<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/NCT01715584</url>
  </required_header>
  <id_info>
    <org_study_id>5982</org_study_id>
    <nct_id>NCT01715584</nct_id>
  </id_info>
  <brief_title>Is There an Adverse Drug Reaction Between Renin-Angiotensin System Blockade and Inhaled Anesthetics</brief_title>
  <official_title>Is There an Adverse Drug Reaction Between Renin-Angiotensin System Blockade and Inhaled Anesthetics? - A Pilot Study. Optional Deoxyribo-Nucleic Acid Donation for the Study of Hypertension.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Lawson Health Research Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Western Ontario, Canada</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Lawson Health Research Institute</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      It is controversial whether or not patients whose Renin Angiotensin System is blocked for the&#xD;
      treatment of hypertension suffer increased risk when undergoing surgery and anaesthesia.&#xD;
&#xD;
      The investigators wish to test the hypothesis: Blockade of the Renin Angiotensin System&#xD;
      causes altered dose response under general anaesthesia in a dose dependant manner. The&#xD;
      investigators wish to look for altered responses across the usual anaesthetic dosing range as&#xD;
      measured by blood pressure and heart responses.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      There has been mixed results in retrospective studies examining the effects of renin&#xD;
      angiotensin blockade for the treatment of cardiovascular disease and post operative outcomes.&#xD;
      Studies done in high risk patients have shown increased risk of death if patients are exposed&#xD;
      to angiotensin converting enzyme inhibitors and angiotensin blocking agents.&#xD;
&#xD;
      The hypothesis is that patients exposed to medications that block the renin angiotensin&#xD;
      system have altered dose response (a type of adverse drug reaction) to inhaled anaesthetic&#xD;
      agents in a dose dependant manner as measured by cardiovascular response, specifically&#xD;
      systemic vascular resistance index.&#xD;
&#xD;
      This is a pilot study of hypertensive patients undergoing anaesthesia and composite head and&#xD;
      neck surgery. The patients will be separated into three groups: Angiotensin converting enzyme&#xD;
      inhibitor exposed, Angiotensin Receptor Blocking Agent exposed, and any other treated&#xD;
      hypertension. Following separation into groups based upon preoperative medication exposures&#xD;
      each group will be randomized to determine the order in which two types of inhaled&#xD;
      anaesthetics are administered. Each subject will be randomized to receive either&#xD;
      Sevoflurane/air/oxygen first or Sevoflurane/50 per cent nitrous oxide/oxygen second or vice&#xD;
      versa. The dose of the anaesthetic will be adjusted across the dosing range from 0.8 MAC&#xD;
      (minimum alveolar concentration) to 1.6 MAC in steps of 0.2 MAC.&#xD;
&#xD;
      Each subject will have hemodynamic parameters measured at each dose of anaesthetic at each&#xD;
      MAC. Five measurements of hemodynamic parameters will be recorded to minimize the effects of&#xD;
      surgery on each measurement. The hemodynamic variables will be measured using a Flotrak and&#xD;
      Vigeleo monitor and the quantities to be measured are: heart rate, blood pressure, systemic&#xD;
      vascular resistance, systemic vascular resistance index, cardiac output, cardiac index,&#xD;
      central venous pressure, stroke volume variation.&#xD;
&#xD;
      The subjects are offered the opportunity to donate DNA for future study of hypertension.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>July 2012</start_date>
  <completion_date type="Anticipated">December 31, 2019</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2019</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Systemic Vascular Resistance Index (SVRI)</measure>
    <time_frame>approximately every 5 minutes for 6 hours</time_frame>
    <description>A calculated hemodyamic parameter that assesses the resistance the heart faces to the forward flow of blood. Corrected for body surface area. SVRI = (cardiac output/blood pressure)/body surface area.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Heart Rate</measure>
    <time_frame>approximately every 5 minutes for 6 hours</time_frame>
    <description>number of heart beats per minute</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Systolic Blood Pressure</measure>
    <time_frame>approximately every 5 minutes for 6 hours</time_frame>
    <description>force of blood flow (measured in mmHg)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Diastolic Blood Pressure</measure>
    <time_frame>approximately every 5 minutes for 6 hours</time_frame>
    <description>force of blood flow (measured in mmHg)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Central Venous Pressure</measure>
    <time_frame>approximately every 5 minutes for 6 hours</time_frame>
    <description>force of blood flow returning to the heart (measured in mmHg)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cardiac Output (CO)</measure>
    <time_frame>approximately every 5 minutes for 6 hours</time_frame>
    <description>Calculated volume of blood flow in Litres per minute(measured in mmHg). Cardiac Output = mean arterial pressure/systemic vascular resistance.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cardiac Index (CI)</measure>
    <time_frame>approximately every 5 minutes for 6 hours</time_frame>
    <description>Calculated volume of blood flow in Litres per minute(measured in mmHg/m2), corrected for body surface area. Cardiac Output = (mean arterial pressure/systemic vascular resistance)/body surface area.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Stroke Volume Varriation</measure>
    <time_frame>approximately every 5 minutes for 6 hours</time_frame>
    <description>Calculated variation in stroke volume between heart beats (blood pressure = stroke volume x rate x systemic vascular resisitance).measured in real time throughout experiment, and at each anesthetic concentration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Systemic Vascular Resistance</measure>
    <time_frame>approximately every 5 minutes for 6 hours</time_frame>
    <description>A calculated parameter reflecting the resistance the heart faces to the forward flow of blood. Not corrected for body surface area. SVR = cardiac ouptut / blood pressure. Measured at each concentraion of inhaled anesthetic</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">80</enrollment>
  <condition>Hypertension</condition>
  <arm_group>
    <arm_group_label>Angiotensin Converting Enzyme Exposed</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Sevoflurane/oxygen/air/nitrous oxide&#xD;
Hypertensive patients exposed to Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors)will make up this arm.&#xD;
Preoperative Exposure to any of the following Angiotensin Converting Enzyme Inhibitors Enalapril (Vasotec/Renitec) Ramipril (Altace/Prilace/Ramace/Ramiwin/Triatec/Tritace) Quinapril (Accupril) Perindopril (Coversyl/Aceon) Lisinopril (Listril/Lopril/Novatec/Prinivil/Zestril) Benazepril (Lotensin) Imidapril (Tanatril) Zofenopril (Zofecard) Trandolapril (Mavik/Odrik/Gopten) Fosinopril (Fositen/Monopril)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Angiotensin Receptor Blocker Exposed</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Sevoflurane/oxygen/air/nitrous oxide&#xD;
Hypertensive patients exposed to Angiotensin Receptor Blocking Agents (ARBs).&#xD;
Preoperative Exposure to any of the following Angiotensin II Receptor Blocking Agents Losartan(Cozaar) Candesartan (Atacand) Valsartan (Diovan) Irbesartan (Avapro) Telmisartan (Micardis) Eprosartan (Teveten) Olemisartan (Benicar) Azilsartan (Edarbi)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Non ACE/ARB Exposed</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Sevoflurane/oxygen/air/nitrous oxide&#xD;
Hypertensive patients not exposed to angiotensin converting enzyme inhibitors or Angiotensin receptor blocking agents will be put into this arm.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Sevoflurane/oxygen/air/nitrous oxide</intervention_name>
    <description>Patients in each arm will be randomized to receive either: 50 per cent oxygen, air, and sevoflurane or 50% nitrous oxide, oxygen and sevoflurane. They will then cross over to the other gas mixture. The depth of each the anesthetic will be varied from 0.8 MAC (minimum alveolar concentration) to 1.6 MAC in 0.2 MAC steps. Hemodyamic variables will be measured at each anesthetic concentration (average of five measurements). Time will be allowed for anesthetic agent equilibration. Paralysis and analgesia using rocuronium and fentanyl will be provided to ensure patients do not move at low (less than 1.0 MAC. It is estimated the time for the cross over experiment will be approximately six hours.</description>
    <arm_group_label>Angiotensin Converting Enzyme Exposed</arm_group_label>
    <arm_group_label>Angiotensin Receptor Blocker Exposed</arm_group_label>
    <arm_group_label>Non ACE/ARB Exposed</arm_group_label>
    <other_name>Sevoflurane (Sevorane, Ultane, Sojourn)</other_name>
    <other_name>1,1,1,3,3,3-hexafluoro-2-(fluoromethoxy)propane</other_name>
    <other_name>fluoromethyl hexafluoroisopropyl ether</other_name>
    <other_name>Nitrous oxide</other_name>
    <other_name>oxgyen</other_name>
    <other_name>air</other_name>
    <other_name>nitrogen</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  age over 40&#xD;
&#xD;
          -  composite head and neck tumor resection&#xD;
&#xD;
          -  treated hypertension&#xD;
&#xD;
          -  hypertension medications taken on morning of surgery (except diuretics)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  patient refusal&#xD;
&#xD;
          -  age less than 40 or over 80 years&#xD;
&#xD;
          -  combined surgical procedures&#xD;
&#xD;
          -  emergency surgery&#xD;
&#xD;
          -  Left ventricular ejection fraction less than 50 per cent&#xD;
&#xD;
          -  calculated creatinine clearance less than 60 mL per minute&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Craig J Railton, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Lawson Health Research Institute</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Craig J Railton, MD PhD FRCPC</last_name>
    <phone>519 685 8500</phone>
    <phone_ext>58525</phone_ext>
    <email>Craig.Railton@lhsc.on.ca</email>
  </overall_contact>
  <location>
    <facility>
      <name>London Health Sciences Centre - Victoria Campus</name>
      <address>
        <city>London</city>
        <state>Ontario</state>
        <zip>N6A 5W9</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Craig J Railton, MD, PhD</last_name>
      <phone>519 685 8500</phone>
      <phone_ext>58525</phone_ext>
      <email>Craig.Railton@lhsc.on.ca</email>
    </contact>
    <investigator>
      <last_name>Craig J Railton, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Jonathan Fairbairn, BSc</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>George Nicoloau, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Robert Gros, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Jason Franklin, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>John Yoo, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Kevin Fung, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Anthony Nichols, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Danielle McNeil, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <link>
    <url>http://www.ncbi.nlm.nih.gov/pubmed/20524103</url>
    <description>Relevant Reference</description>
  </link>
  <link>
    <url>http://www.ncbi.nlm.nih.gov/pubmed?term=J%20Am%20Coll%20Cardiol%202009%3B%2054%3A1778-84</url>
    <description>Relevant Reference</description>
  </link>
  <verification_date>August 2017</verification_date>
  <study_first_submitted>October 1, 2012</study_first_submitted>
  <study_first_submitted_qc>October 24, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 29, 2012</study_first_posted>
  <last_update_submitted>August 22, 2017</last_update_submitted>
  <last_update_submitted_qc>August 22, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">August 23, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Lawson Health Research Institute</investigator_affiliation>
    <investigator_full_name>Craig Railton</investigator_full_name>
    <investigator_title>Assistant Professor</investigator_title>
  </responsible_party>
  <keyword>Hypertension</keyword>
  <keyword>Sevoflurane</keyword>
  <keyword>Inhaled Anesthetic</keyword>
  <keyword>Angiotensin Converting Enzyme Inhibitor</keyword>
  <keyword>Angiotensin II Receptor Blocking Agent</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypertension</mesh_term>
    <mesh_term>Drug-Related Side Effects and Adverse Reactions</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nitrous Oxide</mesh_term>
    <mesh_term>Sevoflurane</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/NCT01715584
org study id: 5982
nct id: NCT01715584
lead sponsor: 
collaborator: 
has dmc: No
It is controversial whether or not patients whose Renin Angiotensin System is blocked for the
      treatment of hypertension suffer increased risk when undergoing surgery and anaesthesia.

      The investigators wish to test the hypothesis: Blockade of the Renin Angiotensin System
      causes altered dose response under general anaesthesia in a dose dependant manner. The
      investigators wish to look for altered responses across the usual anaesthetic dosing range as
      measured by blood pressure and heart responses.
There has been mixed results in retrospective studies examining the effects of renin
      angiotensin blockade for the treatment of cardiovascular disease and post operative outcomes.
      Studies done in high risk patients have shown increased risk of death if patients are exposed
      to angiotensin converting enzyme inhibitors and angiotensin blocking agents.

      The hypothesis is that patients exposed to medications that block the renin angiotensin
      system have altered dose response (a type of adverse drug reaction) to inhaled anaesthetic
      agents in a dose dependant manner as measured by cardiovascular response, specifically
      systemic vascular resistance index.

      This is a pilot study of hypertensive patients undergoing anaesthesia and composite head and
      neck surgery. The patients will be separated into three groups: Angiotensin converting enzyme
      inhibitor exposed, Angiotensin Receptor Blocking Agent exposed, and any other treated
      hypertension. Following separation into groups based upon preoperative medication exposures
      each group will be randomized to determine the order in which two types of inhaled
      anaesthetics are administered. Each subject will be randomized to receive either
      Sevoflurane/air/oxygen first or Sevoflurane/50 per cent nitrous oxide/oxygen second or vice
      versa. The dose of the anaesthetic will be adjusted across the dosing range from 0.8 MAC
      (minimum alveolar concentration) to 1.6 MAC in steps of 0.2 MAC.

      Each subject will have hemodynamic parameters measured at each dose of anaesthetic at each
      MAC. Five measurements of hemodynamic parameters will be recorded to minimize the effects of
      surgery on each measurement. The hemodynamic variables will be measured using a Flotrak and
      Vigeleo monitor and the quantities to be measured are: heart rate, blood pressure, systemic
      vascular resistance, systemic vascular resistance index, cardiac output, cardiac index,
      central venous pressure, stroke volume variation.

      The subjects are offered the opportunity to donate DNA for future study of hypertension.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Systemic Vascular Resistance Index (SVRI)
time frame: approximately every 5 minutes for 6 hours
description: A calculated hemodyamic parameter that assesses the resistance the heart faces to the forward flow of blood. Corrected for body surface area. SVRI = (cardiac output/blood pressure)/body surface area.
measure: Heart Rate
time frame: approximately every 5 minutes for 6 hours
description: number of heart beats per minute
measure: Systolic Blood Pressure
time frame: approximately every 5 minutes for 6 hours
description: force of blood flow (measured in mmHg)
measure: Diastolic Blood Pressure
time frame: approximately every 5 minutes for 6 hours
description: force of blood flow (measured in mmHg)
measure: Central Venous Pressure
time frame: approximately every 5 minutes for 6 hours
description: force of blood flow returning to the heart (measured in mmHg)
measure: Cardiac Output (CO)
time frame: approximately every 5 minutes for 6 hours
description: Calculated volume of blood flow in Litres per minute(measured in mmHg). Cardiac Output = mean arterial pressure/systemic vascular resistance.
measure: Cardiac Index (CI)
time frame: approximately every 5 minutes for 6 hours
description: Calculated volume of blood flow in Litres per minute(measured in mmHg/m2), corrected for body surface area. Cardiac Output = (mean arterial pressure/systemic vascular resistance)/body surface area.
measure: Stroke Volume Varriation
time frame: approximately every 5 minutes for 6 hours
description: Calculated variation in stroke volume between heart beats (blood pressure = stroke volume x rate x systemic vascular resisitance).measured in real time throughout experiment, and at each anesthetic concentration
measure: Systemic Vascular Resistance
time frame: approximately every 5 minutes for 6 hours
description: A calculated parameter reflecting the resistance the heart faces to the forward flow of blood. Not corrected for body surface area. SVR = cardiac ouptut / blood pressure. Measured at each concentraion of inhaled anesthetic
arm group label: Angiotensin Converting Enzyme Exposed
arm group type: Other
description: Sevoflurane/oxygen/air/nitrous oxide
Hypertensive patients exposed to Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors)will make up this arm.
Preoperative Exposure to any of the following Angiotensin Converting Enzyme Inhibitors Enalapril (Vasotec/Renitec) Ramipril (Altace/Prilace/Ramace/Ramiwin/Triatec/Tritace) Quinapril (Accupril) Perindopril (Coversyl/Aceon) Lisinopril (Listril/Lopril/Novatec/Prinivil/Zestril) Benazepril (Lotensin) Imidapril (Tanatril) Zofenopril (Zofecard) Trandolapril (Mavik/Odrik/Gopten) Fosinopril (Fositen/Monopril)
arm group label: Angiotensin Receptor Blocker Exposed
arm group type: Other
description: Sevoflurane/oxygen/air/nitrous oxide
Hypertensive patients exposed to Angiotensin Receptor Blocking Agents (ARBs).
Preoperative Exposure to any of the following Angiotensin II Receptor Blocking Agents Losartan(Cozaar) Candesartan (Atacand) Valsartan (Diovan) Irbesartan (Avapro) Telmisartan (Micardis) Eprosartan (Teveten) Olemisartan (Benicar) Azilsartan (Edarbi)
arm group label: Non ACE/ARB Exposed
arm group type: Other
description: Sevoflurane/oxygen/air/nitrous oxide
Hypertensive patients not exposed to angiotensin converting enzyme inhibitors or Angiotensin receptor blocking agents will be put into this arm.
intervention type: Other
intervention name: Sevoflurane/oxygen/air/nitrous oxide
description: Patients in each arm will be randomized to receive either: 50 per cent oxygen, air, and sevoflurane or 50% nitrous oxide, oxygen and sevoflurane. They will then cross over to the other gas mixture. The depth of each the anesthetic will be varied from 0.8 MAC (minimum alveolar concentration) to 1.6 MAC in 0.2 MAC steps. Hemodyamic variables will be measured at each anesthetic concentration (average of five measurements). Time will be allowed for anesthetic agent equilibration. Paralysis and analgesia using rocuronium and fentanyl will be provided to ensure patients do not move at low (less than 1.0 MAC. It is estimated the time for the cross over experiment will be approximately six hours.
arm group label: Angiotensin Converting Enzyme Exposed
arm group label: Angiotensin Receptor Blocker Exposed
arm group label: Non ACE/ARB Exposed
other name: Sevoflurane (Sevorane, Ultane, Sojourn)
other name: 1,1,1,3,3,3-hexafluoro-2-(fluoromethoxy)propane
other name: fluoromethyl hexafluoroisopropyl ether
other name: Nitrous oxide
other name: oxgyen
other name: air
other name: nitrogen
criteria: 
gender: All
minimum age: 40 Years
maximum age: N/A
healthy volunteers: No
last name: Craig J Railton, MD, PhD
role: Principal Investigator
affiliation: Lawson Health Research Institute
last name: Craig J Railton, MD PhD FRCPC
phone: 519 685 8500
phone ext: 58525
email: Craig.Railton@lhsc.on.ca
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
country: Canada
url: http://www.ncbi.nlm.nih.gov/pubmed/20524103
description: Relevant Reference
url: http://www.ncbi.nlm.nih.gov/pubmed?term=J%20Am%20Coll%20Cardiol%202009%3B%2054%3A1778-84
description: Relevant Reference
responsible party type: Principal Investigator
investigator affiliation: Lawson Health Research Institute
investigator full name: Craig Railton
investigator title: Assistant Professor
mesh term: Hypertension
mesh term: Drug-Related Side Effects and Adverse Reactions
mesh term: Nitrous Oxide
mesh term: Sevoflurane