A Comparison of Ketofol (Ketamine and Propofol Admixture) Versus Propofol as Induction Agents on Hemodynamic Parameters

• ClinicalTrials.gov Identifier: NCT01065350
• Recruitment Status: Completed
• First Posted: February 9, 2010
• Results First Posted: May 3, 2013
• Last Update Posted: May 3, 2013
• Sponsor: Mayo Clinic
• Collaborator: Dartmouth-Hitchcock Medical Center
• Information provided by (Responsible Party): Nathan J. Smischney, Mayo Clinic

Tracking Information

• First Submitted Date: February 7, 2010
• First Posted Date: February 9, 2010
• Results First Submitted Date: February 15, 2013
• Results First Posted Date: May 3, 2013
• Last Update Posted Date: May 3, 2013
• Study Start Date: December 2010
• Actual Primary Completion Date: March 2011 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 21, 2013)

Percent of Subjects With a Greater Than 20% Decrease in Systolic Blood Pressure (SBP) Following Induction of General Anesthesia [ Time Frame: Baseline, 5 minutes, 10 minutes, 30 minutes post induction ]

Blood pressure was recorded every minute for a total of 30 minutes after anesthesia was induced and readings were captured via a Non-Invasive Cardiac Output Monitor [NICOM], Cheetah Medical, Israel. The percentage of subjects experiencing decreases in SBP of greater than 20% during the specified time intervals is reported, as compared to the baseline systolic blood pressure reading. There are two numbers in a blood pressure reading, and they are expressed in millimeters of mercury (mm Hg). This tells how high in millimeters the pressure of your blood raises a column of mercury. The numbers usually are expressed in the form of a fraction; an example of a blood pressure reading is 120/80 mm Hg. The first, or top, number (120 in the example) is the systolic pressure. The systolic pressure is the measure of your blood pressure as the heart contracts and pumps blood.

• Original Primary Outcome Measures (submitted: February 8, 2010): Our primary hypothesis is that ketofol would have more favorable hemodynamics than the gold standard prototypic induction agent (propofol) in a healthy patient population. [ Time Frame: 6-12 months ]

Current Secondary Outcome Measures (submitted: March 21, 2013)

• Percent of Subjects With a Greater Than 20% Decrease in Diastolic Blood Pressure (DBP) Following Induction of General Anesthesia [ Time Frame: Baseline, 5 minutes, 10 minutes, 30 minutes post induction ]
  Blood pressure was recorded every minute for a total of 30 minutes after anesthesia was induced and readings were captured via a Non-Invasive Cardiac Output Monitor [NICOM], Cheetah Medical, Israel. The percentage of subjects experiencing decreases in DBP of greater than 20% during the specified time intervals is reported, as compared to the baseline DBP reading. The second or lower number of a blood pressure reading is the DBP and is the measure taken when your heart is at rest.
• Percent of Subjects With a Greater Than 20% Decrease in Mean Arterial Pressure (MAP) Following Induction of General Anesthesia [ Time Frame: Baseline, 5 minutes, 10 minutes, 30 minutes post induction ]
  MAP was recorded every minute for a total of 30 minutes after anesthesia was induced and readings were captured via a Non-Invasive Cardiac Output Monitor [NICOM], Cheetah Medical, Israel. The percentage of subjects experiencing decreases in MAP of greater than 20% during the specified time intervals is reported, as compared to the baseline MAP reading.
• Average Change in Cardiac Output (CO) [ Time Frame: Baseline, 5 minutes, 10 minutes post induction ]
  CO was recorded every minute for a total of 30 minutes after anesthesia was induced and readings were captured via a Non-Invasive Cardiac Output Monitor [NICOM], Cheetah Medical, Israel. The average change in CO as compared to baseline CO during the specified time intervals is reported. CO is defined as the quantity of blood ejected per minute by the heart into the systemic circulation. It is the product of the heart rate (HR) (beats per minute) times the stroke volume (SV) (milliliters of blood ejected during each contraction).
• Average Change in Cardiac Index (CI) [ Time Frame: Baseline, 5 minutes, 10 minutes post induction ]
  CI was recorded every minute for a total of 30 minutes after anesthesia was induced and readings were captured via a Non-Invasive Cardiac Output Monitor [NICOM], Cheetah Medical, Israel. The average change in CI as compared to the baseline CI during the specified time intervals is reported. To determine CI, cardiac output is divided by the body surface area in order to account for body size.
• Average Change in Heart Rate (HR) [ Time Frame: Baseline, 5 minutes, 10 minutes post induction ]
  HR was recorded every minute for a total of 30 minutes after anesthesia was induced and readings were captured via a Non-Invasive Cardiac Output Monitor [NICOM], Cheetah Medical, Israel. The average change in HR (as compared to baseline HR) during the specified time intervals is reported.
• Average Change in Systolic Blood Pressure (SBP) [ Time Frame: Baseline, 5 minutes, 10 minutes post induction ]
  Blood pressure was recorded every minute for a total of 30 minutes after anesthesia was induced and readings were captured via a Non-Invasive Cardiac Output Monitor [NICOM], Cheetah Medical, Israel. The average change in SBP (as compared to baseline SBP) during the specified time intervals is reported.
• Average Change in Diastolic Blood Pressure (DBP) [ Time Frame: Baseline, 5 minutes, 10 minutes post induction ]
  Blood pressure was recorded every minute for a total of 30 minutes after anesthesia was induced and readings were captured via a Non-Invasive Cardiac Output Monitor [NICOM], Cheetah Medical, Israel. The average change in DBP (as compared to baseline DBP) during the specified time intervals is reported.
• Average Change in Mean Arterial Pressure (MAP) [ Time Frame: Baseline, 5 minutes, 10 minutes post induction ]
  MAP was recorded every minute for a total of 30 minutes after anesthesia was induced and readings were captured via a Non-Invasive Cardiac Output Monitor [NICOM], Cheetah Medical, Israel. The average change in MAP from baseline during the specified time intervals is reported. MAP is a term used in medicine to describe an average blood pressure in an individual. It is defined as the average arterial pressure during a single cardiac cycle.
• Average Change in Total Peripheral Resistance (TPR) [ Time Frame: Baseline, 5 minutes, 10 minutes post induction ]
  TPR was recorded every minute for a total of 30 minutes after anesthesia was induced and readings were captured via a Non-Invasive Cardiac Output Monitor [NICOM], Cheetah Medical, Israel. The average change in TPR from baseline during the specified time intervals is reported. TPR is the overall resistance to blood flow through the systemic blood vessels.
• Average Change in Total Peripheral Resistance Index (TPRI) [ Time Frame: Baseline, 5 minutes, 10 minutes post induction ]
  TPRI was recorded every minute for a total of 30 minutes after anesthesia was induced and results were captured via a Non-Invasive Cardiac Output Monitor [NICOM], Cheetah Medical, Israel. The average change in TPRI from baseline during the specified time intervals is reported.
• Average Change in Stroke Volume (SV) [ Time Frame: Baseline, 5 minutes, 10 minutes post induction ]
  SV was recorded every minute for a total of 30 minutes after anesthesia was induced and results were captured via a Non-Invasive Cardiac Output Monitor [NICOM], Cheetah Medical, Israel. The average change in SV from baseline during the specified time intervals is reported. SV is the milliliters of blood ejected during each contraction of the heart.
• Average Change in Stroke Volume Index (SVI) [ Time Frame: Baseline, 5 minutes, 10 minutes post induction ]
  SVI was recorded every minute for a total of 30 minutes after anesthesia was induced and results were captured via a Non-Invasive Cardiac Output Monitor [NICOM], Cheetah Medical, Israel. The average change in SVI (as compared to baseline SVI) during the specified time intervals is reported. To determine SVI, stroke volume is divided by the body surface area in order to account for body size.
• Average Change in Stroke Volume Variation (SVV) [ Time Frame: Baseline, 5 minutes, 10 minutes post induction ]
  SVV was recorded every minute for a total of 30 minutes after anesthesia was induced and results were captured via a Non-Invasive Cardiac Output Monitor [NICOM], Cheetah Medical, Israel. SVV is a dynamic flow-based parameter and together with cardiac output provides an indication of fluid responsiveness. The average change in SVV (as compared to baseline SVV) during the specified time intervals is reported. SVV is calculated by taking the SVmax - SVmin /*100/ SV mean.

Original Secondary Outcome Measures (submitted: February 8, 2010)

• We hypothesize there will be less requirement for post operative narcotics both intraoperatively and post-operatively in the ketofol arm. [ Time Frame: 6-12 months ]
• There will be less vasoactive agents used in the ketofol arm versus the propofol arm [ Time Frame: 6-12 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Comparison of Ketofol (Ketamine and Propofol Admixture) Versus Propofol as Induction Agents on Hemodynamic Parameters
• Official Title: A Comparison of Ketofol (Ketamine and Propofol Admixture) vs. Propofol as Induction Agents on Hemodynamic Parameters
• Brief Summary: This is a pilot study to compare the hemodynamic changes that occur during induction with a novel drug combination known as ketofol (propofol and ketamine admixture with that of propofol alone (prototypic anesthesia induction agent). Propofol and ketamine are widely used as induction agents and their effects on patient hemodynamics are well known. Some of these drug-induced hemodynamic changes are undesirable and lead to deleterious effects on patient hemodynamics. We seek to investigate the hemodynamic changes associated with a novel drug combination known as ketofol (ketamine/propofol admixture) during induction and compare them to propofol. If we determine that the changes produced by ketofol are favorable compared with propofol, we then will seek to test its use in the trauma setting in a subsequent randomized controlled trial.

Detailed Description

This is a pilot study to compare the hemodynamic changes that occur during induction with a novel drug combination known as ketofol with that of propofol. Propofol and ketamine are widely used as induction agents and their effects on patient hemodynamics are well known. Many of these drug-induced changes are undesirable and when used alone sometimes lead to hemodynamic effects on opposite ends of the spectrum, ie. hypotension (propofol) and hypertension (ketamine). We will investigate the hemodynamic changes associated with this drug combination referred to as "ketofol" (ketamine/propofol admixture) during induction compared with propofol as the gold standard induction agent used widely in anesthetic practice. If we validate that the changes produced by the ketofol admixture are favorable, we will then test its use in a wider setting of patient populations including emergency department intubations and the trauma setting.

Background: Propofol is a non-opioid, non-barbiturate, sedative-hypnotic agent with rapid onset and short duration of action. It possesses many favorable effects such as an antiemetic effect and reliably produces sedation and amnesia (Felfernig Jour of Royal Naval Medical Service, '06; White International Anesth Clinics, '88; Willman Ann of Emer Med, '07). However, there are several undesirable side effects such as cardiovascular and respiratory depression. In addition, Propofol as a sole agent has no analgesic properties. These drug-induced side effects have led to alternative drugs being used with the hopes of a more favorable side effect profile. Ketamine is an example of one such drug. Ketamine is a phencyclidine derivative commonly classified as a dissociative sedative with fairly rapid onset and short duration of action (Felfernig Jour of Royal Naval Medical Service, '06; White International Anesth Clinics, '88; Willman Ann of Emer Med, '07). It causes little or no respiratory and cardiovascular depression and unlike propofol, has pain relieving properties. Ketamine as a single induction agent, however, is limited by emergence phenomena including postoperative dreaming and hallucinations, however these are attenuated by the administration of benzodiazepines. Also ketamine in induction doses 1-4.5 mg/kg can have some undesirable effects on hemodynamics (opposite of propofol) in certain patient populations including ischemic heart disease (IHD), and patients with increases in intracranial hypertension and intracranial pressure (ICP). Effectiveness of the two agents in combination has been recently demonstrated and this new combination could allow a novel induction agent with favorable effects on hemodynamics (Felfernig Jour of Royal Naval Medical Service, '06; Hui Jour of Amer Soc of Anesth, '95; Willman Ann of Emer Med, '07). To date, this combination known as ketofol has been used most extensively for procedural sedation in the Emergency Department but has not yet been standardized as an induction agent. We are obtaining funding for a pilot study to validate the use of ketofol as an induction agent.

• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Prevention
• Condition: Blood Pressure

Intervention

• Drug: Propofol
  As part of the induction, subjects will be given 2 milligrams per kilogram of body weight (mg/kg) of propofol. The clinician will receive a 20 milliliter (mL) syringe of propofol. If the dose, 2 mg/kg, does not add up to a total of 20 mL, normal saline will be added to make up for the 20 mL. The clinician and observer will be blinded to the medication and doses being administered during induction given that both syringes, syringes in the propofol and ketofol groups, will look identical (will both appear to be propofol only). The propofol group will also be given an additional 10 mL syringe of propofol due to any patient responding to stimulus after induction. The 10 mL syringe represents 1 mg/kg of propofol. If patient receives both the 20 and 10ml syringe, he or she will receive a total of 3mg/kg of propofol.
  Other Name: Diprivan
• Drug: Ketamine
  As part of the induction, patients will be given 20ml syringe of ketofol which is weight based such that ketamine will represent 0.75mg/kg of the dose and propofol, 1.5mg/kg. The clinician and observer will be blinded to the medication and doses being administered during induction given that both 20ml syringes (propofol group and ketofol group) will look identical (will both appear to be propofol only). Additional 10ml syringe will be given due to any patient responding to stimulus after induction. The 10ml syringe will represent 0.25mg/kg of ketamine and 0.5mg/kg of propofol. If the patient receives both the 20 and 10ml rescue syringe, he or she will receive a total of 1mg/kg of ketamine and 2mg/kg of propofol.
  Other Name: Ketalar

Study Arms

• Active Comparator: Propofol
  As part of the induction, patients will be given 2 milligrams of propofol per kilogram (mg/kg) of body weight. The clinician will receive a 20 milliliter (mL) syringe of propofol. If the dose, 2 mg/kg, does not add up to a total of 20 mL, normal saline will be added to make up for the 20 mL.
  Intervention: Drug: Propofol
• Experimental: Ketofol
  As part of the induction, patients will be given 20 mL syringe of an admixture called "ketofol," which combines ketamine and propofol in one syringe. The dose is weight-based such that ketamine will represent 0.75 mg/kg of the dose and propofol, 1.5 mg/kg of the dose.
  Intervention: Drug: Ketamine

• Publications *: Smischney NJ, Beach ML, Loftus RW, Dodds TM, Koff MD. Ketamine/propofol admixture (ketofol) is associated with improved hemodynamics as an induction agent: a randomized, controlled trial. J Trauma Acute Care Surg. 2012 Jul;73(1):94-101. doi: 10.1097/TA.0b013e318250cdb8.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 22, 2011): 85
• Original Estimated Enrollment (submitted: February 8, 2010): 100
• Actual Study Completion Date: March 2011
• Actual Primary Completion Date: March 2011 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• American Society of Anesthesiologists (ASA) physical status I and II who are to undergo elective general, urologic, orthopedic, plastic, or gynecologic surgery.

Exclusion Criteria:

• patients with age less than 18 yr or over 60 yr,
• emergency surgery,
• patients undergoing neurosurgical procedures,
• any procedure with adjunctive analgesia,
• any patient on chronic opiate use,
• females who are known to be pregnant,
• patients who had ingested psychotropic or sedative medication within one month of investigation,
• patients with personality disorders,
• weight greater than 20% of ideal, and
• any known contraindications to ketamine or propofol.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 60 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01065350
• Other Study ID Numbers: 22063
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Nathan J. Smischney, Mayo Clinic
• Study Sponsor: Mayo Clinic
• Collaborators: Dartmouth-Hitchcock Medical Center

Investigators

• Principal Investigator: Nathan J Smischney, MD; Mayo Clinic
• Study Director: Matthew Koff, MD; Dartmouth-Hitchcock Medical Center

• PRS Account: Mayo Clinic
• Verification Date: March 2013