Safety and Efficacy of Oral Midazolam for Perioperative Anxiety Relief of Patients Undergoing Mohs Micrographic Surgery

Study Overview
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Brief Summary
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Midazolam is an approved sedative medication used for medical procedures. This study was being done to document the safety and efficacy of midazolam in improving anxiety, heart rate, and blood pressure in patients prior to undergoing Mohs micrographic surgery for the treatment of skin cancer (basal cell carcinoma or squamous cell carcinoma). Midazolam may make a patient relaxed and sleepy, and lower blood pressure. These effects last for about 2 hours. This study had two parts. In the first part, eligible patients were randomized to either receiving one standard dose of midazolam syrup or placebo syrup before their surgery, with neither the patient nor the study team knowing which patient received the study drug. In the second part, patients who were not eligible to participate in the randomized study or who refused to participate in the randomized study were enrolled in a prospective arm where they knew they were receiving midazolam syrup. In the prospective arm, the doses were based on the patient's weight, and patients were given additional doses of midazolam syrup as necessary to control their anxiety. The primary hypothesis of this study was that a single dose of oral midazolam syrup to patients prior undergoing outpatient Mohs micrographic surgery for skin cancer would result in lower anxiety scores at 60 minutes compared to placebo. In addition, the second hypothesis of this study was that patients given oral midazolam would have the rate of adverse events that was not worse than 25% higher than in the placebo group.

Detailed Description
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The main objective of this study was to establish the safety and efficacy of midazolam in patients with skin cancer undergoing outpatient Mohs micrographic surgery. Patients were randomized in a double-blind placebo-controlled study of a single-dose midazolam syrup for efficacy in producing safe anxiolysis of short duration. A parallel prospective arm of the study involved administration of midazolam in an unblinded fashion. Based on available studies of orally administered midazolam, the expectation was that the only observed adverse events will be minor and the major adverse event rate for midazolam would be similar to placebo. Data was collected on vital signs, anxiety, adverse events, and overall satisfaction with the anxiolytic agent.

Official Title
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Randomized Controlled and Prospective Studies of Safety and Efficacy of Oral Midazolam for Perioperative Anxiolysis of Patients Undergoing Mohs Micrographic Surgery.

Conditions
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Basal Cell Carcinoma, Squamous Cell Carcinoma, Skin Cancer, Anxiety

Intervention / Treatment
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* Drug: Randomized Midazolam
* Other: Placebo
* Drug: Local Anesthesia
* Drug: Prospective Midazolam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - 1 or 2 sites of biopsy-confirmed squamous cell or basal cell carcinomas limited to head and neck regions Inclusion Criteria for Prospective Arm: Patients wishing to receive oral midazolam in a non-blinded fashion will not be excluded based on the size of an individual tumor, total number of tumors, or prior history of oral midazolam No upper weight limitation Exclusion Criteria: Prior history of allergy to midazolam or any of the syrup components History of hypersensitivity to other benzodiazepines Congestive heart failure (AHA Class III and IV) Renal failure requiring hemodialysis End-stage liver failure Chronic alcoholism or alcohol intoxication within 24 hours of surgery Untreated or uncontrolled open angle glaucoma Uncontrolled hypertension History of psychoses or affective disorders Neuromuscular disorders such as myasthenia gravis Chronic obstructive pulmonary disease Patients on medications interfering with renal excretion or microsomal metabolism unless the last dose was taken greater than or equal to 5 half-lives prior to surgery Patients weighing less than 100 lb (45 kg) Pregnant women; women of childbearing potential will be required to take an in-office urine pregnancy test. Breast-feeding mothers must stop breast-feeding for 7 days after taking midazolam to take part in this study Additional Exclusion Criteria for Randomized Arms: Patients with a single cancer > 5 cm in the greatest dimension or with more than 2 cancers Patients who were previously premedicated with oral midazolam during prior Mohs micrographic surgery episodes Patients weighing more than 220 lb (100 kg)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Randomized Midazolam<br>Single-dose midazolam | Drug: Randomized Midazolam<br>* Midazolam was prepared in a 2 mg/ml cherry flavored syrup. In the randomized arm, patients received a single-dose administration of 5 ml (10 mg) of the midazolam syrup.<br>* Other names: Versed;Drug: Local Anesthesia<br>* Lidocaine 1% with 1:100,000 epinephrine<br>|
| Placebo Comparator: Placebo<br> | Other: Placebo<br>* The placebo was prepared as a color- and texture-matched cherry flavored syrup without midazolam.<br>Drug: Local Anesthesia<br>* Lidocaine 1% with 1:100,000 epinephrine<br>|
| Experimental: Prospective Midazolam<br> | Drug: Local Anesthesia<br>* Lidocaine 1% with 1:100,000 epinephrine<br>Drug: Prospective Midazolam<br>* Midazolam was prepared in a 2 mg/ml cherry flavored syrup. Dosing in the prospective arm was based on weight (>45 to 77 kg, 10 mg; >77 to 100 kg, 15 mg; greater than or equal to 100 kg, 20 mg). In the prospective arm patients were given additional doses of midazolam as necessary (in 5 mg increments) to achieve and maintain the desired level of anxiolysis.<br>* Other names: Versed;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient Anxiety at Baseline | A 10-point visual analog scale (VAS) was used to measure anxiety. The patients marked on the scale their feeling of anxiety. The lowest value possible was 0 (no anxiety) and the highest value possible was 10 (highest possible anxiety). | Baseline (prior to drug administration) | 
| Patient Anxiety at 60 and 120 Minutes | A 10-point visual analog scale (VAS) was used to measure anxiety. The patients marked on the scale their feeling of anxiety. The lowest value possible was 0 (no anxiety) and the highest value possible was 10 (highest possible anxiety). | 60 and 120 minutes after drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient Alertness at Baseline | A 10-point visual analog scale (VAS) was used to measure alertness. The patients marked on the scale their feeling of alertness. The lowest value possible was 0 (awake) and the highest value possible was 10 (barely awake). | Baseline (prior to drug administration) | 
| Patient Alertness at 60 and 120 Minutes | A 10-point visual analog scale (VAS) was used to measure alertness. The patients marked on the scale their feeling of alertness. The lowest value possible was 0 (awake) and the highest value possible was 10 (barely awake). | 60 and 120 minutes after drug administration | 
| Patient Cognitive Function at Baseline and 60 Minutes | Cognitive function was measured by the Mini-Mental State Examination (MMSE), a brief 30 point questionnaire test. The scores can range from 0 (low cognitive function) to 30 (high cognitive function). | baseline (prior to drug administration) and 60 minutes after drug administration | 
| Patient Cognitive Function at 120 Minutes | Cognitive function was measured by the Mini-Mental State Examination (MMSE), a brief 30 point questionnaire test. The scores can range from 0 (low cognitive function) to 30 (high cognitive function). | 120 minutes after drug administration | 
| Blood Pressure at 30 Minutes |  | 30 minutes after drug administration | 
| Heart Rate at 30 Minutes |  | 30 minutes after drug administration | 
| Respiratory Rate at 30 Minutes |  | 30 minutes after drug administration | 
| Pulse Oximetry at 30 Minutes | Pulse oximetry measures the oxygenation of a patient's hemoglobin. A sensor is placed on the patient's finger. Light at red and infrared wavelengths is passed sequentially through the patient to a photodetector. The changing absorbance at each of the two wavelengths is measured, allowing determination of the absorbance. The color of the blood provides a measure of oxygenation (the percentage of hemoglobin molecules bound with oxygen molecules). A healthy young person will probably have an oxygen saturation of 95-99%. | 30 minutes after drug administration | 
| Blood Pressure at 60 Minutes |  | 60 minutes after drug administration | 
| Heart Rate at 60 Minutes |  | 60 minutes after drug administration | 
| Respiratory Rate at 60 Minutes |  | 60 minutes after drug administration | 
| Pulse Oximetry at 60 Minutes | Pulse oximetry measures the oxygenation of a patient's hemoglobin. A sensor is placed on the patient's finger. Light at red and infrared wavelengths is passed sequentially through the patient to a photodetector. The changing absorbance at each of the two wavelengths is measured, allowing determination of the absorbance. The color of the blood provides a measure of oxygenation (the percentage of hemoglobin molecules bound with oxygen molecules). A healthy young person will probably have an oxygen saturation of 95-99%. | 60 minutes after drug administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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mohs micrographic surgery, skin cancer, anxiety, basal cell carcinoma, squamous cell carcinoma, midazolam, versed