<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/NCT03816280</url>
  </required_header>
  <id_info>
    <org_study_id>WHO2788-b</org_study_id>
    <nct_id>NCT03816280</nct_id>
  </id_info>
  <brief_title>Cerebrovascular Effects of the Use of Alpha-stat or pH-stat Management of Cardiopulmonary Bypass</brief_title>
  <official_title>Cerebrovascular Effects of the Use of Alpha-stat or pH-stat Management of Cardiopulmonary Bypass</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Szeged University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>GINOP</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Hungarian Basic Research Council</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Szeged University</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>
      Type 2 diabetes mellitus (T2DM) poses a significant burden on the patients and the health&#xD;
      care system. The increasing number of surgery performed in elderly population results in an&#xD;
      increased number of perioperative T2DM-related adverse effects. T2DM has a prevalence of&#xD;
      30-40% in a population undergoing cardiovascular surgery. Cardiac surgery, especially&#xD;
      cardiopulmonary bypass (CPB) is also known to deteriorate cerebral oxygenation.&#xD;
&#xD;
      Furthermore, acid-base balance of patients undergoing CPB can be managed using two main&#xD;
      regimes: alpha-stat and pH-stat. The use of pH-stat acid-base management involves maintaining&#xD;
      the patient's temperature-corrected pH at a constant level (7.40) and maintaining normocapnia&#xD;
      (pCO2 of 40 mmHg). Alpha-stat acid-base management on the other hand is performed by&#xD;
      maintaining the ionization state of histidine by keeping the pH stable when a standardized&#xD;
      temperature of 37C is used. Therefore, while a constant pH (7.40) and normocapnia (pCO2 of 40&#xD;
      mmHg) are targeted when measured at 37C, the hypothermia applied during CPB will result in a&#xD;
      lower pCO2 and in a relative respiratory alkalosis. Previous studies investigating alpha-stat&#xD;
      and pH-stat managements demonstrated increased jugular venous oxygen concentrations when&#xD;
      pH-stat management was applied.&#xD;
&#xD;
      Therefore, our study is aimed at characterizing the effects of an alpha-stat or pH-stat&#xD;
      acid-base management regime on the cerebral oxygenation, parameters of regional cerebral&#xD;
      oxygen supply and demand during and following CPB in diabetic patients. These parameters&#xD;
      include regional cerebral tissue oxygen saturation (rSO2), central venous oxygen saturation&#xD;
      ScvO2) and the physiological saturation gap between ScvO2 and rSO2 (gSO2).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      One hour before the surgery, patients are premedicated with lorazepam (per os, 2.5 mg).&#xD;
      Induction of anaesthesia is achieved by iv midazolam (30 μg/kg), sufentanyl (0.4-0.5 μg/kg),&#xD;
      and propofol (0.3-0.5 mg/kg), and iv propofol (50 mg/kg/min) is administered to maintain&#xD;
      anaesthesia. Intravenous boluses of rocuronium (0.6 mg/kg for induction and 0.2 mg/kg every&#xD;
      30 minutes for maintenance) is administered iv to ensure neuromuscular blockade. A cuffed&#xD;
      tracheal tube (internal diameter of 7, 8, or 9 mm) is used for tracheal intubation, and&#xD;
      patients are mechanically ventilated (Dräger Zeus, Lübeck, Germany) in volume-controlled mode&#xD;
      with decelerating flow. A tidal volume of 7 ml/kg and a positive end-expiratory pressure of 4&#xD;
      cmH2O are applied, and the ventilation frequency is adjusted to 12-14 breaths/min to maintain&#xD;
      end-tidal CO2 partial pressure of 36 38 mmHg. Mechanical ventilation is performed with a&#xD;
      fraction of inspired oxygen of 0.5 before CPB, and it is increased to 0.8 after CPB. As a&#xD;
      standard part of the cardiac anaesthesia procedure, oesophageal and rectal temperature probes&#xD;
      are introduced, and a central venous line is inserted into the right jugular vein. The left&#xD;
      radial artery is also cannulated to monitor systolic, diastolic and mean arterial (MAP) blood&#xD;
      pressures and arterial blood gas samples.&#xD;
&#xD;
      The membrane oxygenator is primed with 1,500 ml lactated Ringer's solution prior to CPB.&#xD;
      Intravenous heparin (300 U/kg) is injected into the patient, to achieve an activated clotting&#xD;
      time of 400 s during CPB procedures. During CPB, mild hypothermia is allowed, the mechanical&#xD;
      ventilation is stopped, and the ventilator is disconnected without applying positive airway&#xD;
      pressure. Before restoring ventilation, the lungs are inflated 3-5 times to a peak airway&#xD;
      pressure of 30 cmH2O to facilitate lung recruitment.&#xD;
&#xD;
      After securing arterial and peripheral venous lines and placement of NIRS and entropy&#xD;
      sensors, data collection is initiated immediately before anesthesia induction in all groups&#xD;
      of patients. Since catheterization of the jugular vein is scheduled after anesthesia&#xD;
      induction, ScvO2 and gSO2 data are not available at the first protocol stage. After induction&#xD;
      and before surgical incision, all measurements are repeated. The whole data set is registered&#xD;
      at the beginning of CPB after clamping the aorta and 5 min before the end of CPB. The final&#xD;
      stage of the protocol is allocated to the end of the operation after sternal closure. All&#xD;
      invasive (i.e. arterial and venous blood gas) and non-invasive (i.e. NIRS) data are&#xD;
      registered simultaneously at each protocol stage.&#xD;
&#xD;
      Sample sizes are estimated to enable the detection of a 10% difference in the primary outcome&#xD;
      parameter gSO2 that we considered clinically significant. Accordingly, sample-size estimation&#xD;
      based on an ANOVA test with 4 groups of patients (diabetic and control patients undergoing&#xD;
      CPB with alpha-stat or pH-stat acid-base regime) indicated that 100 patients were required in&#xD;
      each group to detect a significant difference between the protocol groups.&#xD;
&#xD;
      Two-way repeated measures ANOVA with the inclusion of an interaction term is used for all&#xD;
      measured variables with the protocol stage as within-subject factor (protocol stages) and&#xD;
      group allocation as between-subject factor to establish the effects of T2DM and the acid-base&#xD;
      management regime on the parameters of cerebral oxygenation. At half-way of the data&#xD;
      collection, an interim analyses will be performed and the further data collection will be&#xD;
      proceeded based on the results of this analysis.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">February 1, 2019</start_date>
  <completion_date type="Anticipated">July 2020</completion_date>
  <primary_completion_date type="Anticipated">July 2020</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Cerebral tissue oxygen saturation</measure>
    <time_frame>Intraoperative interval during cardiac surgery starting from anaesthesia induction until end of the surgery. (approx. 180 minutes, measurements at ~0-40-140-160 minutes).</time_frame>
    <description>The spatially resolved continuous-wave NIRS technique is applied to estimate cerebral tissue oxygen saturation. This monitor uses two different wavelengths (730 and 810 nm) and has two detectors positioned 3 and 4 cm from the light source. Computing the differences between the intensity of the emitted and the reflected light with two receivers allows the measurement of the oxygen saturation of the cerebral cortex. In this study, two adult sensors are applied on the left and right sides of the patient's forehead symmetrically, and the cerebral-tissue oxygen saturation is monitored continuously during the surgical procedures and the data are registered in each protocol stage. The mean value of the rSO2 measured by the sensors is calculated for each protocol stage and used for further analyses.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Central venous oxygen saturation</measure>
    <time_frame>Intraoperative interval during cardiac surgery starting from anaesthesia induction until end of the surgery. (approx. 180 minutes, measurements at ~0-40-140-160 minutes).</time_frame>
    <description>The central venous oxygen saturation is measured from central venous blood samples (Radiometer ABL 505, Copenhagen, Denmark). The proper positioning of the central venous catheter is verified by the surgeon via manually palpating the catheter tip.</description>
  </primary_outcome>
  <number_of_groups>4</number_of_groups>
  <enrollment type="Anticipated">200</enrollment>
  <condition>Diabetes Mellitus</condition>
  <condition>Cardiac Surgical Procedures</condition>
  <arm_group>
    <arm_group_label>Group T2DM-alpha</arm_group_label>
    <description>Patients with diabetes mellitus undergoing CPB with alpha-stat acid-base management</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group T2DM-pH</arm_group_label>
    <description>Patients with diabetes mellitus undergoing CPB with pH-stat acid-base management</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group Ctrl-alpha</arm_group_label>
    <description>Control patients undergoing CPB with alpha-stat acid-base management</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group Ctrl-pH</arm_group_label>
    <description>Control patients undergoing CPB with pH-stat acid-base management</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Elective cardiopulmonary bypass (CPB)</intervention_name>
    <description>All groups undergo elective cardiopulmonary bypass (CPB)</description>
    <arm_group_label>Group Ctrl-alpha</arm_group_label>
    <arm_group_label>Group Ctrl-pH</arm_group_label>
    <arm_group_label>Group T2DM-alpha</arm_group_label>
    <arm_group_label>Group T2DM-pH</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Alpha-stat acid-base management</intervention_name>
    <description>Acid-base status during CPB will be maintained using the alpha-stat regime</description>
    <arm_group_label>Group Ctrl-alpha</arm_group_label>
    <arm_group_label>Group T2DM-alpha</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>pH-stat acid-base management</intervention_name>
    <description>Acid-base status during CPB will be maintained using the pH-stat regime</description>
    <arm_group_label>Group Ctrl-pH</arm_group_label>
    <arm_group_label>Group T2DM-pH</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        The patients enrolled at the Second Department of Internal Medicine and Cardiology Centre&#xD;
        Cardiac Surgical Unit, University of Szeged&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients undergoing cardiac surgery with or without diabetes mellitus&#xD;
&#xD;
          -  age between 18-80 years&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  patients older than 80 years of age&#xD;
&#xD;
          -  poor ejection fraction (&lt;40%)&#xD;
&#xD;
          -  unilateral internal carotid stenosis (&gt;75%)&#xD;
&#xD;
          -  medical history of smoking&#xD;
&#xD;
          -  medical history of chronic obstructive pulmonary disease&#xD;
&#xD;
          -  medical history of stroke&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Barna Babik, MD, PhD</last_name>
    <phone>+36 20 3876480</phone>
    <phone_ext>+36 62 542349</phone_ext>
    <email>babikbarna@gmail.com</email>
  </overall_contact>
  <location>
    <facility>
      <name>Cardiology Centre Cardiac Surgical Unit and Second Department of Internal Medicine, University of Szeged</name>
      <address>
        <city>Szeged</city>
        <state>Csongrad Megye</state>
        <zip>6725</zip>
        <country>Hungary</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Barna Babik, MD, PhD</last_name>
      <phone>+36 62 542349</phone>
      <email>babikbarna@gmail.com</email>
    </contact>
    <investigator>
      <last_name>Barna Babik, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Ferenc Petak, PhD, DSc</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Gergely Fodor, MD, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Roberta Sudy, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Liliana Kiss</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Adam L Balogh, MD, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Hungary</country>
  </location_countries>
  <verification_date>May 2019</verification_date>
  <study_first_submitted>January 22, 2019</study_first_submitted>
  <study_first_submitted_qc>January 22, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 25, 2019</study_first_posted>
  <last_update_submitted>May 14, 2019</last_update_submitted>
  <last_update_submitted_qc>May 14, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">May 16, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Szeged University</investigator_affiliation>
    <investigator_full_name>Barna Babik</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>Spectroscopy, Near-Infrared</keyword>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03816280
org study id: WHO2788-b
nct id: NCT03816280
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Type 2 diabetes mellitus (T2DM) poses a significant burden on the patients and the health
      care system. The increasing number of surgery performed in elderly population results in an
      increased number of perioperative T2DM-related adverse effects. T2DM has a prevalence of
      30-40% in a population undergoing cardiovascular surgery. Cardiac surgery, especially
      cardiopulmonary bypass (CPB) is also known to deteriorate cerebral oxygenation.

      Furthermore, acid-base balance of patients undergoing CPB can be managed using two main
      regimes: alpha-stat and pH-stat. The use of pH-stat acid-base management involves maintaining
      the patient's temperature-corrected pH at a constant level (7.40) and maintaining normocapnia
      (pCO2 of 40 mmHg). Alpha-stat acid-base management on the other hand is performed by
      maintaining the ionization state of histidine by keeping the pH stable when a standardized
      temperature of 37C is used. Therefore, while a constant pH (7.40) and normocapnia (pCO2 of 40
      mmHg) are targeted when measured at 37C, the hypothermia applied during CPB will result in a
      lower pCO2 and in a relative respiratory alkalosis. Previous studies investigating alpha-stat
      and pH-stat managements demonstrated increased jugular venous oxygen concentrations when
      pH-stat management was applied.

      Therefore, our study is aimed at characterizing the effects of an alpha-stat or pH-stat
      acid-base management regime on the cerebral oxygenation, parameters of regional cerebral
      oxygen supply and demand during and following CPB in diabetic patients. These parameters
      include regional cerebral tissue oxygen saturation (rSO2), central venous oxygen saturation
      ScvO2) and the physiological saturation gap between ScvO2 and rSO2 (gSO2).
One hour before the surgery, patients are premedicated with lorazepam (per os, 2.5 mg).
      Induction of anaesthesia is achieved by iv midazolam (30 μg/kg), sufentanyl (0.4-0.5 μg/kg),
      and propofol (0.3-0.5 mg/kg), and iv propofol (50 mg/kg/min) is administered to maintain
      anaesthesia. Intravenous boluses of rocuronium (0.6 mg/kg for induction and 0.2 mg/kg every
      30 minutes for maintenance) is administered iv to ensure neuromuscular blockade. A cuffed
      tracheal tube (internal diameter of 7, 8, or 9 mm) is used for tracheal intubation, and
      patients are mechanically ventilated (Dräger Zeus, Lübeck, Germany) in volume-controlled mode
      with decelerating flow. A tidal volume of 7 ml/kg and a positive end-expiratory pressure of 4
      cmH2O are applied, and the ventilation frequency is adjusted to 12-14 breaths/min to maintain
      end-tidal CO2 partial pressure of 36 38 mmHg. Mechanical ventilation is performed with a
      fraction of inspired oxygen of 0.5 before CPB, and it is increased to 0.8 after CPB. As a
      standard part of the cardiac anaesthesia procedure, oesophageal and rectal temperature probes
      are introduced, and a central venous line is inserted into the right jugular vein. The left
      radial artery is also cannulated to monitor systolic, diastolic and mean arterial (MAP) blood
      pressures and arterial blood gas samples.

      The membrane oxygenator is primed with 1,500 ml lactated Ringer's solution prior to CPB.
      Intravenous heparin (300 U/kg) is injected into the patient, to achieve an activated clotting
      time of 400 s during CPB procedures. During CPB, mild hypothermia is allowed, the mechanical
      ventilation is stopped, and the ventilator is disconnected without applying positive airway
      pressure. Before restoring ventilation, the lungs are inflated 3-5 times to a peak airway
      pressure of 30 cmH2O to facilitate lung recruitment.

      After securing arterial and peripheral venous lines and placement of NIRS and entropy
      sensors, data collection is initiated immediately before anesthesia induction in all groups
      of patients. Since catheterization of the jugular vein is scheduled after anesthesia
      induction, ScvO2 and gSO2 data are not available at the first protocol stage. After induction
      and before surgical incision, all measurements are repeated. The whole data set is registered
      at the beginning of CPB after clamping the aorta and 5 min before the end of CPB. The final
      stage of the protocol is allocated to the end of the operation after sternal closure. All
      invasive (i.e. arterial and venous blood gas) and non-invasive (i.e. NIRS) data are
      registered simultaneously at each protocol stage.

      Sample sizes are estimated to enable the detection of a 10% difference in the primary outcome
      parameter gSO2 that we considered clinically significant. Accordingly, sample-size estimation
      based on an ANOVA test with 4 groups of patients (diabetic and control patients undergoing
      CPB with alpha-stat or pH-stat acid-base regime) indicated that 100 patients were required in
      each group to detect a significant difference between the protocol groups.

      Two-way repeated measures ANOVA with the inclusion of an interaction term is used for all
      measured variables with the protocol stage as within-subject factor (protocol stages) and
      group allocation as between-subject factor to establish the effects of T2DM and the acid-base
      management regime on the parameters of cerebral oxygenation. At half-way of the data
      collection, an interim analyses will be performed and the further data collection will be
      proceeded based on the results of this analysis.
observational model: Case-Control
time perspective: Prospective
measure: Cerebral tissue oxygen saturation
time frame: Intraoperative interval during cardiac surgery starting from anaesthesia induction until end of the surgery. (approx. 180 minutes, measurements at ~0-40-140-160 minutes).
description: The spatially resolved continuous-wave NIRS technique is applied to estimate cerebral tissue oxygen saturation. This monitor uses two different wavelengths (730 and 810 nm) and has two detectors positioned 3 and 4 cm from the light source. Computing the differences between the intensity of the emitted and the reflected light with two receivers allows the measurement of the oxygen saturation of the cerebral cortex. In this study, two adult sensors are applied on the left and right sides of the patient's forehead symmetrically, and the cerebral-tissue oxygen saturation is monitored continuously during the surgical procedures and the data are registered in each protocol stage. The mean value of the rSO2 measured by the sensors is calculated for each protocol stage and used for further analyses.
measure: Central venous oxygen saturation
time frame: Intraoperative interval during cardiac surgery starting from anaesthesia induction until end of the surgery. (approx. 180 minutes, measurements at ~0-40-140-160 minutes).
description: The central venous oxygen saturation is measured from central venous blood samples (Radiometer ABL 505, Copenhagen, Denmark). The proper positioning of the central venous catheter is verified by the surgeon via manually palpating the catheter tip.
arm group label: Group T2DM-alpha
description: Patients with diabetes mellitus undergoing CPB with alpha-stat acid-base management
arm group label: Group T2DM-pH
description: Patients with diabetes mellitus undergoing CPB with pH-stat acid-base management
arm group label: Group Ctrl-alpha
description: Control patients undergoing CPB with alpha-stat acid-base management
arm group label: Group Ctrl-pH
description: Control patients undergoing CPB with pH-stat acid-base management
intervention type: Procedure
intervention name: Elective cardiopulmonary bypass (CPB)
description: All groups undergo elective cardiopulmonary bypass (CPB)
arm group label: Group Ctrl-alpha
arm group label: Group Ctrl-pH
arm group label: Group T2DM-alpha
arm group label: Group T2DM-pH
intervention type: Procedure
intervention name: Alpha-stat acid-base management
description: Acid-base status during CPB will be maintained using the alpha-stat regime
arm group label: Group Ctrl-alpha
arm group label: Group T2DM-alpha
intervention type: Procedure
intervention name: pH-stat acid-base management
description: Acid-base status during CPB will be maintained using the pH-stat regime
arm group label: Group Ctrl-pH
arm group label: Group T2DM-pH
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Barna Babik, MD, PhD
phone: +36 20 3876480
phone ext: +36 62 542349
email: babikbarna@gmail.com
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
country: Hungary
responsible party type: Principal Investigator
investigator affiliation: Szeged University
investigator full name: Barna Babik
investigator title: Professor
sharing ipd: Undecided