Ketamine / Propofol Admixture "Ketofol" at Induction in the Critically Ill Against Etomidate: KEEP PACE Trial

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT02105415
• Collaborator: (none)
• Enrollment: 160
• Location: 1
• Arms: 2
• Duration (Months): 52
• Patients Per Site Per Month: 3.1

Study Details

Study Description

Brief Summary

The hypothesis of this study is that a Ketamine / Propofol mixture will produce more stable hemodynamics as compared to Etomidate during emergent intubations in the intensive care unit. Patients that require a breathing tube to be placed in the ICU will be randomized to receIve either a Ketamine / Propofol mixture or Etomidate for sedation in order to place the breathing tube.

Condition or Disease	Intervention/Treatment	Phase
Critical Illness	Drug: Ketamine / Propofol Admixture; Drug: Etomidate	Phase 2/Phase 3

Detailed Description

Endotracheal intubation is a procedure that may cause significant hemodynamic perturbations and can severely impact the outcome of the critically ill. To ensure a safe outcome during this particular procedure, there are many factors that the clinician is faced with. One decision that confronts the critical care physician involves the correct combination of medications with which to facilitate such a safe outcome. Given the reported hemodynamic stability, etomidate is a medication that is chosen by many providers in this particular situation. However, its association with a possible increase in mortality makes it less than ideal for a number of critical care physicians. In recent years, an admixture of propofol and ketamine has been studied that demonstrates hemodynamic stability based on the balancing of the hemodynamic effects of these two individual agents alone. This novel medication combination, sometimes referred to as "ketofol", may offer a valuable alternative to the critical care physician. Therefore, a randomized parallel-group clinical trial of adult critically ill patients admitted to a medical and/or surgical intensive care unit at Mayo Clinic Rochester who meet the criteria designated below for which urgent and/or emergent intubation is needed will receive one of two interventions based on stratified randomization. The "active" intervention arm will receive ketamine/propofol (ketofol) to facilitate endotracheal intubation. The comparison arm will receive etomidate. The primary outcome will focus on hemodynamic data recorded during the first 5 minutes post-administration with secondary outcomes looking at hemodynamic data at 10 and 15 minutes and addressing intensive care unit length of stay, mortality, adrenal function, and vasoactive medication use, among others.

Study Design

• Study Type: Interventional
• Actual Enrollment: 160 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Ketamine / Propofol Admixture "Ketofol" at Induction in the Critically Ill Against Etomidate: KEEP PACE Trial
• Study Start Date: Apr 1, 2014
• Actual Primary Completion Date: Nov 28, 2017
• Actual Study Completion Date: Aug 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Etomidate weight based dose of 0.15mg/kg	Drug: Etomidate
Experimental: Ketamine / Propofol Admixture weight based dose of 0.5mg/kg of ketamine and 0.5mg/kg of propofol	Drug: Ketamine / Propofol Admixture

Outcome Measures

Primary Outcome Measures

1. Mean Arterial Pressure [baseline and every 5 minutes up to 15 minutes minutes post study drug administration]

   Mean arterial pressure for the ketamine/propofol group at a 1:1 dose ratio compared to the etomidate group within the first 15 minutes post-administration in patients in need of urgent and/or emergent endotracheal intubation, as defined by any intubation within the intensive care unit excluding intubations for elective procedural events and codes.

Secondary Outcome Measures

1. Mortality [Hospital Discharge or Day 28, whichever comes first]

   In-hospital/28 day mortality among patients in ketamine/propofol combination compared to in-hospital/28-day mortality in etomidate.

2. Vasopressor Use [up to 24 hours post study drug administration]

   The use of vasoactive medications to restore the blood pressure post-administration in the ketamine/propofol combination as compared to the etomidate group.

3. Number of Participants With Adrenal Insufficiency [up to 24 hours post study drug administration]

   Incidence of adrenal insufficiency between ketamine/propofol admixture and etomidate. Adrenal insuffiency was evaluated with co-syntropin stimulation test.

4. Mechanical Ventilation Free Days [hospital discharge or day 28, whichever comes first]

   comparison of mechanical ventilation free days between the two groups

5. Blood Product Transfusions [hospital discharge or day 28, whichever comes first]

   blood product transfusions [Red Blood Cells vs. non-Red Blood Cells] between the two groups

6. Intensive Care Unit Free Days [hospital discharge or day 28, whichever comes first]

   comparison of intensive care unit free days between the two groups

7. Number of Participants Experiencing Delirium Using Confusion Assessment Method in ICU [up to 24 hours post study drug administration]

   Comparison of number of participants who were positive for delirium using CAM-ICU between groups

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 99 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• 18 years of age or older

• Surgical or medical intensive care unity patients requiring endotracheal intubation

• Consulting physician agrees to study plan and will follow drug randomization

Exclusion Criteria:

• Known intracranial pathology

• Known chronic opiate-dependence

• Received continuous sedative infusion in the last 24 hours

• Known severe psychiatric illness

• Known egg allergies

• Known contraindication to fentanyl, midazolam, ketamine, propofol or etomidate

• Intubation in which standard practice is not to use sedation

• No known documented weight or weight greater than 140 kg or less than 30 kg

• Prior participation in the study

• Of childbearing age (18-50) with no known negative pregnancy test on this admission.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic

Investigators

• Principal Investigator: Nathan J Smischney, MD, Mayo Clinic

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 30, 2018

More Information

Publications

None provided.

• Responsible Party: Nathan J. Smischney, PI, Mayo Clinic
• ClinicalTrials.gov Identifier: NCT02105415
• Other Study ID Numbers: 13-000506
• First Posted: Apr 7, 2014
• Last Update Posted: Jun 16, 2020
• Last Verified: May 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Nathan J. Smischney, PI, Mayo Clinic: Critical care; Emergent; Etomidate; Hemodynamics; Intensive care unit; Intubation; Ketamine-Propofol admixture
• Additional relevant MeSH terms: Critical Illness; Ketamine; Propofol; Etomidate

Study Results

Participant Flow

Arm/Group Title	Etomidate	Ketamine / Propofol Admixture
Arm/Group Description	Etomidate 0.15mg/kg weight based dose	Ketamine / Propofol Admixture; weight based dose 0.5 mg/kg ketamine and 0.5 mg/kg propofol.
Period Title: Overall Study
STARTED	76	84
COMPLETED	73	79
NOT COMPLETED	3	5

Baseline Characteristics

Arm/Group Title	Etomidate	Ketamine / Propofol Admixture	Total
Arm/Group Description	Etomidate 0.15mg/kg weight based dose	Ketamine / Propofol Admixture weight based dose 0.5 mg/kg ketamine and 0.5 mg/kg propofol	Total of all reporting groups
Overall Participants	73	79	152
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.0 (18.3)	62.1 (17.2)	61.1 (17.8)
Sex: Female, Male (Count of Participants)
Female	35 47.9%	31 39.2%	66 43.4%
Male	38 52.1%	48 60.8%	86 56.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	57 78.1%	76 96.2%	133 87.5%
Unknown or Not Reported	16 21.9%	3 3.8%	19 12.5%
Region of Enrollment (participants) [Number]
United States	73 100%	79 100%	152 100%

Outcome Measures

1. Primary Outcome

Title	Mean Arterial Pressure
Description	Mean arterial pressure for the ketamine/propofol group at a 1:1 dose ratio compared to the etomidate group within the first 15 minutes post-administration in patients in need of urgent and/or emergent endotracheal intubation, as defined by any intubation within the intensive care unit excluding intubations for elective procedural events and codes.
Time Frame	baseline and every 5 minutes up to 15 minutes minutes post study drug administration

Outcome Measure Data

Analysis Population Description

Data are presented for patients who had blood pressure measurements at baseline (within 15 minutes prior to study drug administration).

Arm/Group Title	Etomidate	Ketamine / Propofol Admixture
Arm/Group Description	Etomidate 0.15mg/kg weight based dose	Ketamine / Propofol Admixture weight based dose 0.5 mg/kg ketamine and 0.5 mg/kg propofol
Measure Participants	70	76
Baseline	82.8 (17.9)	80.9 (13.3)
5 minutes	81.7 (17.2)	77.6 (15.4)
10 minutes	81.9 (20.0)	75.3 (20.3)
15 minutes	79.1 (19.5)	75.5 (18.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Etomidate, Ketamine / Propofol Admixture
	Comments	5 minutes
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.385
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.1
	Confidence Interval	(2-Sided) 95%; -6.9 to 2.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Etomidate, Ketamine / Propofol Admixture
	Comments	10 minutes
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.241
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.0
	Confidence Interval	(2-Sided) 95%; -10.8 to 2.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Etomidate, Ketamine / Propofol Admixture
	Comments	15 minutes
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.802
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.8
	Confidence Interval	(2-Sided) 95%; -7.2 to 5.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Mortality
Description	In-hospital/28 day mortality among patients in ketamine/propofol combination compared to in-hospital/28-day mortality in etomidate.
Time Frame	Hospital Discharge or Day 28, whichever comes first

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Etomidate	Ketamine / Propofol Admixture
Arm/Group Description	Etomidate 0.15mg/kg weight based dose	Ketamine / Propofol Admixture weight based dose 0.5 mg/kg ketamine and 0.5 mg/kg propofol
Measure Participants	73	79
Count of Participants [Participants]	26 35.6%	25 31.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Etomidate, Ketamine / Propofol Admixture
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.605
	Comments
	Method	ANCOVA
	Comments

3. Secondary Outcome

Title	Vasopressor Use
Description	The use of vasoactive medications to restore the blood pressure post-administration in the ketamine/propofol combination as compared to the etomidate group.
Time Frame	up to 24 hours post study drug administration

Outcome Measure Data

Analysis Population Description

Data are presented for patients who had vasopressor data within the time frame

Arm/Group Title	Etomidate	Ketamine / Propofol Admixture
Arm/Group Description	Etomidate 0.15mg/kg weight based dose	Ketamine / Propofol Admixture; weight based dose 0.5 mg/kg ketamine and 0.5 mg/kg propofol.
Measure Participants	73	79
Pre-treament	1 1.4%	5 6.3%
New-onset pressors (within 3 minutes)	12 16.4%	18 22.8%
Delayed-onset pressors (within 24 hours)	57 78.1%	64 81%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Etomidate, Ketamine / Propofol Admixture
	Comments	Pre-treatment
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.212
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Etomidate, Ketamine / Propofol Admixture
	Comments	New-onset pressors (within 3 minutes)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.308
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Etomidate, Ketamine / Propofol Admixture
	Comments	Delayed-onset pressors (within 24 hrs)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.691
	Comments
	Method	ANCOVA
	Comments

4. Secondary Outcome

Title	Number of Participants With Adrenal Insufficiency
Description	Incidence of adrenal insufficiency between ketamine/propofol admixture and etomidate. Adrenal insuffiency was evaluated with co-syntropin stimulation test.
Time Frame	up to 24 hours post study drug administration

Outcome Measure Data

Analysis Population Description

A secondary outcome included adrenal testing in a subset of patients. Thus, cortisol levels were available for 29 subjects at 3 and 5 hours and 30 subjects at 23 and 25 hours.

Arm/Group Title	Etomidate (3-5 Hours)	Ketamine/Propofol Admixture (3-5 Hours)	Etomidate (23-25 Hours)	Ketamine/Propofol Admixture (23-25 Hours)
Arm/Group Description	Cortisol levels at 3-5 hours	Cortisol levels at 3-5 hours	Cortisol levels at 23-25 hours	Cortisol levels at 23-25 hours
Measure Participants	16	13	15	15
Count of Participants [Participants]	13 17.8%	5 6.3%	9 5.9%	6 NaN

5. Secondary Outcome

Title	Mechanical Ventilation Free Days
Description	comparison of mechanical ventilation free days between the two groups
Time Frame	hospital discharge or day 28, whichever comes first

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Etomidate	Ketamine / Propofol Admixture
Arm/Group Description	Etomidate 0.15mg/kg weight based dose	Ketamine / Propofol Admixture; weight based dose 0.5 mg/kg ketamine and 0.5 mg/kg propofol.
Measure Participants	73	79
Median (Inter-Quartile Range) [days]	22	20

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Etomidate, Ketamine / Propofol Admixture
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.911
	Comments
	Method	ANCOVA
	Comments

6. Secondary Outcome

Title	Blood Product Transfusions
Description	blood product transfusions [Red Blood Cells vs. non-Red Blood Cells] between the two groups
Time Frame	hospital discharge or day 28, whichever comes first

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Etomidate	Ketamine / Propofol Admixture
Arm/Group Description	Etomidate 0.15mg/kg weight based dose	Ketamine / Propofol Admixture; weight based dose 0.5 mg/kg ketamine and 0.5 mg/kg propofol.
Measure Participants	73	79
Red blood cell	21 28.8%	13 16.5%
Non-red blood cell	16 21.9%	8 10.1%
Colloid	28 38.4%	26 32.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Etomidate, Ketamine / Propofol Admixture
	Comments	Red blood cell
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.069
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Etomidate, Ketamine / Propofol Admixture
	Comments	Non-red blood cell
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.046
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Etomidate, Ketamine / Propofol Admixture
	Comments	Colloid
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.502
	Comments
	Method	ANCOVA
	Comments

7. Secondary Outcome

Title	Intensive Care Unit Free Days
Description	comparison of intensive care unit free days between the two groups
Time Frame	hospital discharge or day 28, whichever comes first

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Etomidate	Ketamine / Propofol Admixture
Arm/Group Description	Etomidate 0.15mg/kg weight based dose	Ketamine / Propofol Admixture weight based dose 0.5 mg/kg ketamine and 0.5 mg/kg propofol
Measure Participants	73	79
Median (Inter-Quartile Range) [days]	16	17

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Etomidate, Ketamine / Propofol Admixture
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.994
	Comments
	Method	ANCOVA
	Comments

8. Secondary Outcome

Title	Number of Participants Experiencing Delirium Using Confusion Assessment Method in ICU
Description	Comparison of number of participants who were positive for delirium using CAM-ICU between groups
Time Frame	up to 24 hours post study drug administration

Outcome Measure Data

Analysis Population Description

The analysis of new onset delirium was restricted to subjects (54 etomidate, 62 KPA) who did not experience delirium pre-study drug.

Arm/Group Title	Etomidate	Ketamine / Propofol Admixture
Arm/Group Description	Etomidate 0.15mg/kg weight based dose	Ketamine / Propofol Admixture; weight based dose 0.5 mg/kg ketamine and 0.5 mg/kg propofol.
Measure Participants	54	62
Count of Participants [Participants]	7 9.6%	4 5.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Etomidate, Ketamine / Propofol Admixture
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.233
	Comments
	Method	ANCOVA
	Comments

Adverse Events

Time Frame	Given the context of the study and the emergent nature in which the interventions were conducted, adverse events were collected up to 72 hours after enrollment.
Arm/Group Title	Etomidate		Ketamine / Propofol Admixture
Arm/Group Description	Etomidate 0.15mg/kg weight based dose		Ketamine / Propofol Admixture weight based dose 0.5 mg/kg ketamine and 0.5 mg/kg propofol
All Cause Mortality
	Etomidate		Ketamine / Propofol Admixture
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	26/73 (35.6%)		25/79 (31.6%)
Serious Adverse Events
	Etomidate		Ketamine / Propofol Admixture
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/73 (8.2%)		5/79 (6.3%)
Cardiac disorders
Cardiac arrest	0/73 (0%)		2/79 (2.5%)
Vascular disorders
Hypertensive urgency	2/73 (2.7%)		0/79 (0%)
Severe hypotension	4/73 (5.5%)		3/79 (3.8%)
Other (Not Including Serious) Adverse Events
	Etomidate		Ketamine / Propofol Admixture
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/73 (26%)		14/79 (17.7%)
Cardiac disorders
Tachycardia	2/73 (2.7%)	2	0/79 (0%)	0
arrythmia	1/73 (1.4%)	1	0/79 (0%)	0
General disorders
IV infiltration	2/73 (2.7%)	2	0/79 (0%)	0
Multi organ failure	4/73 (5.5%)	4	1/79 (1.3%)	1
Vomiting/Aspiration	3/73 (4.1%)	3	2/79 (2.5%)	2
Respiratory, thoracic and mediastinal disorders
Intubation Complication	1/73 (1.4%)	1	2/79 (2.5%)	2
Respiratory failure	2/73 (2.7%)	2	6/79 (7.6%)	6
Vascular disorders
shock	4/73 (5.5%)	4	3/79 (3.8%)	3

Limitations/Caveats

Single center study with non-blinded interventions and non-controlled co-interventions all of which can impact hemodynamics. Selection bias with 92 non-enrollees.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.