Assessing the Effectiveness of Midazolam Premedication

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Midazolam Premedication, Anxiety Preoperative, Premedication

Intervention / Treatment
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* Drug: Midazolam premedication
* Drug: Remifentanil infusion
* Drug: Propofol infusion


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Midazolam premedication group (Group P)<br>Patients of group P were premedicated with intramuscular midazolam 0.05 mg/kg 30 minutes before surgery. | Drug: Midazolam premedication<br>* Patients in Group P received midazolam (0.05 mg/kg, intramuscular injection) 30 minutes before induction of general anesthesia.<br>* Other names: Intramuscular midazolam;Drug: Remifentanil infusion<br>* 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)<br>* Other names: Target-controlled infusion (TCI) of remifentanil;Drug: Propofol infusion<br>* 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)<br>* Other names: Target-controlled infusion (TCI) of propofol;|
| Other: Control group (Group N)<br>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<br>* 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)<br>* Other names: Target-controlled infusion (TCI) of remifentanil;Drug: Propofol infusion<br>* 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)<br>* Other names: Target-controlled infusion (TCI) of propofol;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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midazolam premedication