Impact of Preoperative Midazolam on Outcome of Elderly Patients (I-PROMOTE)

Impact of Preoperative Midazolam on Outcome of Elderly Patients: a Multicentre Randomised Controlled Trial

We aim to assess, if placebo compared to preoperative administration of midazolam in elderly patients is equal in regard to the global postoperative patient satisfaction

Study Overview

• Status: Completed
• Conditions: Preanesthetic Medication
• Intervention / Treatment: Drug: Midazolam; Drug: Placebo oral capsule

Detailed Description

Generalised premedication with benzodiazepines in all surgical patients has become questionable, regarding the risk-benefit assessment and the lack of evidence for this practice. Particularly, in elderly patients (≥65 years), a higher risk for adverse events is described.

Patients will be randomly assigned to one of the following two study groups. Preoperatively, group 1 will receive midazolam and group 2 will receive placebo.

Anaesthesia will be performed according to the clinical routine.

All possible side effects are described in the SmPC for midazolam. For the placebo-group, we do not expect any harm, as in the case of strong preoperative anxiety or agitation, additional midazolam application may occur on behalf of the attending anaesthesist at any time.

The sample size was calculated based on detecting a minimum of 5 unit difference in the primary outcome variable overall patient satisfaction measured with the EVAN-G. Setting a type 1 error of 0.05, a power of 0.8 and assuming the standard deviation of EVAN-G to be 14 units, 248 patients per group are needed to detect a 5 unit difference.

Considering a drop-out of 10% and a screening failure of 10%, we decided to include 614 patients in total.

The hypothesis of the study is that global patient satisfaction after surgery in elderly patients is similar after preoperative placebo application compared to midazolam application.

• Study Type: Interventional
• Enrollment (Actual): 782
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Herne, Germany, 44625
    • Marien-Hospital Herne
  • Magdeburg, Germany, 39120
    • Universitatsklinikum Magdeburg A.O.R.
  • Munich, Germany, 81675
    • Department of Anaesthesiology, University Hospital Klinikum rechts der Isar Munich
  • München, Germany, 81377
    • LMU Munchen
  • Reutlingen, Germany, 72764
    • Kreiskliniken Reutlingen, Klinikum am steinenberg
  • Tubingen, Germany, 72076
    • Klinik für Anästhesiologie und Intensivmedizin, Universitätsklinikum Tübingen
  • NRW
    • Aachen, NRW, Germany, 52074
      • Department of Anesthesiology, University Hospital Aachen
    • Bonn, NRW, Germany, 53127
      • Klinik für Anästhesiologie und Operative Intensivmedizin, Universitätsklinikum Bonn
    • Dusseldorf, NRW, Germany, 40225
      • Klinik für Anästhesiologie, Universitätsklinikum Düsseldorf

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years to 80 years (OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. 1. Only legally competent patients
2. Written informed consent prior to study participation
3. 65-80 years
4. Elective surgery
5. Expected surgery duration ≥ 30 minutes
6. Planned general or combined regional and general anaesthesia
7. Planned extubation at the end of surgery

Exclusion Criteria:

1. Age > 80 years
2. Age < 65 years
3. Non-fluency in German language
4. Alcohol and/ or drugs abuse
5. Chronic benzodiazepine treatment
6. Intracranial surgery
7. Local and stand by anaesthesia or solely regional anaesthesia
8. Monitored anaesthesia care
9. Cardiac surgery
10. Ambulatory surgery
11. Repeated surgery
12. Contraindications for benzodiazepine application (e.g. sleep apnoea syndrome, severe chronic obstructive pulmonary disease, allergy)
13. Allergy against any component of the Placebo (lactose monohydrate, cellulose powder, magnesium stearate, microcrystalline cellulose) or investigational drug (midazolam, lactose) or the capsules (gelatine, E171 titanium dioxide, E132 indigotine).
14. Expected benzodiazepine requirement after surgery
15. Expected continuous mandatory ventilation after surgery
16. Patients who explicitly request anxiolytic premedication
17. Patients with severe neurological or psychiatric disorders
18. Refusal of study participation by the patient
19. Parallel participation in interventional clinical studies within the last 30 days

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Midazolam; Midazolam, 3.75 mg , oral, once, 30-45 minutes before surgery	Drug: Midazolam; Oral administration preoperatively; Other Names: Dormicum
PLACEBO_COMPARATOR: Placebo; Placebo, oral, once, 30-45 minutes before surgery	Drug: Placebo oral capsule; Oral administration preoperatively

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Global patient satisfaction on the first postoperative day	measured with the EVAN-G questionnaire on the first postoperative day	on the first postoperative day (1 day)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cognitive testing	Measured by the short blessed test	preoperative, day 1 and day 30 after surgery (31 days)
Delirium testing	Measured by Confusion Assessment Method (CAM)	preoperative, day 1 after surgery (2 days)
Preoperative anxiety	Measured by Amsterdam Preoperative Anxiety and Information Scale (APAIS)	preoperatively (1 day)
Change of health-related quality of life	Measured by the individual health-related quality of life assessment EQ-5D-5L	preoperative and day 30 after surgery (31 days)
Activities of daily living	Measured by Instrumental Activities of Daily Living scale (IADL)	preoperative and day 30 after surgery (31 days)
Perception of pain, well-being, and sleeping	Self-reported by visual analogue scale (VAS)	preoperative until first postoperative day (3 days)
Number of participants with adverse events and serious adverse events	Review of medical charts and patient interview	surgery and first postoperative day (2 days)
Patient cooperation	Self-reported by visual analogue scale (VAS) by the attending anesthetist	surgery day (1 day)
Anaesthesia related data	Anesthesia drugs, type of anesthesia, duration, extubation-time	surgery day (1 day)
Surgery related data	Duration and kind of surgery	surgery day (1 day)
Rescue benzodiazepine application	assessment of additional requirement of midazolam in the operating area	surgery day (1 day)
Patients vital data	Measurement of SpO2, RRsys, HR on arrival in the operating room and at the end of surgery	surgery day (1 day)
Mortality	Patient chart review and telephone interview after discharge	30 days
Major adverse events	Assessment of postoperative major adverse cardiovascular and cerebral events by patient chart review and telephone interview after discharge	30 days
Hospital length of stay	Patient chart review	on postoperative day 30 (1 day)
Intensive care unit length of stay	Patient chart review	on postoperative day 30 (1 day)

Collaborators and Investigators

• Sponsor: RWTH Aachen University
• Investigators: Study Chair: Mark Coburn, Professor, Department of Anesthesiology, University Hospital Aachen, Germany

Publications and helpful links

General Publications

• Auquier P, Pernoud N, Bruder N, Simeoni MC, Auffray JP, Colavolpe C, Francois G, Gouin F, Manelli JC, Martin C, Sapin C, Blache JL. Development and validation of a perioperative satisfaction questionnaire. Anesthesiology. 2005 Jun;102(6):1116-23. doi: 10.1097/00000542-200506000-00010.
• American Geriatrics Society Expert Panel on Postoperative Delirium in Older Adults. American Geriatrics Society abstracted clinical practice guideline for postoperative delirium in older adults. J Am Geriatr Soc. 2015 Jan;63(1):142-50. doi: 10.1111/jgs.13281. Epub 2014 Dec 12.
• Maurice-Szamburski A, Auquier P, Viarre-Oreal V, Cuvillon P, Carles M, Ripart J, Honore S, Triglia T, Loundou A, Leone M, Bruder N; PremedX Study Investigators. Effect of sedative premedication on patient experience after general anesthesia: a randomized clinical trial. JAMA. 2015 Mar 3;313(9):916-25. doi: 10.1001/jama.2015.1108.
• Wang ML, Min J, Sands LP, Leung JM; Perioperative Medicine Research Group. Midazolam Premedication Immediately Before Surgery Is Not Associated With Early Postoperative Delirium. Anesth Analg. 2021 Sep 1;133(3):765-771. doi: 10.1213/ANE.0000000000005482.
• Kowark A, Rossaint R, Keszei AP, Bischoff P, Czaplik M, Drexler B, Kienbaum P, Kretzschmar M, Rex C, Saller T, Schneider G, Soehle M, Coburn M; I-PROMOTE study group. Impact of PReOperative Midazolam on OuTcome of Elderly patients (I-PROMOTE): study protocol for a multicentre randomised controlled trial. Trials. 2019 Jul 15;20(1):430. doi: 10.1186/s13063-019-3512-3.

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 12, 2017
• Primary Completion (ACTUAL): June 24, 2019
• Study Completion (ACTUAL): June 24, 2019

Study Registration Dates

• First Submitted: February 7, 2017
• First Submitted That Met QC Criteria: February 9, 2017
• First Posted (ACTUAL): February 14, 2017

Study Record Updates

• Last Update Posted (ACTUAL): November 18, 2019
• Last Update Submitted That Met QC Criteria: November 14, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: Anxiety; Clinical trial; Midazolam; Patient Satisfaction
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam
• Other Study ID Numbers: 16-115

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No