Propofol vs. Midazolam-based Balanced Propofol for Nonanesthesiologist Moderate Sedation in Colonoscopy

Study Overview
=================
Brief Summary
-----------------
Nonanesthesiologist administration of propofol for sedation is actually a field of growing interest for endoscopists, as demonstrated by recent American and European guidelines on this issue. Propofol is a hypnotic drug with rapid onset and offset of action. Used as a single agent, it is commonly titrated to deep sedation, whereas balanced propofol sedation (BPS), which combines propofol with small doses of a benzodiazepine and/or an opioid, can be successfully titrated to moderate sedation. However, nonanesthesiologists propofol administration remains controversial on account of the possibility of deep sedation/general anesthesia related adverse events. On the other hand, the use of longer elimination half-life drugs, such as opioids and benzodiazepines, may theoretically prolong sedation and recovery. Up to date, no study has addressed a head-to-head comparison of both regimens administered by non-anesthesiologists and titrated to moderate sedation. This study aims to evaluate the impact on propofol sedation of premedication with a fixed dose of midazolam (2 mg)2 minutes before propofol administration targeted to moderate sedation, in terms of depth of sedation, recovery times, safety and satisfaction. The onset of sedative action of midazolam has been reported to be 1-2.5 minutes and the peak effect of midazolam occurs 8-12 minutes. Taking into account that colonoscopy usually lasts a minimum of 15-20 minutes, our hypothesis is that synergy between propofol and midazolam may increase the depth of sedation through the initial phases of the procedure, diminishing propofol requirements, but not prolonging significantly recovery times.

Detailed Description
-----------------
Justification of the study: Nonanesthesiologist administration of propofol is controversial owing to deep sedation concerns. One of the latest therapeutic innovations on this issue has been the development of balanced propofol sedation, which consists of adding low doses of opioids or benzodiazepins. Several studies have recently demonstrated that BPS allows successfully moderate sedation, maintains a reversible drug component, reduces the total dose of propofol even by more than 50% without increasing adverse events and maintains high levels of physician and patient satisfaction, even for advanced endoscopic procedure. However, recovery may be prolonged by using midazolam or meperidine as they have a longer elimination half-life than propofol has. Up to date, nonanesthesiologist administration of propofol and BPS, using either midazolam or fentanyl, for outpatient colonoscopy have been compared in a single non-placebo controlled randomized trial (VanNatta and Rex, 2006). In this study, the authors obtained shorter recovery times with BPS compared to propofol alone, in contrast with the expected on account of pharmacokinetics. These results can be easily understood yet single-agent propofol was titrated to deep sedation, whereas BPS was titrated to moderate sedation. Therefore, it is necessary to make a randomized, double-blinded, placebo-controlled trial to directly compare both sedation regimens targeted to a similar moderate level of sedation. The results of this study will conclude which should be the first line treatment for moderate sedation in colonoscopy, providing further insight in drug synergy and its impact on the depth of sedation and recovery times

Official Title
-----------------
Phase 4, Prospective, Randomized, Double-blinded, Placebo-controlled Study Comparing Propofol vs. Midazolam Plus Propofol for Nonanesthesiologist Targeted Moderate Sedation in Outpatient Colonoscopy

Conditions
-----------------
Procedural Sedation

Intervention / Treatment
-----------------
* Drug: Midazolam
* Drug: Propofol


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: All patients undergoing elective outpatient colonoscopy Exclusion Criteria: Age less than 18 years Allergy to propofol, soybeans, eggs or midazolam Chronic intake of benzodiazepines History of colorectal surgery ASA class IV, short and tick neck, difficult intubation due to inability to open the mouth widely Pregnancy Refusal, inability or unwillingness to give written consent Patients scheduled for advanced therapeutic colonoscopy or for more than one endoscopic procedure

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Midazolam balanced propofol sedation<br>2 mg midazolam in 2 ml saline midazolam followed by continuous propofol iv infusion | Drug: Midazolam<br>* Midazolam (5 mg/5 mL) 2 mg before standard propofol induction (0.5-1.5 mg/Kg) and boluses-based sedation during colonoscopy, targeted to a moderate sedation level<br>* Other names: Not necessary;|
| Placebo Comparator: Single-agent propofol sedation<br>2 ml saline followed by continuous propofol iv infusion | Drug: Propofol<br>* Placebo (normal saline 2 ml) before standard propofol induction (0.5-1.5 mg/Kg) and boluses-based sedation during colonoscopy, targeted to a moderate sedation level<br>* Other names: Not necessary;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Level of Sedation Throughout the Entire Procedure | Assessment every two minutes of the level of sedation during the endoscopic procedure, rating it as minimal, moderate or deep. | Up to 1 hour after introduction of the colonoscope | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Recovery After the Endoscopic Procedure | After completion of the procedure, the patient stood in the examination room monitored continuously by a nurse. When patients responded to normal verbal command, they were asked to sit up and were offered a drink. This was considered the early recovery time. If they were able to stand unassisted by the bed and had stable hemodynamics parameters (saturation>90 % on room air and blood pressure and heart rate within 20 % of baseline), they were transferred to a locker room accompanied by a relative. The discharge criteria included ability to stand unassisted and tolerate clear liquids once dressed. Once a patient met discharge criteria, they were allowed to leave at their own discretion | Up to 1 hour after colonoscopy | 
| Rate of Sedation-related Complications During the Procedure and the Recovery Phases | The following events were considered complications of procedural sedation: a decline in oxygen saturation to less than 85 % longer than 30 s after increasing the oxygen flow rate to 5 L/min and transient propofol interruption, a heart rate less than 40 beats per minute and blood pressure less than 80/50 mmHg. Major complications were defined as need for mechanical ventilation or any cardiorespiratory event requiring anaesthesiologist assistance. | Up to two hours, including colonoscopy performance and recovery period | 
| Rate of Patients and Physician Satisfaction With Sedation | Endoscopists and patients rated their satisfaction with sedation in a 10-cm visual analogue scale after discharge.The patients were contacted 24-48 h after the procedure to answer a questionnaire regarding if they remembered scope insertion or scope removal and willingness to repeat it with a similar protocol and rated their satisfaction and pain perception from 0 to 10. This phone survey was done by the nurse specifically making the measurements in the endoscopy room, who was blinded to the sedation regimen. For the interpretation of results of the 0-10 point numerical scale, 0 stands for 'extremely dissatisfied with sedation level during the endoscopic procedure', whereas 10 stands for 'extremely satisfied with sedation level during the endoscopic procedure. | Up to 1 hour after colonoscopy for endoscopists and up to 48 hours for patients | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Propofol, Midazolam, Moderate sedation, Deep sedation, Colonoscopy