Assessing the Effectiveness of Midazolam Premedication

Randomized Controlled Trial Assessing the Effectiveness of Midazolam Premedication as an Anxiolytic, Analgesic, Sedative, and Hemodynamic Stabilizer

Pre-anesthetic dosing of midazolam is commonly used in many hospitals for the induction of anesthesia, but the effect is still controversial. The purpose of this study was to evaluate the effectiveness of midazolam premedication in four aspects: anxiety reduction, pain relief, sedation and hemodynamic stability.

Study Overview

• Status: Completed
• Conditions: Premedication; Anxiety Preoperative; Midazolam Premedication
• Intervention / Treatment: Drug: Midazolam premedication; Drug: Remifentanil infusion; Drug: Propofol infusion

Detailed Description

Background

• Midazolam premedication is a routine practice in many hospitals, but its efficacy remains controversial. We evaluated the effectiveness of midazolam premedication with respect to anxiety and sedation levels, hemodynamic parameters, and analgesic profiles.

Methods

• Subjects

  • This randomized, prospective, open-label study was approved by IRB. After written informed consent, a total of 128 female patients aged between 20 and 65 years, ASA physical status Ⅰ or Ⅱ, scheduled for elective thyroidectomy were enrolled. Exclusion criteria were: central nervous system disorders, major cardiovascular disease, chronic pain disorders, peripheral neuropathy, diabetes mellitus neuropathy, nephropathy, hepatopathy, taking any medication affecting the central nervous system or heart rate, alcohol or drug abuse, pregnancy, and contraindication to midazolam premedication. Enrolled all subjects were randomly allocated to either midazolam premedication group (Group P, n=64) or control group (Group N, n=64). Patients of group P were premedicated with intramuscular glycopyrrolate 0.2mg and midazolam 0.05 mg/kg 30 minutes before surgery, while patients assigned to Group N were only received glycopyrrolate.

• Anesthetic management

  • In the operating room, we did standard monitoring(ECG, pulse oximetry, noninvasive blood pressure, esophageal stethoscope temperature), train of four (TOF) and entropy and surgical pleth index(SPI). Target controlled infusion of propofol (4.0 μg/ml) and remifentanil (4 ng/ml) were used for induction of anesthesia based on the pharmacological models of Marsh and Minto, respectively. Intravenous rocuronium 1.0 mg/kg was administered for muscle relaxation. After intubation, propofol (3.0μg/ml) and remifentanil (2 ng/ml) were infused until incision time. 30 mg of ketorolac was administered 30 minutes before the end of the operation to control postoperative pain.

• Assessment of response to midazolam

  • To evaluate the degree of anxiety, the Beck anxiety inventory was conducted at the preoperative day before surgery and immediately after arrival at the operating room. For analgesic profile assessment, SPI monitoring was performed in the operating room and NRS (numeric rating scale) measured in the recovery room and the general ward until the transition to oral analgesics. Also, additional medications for pain control were reviewed. Noninvasive blood pressure, heart rate, and entropy value were recorded at each measuring points in order to evaluate the hemodynamic stability and sedation level during anesthesia induction. Measuring points were initial time, prior to intubation, intubation, prior to incision and incision time. The time taken to induce anesthesia was also recorded.

• Sample size and statistical analysis

  • In this study, sample size was determined based on Cohen's study. According to this analysis, when comparing the mean of two groups with α (significance criterion) = 0.05, β (probability of occurring type II error) = 0.2 and medium effect size (Cohen's d = 0.5), 64 subjects were needed per group.
  • After a normality test, continuous variables were analyzed with the use of an independent t-test, paired t-test, and repeated-measures ANOVA. Differences between categorical variables were calculated with the use of the chi-square test.

• Study Type: Interventional
• Enrollment (Actual): 128
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Korea, Republic of
  • Busan, Korea, Republic of
    • Pusan National University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• American Society of Anesthesiologists physical status classification I or II
• Scheduled for elective thyroidectomy under general anesthesia

Exclusion Criteria:

• Central nervous system disorders
• Major cardiovascular disease
• Chronic pain disorders
• Peripheral neuropathy
• Diabetes mellitus neuropathy
• Nephropathy
• Hepatopathy
• Taking any medication affecting the central nervous system or heart rate
• Alcohol or drug abuse
• Pregnancy
• Contraindication to midazolam premedication

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Midazolam premedication group (Group P); Patients of group P were premedicated with intramuscular midazolam 0.05 mg/kg 30 minutes before surgery.	Drug: Midazolam premedication; Patients in Group P received midazolam (0.05 mg/kg, intramuscular injection) 30 minutes before induction of general anesthesia.; Other Names: Intramuscular midazolam; Drug: Remifentanil infusion; Target controlled infusion of remifentanil (4ng/ml) was used for induction of anesthesia based on the pharmacological models of Minto. After intubation, remifentanil (2 ng/ml) was infused until incision time. (Both groups); Other Names: Target-controlled infusion (TCI) of remifentanil; Drug: Propofol infusion; Target controlled infusion of propofol (4.0 μg/ml) was used for induction of anesthesia based on the pharmacological models of Marsh. After intubation, propofol (3.0μg/ml) was infused until incision time. (Both groups); Other Names: Target-controlled infusion (TCI) of propofol
Other: Control group (Group N); Patients of group N were not premedicated with midazolam (Do not use placebo). [Treatment of Glycopyrrolate (0.2 mg, IM) 30 minutes prior to surgery is not intervention because it is a routine practice of this center. (-> removed from interventions)]	Drug: Remifentanil infusion; Target controlled infusion of remifentanil (4ng/ml) was used for induction of anesthesia based on the pharmacological models of Minto. After intubation, remifentanil (2 ng/ml) was infused until incision time. (Both groups); Other Names: Target-controlled infusion (TCI) of remifentanil; Drug: Propofol infusion; Target controlled infusion of propofol (4.0 μg/ml) was used for induction of anesthesia based on the pharmacological models of Marsh. After intubation, propofol (3.0μg/ml) was infused until incision time. (Both groups); Other Names: Target-controlled infusion (TCI) of propofol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in degree of anxiety	Patients completed the Beck anxiety inventory (BAI) on two separate occasions, the anesthesiologist's visit on the day before surgery and pre-induction time after randomization. The BAI was a self-report questionnaire consisting of 21 questions.	the anesthesiologist's visit on the day before surgery and pre-induction time after randomization
Change in sedation level	Measuring the entropy value (CARESCAPE Monitor B850, GE Healthcare, Milwaukee, WI, USA).	At the time of pre-induction (initial), prior to intubation, intubation, prior to incision, and surgical incision
Change in noninvasive blood pressure (hemodynamic parameters 1)	Measuring noninvasive blood pressure (CARESCAPE Monitor B850, GE Healthcare, Milwaukee, WI, USA)	At the time of pre-induction (initial), prior to intubation, intubation, prior to incision, and surgical incision
Change in SPI value (Analgesic profile 1)	Measuring SPI (CARESCAPE Monitor B850, GE Healthcare, Milwaukee, WI, USA), which was calculated from the pulse oximetry wave	At the time of pre-induction (initial), prior to intubation, intubation, prior to incision, and surgical incision
Numeric rating scale (Analgesic profile 2)	Reviewing numeric rating scale (NRS) : 0 (No pain) ~ 10 (Worst possible pain)	Postoperative period (until transition to oral analgesics, up to 12 hours)
Analgesic requirement (Analgesic profile 3)	Reviewing additional medications for pain control	Postoperative period (until transition to oral analgesics, up to 12 hours)
Change in heart rate (hemodynamic parameters 2)	Measuring heart rate (CARESCAPE Monitor B850, GE Healthcare, Milwaukee, WI, USA)	At the time of pre-induction (initial), prior to intubation, intubation, prior to incision, and surgical incision

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Procedure time of intubation	Total time taken for intubation was recorded	From the beginning of anesthesia to the completion of intubation
Correlation analysis between the SPI values and other parameters (heart rate, blood pressure, and entropy values)	Measuring SPI, noninvasive blood pressure, heart rate, and entropy values (CARESCAPE Monitor B850, GE Healthcare, Milwaukee, WI, USA)	At the time of pre-induction (initial), prior to intubation, intubation, prior to incision, and surgical incision

Collaborators and Investigators

• Sponsor: Pusan National University Hospital
• Investigators: Principal Investigator: Hyeon-Jeong Lee, PhD, Pusan National University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): July 19, 2016
• Primary Completion (Actual): August 14, 2017
• Study Completion (Actual): August 15, 2017

Study Registration Dates

• First Submitted: October 22, 2017
• First Submitted That Met QC Criteria: October 24, 2017
• First Posted (Actual): October 30, 2017

Study Record Updates

• Last Update Posted (Actual): October 31, 2017
• Last Update Submitted That Met QC Criteria: October 28, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: midazolam premedication
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Analgesics, Opioid; Narcotics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Remifentanil; Midazolam; Propofol
• Other Study ID Numbers: 1607-003-057

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