The Use of Midazolam and Remifentanil During Dialysis Access Procedures

Study Overview
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Brief Summary
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BACKGROUND: Sedation and analgesia are related to unexpected adverse events in chronic renal failure patients undergoing arteriovenous fistula placement procedures under monitored anesthesia care (MAC). OBJECTIVE: Our goal was to investigate and compare the sedation and analgesia related effects and adverse effects of continuous intravenous use of midazolam and intermittent bolus doses of midazolam while intravenous remifentanil is used as a rescue medication in patients with chronic renal failure.

Detailed Description
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BACKGROUND: Sedation and analgesia are related to unexpected adverse events in chronic renal failure patients undergoing arteriovenous fistula placement procedures under monitored anesthesia care (MAC). OBJECTIVE: Our goal was to investigate and compare the sedation and analgesia related effects and adverse effects of continuous intravenous use of midazolam to intermittent bolus doses of midazolam while intravenous remifentanil is used as a rescue medication in patients with chronic renal failure. DESIGN: From a total of 116 patients, 99 patients with chronic renal failure undergoing arteriovenous fistula procedures were included in a prospective randomized study. SETTINGS: Two tertiary care hospitals. PATIENTS: The patients were divided into Group 1 (continuous)(n=50); patients receiving intravenous midazolam infusion at a dose of 0.02 to 0.04 mg/kg/h and Group 2 (intermittent)(n=49); patients receiving intermittent intravenous bolus doses of 0.015 mg/kg every 10 minutes. MAIN OUTCOME MEASURES: Primary outcomes were; 1- The total amount of doses of the use of midazolam and remifentanil in both groups of patients, 2- The evaluation of satisfaction of patient and surgeon at the end of the operation, in the recovery room during the period of recovery from sedation and before discharge. Other outcome measures include; the sedative, analgesic and hemodynamical effects of sedative medications that were compared in both groups of patients during the operation time period. The hospital stay duration was recorded and compared between groups. The maximum dose of midazolam was limited to 4 mg intravenously. The intensity of pain was assessed using a verbal numerical sedation scale (range 1 to 10) (VNRS) and the sedation level was recorded by Modified Observer's Assessment of Alertness/Sedation Scale (MOSS/A) (range 0 to 6). MOSS/A Scale includes; Score 0: Does not respond to deep stimulus, Score 1: Does not respond to mild prodding or shaking, Score 2: Responds only after mild prodding or shaking, Score 3: Responds only after name is called loudly and/or repeatedly, Score 4: Lethargic response to name spoken in normal tone, Score 5: Responds readily to name spoken in normal tone, Score 6: Agitated. An intravenous bolus dose of remifentanil as a rescue medication was administered for pain scores greater than 3 at a dose of 5µg/mL. Adverse events were recorded. Patient satisfaction level depending on the experience in general were evaluated at discharge from 0 to 4 point numerical scale: 0 = extremely dissatisfied; 1 = dissatisfied; 2 = neither satisfied nor dissatisfied; 3 = satisfied; 4 = extremely satisfied. Surgeon satisfaction level depending on the experience in general were evaluated at discharge from five-point numerical scale: 0 = extremely poor; 1 = poor; 2 = fair; 3 = good; 4 = excellent. SAMPLE SIZE: The sample size was calculated based on a power of 80% and a 5% type-I error and for each group, thirty patients were required.

Official Title
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The Use of Midazolam and Remifentanil During Arteriovenous Fistula Placement Procedure and Monitored Anesthesia Care

Conditions
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Sedative Adverse Reaction, Analgesic Adverse Reaction, Midazolam Adverse Reaction, Adverse Reaction to Drug, Patient Satisfaction, Chronic Kidney Diseases, Arteriovenous Fistula

Intervention / Treatment
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* Drug: Midazolam intravenous injection
* Drug: Remifentanil intravenous bolus dose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: Forty-three to eighty-one years of age, ASA status: American Society of Anesthesiologist (ASA) status I-III, The diagnosis: A diagnosis of chronic renal failure, The operation type: An arteriovenous fistula procedure Exclusion Criteria: Body mass index greater than 40 that are considered morbidly obese patients, Lung disorders leading to severe respiratory insufficiency such as; severe asthma, chronic obstructive lung disease, Severe cardiovascular insufficiency or dysfunction, Insulin-dependent diabetes mellitus, Severe hepatic diseases, ASA status of 4 and 5, Neurologic disorders such as; the presence of epilepsy, arterial aneurysm, intracranial mass, Patients complaining about intense pain before the procedure and patients with a history of long term opioid use or chronic pain, Patients with a history of allergy to the study drugs, Patients without written informed consent.

Ages Eligible for Study
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Minimum Age: 43 Years
Maximum Age: 81 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
Interventional Model Description: This is a prospective, randomized clinical study. The patients were divided into two groups with a 1: 1 allocation and sealed envelope randomization method. Both groups of patients received intravenous midazolam, in Group 1, intravenous midazolam was administered continuously whereas, in Group 2, intravenous midazolam was administered as intermittent bolus doses. Both groups received intravenous remifentanil bolus doses as a rescue medication.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group 1<br>In Group 1(n=50); continuous infusion of intravenous midazolam (Dormicum, Deva Pharmaceutical, Turkey) at a dose of 0.02 to 0.04 mg/kg/h was started at the beginning of the operation and the dose was adjusted depending on pain level and sedation level using appropriate scales for monitoring throughout the surgical time period. An intravenous bolus dose of midazolam at a dose of 0.015 mg/kg was administered before the start of the surgery. A rescue medication of intravenous bolus dose of remifentanil at a concentration of 5 μg/mL was used every 5 to 10 minutes in doses of 1 to 3 mL if necessary for pain scores greater than 3. The medications were stopped prior to the end of the surgery. | Drug: Midazolam intravenous injection<br>* The midazolam was prepared as 5 mg midazolam in 20 mL syringe of 5% dextrose water solution (0.25 mg/mL) in both arms. Both groups of patients received an intravenous bolus dose of midazolam was administered before the start of the surgery. In Group 1, continuous infusion of intravenous midazolam was started and in Group 2, intravenous bolus doses of midazolam were administered. The doses were adjusted depending on pain level and sedation level using appropriate scales for monitoring during the surgical time period. The drip rate was adjusted according to pain intensity. The infusion of drugs was discontinued at the end of the procedure.<br>* Other names: Dormicum, Deva Pharmaceutical, Turkey;Drug: Remifentanil intravenous bolus dose<br>* A remifentanil infusion was prepared as follows; 0.5 mg remifentanil was added into 100 mL of 0.9% saline at a concentration of 5 μg/mL. The preparation of remifentanil solution and installation of the device was done by an anesthesiologist who was blinded for the study groups. The dose and number of patients that required remifentanil were recorded. The infusion of drugs was discontinued at the end of the procedure. A rescue medication of intravenous remifentanil bolus dose was used as 1 to 3 mL (5 μg or 15 μg) every 5 minutes if necessary for pain scores greater than 3. This infusion was prepared prior to the use during the study and was discontinued at the end of the procedure.<br>* Other names: Ultiva, Glaxo Smith Kline Pharmaceutical, England;|
| Active Comparator: Group 2<br>in Group 2 (n=49), intravenous bolus doses of midazolam at a dose of 0.015 mg/kg every 10 minutes were administered at the beginning of the operation and the dose was adjusted depending on pain level and sedation level using appropriate scales for monitoring throughout the surgical time period. An intravenous bolus dose of midazolam at a dose of 0.015 mg/kg was administered before the start of the surgery. A rescue medication of intravenous bolus dose of remifentanil at a concentration of 5 μg/mL was used every 5 to 10 minutes in doses of 1 to 3 mL if necessary for pain scores greater than 3. The medications were stopped prior to the end of the surgery. | Drug: Midazolam intravenous injection<br>* The midazolam was prepared as 5 mg midazolam in 20 mL syringe of 5% dextrose water solution (0.25 mg/mL) in both arms. Both groups of patients received an intravenous bolus dose of midazolam was administered before the start of the surgery. In Group 1, continuous infusion of intravenous midazolam was started and in Group 2, intravenous bolus doses of midazolam were administered. The doses were adjusted depending on pain level and sedation level using appropriate scales for monitoring during the surgical time period. The drip rate was adjusted according to pain intensity. The infusion of drugs was discontinued at the end of the procedure.<br>* Other names: Dormicum, Deva Pharmaceutical, Turkey;Drug: Remifentanil intravenous bolus dose<br>* A remifentanil infusion was prepared as follows; 0.5 mg remifentanil was added into 100 mL of 0.9% saline at a concentration of 5 μg/mL. The preparation of remifentanil solution and installation of the device was done by an anesthesiologist who was blinded for the study groups. The dose and number of patients that required remifentanil were recorded. The infusion of drugs was discontinued at the end of the procedure. A rescue medication of intravenous remifentanil bolus dose was used as 1 to 3 mL (5 μg or 15 μg) every 5 minutes if necessary for pain scores greater than 3. This infusion was prepared prior to the use during the study and was discontinued at the end of the procedure.<br>* Other names: Ultiva, Glaxo Smith Kline Pharmaceutical, England;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The amount of total use of midazolam and remifentanil drug consumptions in milligrams during operation time period. | The comparison of total use of midazolam and remifentanil drug consumptions in milligrams during operation time period between the two groups. | Through the operative time period up to two hours of time. | 
| The evaluation of satisfaction of patient and surgeon by a questionnaire at the end of operation. | The evaluation and comparison of satisfaction of patient and surgeon at the end of operation by a questionnaire between the two groups. Patient satisfaction level depending on the experience in general was evaluated at discharge from 0 to 4 point numerical scale: 0 = extremely dissatisfied; 1 = dissatisfied; 2 = neither satisfied nor dissatisfied; 3 = satisfied; 4 = extremely satisfied. Surgeon satisfaction level depending on the experience in general was evaluated at discharge from five point numerical scale: 0 = extremely poor; 1 = poor; 2 = fair; 3 = good; 4 = excellent. | The collection of questionnaire at the end of operation in recovery room after recovery from sedation in a total of ten minutes time. | 
| Modified Observer's Assessment of Alertness/Sedation Scale (MOSS/A) Scale | The comparison of level of sedation using MOSS/A scale that ranges from 0 to 6, with a score of 6 defined as awake or minimally sedated, and a score of 0 defined as general anesthesia every 10 to 15 minutes between the two groups. | Through the operative time period up to two hours of time. | 
| Modified Observer's Assessment of Alertness/Sedation Scale (MOSS/A) Scale | Repeated measure analysis of level of sedation by the use of the collected MOSS/A scale that ranges from 0 to 6, with a score of 6 defined as awake or minimally sedated, and a score of 0 defined as general anesthesia every 10 to 15 minutes within groups. | Through the operative time period up to two hours of time. | 
| Verbal Numerical Rating Scale | The comparison of level of pain using Verbal Numerical Rating Scale (VNRS; 0= no pain, 10=the worst possible pain imaginable) scale every 10 to 15 minutes between the two groups. | Through the operative time period up to two hours of time. | 
| Verbal Numerical Rating Scale | Repeated measure analysis of level of sedation by the use of the collected Verbal Numerical Rating Scale (VNRS; 0= no pain, 10=the worst possible pain imaginable) scale every 10 to 15 minutes between the two groups. | Through the operative time period up to two hours of time. | 
| Recovery time | The comparison of recovery time duration presented in minutes unit of time between the two groups. | Through the recovery room time period before discharge up to one hour time. | 
| Hospital stay | The comparison of hospital stay duration presented in hours unit of time between the two groups. | Through the duration of stay in hospital before discharge up to seventy two hours time. | 
| Systolic blood pressure values during operation and in the recovery room. | The comparison of systolic blood pressure in mmHg unit values every 15 minutes between the two groups. | Through the operative time period up to two hours of time and through the recovery room time period before discharge up to one hour time. | 
| Heart rate values during operation and in the recovery room. | The comparison of heart rate values in beats per minute unit every fifteen minutes between the two groups. | Through the operative time period up to two hours of time and through the recovery room time period before discharge up to one hour time. | 
| Pulse oximetry values during operation and in the recovery room. | The comparison of pulse oximetry values in percent unit every fifteen minutes between the two groups. | Through the operative time period up to two hours of time and through the recovery room time period before discharge up to one hour time. | 
| Adverse events during operation and in the recovery room. | Number of Participants With Adverse Events as Assessed by CTCAE Version 4.03. | Through the operative time period up to two hours of time and through the recovery room time period before discharge up to one hour time. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Midazolam, Remifentanil, Benzodiazepine, Opioid, Chronic Kidney Diseases, Analgesia, Sedation, Adverse Reaction, Patient Satisfaction, Arteriovenous Fistula