Critical Illness
Conditions
Keywords
Critical care, Emergent, Etomidate, Hemodynamics, Intensive care unit, Intubation, Ketamine-Propofol admixture
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.
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.
Interventions
DRUGEtomidate
Sponsors
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| Mechanical Ventilation Free Days | hospital discharge or day 28, whichever comes first | comparison of mechanical ventilation free days between the two groups |
| 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 |
| Intensive Care Unit Free Days | hospital discharge or day 28, whichever comes first | comparison of intensive care unit free days between the two groups |
| 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Etomidate Etomidate 0.15mg/kg weight based dose | 73 |
| Ketamine / Propofol Admixture Ketamine / Propofol Admixture weight based dose 0.5 mg/kg ketamine and 0.5 mg/kg propofol | 79 |
| Total | 152 |
Baseline characteristics
| Characteristic | Etomidate | Ketamine / Propofol Admixture | Total |
|---|---|---|---|
| Age, Continuous | 60.0 years STANDARD_DEVIATION 18.3 | 62.1 years STANDARD_DEVIATION 17.2 | 61.1 years STANDARD_DEVIATION 17.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 57 Participants | 76 Participants | 133 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 16 Participants | 3 Participants | 19 Participants |
| Region of Enrollment United States | 73 participants | 79 participants | 152 participants |
| Sex: Female, Male Female | 35 Participants | 31 Participants | 66 Participants |
| Sex: Female, Male Male | 38 Participants | 48 Participants | 86 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 26 / 73 | 25 / 79 |
| other Total, other adverse events | 19 / 73 | 14 / 79 |
| serious Total, serious adverse events | 6 / 73 | 5 / 79 |
Outcome results
Primary
Mean Arterial Pressure
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
Population: Data are presented for patients who had blood pressure measurements at baseline (within 15 minutes prior to study drug administration).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Etomidate | Mean Arterial Pressure | Baseline | 82.8 mm Hg | Standard Deviation 17.9 |
| Etomidate | Mean Arterial Pressure | 5 minutes | 81.7 mm Hg | Standard Deviation 17.2 |
| Etomidate | Mean Arterial Pressure | 10 minutes | 81.9 mm Hg | Standard Deviation 20 |
| Etomidate | Mean Arterial Pressure | 15 minutes | 79.1 mm Hg | Standard Deviation 19.5 |
| Ketamine / Propofol Admixture | Mean Arterial Pressure | 15 minutes | 75.5 mm Hg | Standard Deviation 18.1 |
| Ketamine / Propofol Admixture | Mean Arterial Pressure | Baseline | 80.9 mm Hg | Standard Deviation 13.3 |
| Ketamine / Propofol Admixture | Mean Arterial Pressure | 10 minutes | 75.3 mm Hg | Standard Deviation 20.3 |
| Ketamine / Propofol Admixture | Mean Arterial Pressure | 5 minutes | 77.6 mm Hg | Standard Deviation 15.4 |
Comparison: 5 minutesp-value: 0.38595% CI: [-6.9, 2.7]ANCOVA
Comparison: 10 minutesp-value: 0.24195% CI: [-10.8, 2.8]ANCOVA
Comparison: 15 minutesp-value: 0.80295% CI: [-7.2, 5.6]ANCOVA
Secondary
Blood Product Transfusions
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
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Etomidate | Blood Product Transfusions | Red blood cell | 21 Participants |
| Etomidate | Blood Product Transfusions | Non-red blood cell | 16 Participants |
| Etomidate | Blood Product Transfusions | Colloid | 28 Participants |
| Ketamine / Propofol Admixture | Blood Product Transfusions | Red blood cell | 13 Participants |
| Ketamine / Propofol Admixture | Blood Product Transfusions | Non-red blood cell | 8 Participants |
| Ketamine / Propofol Admixture | Blood Product Transfusions | Colloid | 26 Participants |
Comparison: Red blood cellp-value: 0.069ANCOVA
Comparison: Non-red blood cellp-value: 0.046ANCOVA
Comparison: Colloidp-value: 0.502ANCOVA
Secondary
Intensive Care Unit Free Days
comparison of intensive care unit free days between the two groups
Time frame: hospital discharge or day 28, whichever comes first
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Etomidate | Intensive Care Unit Free Days | 16 days |
| Ketamine / Propofol Admixture | Intensive Care Unit Free Days | 17 days |
p-value: 0.994ANCOVA
Secondary
Mechanical Ventilation Free Days
comparison of mechanical ventilation free days between the two groups
Time frame: hospital discharge or day 28, whichever comes first
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Etomidate | Mechanical Ventilation Free Days | 22 days |
| Ketamine / Propofol Admixture | Mechanical Ventilation Free Days | 20 days |
p-value: 0.911ANCOVA
Secondary
Mortality
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Etomidate | Mortality | 26 Participants |
| Ketamine / Propofol Admixture | Mortality | 25 Participants |
p-value: 0.605ANCOVA
Secondary
Number of Participants Experiencing Delirium Using Confusion Assessment Method in ICU
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
Population: The analysis of new onset delirium was restricted to subjects (54 etomidate, 62 KPA) who did not experience delirium pre-study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Etomidate | Number of Participants Experiencing Delirium Using Confusion Assessment Method in ICU | 7 Participants |
| Ketamine / Propofol Admixture | Number of Participants Experiencing Delirium Using Confusion Assessment Method in ICU | 4 Participants |
p-value: 0.233ANCOVA
Secondary
Number of Participants With Adrenal Insufficiency
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
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Etomidate | Number of Participants With Adrenal Insufficiency | 13 Participants |
| Ketamine / Propofol Admixture | Number of Participants With Adrenal Insufficiency | 5 Participants |
| Etomidate (23-25 Hours) | Number of Participants With Adrenal Insufficiency | 9 Participants |
| Ketamine/Propofol Admixture (23-25 Hours) | Number of Participants With Adrenal Insufficiency | 6 Participants |
Secondary
Vasopressor Use
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
Population: Data are presented for patients who had vasopressor data within the time frame
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Etomidate | Vasopressor Use | Pre-treament | 1 Participants |
| Etomidate | Vasopressor Use | New-onset pressors (within 3 minutes) | 12 Participants |
| Etomidate | Vasopressor Use | Delayed-onset pressors (within 24 hours) | 57 Participants |
| Ketamine / Propofol Admixture | Vasopressor Use | Pre-treament | 5 Participants |
| Ketamine / Propofol Admixture | Vasopressor Use | New-onset pressors (within 3 minutes) | 18 Participants |
| Ketamine / Propofol Admixture | Vasopressor Use | Delayed-onset pressors (within 24 hours) | 64 Participants |
Comparison: Pre-treatmentp-value: 0.212ANCOVA
Comparison: New-onset pressors (within 3 minutes)p-value: 0.308ANCOVA
Comparison: Delayed-onset pressors (within 24 hrs)p-value: 0.691ANCOVA