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

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.

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.

Study Overview

• Status: Unknown
• Conditions: Hypertension
• Intervention / Treatment: Other: Sevoflurane/oxygen/air/nitrous oxide

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.

• Study Type: Interventional
• Enrollment (Anticipated): 80
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • London, Ontario, Canada, N6A 5W9
      • Recruiting
      • London Health Sciences Centre - Victoria Campus
      • Contact: Craig J Railton, MD, PhD; Phone Number: 58525 519 685 8500; Email: Craig.Railton@lhsc.on.ca
      • Principal Investigator: Craig J Railton, MD, PhD
      • Sub-Investigator: Jonathan Fairbairn, BSc
      • Sub-Investigator: George Nicoloau, 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
      • Sub-Investigator: Danielle McNeil, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
OTHER: 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: air; Sevoflurane (Sevorane, Ultane, Sojourn); 1,1,1,3,3,3-hexafluoro-2-(fluoromethoxy)propane; fluoromethyl hexafluoroisopropyl ether; Nitrous oxide; oxgyen; nitrogen
OTHER: 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: air; Sevoflurane (Sevorane, Ultane, Sojourn); 1,1,1,3,3,3-hexafluoro-2-(fluoromethoxy)propane; fluoromethyl hexafluoroisopropyl ether; Nitrous oxide; oxgyen; nitrogen
OTHER: 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: air; Sevoflurane (Sevorane, Ultane, Sojourn); 1,1,1,3,3,3-hexafluoro-2-(fluoromethoxy)propane; fluoromethyl hexafluoroisopropyl ether; Nitrous oxide; oxgyen; nitrogen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Systemic Vascular Resistance Index (SVRI)	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.	approximately every 5 minutes for 6 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Heart Rate	number of heart beats per minute	approximately every 5 minutes for 6 hours
Systolic Blood Pressure	force of blood flow (measured in mmHg)	approximately every 5 minutes for 6 hours
Diastolic Blood Pressure	force of blood flow (measured in mmHg)	approximately every 5 minutes for 6 hours
Central Venous Pressure	force of blood flow returning to the heart (measured in mmHg)	approximately every 5 minutes for 6 hours
Cardiac Output (CO)	Calculated volume of blood flow in Litres per minute(measured in mmHg). Cardiac Output = mean arterial pressure/systemic vascular resistance.	approximately every 5 minutes for 6 hours
Cardiac Index (CI)	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.	approximately every 5 minutes for 6 hours
Stroke Volume Varriation	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	approximately every 5 minutes for 6 hours
Systemic Vascular Resistance	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	approximately every 5 minutes for 6 hours

Collaborators and Investigators

• Sponsor: Lawson Health Research Institute
• Collaborators: University of Western Ontario, Canada
• Investigators: Principal Investigator: Craig J Railton, MD, PhD, Lawson Health Research Institute

Publications and helpful links

Helpful Links

• Relevant Reference
• Relevant Reference

Study record dates

Study Major Dates

• Study Start: July 1, 2012
• Primary Completion (ANTICIPATED): December 31, 2019
• Study Completion (ANTICIPATED): December 31, 2019

Study Registration Dates

• First Submitted: October 1, 2012
• First Submitted That Met QC Criteria: October 24, 2012
• First Posted (ESTIMATE): October 29, 2012

Study Record Updates

• Last Update Posted (ACTUAL): August 23, 2017
• Last Update Submitted That Met QC Criteria: August 22, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: Hypertension; Sevoflurane; Inhaled Anesthetic; Angiotensin Converting Enzyme Inhibitor; Angiotensin II Receptor Blocking Agent
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Cardiovascular Diseases; Vascular Diseases; Hypertension; Drug-Related Side Effects and Adverse Reactions; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, General; Anesthetics; Analgesics, Non-Narcotic; Platelet Aggregation Inhibitors; Anesthetics, Inhalation; Sevoflurane; Nitrous Oxide
• Other Study ID Numbers: 5982