Probability Ramp Control of Propofol for EGD

• Sponsor: University of Pennsylvania (Other)
• Overall Status: Completed
• CT.gov ID: NCT01838304
• Collaborator: (none)
• Enrollment: 40
• Location: 1
• Arms: 2
• Duration (Months): 2
• Patients Per Site Per Month: 20

Study Details

Study Description

Brief Summary

Endoscopic sedation requires titration of propofol to deep sedation without minimum overshoot into general anesthesia. This skill is demanding and acquired slowly. Probability Ramp Control (PRC) simplifies this by providing the clinician with a simple infusion sequence that permits gradual titration of propofol. The purpose of this study is to compare the performance of this technology to that of experienced anesthesia providers in endoscopic sedation.

Condition or Disease	Intervention/Treatment	Phase
Gastrointestinal Disease	Device: Probability ramp control; Device: Monitoring	N/A

Detailed Description

Administration of propofol to achieve a target of moderate sedation is a challenging task for which anesthesia providers receive minimal training. Undersedation results in a noncompliant patient, while oversedation results in airway obstruction, respiratory depression, and hypotension. Considerable variability in patient pharmacokinetics (the distribution of drug within the body) and pharmacodynamics (the translation of drug concentration to clinical effect) has been demonstrated. The skill of titrating propofol to the desired target and maintaining this state is slowly acquired in the clinical environment of the endoscopy center with frequent reliance on rescue skills. An automated system that facilitates this process would be useful.

Pharmacokinetic models allow us to make predictions of the results of drug administration. If we know the age and size of the patient, we can determine a quantity of propofol that will attain a desired concentration at some point in the future (within the predictive accuracy of the model). If they are old, this is less than if they are young. If they are obese, this is more than if they are thin. By adjusting the dosing, we can achieve similar concentrations at a specified time in a wide range of patients.

Pharmacodynamic models allow us to relate drug concentration to a probability of response. Sensitivity is a randomly distributed variable, and the cumulative probability of response to propofol is well represented by a sigmoid curve. While we do not know the concentration that will suffice for a given individual, we can determine the probability that this individual will lose responsiveness within an interval of concentrations. For example, the probability of loss of responsiveness between 1 µg/ml and 6 µg/ml is around 99%. For any given age and size, an infusion sequence can be determined so that we traverse this interval smoothly. The infusion sequence is determined by minimization of the difference between the simulated probability and the target (1). We predict that 90% of 50 year old 70 kg patients will lose responsiveness between one minute and three minutes after initiating the infusion, and 99% by five minutes. The infusion sequence for this patient is comprised of a bolus of 287 µg/kg followed by an initial infusion of 216 µg/kg/min, with an increase to 550 µg/kg/min after 147 seconds. By selecting the infusion sequence based on the age and size of the patient, all patients will track the same target line. These infusion rates are determined prior to initiation of sedation, and the clinician can verify that they are appropriate for the patient before beginning sedation.

Once the endpoint of adequate sedation is observed, the effect site concentration associated with this endpoint is inferred, and the infusion that will maintain this concentration can be determined. This allows the clinical observation to be translated into an infusion rate, much as a driver accelerates to a desired speed and then engages the cruise control to maintain that speed.

The intent of this study is to demonstrate equivalent safety and efficacy of PRC to control by a skilled clinician.

References

1. Mandel JE, Sarraf E. The Variability of Response to Propofol Is Reduced When a Clinical Observation Is Incorporated in the Control: A Simulation Study. Anesthesia & Analgesia. 2012;114:1221-9.

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Prospective, Randomized Comparison of Depth of Sedation With Propofol Titrated by Probability Ramp Control to Control by Anesthesia Providers During Esophagogastroduodenoscopy (EGD)
• Study Start Date: Mar 1, 2013
• Actual Primary Completion Date: May 1, 2013
• Actual Study Completion Date: May 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Monitoring Standard of care sedation by CRNA using proposal with manual recording of drug dosing	Device: Monitoring; Manual recording of drug doses determined by CRNA; Other Names: Manual recording of drug doses determined by CRNA
Experimental: Probability ramp control Propofol titrated to deep sedation using PRC software.	Device: Probability ramp control; Decision support software that calculates propofol doses appropriate for age and weight of the patient

Outcome Measures

Primary Outcome Measures

1. Number of Participants Requiring Adjustment in Propofol Dosing [Intraprocedure (average of 9 minutes)]

   Following initial sedation, an infusion rate for propofol is determined by the CRNA (control) or software (experimental). If this rate is appropriate for the duration of the brief procedure, no adjustment to the rate will be required. A greater requirement for rate changes suggests that the anesthesia provider needs to be immediately available to perform these adjustments.

Secondary Outcome Measures

1. Decrease in Minute Ventilation From Baseline [Duration of sedation (average of 25 minutes)]

   Minute ventilation as determined by respiratory inductance plethysmography from initiation of sedation until emergence.

2. Time Spent Below a Saturation of 80% [Duration of sedation (mean 25 minutes)]

   Number of seconds spent below saturation of 80%, reported as the total per group

3. Procedure Time [Procedure time (average of 9 minutes)]

   Time from endoscopic intubation until completion of the procedure. This is not really an outcome measure, but is used to assess balance between groups.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• scheduled for elective EGD

Exclusion Criteria:

• Unable to provide informed consent

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Endoscopy Center, Perelman Center for Advanced Medicine	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• University of Pennsylvania

Investigators

• Principal Investigator: Jeff E Mandel, MD MS, University of Pennsylvania

Study Documents (Full-Text)

None provided.

More Information

Publications

• Mandel JE, Sarraf E. The variability of response to propofol is reduced when a clinical observation is incorporated in the control: a simulation study. Anesth Analg. 2012 Jun;114(6):1221-9. doi: 10.1213/ANE.0b013e31824cb853. Epub 2012 Mar 30.

• Responsible Party: University of Pennsylvania
• ClinicalTrials.gov Identifier: NCT01838304
• Other Study ID Numbers: 817166
• First Posted: Apr 24, 2013
• Last Update Posted: Jan 23, 2018
• Last Verified: Jan 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by University of Pennsylvania: propofol sedation endoscopy
• Additional relevant MeSH terms: Gastrointestinal Diseases; Digestive System Diseases

Study Results

Participant Flow

Arm/Group Title	Monitoring	Probability Ramp Control
Arm/Group Description	Standard of care sedation by CRNA using proposal with manual recording of drug dosing Monitoring: Manual recording of drug doses determined by CRNA	Propofol titrated to deep sedation using PRC software. Probability ramp control: Decision support software that calculates propofol doses appropriate for age and weight of the patient
Period Title: Overall Study
STARTED	20	20
COMPLETED	19	20
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Monitoring	Probability Ramp Control	Total
Arm/Group Description	Standard of care sedation by CRNA using proposal with manual recording of drug dosing Monitoring: Manual recording of drug doses determined by CRNA	Propofol titrated to deep sedation using PRC software. Probability ramp control: Decision support software that calculates propofol doses appropriate for age and weight of the patient	Total of all reporting groups
Overall Participants	20	20	40
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.5 (14.2)	52.8 (16.5)	50.625 (15.345)
Sex: Female, Male (Count of Participants)
Female	8 40%	13 65%	21 52.5%
Male	12 60%	7 35%	19 47.5%
ASA 3 (Count of Participants)
Count of Participants [Participants]	7 35%	8 40%	15 37.5%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	82.3 (27.4)	82.1 (23.9)	82.22 (25.4)

Outcome Measures

1. Primary Outcome

Title	Number of Participants Requiring Adjustment in Propofol Dosing
Description	Following initial sedation, an infusion rate for propofol is determined by the CRNA (control) or software (experimental). If this rate is appropriate for the duration of the brief procedure, no adjustment to the rate will be required. A greater requirement for rate changes suggests that the anesthesia provider needs to be immediately available to perform these adjustments.
Time Frame	Intraprocedure (average of 9 minutes)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Monitoring	Probability Ramp Control
Arm/Group Description	Standard of care sedation by CRNA using proposal with manual recording of drug dosing Monitoring: Manual recording of drug doses determined by CRNA	Propofol titrated to deep sedation using PRC software. Probability ramp control: Decision support software that calculates propofol doses appropriate for age and weight of the patient
Measure Participants	19	20
Count of Participants [Participants]	16 80%	2 10%

2. Secondary Outcome

Title	Decrease in Minute Ventilation From Baseline
Description	Minute ventilation as determined by respiratory inductance plethysmography from initiation of sedation until emergence.
Time Frame	Duration of sedation (average of 25 minutes)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Monitoring	Probability Ramp Control
Arm/Group Description	Standard of care sedation by CRNA using proposal with manual recording of drug dosing Monitoring: Manual recording of drug doses determined by CRNA	Propofol titrated to deep sedation using PRC software. Probability ramp control: Decision support software that calculates propofol doses appropriate for age and weight of the patient
Measure Participants	19	20
Median (97.5% Confidence Interval) [percentage of baseline]	25	50

3. Secondary Outcome

Title	Time Spent Below a Saturation of 80%
Description	Number of seconds spent below saturation of 80%, reported as the total per group
Time Frame	Duration of sedation (mean 25 minutes)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Monitoring	Probability Ramp Control
Arm/Group Description	Standard of care sedation by CRNA using proposal with manual recording of drug dosing Monitoring: Manual recording of drug doses determined by CRNA	Propofol titrated to deep sedation using PRC software. Probability ramp control: Decision support software that calculates propofol doses appropriate for age and weight of the patient
Measure Participants	20	20
Measure seconds	29686	30552
Count of Units [seconds]	168	22

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Monitoring, Probability Ramp Control
	Comments	Fisher's exact test for odd's ratio of time below a saturation of 80% to total time
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	7.9
	Confidence Interval	(2-Sided) 95%; 4.21 to 14.81
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Procedure Time
Description	Time from endoscopic intubation until completion of the procedure. This is not really an outcome measure, but is used to assess balance between groups.
Time Frame	Procedure time (average of 9 minutes)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Monitoring	Probability Ramp Control
Arm/Group Description	Standard of care sedation by CRNA using proposal with manual recording of drug dosing Monitoring: Manual recording of drug doses determined by CRNA	Propofol titrated to deep sedation using PRC software. Probability ramp control: Decision support software that calculates propofol doses appropriate for age and weight of the patient
Measure Participants	20	20
Mean (Standard Deviation) [minutes]	9.03 (3.75)	8.9 (4.75)

Adverse Events

Time Frame	Duration of sedation (mean 25 minutes)
Arm/Group Title	Monitoring		Probability Ramp Control
Arm/Group Description	Standard of care sedation by CRNA using proposal with manual recording of drug dosing Monitoring: Manual recording of drug doses determined by CRNA		Propofol titrated to deep sedation using PRC software. Probability ramp control: Decision support software that calculates propofol doses appropriate for age and weight of the patient
All Cause Mortality
	Monitoring		Probability Ramp Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/20 (0%)
Serious Adverse Events
	Monitoring		Probability Ramp Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	Monitoring		Probability Ramp Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/20 (5%)		0/20 (0%)
Respiratory, thoracic and mediastinal disorders
Desaturation	1/20 (5%)	1	0/20 (0%)	0

Limitations/Caveats

Choice of processed EEG scores in power analyasis; variability of PSI scores; lack of concealed allocation, as it was deemed unethical to ask the CRNAs to deliver "sham propofol" in the experimental arm.

More Information

Certain Agreements

Principal Investigators are NOT 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.