<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/NCT02203097</url>
  </required_header>
  <id_info>
    <org_study_id>030167-006/2014/OTIG</org_study_id>
    <secondary_id>2345</secondary_id>
    <nct_id>NCT02203097</nct_id>
  </id_info>
  <brief_title>The Effect of Different End-tidal Carbon-dioxide Levels on Cerebral CO2 Vasoreactivity and the Stiffness of Systemic Arteries During Propofol Anesthesia</brief_title>
  <official_title>The Effect of Different End-tidal Carbon-dioxide Levels on Cerebral CO2 Vasoreactivity and the Stiffness of Systemic Arteries During Propofol Anesthesia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Debrecen</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Debrecen</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Purpose:&#xD;
&#xD;
      The purpose of this study is to examine the effect of different carbon-dioxide concentrations&#xD;
      on cerebral CO2 sensitivity and the resistance and stiffness of systemic arteries during&#xD;
      anesthesia with target-controlled infusion anesthesia using intravenous propofol. Propofol is&#xD;
      a widely and commonly used intravenous anaesthetic, that is mainly used for the induction of&#xD;
      general anesthesia and the maintenance of total intravenous anaesthesia (TIVA).&#xD;
&#xD;
      Changes in the velocity of cerebral blood flow and arterial stiffness due to the different&#xD;
      exhaled carbon-dioxide concentrations will allow us to conclude how propofol affects these&#xD;
      parameters during the course of the narcosis.&#xD;
&#xD;
      Instruments:&#xD;
&#xD;
      An ultrasound device called transcranial doppler (TCD) is used to measure the velocity of&#xD;
      blood flow within a main artery located inside the skull.&#xD;
&#xD;
      A tonometry device named SphygmoCor is used to assess the pressure wave proceeding in the&#xD;
      radial artery, from which the stiffness of the systemic vessels can be concluded.&#xD;
&#xD;
      Measurements:&#xD;
&#xD;
      - Examinations with the ultrasound and tonometry devices are carried out once before the&#xD;
      operation, three times during the intervention, with different exhaled CO2 values and once&#xD;
      after the operation is completed.&#xD;
&#xD;
      Hypothesis:&#xD;
&#xD;
      - Propofol alters cerebral carbon-dioxide sensitivity and the stiffness of systemic arteries&#xD;
      during TCI anaesthesia.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study protocol:&#xD;
&#xD;
      - The study is conducted in four stages: in the first stage, measurements are performed&#xD;
      preoperatively in awake patients. Patients are placed in supine position and mean arterial&#xD;
      blood pressure (MAP), heart rate, oxygen saturation are measured. The transcranial doppler&#xD;
      (TCD) probe is fixed in place by applying a headband to maintain a constant angle of&#xD;
      insonation. Mean blood flow velocity (MBFV) and pulsatility index (PI) in the middle cerebral&#xD;
      artery (MCA) are obtained. MCA is insonated through the right temporal window by using pulsed&#xD;
      2 megahertz TCD ultrasound probe. Identification of the MCA is confirmed by using standard&#xD;
      criteria, at a depth of 45-55 mm. Cerebral CO2 vasoreactivity is calculated as the percentage&#xD;
      change in MBFV or PI for mmHg change in end-tidal CO2 (ETCO2).&#xD;
&#xD;
      SphygmoCor is placed on the left radial artery to obtain data about the central aortic blood&#xD;
      pressure, augmentation pressure (AP) and augmentation index normalised to a 75 beat per&#xD;
      minute heart rate (Alx75). From the derived aortic pulse, calculations can be made, using the&#xD;
      area under the systolic and diastolic part of the curve, to determine the heart's ratio of&#xD;
      oxygen supply and demand, it is called the subendocardial viability ratio (SEVR).&#xD;
&#xD;
      As part of the premedication each patient receives 100 mg diclofenac per os 30 minutes and&#xD;
      500 ml Lactated-Ringer infusion 60 minutes prior to the operation.&#xD;
&#xD;
      Anesthesia is induced and maintained with target-controlled infusion anesthesia (TCI) using&#xD;
      intravenous propofol at 4 mcg/ml constant plasma concentration. Analgesia is provided by&#xD;
      using 2 ug/kg sufentanyl bolus dose at the time of induction. Afterwards 0.6 mg/kg rocuronium&#xD;
      is given for muscle paralysis and subsequently patients were intubated with a suitable&#xD;
      intratracheal tube. After induction of anaesthesia, the patients are placed on a mechanical&#xD;
      ventilation system, using a volume-controlled setting with an air and oxygen mixture set to&#xD;
      0.4 fraction of inspired oxygen (FiO2) , the fresh gas flow rate to 2 l/min. .&#xD;
&#xD;
      Differences in the depth of anesthesia could influence cerebral activity, thereby cerebral&#xD;
      metabolism and blood flow. Bispectral index is placed onto every patient in order to assure&#xD;
      constant depth of anaesthesia during the intervention.&#xD;
&#xD;
      The second series of TCD and SphygmoCor measurements are performed 20 minutes after the&#xD;
      respiratory rate is set to maintain end-tidal CO2 at 40 mmHg in order to allow sufficient&#xD;
      time for equilibrium to be reached and the effect of drugs used for the induction of&#xD;
      anesthesia to be terminated. Subsequently the examinations are repeated twice again at 35 and&#xD;
      30 mmHg ETCO2. The measurements were carried out 5-5 minutes after adjusting the minute&#xD;
      ventilation to reach target ETCO2 values.&#xD;
&#xD;
      Statistical methods:&#xD;
&#xD;
      - Comparisons between the preoperative and three intraoperative stages of the study are made&#xD;
      using repeated measures ANOVA with the Bonferroni post hoc correction. The relationship&#xD;
      between MBFV, PI and ETCO2 is assessed using linear regression, while the connection between&#xD;
      SEVR, pulse and Alx75 is calculated with bivariate correlation.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 2014</start_date>
  <completion_date type="Actual">December 2016</completion_date>
  <primary_completion_date type="Actual">December 2016</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Blood flow velocity in the middle cerebral artery</measure>
    <time_frame>Changes from baseline in blood flow velocity at the 15th, 20th and 25th minutes of the operation</time_frame>
    <description>Systolic, diastolic and mean blood flow velocities are measured with transcranial doppler device.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Arterial wall stiffness of the radial artery</measure>
    <time_frame>Changes from baseline in arterial stiffness at the 15th, 20th and 25th minutes of the operation</time_frame>
    <description>The stiffness of the radial artery is assessed. Stiffness rate is concluded from the augmentation pressure and augmentation index, from which both values are provided by the tonometry device.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in the central systolic and diastolic blood pressure</measure>
    <time_frame>Changes from baseline in central blood pressure at the 15th, 20th and 25th minutes of the operation</time_frame>
    <description>Central blood pressure values are measured by means of tonometry device on the radial artery.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Changes in subendocardial viability ratio (SEVR)</measure>
    <time_frame>Changes form baseline in SEVR at the 15th, 20th and 25th minutes of the operation</time_frame>
    <description>From the derived central aortic pulse pressure, calculations can be made, using the area under the systolic and diastolic part of the curve.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">25</enrollment>
  <condition>Propofol-anaesthesia Via Target-controlled Infusion</condition>
  <arm_group>
    <arm_group_label>Propofol</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Propofol is administered to all patients via target-controlled infusion (TCI) to reach 4 mcg/ml constant plasma concentration according to the Schneider model during the course of the narcosis.</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Partial pressure of CO2 at the end of an exhaled breath</intervention_name>
    <description>Three previously defined EtCO2 levels (partial pressure of CO2 at the end of an exhaled breath) were adjusted during anesthesia.</description>
    <arm_group_label>Propofol</arm_group_label>
    <other_name>EtCO2</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Propofol</intervention_name>
    <description>Propofol is administered to all patients via target-controlled infusion (TCI) to reach 4 mcg/ml constant plasma concentration according to the Schneider model during the course of the narcosis.</description>
    <arm_group_label>Propofol</arm_group_label>
    <other_name>Diprivan</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Above the age 18&#xD;
&#xD;
          -  American Society of Anesthesiologists (ASA) physical classification I. or II.&#xD;
&#xD;
          -  Patients undergoing elective varicotomy, inguinal hernioplasty or breast surgery in&#xD;
             general anesthesia&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with cerebral, cardiac or systemic vascular disorders (hypertension,&#xD;
             diabetes)&#xD;
&#xD;
          -  Patients receiving medication that affects the blood vessels (antihypertensive,&#xD;
             antidiabetic, antiarrhythmic medications)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>50 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Csilla Molnár, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Debrecen Medical and Health Science Center Department of Anesthesiology and Intensive Care 4032-Debrecen, Nagyerdei krt 98. Hungary Tel/fax: +36-52-255-347</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Debrecen Medical and Health Science Center Department of Anesthesiology and Intensive Care</name>
      <address>
        <city>Debrecen</city>
        <zip>4032</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Hungary</country>
  </location_countries>
  <results_reference>
    <citation>Fulesdi B, Limburg M, Bereczki D, Kaplar M, Molnar C, Kappelmayer J, Neuwirth G, Csiba L. Cerebrovascular reactivity and reserve capacity in type II diabetes mellitus. J Diabetes Complications. 1999 Jul-Aug;13(4):191-9. doi: 10.1016/s1056-8727(99)00044-6.</citation>
    <PMID>10616858</PMID>
  </results_reference>
  <results_reference>
    <citation>McCulloch TJ, Thompson CL, Turner MJ. A randomized crossover comparison of the effects of propofol and sevoflurane on cerebral hemodynamics during carotid endarterectomy. Anesthesiology. 2007 Jan;106(1):56-64. doi: 10.1097/00000542-200701000-00012.</citation>
    <PMID>17197845</PMID>
  </results_reference>
  <results_reference>
    <citation>Lan YC, Shen CH, Kang HM, Chong FC. Pulse transit time reveals drug kinetics on vascular changes affected by propofol. Comput Methods Biomech Biomed Engin. 2012;15(9):949-52. doi: 10.1080/10255842.2011.567981. Epub 2011 May 24.</citation>
    <PMID>21547779</PMID>
  </results_reference>
  <results_reference>
    <citation>Strebel S, Kaufmann M, Guardiola PM, Schaefer HG. Cerebral vasomotor responsiveness to carbon dioxide is preserved during propofol and midazolam anesthesia in humans. Anesth Analg. 1994 May;78(5):884-8. doi: 10.1213/00000539-199405000-00009.</citation>
    <PMID>8160985</PMID>
  </results_reference>
  <results_reference>
    <citation>Holzer A, Winter W, Greher M, Reddy M, Stark J, Donner A, Zimpfer M, Illievich UM. A comparison of propofol and sevoflurane anaesthesia: effects on aortic blood flow velocity and middle cerebral artery blood flow velocity. Anaesthesia. 2003 Mar;58(3):217-22. doi: 10.1046/j.1365-2044.2003.03041.x.</citation>
    <PMID>12603451</PMID>
  </results_reference>
  <results_reference>
    <citation>Previgliano IJ. Assessment: transcranial Doppler ultrasonography: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2004 Dec 28;63(12):2457-8; author reply 2457-8. No abstract available.</citation>
    <PMID>15630765</PMID>
  </results_reference>
  <verification_date>March 2017</verification_date>
  <study_first_submitted>July 25, 2014</study_first_submitted>
  <study_first_submitted_qc>July 25, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 29, 2014</study_first_posted>
  <last_update_submitted>March 8, 2017</last_update_submitted>
  <last_update_submitted_qc>March 8, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">March 9, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Debrecen</investigator_affiliation>
    <investigator_full_name>Tamas Vegh, MD</investigator_full_name>
    <investigator_title>assistant lecturer anesthesiologist and intensive care specialist</investigator_title>
  </responsible_party>
  <keyword>Target controlled infusion</keyword>
  <keyword>propofol</keyword>
  <keyword>cerebral vasoreactivity</keyword>
  <keyword>arterial stiffness</keyword>
  <keyword>Transcranial Doppler</keyword>
  <keyword>SphygmoCor</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Propofol</mesh_term>
  </intervention_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/NCT02203097
org study id: 030167-006/2014/OTIG
secondary id: 2345
nct id: NCT02203097
lead sponsor: 
has dmc: Yes
Purpose:

      The purpose of this study is to examine the effect of different carbon-dioxide concentrations
      on cerebral CO2 sensitivity and the resistance and stiffness of systemic arteries during
      anesthesia with target-controlled infusion anesthesia using intravenous propofol. Propofol is
      a widely and commonly used intravenous anaesthetic, that is mainly used for the induction of
      general anesthesia and the maintenance of total intravenous anaesthesia (TIVA).

      Changes in the velocity of cerebral blood flow and arterial stiffness due to the different
      exhaled carbon-dioxide concentrations will allow us to conclude how propofol affects these
      parameters during the course of the narcosis.

      Instruments:

      An ultrasound device called transcranial doppler (TCD) is used to measure the velocity of
      blood flow within a main artery located inside the skull.

      A tonometry device named SphygmoCor is used to assess the pressure wave proceeding in the
      radial artery, from which the stiffness of the systemic vessels can be concluded.

      Measurements:

      - Examinations with the ultrasound and tonometry devices are carried out once before the
      operation, three times during the intervention, with different exhaled CO2 values and once
      after the operation is completed.

      Hypothesis:

      - Propofol alters cerebral carbon-dioxide sensitivity and the stiffness of systemic arteries
      during TCI anaesthesia.
Study protocol:

      - The study is conducted in four stages: in the first stage, measurements are performed
      preoperatively in awake patients. Patients are placed in supine position and mean arterial
      blood pressure (MAP), heart rate, oxygen saturation are measured. The transcranial doppler
      (TCD) probe is fixed in place by applying a headband to maintain a constant angle of
      insonation. Mean blood flow velocity (MBFV) and pulsatility index (PI) in the middle cerebral
      artery (MCA) are obtained. MCA is insonated through the right temporal window by using pulsed
      2 megahertz TCD ultrasound probe. Identification of the MCA is confirmed by using standard
      criteria, at a depth of 45-55 mm. Cerebral CO2 vasoreactivity is calculated as the percentage
      change in MBFV or PI for mmHg change in end-tidal CO2 (ETCO2).

      SphygmoCor is placed on the left radial artery to obtain data about the central aortic blood
      pressure, augmentation pressure (AP) and augmentation index normalised to a 75 beat per
      minute heart rate (Alx75). From the derived aortic pulse, calculations can be made, using the
      area under the systolic and diastolic part of the curve, to determine the heart's ratio of
      oxygen supply and demand, it is called the subendocardial viability ratio (SEVR).

      As part of the premedication each patient receives 100 mg diclofenac per os 30 minutes and
      500 ml Lactated-Ringer infusion 60 minutes prior to the operation.

      Anesthesia is induced and maintained with target-controlled infusion anesthesia (TCI) using
      intravenous propofol at 4 mcg/ml constant plasma concentration. Analgesia is provided by
      using 2 ug/kg sufentanyl bolus dose at the time of induction. Afterwards 0.6 mg/kg rocuronium
      is given for muscle paralysis and subsequently patients were intubated with a suitable
      intratracheal tube. After induction of anaesthesia, the patients are placed on a mechanical
      ventilation system, using a volume-controlled setting with an air and oxygen mixture set to
      0.4 fraction of inspired oxygen (FiO2) , the fresh gas flow rate to 2 l/min. .

      Differences in the depth of anesthesia could influence cerebral activity, thereby cerebral
      metabolism and blood flow. Bispectral index is placed onto every patient in order to assure
      constant depth of anaesthesia during the intervention.

      The second series of TCD and SphygmoCor measurements are performed 20 minutes after the
      respiratory rate is set to maintain end-tidal CO2 at 40 mmHg in order to allow sufficient
      time for equilibrium to be reached and the effect of drugs used for the induction of
      anesthesia to be terminated. Subsequently the examinations are repeated twice again at 35 and
      30 mmHg ETCO2. The measurements were carried out 5-5 minutes after adjusting the minute
      ventilation to reach target ETCO2 values.

      Statistical methods:

      - Comparisons between the preoperative and three intraoperative stages of the study are made
      using repeated measures ANOVA with the Bonferroni post hoc correction. The relationship
      between MBFV, PI and ETCO2 is assessed using linear regression, while the connection between
      SEVR, pulse and Alx75 is calculated with bivariate correlation.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Blood flow velocity in the middle cerebral artery
time frame: Changes from baseline in blood flow velocity at the 15th, 20th and 25th minutes of the operation
description: Systolic, diastolic and mean blood flow velocities are measured with transcranial doppler device.
measure: Arterial wall stiffness of the radial artery
time frame: Changes from baseline in arterial stiffness at the 15th, 20th and 25th minutes of the operation
description: The stiffness of the radial artery is assessed. Stiffness rate is concluded from the augmentation pressure and augmentation index, from which both values are provided by the tonometry device.
measure: Changes in the central systolic and diastolic blood pressure
time frame: Changes from baseline in central blood pressure at the 15th, 20th and 25th minutes of the operation
description: Central blood pressure values are measured by means of tonometry device on the radial artery.
measure: Changes in subendocardial viability ratio (SEVR)
time frame: Changes form baseline in SEVR at the 15th, 20th and 25th minutes of the operation
description: From the derived central aortic pulse pressure, calculations can be made, using the area under the systolic and diastolic part of the curve.
arm group label: Propofol
arm group type: Experimental
description: Propofol is administered to all patients via target-controlled infusion (TCI) to reach 4 mcg/ml constant plasma concentration according to the Schneider model during the course of the narcosis.
intervention type: Procedure
intervention name: Partial pressure of CO2 at the end of an exhaled breath
description: Three previously defined EtCO2 levels (partial pressure of CO2 at the end of an exhaled breath) were adjusted during anesthesia.
arm group label: Propofol
other name: EtCO2
intervention type: Drug
intervention name: Propofol
description: Propofol is administered to all patients via target-controlled infusion (TCI) to reach 4 mcg/ml constant plasma concentration according to the Schneider model during the course of the narcosis.
arm group label: Propofol
other name: Diprivan
criteria: 
gender: All
minimum age: 18 Years
maximum age: 50 Years
healthy volunteers: No
last name: Csilla Molnár, MD, PhD
role: Principal Investigator
affiliation: University of Debrecen Medical and Health Science Center Department of Anesthesiology and Intensive Care 4032-Debrecen, Nagyerdei krt 98. Hungary Tel/fax: +36-52-255-347
facility: 
country: Hungary
citation: Fulesdi B, Limburg M, Bereczki D, Kaplar M, Molnar C, Kappelmayer J, Neuwirth G, Csiba L. Cerebrovascular reactivity and reserve capacity in type II diabetes mellitus. J Diabetes Complications. 1999 Jul-Aug;13(4):191-9. doi: 10.1016/s1056-8727(99)00044-6.
PMID: 10616858
citation: McCulloch TJ, Thompson CL, Turner MJ. A randomized crossover comparison of the effects of propofol and sevoflurane on cerebral hemodynamics during carotid endarterectomy. Anesthesiology. 2007 Jan;106(1):56-64. doi: 10.1097/00000542-200701000-00012.
PMID: 17197845
citation: Lan YC, Shen CH, Kang HM, Chong FC. Pulse transit time reveals drug kinetics on vascular changes affected by propofol. Comput Methods Biomech Biomed Engin. 2012;15(9):949-52. doi: 10.1080/10255842.2011.567981. Epub 2011 May 24.
PMID: 21547779
citation: Strebel S, Kaufmann M, Guardiola PM, Schaefer HG. Cerebral vasomotor responsiveness to carbon dioxide is preserved during propofol and midazolam anesthesia in humans. Anesth Analg. 1994 May;78(5):884-8. doi: 10.1213/00000539-199405000-00009.
PMID: 8160985
citation: Holzer A, Winter W, Greher M, Reddy M, Stark J, Donner A, Zimpfer M, Illievich UM. A comparison of propofol and sevoflurane anaesthesia: effects on aortic blood flow velocity and middle cerebral artery blood flow velocity. Anaesthesia. 2003 Mar;58(3):217-22. doi: 10.1046/j.1365-2044.2003.03041.x.
PMID: 12603451
citation: Previgliano IJ. Assessment: transcranial Doppler ultrasonography: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2004 Dec 28;63(12):2457-8; author reply 2457-8. No abstract available.
PMID: 15630765
responsible party type: Principal Investigator
investigator affiliation: University of Debrecen
investigator full name: Tamas Vegh, MD
investigator title: assistant lecturer anesthesiologist and intensive care specialist
mesh term: Propofol