down tilt. They
      will be connected to a Siemens SC9000 monitor showing their ECG waves and to a Nexfin (BMEYE)
      monitor for continuous noninvasive blood pressure (NBP) assessment. Both waves (ECG and NBP)
      will be recorded on a laptop PC through analogic/digital input/output converter (PowerLab
      8/35, ADinstruments). The studied subjects will undergo to a sequence of (1) spontaneous
      breathing at 10 degrees head up, (2) spontaneous breathing at 7 degrees head down, (3)
      noninvasive ventilation at 10 degrees head up, and (4) noninvasive ventilation at 7 degrees
      head down. The sequence 1-2-3-4 will be randomized. After this four phases, a fluid challenge
      of ringer acetate 15ml*kg will be intravenously administered and the a sequence 1-2-3-4 will
      be repeated after a new randomization. Noninvasive ventilation will be provided with a facial
      mask with ventilatory setting: Psupp 8 cmH2O, PEEP 5 cmH2O, FiO2 0.28. Psupp will be
      decreased by 2 cmH2O steps if the inspiratory tidal volume will be >10ml*kg. During both
      spontaneous breathing and noninvasive ventilation the subjects will breathe following a
      metronome at 18bpm.

      HRV analysis will be conducted following the recommendation of the Task Force of the European
      Society of Cardiology and the North American Society of Pacing and Electrophysiology (see
      reference).

      Furthermore, the healthy volunteers will be studied by trans-thoracic ultrasound assessment
      with a Philips EPIQ7 sonographer, during each study phase.
intervention model: Sequential Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Effects of increasing central blood volume on heart rate variability
time frame: 10 mins each step
description: The studied subjects will undergo to increase of central blood volume in two steps:
passive head down tilt at -7 degrees
intravenous infusion of ringer acetate of 15ml*kg body weight
measure: Effect of cyclic intrathoracic pressure oscillations on heart rate variability
time frame: 10 min each step
description: The studied subject will undergo to two ventilatory modes:
spontaneous breathing at 18 breaths per min
positive pressure ventilation via face mask
measure: Effects of increasing central blood volume and of cyclic intrathoracic pressure oscillations on echographic cardiac function variables
time frame: 10 mins each step
description: At each step cardiac functionality assessment will be done by transthoracic echocardiography
arm group label: Studied subjects
arm group type: Experimental
description: Each subject will be studied during two sequential phases:
before fluid challenge
after fluid challenge
During each phase, the subjects will be studied at:
baseline - spontaneously breathing
head down position - spontaneously breathing
baseline - positive pressure ventilation
head down position - positive pressure ventilation The sequence a-b-c-d will be randomized for each subject and for each phase
intervention type: Other
intervention name: Increase of central volume
description: Mild hypovolemia will be induced in healthy volunteers by 12 hours fasting. Three conditions will be considered for the analysis, each of them both during spontaneous breathing and positive pressure ventilation:
baseline
after fluid shift induced by passive head down position at 15 degrees
after fluid challenge with Ringer acetate 15ml*kg in head down position
A total of six steps will be considered for the analysis
arm group label: Studied subjects
intervention type: Other
intervention name: Ventilation mode
description: Each previous step will be done in two respiratory conditions:
spontaneous breathing
noninvasive ventilation via facial mask in pressure support mode at 8 cmH2O above positive end expiratory pressure of 5 cmH2O, inspiratory fraction of oxygen of 0.25 In both conditions respiratory rate will be set at 18 breaths per min following a metronome
arm group label: Studied subjects
criteria: 
gender: All
minimum age: 18 Years
maximum age: 35 Years
healthy volunteers: Accepts Healthy Volunteers
facility: 
country: Italy
citation: Guyton JE, Arthur C. The Autonomic Nervous System and The Adrenal Medulla, in Textbook of Medical Physiology, 12th ed., Saunders Elsevier, Ed. Philadelphia, 2011, pp. 738-739
citation: Akselrod S, Gordon D, Ubel FA, Shannon DC, Berger AC, Cohen RJ. Power spectrum analysis of heart rate fluctuation: a quantitative probe of beat-to-beat cardiovascular control. Science. 1981 Jul 10;213(4504):220-2. doi: 10.1126/science.6166045.
PMID: 6166045
citation: Ferrario M, Moissl U, Garzotto F, Cruz DN, Tetta C, Signorini MG, Ronco C, Grassmann A, Cerutti S, Guzzetti S. The forgotten role of central volume in low frequency oscillations of heart rate variability. PLoS One. 2015 Mar 20;10(3):e0120167. doi: 10.1371/journal.pone.0120167. eCollection 2015.
PMID: 25793464
citation: Galletly DC, Larsen PD. Relationship between cardioventilatory coupling and respiratory sinus arrhythmia. Br J Anaesth. 1998 Feb;80(2):164-8. doi: 10.1093/bja/80.2.164.
PMID: 9602579
citation: Monnet X, Rienzo M, Osman D, Anguel N, Richard C, Pinsky MR, Teboul JL. Passive leg raising predicts fluid responsiveness in the critically ill. Crit Care Med. 2006 May;34(5):1402-7. doi: 10.1097/01.CCM.0000215453.11735.06.
PMID: 16540963
citation: Heart rate variability: standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Circulation. 1996 Mar 1;93(5):1043-65. No abstract available.
PMID: 8598068
responsible party type: Principal Investigator
investigator affiliation: ASST Fatebenefratelli Sacco
investigator full name: Riccardo Colombo
investigator title: Principal Investigator
mesh term: Hypovolemia
sharing ipd: No