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Is There an Adverse Drug Reaction Between Renin-Angiotensin System Blockade and Inhaled Anesthetics

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2012 by Lawson Health Research Institute
Sponsor:
Collaborator:
University of Western Ontario, Canada
Information provided by (Responsible Party):
Craig Railton, Lawson Health Research Institute
ClinicalTrials.gov Identifier:
NCT01715584
First received: October 1, 2012
Last updated: October 24, 2012
Last verified: October 2012
  Purpose

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.


Condition Intervention Phase
Hypertension
Other: Sevoflurane/oxygen/air/nitrous oxide
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Basic Science
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.

Resource links provided by NLM:


Further study details as provided by Lawson Health Research Institute:

Primary Outcome Measures:
  • Systemic Vascular Resistance Index (SVRI) [ Time Frame: approximately every 5 minutes for 6 hours ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Heart Rate [ Time Frame: approximately every 5 minutes for 6 hours ] [ Designated as safety issue: No ]
    number of heart beats per minute

  • Systolic Blood Pressure [ Time Frame: approximately every 5 minutes for 6 hours ] [ Designated as safety issue: No ]
    force of blood flow (measured in mmHg)

  • Diastolic Blood Pressure [ Time Frame: approximately every 5 minutes for 6 hours ] [ Designated as safety issue: No ]
    force of blood flow (measured in mmHg)

  • Central Venous Pressure [ Time Frame: approximately every 5 minutes for 6 hours ] [ Designated as safety issue: No ]
    force of blood flow returning to the heart (measured in mmHg)

  • Cardiac Output (CO) [ Time Frame: approximately every 5 minutes for 6 hours ] [ Designated as safety issue: No ]
    Calculated volume of blood flow in Litres per minute(measured in mmHg). Cardiac Output = mean arterial pressure/systemic vascular resistance.

  • Cardiac Index (CI) [ Time Frame: approximately every 5 minutes for 6 hours ] [ Designated as safety issue: No ]
    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.

  • Stroke Volume Varriation [ Time Frame: approximately every 5 minutes for 6 hours ] [ Designated as safety issue: No ]
    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

  • Systemic Vascular Resistance [ Time Frame: approximately every 5 minutes for 6 hours ] [ Designated as safety issue: No ]
    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


Estimated Enrollment: 80
Study Start Date: July 2012
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Angiotensin Converting Enzyme Exposed

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)

Other: Sevoflurane/oxygen/air/nitrous oxide
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.
Other Names:
  • Sevoflurane (Sevorane, Ultane, Sojourn)
  • 1,1,1,3,3,3-hexafluoro-2-(fluoromethoxy)propane
  • fluoromethyl hexafluoroisopropyl ether
  • Nitrous oxide
  • oxgyen
  • air
  • nitrogen
Angiotensin Receptor Blocker Exposed

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)

Other: Sevoflurane/oxygen/air/nitrous oxide
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.
Other Names:
  • Sevoflurane (Sevorane, Ultane, Sojourn)
  • 1,1,1,3,3,3-hexafluoro-2-(fluoromethoxy)propane
  • fluoromethyl hexafluoroisopropyl ether
  • Nitrous oxide
  • oxgyen
  • air
  • nitrogen
Non ACE/ARB Exposed

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.

Other: Sevoflurane/oxygen/air/nitrous oxide
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.
Other Names:
  • Sevoflurane (Sevorane, Ultane, Sojourn)
  • 1,1,1,3,3,3-hexafluoro-2-(fluoromethoxy)propane
  • fluoromethyl hexafluoroisopropyl ether
  • Nitrous oxide
  • oxgyen
  • air
  • nitrogen

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   40 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • age over 40
  • composite head and neck tumor resection
  • treated hypertension
  • hypertension medications taken on morning of surgery (except diuretics)

Exclusion Criteria:

  • patient refusal
  • age less than 40 or over 80 years
  • combined surgical procedures
  • emergency surgery
  • Left ventricular ejection fraction less than 50 per cent
  • calculated creatinine clearance less than 60 mL per minute
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01715584

Contacts
Contact: Craig J Railton, MD PhD FRCPC 519 685 8500 ext 58525 Craig.Railton@lhsc.on.ca

Locations
Canada, Ontario
London Health Sciences Centre - Victoria Campus Recruiting
London, Ontario, Canada, N6A 5W9
Contact: Craig J Railton, MD, PhD    519 685 8500 ext 58525    Craig.Railton@lhsc.on.ca   
Principal Investigator: Craig J Railton, MD, PhD         
Sub-Investigator: Jonathan Fairbairn, BSc         
Sub-Investigator: George Nicoloau, MD         
Sub-Investigator: Rujin Zhang, MD         
Sub-Investigator: Robert Gros, PhD         
Sub-Investigator: Jason Franklin, MD         
Sub-Investigator: John Yoo, MD         
Sub-Investigator: Kevin Fung, MD         
Sub-Investigator: Anthony Nichols, MD         
Sponsors and Collaborators
Lawson Health Research Institute
University of Western Ontario, Canada
Investigators
Principal Investigator: Craig J Railton, MD, PhD Lawson Health Research Institute
  More Information

Additional Information:
No publications provided

Responsible Party: Craig Railton, Assistant Professor, Lawson Health Research Institute
ClinicalTrials.gov Identifier: NCT01715584     History of Changes
Other Study ID Numbers: 5982
Study First Received: October 1, 2012
Last Updated: October 24, 2012
Health Authority: Canada: Ethics Review Committee

Keywords provided by Lawson Health Research Institute:
Hypertension
Sevoflurane
Inhaled Anesthetic
Angiotensin Converting Enzyme Inhibitor
Angiotensin II Receptor Blocking Agent

Additional relevant MeSH terms:
Drug-Related Side Effects and Adverse Reactions
Hypertension
Cardiovascular Diseases
Chemically-Induced Disorders
Vascular Diseases
Anesthetics
Angiotensin-Converting Enzyme Inhibitors
Enzyme Inhibitors
Nitrous Oxide
Sevoflurane
Analgesics
Analgesics, Non-Narcotic
Anesthetics, General
Anesthetics, Inhalation
Central Nervous System Agents
Central Nervous System Depressants
Hematologic Agents
Molecular Mechanisms of Pharmacological Action
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Platelet Aggregation Inhibitors
Protease Inhibitors
Sensory System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on November 25, 2014